Podcasts about Orr

Buckeye Weekly Podcast: Breaking Down Michigan vs. Wisconsin and Looking Ahead to Ohio StateJoin Tony Gerdeman and Tom Orr in the latest episode of the Buckeye Weekly Podcast as they discuss Michigan's 24-10 victory over Wisconsin. The hosts express their frustrations with Wisconsin's football team and analyze Michigan's performance, focusing on the stand-out play of Donavon McCulley and Bryce Underwood. Additionally, they explore the potential implications of this game for Michigan's upcoming schedules and their significant matchups against USC and Ohio State. Gerdeman and Orr also touch on broader Big Ten developments and share their thoughts on the challenges ahead for both Michigan and USC. Don't miss this insightful episode where the hosts delve deep into the Michigan Wolverines' strategies, player performances, and prospects for the rest of the season.00:00 Introduction and Podcast Welcome00:10 Discussing Michigan and Wisconsin Games02:21 Michigan's Offensive Highlights13:21 Upcoming Michigan vs. USC Game14:56 Michigan's Defensive Performance28:48 Conclusion and Sign-Off

At the height of the civil rights movement, Charles C. Diggs Jr. (1922-1998) was the consummate power broker. In a political career spanning 1951 to 1980, Diggs, Michigan's first Black member of Congress, was the only federal official to attend the trial of Emmett Till's killers, worked behind the scenes with Martin Luther King Jr., and founded the Congressional Black Caucus. He was also the chief architect of legislation that restored home rule to Washington, DC, and almost single-handedly ignited the American anti-apartheid movement in the 1960s. Drawing on extensive archival research, including Diggs's rarely seen personal papers, FBI documents, and original interviews with family members and political associates, political scientist Marion Orr reveals that Diggs practiced a politics of strategic moderation. Orr argues that this quiet approach was more effective than the militant race politics practiced by Adam Clayton Powell and more appealing than the conservative Chicago-style approach of William Dawson--two of Diggs's better-known Black contemporaries.Vividly written and deeply researched, House of Diggs is the first biography of Congressman Charles C. Diggs Jr., one of the most consequential Black federal legislators in US history. Congressman Diggs was a legislative lion whose unfortunate downfall punctuated his distinguished career and pushed him and his historic accomplishments out of sight. Now, for the first time, House of Diggs restores him to his much-deserved place in the history of American politics. Marion Orr is the Frederick Lippitt Professor of Public Policy and professor of political science and urban studies at Brown University. Learn more about your ad choices. Visit megaphone.fm/adchoices Support our show by becoming a premium member! https://newbooksnetwork.supportingcast.fm/african-american-studies

At the height of the civil rights movement, Charles C. Diggs Jr. (1922-1998) was the consummate power broker. In a political career spanning 1951 to 1980, Diggs, Michigan's first Black member of Congress, was the only federal official to attend the trial of Emmett Till's killers, worked behind the scenes with Martin Luther King Jr., and founded the Congressional Black Caucus. He was also the chief architect of legislation that restored home rule to Washington, DC, and almost single-handedly ignited the American anti-apartheid movement in the 1960s. Drawing on extensive archival research, including Diggs's rarely seen personal papers, FBI documents, and original interviews with family members and political associates, political scientist Marion Orr reveals that Diggs practiced a politics of strategic moderation. Orr argues that this quiet approach was more effective than the militant race politics practiced by Adam Clayton Powell and more appealing than the conservative Chicago-style approach of William Dawson--two of Diggs's better-known Black contemporaries.Vividly written and deeply researched, House of Diggs is the first biography of Congressman Charles C. Diggs Jr., one of the most consequential Black federal legislators in US history. Congressman Diggs was a legislative lion whose unfortunate downfall punctuated his distinguished career and pushed him and his historic accomplishments out of sight. Now, for the first time, House of Diggs restores him to his much-deserved place in the history of American politics. Marion Orr is the Frederick Lippitt Professor of Public Policy and professor of political science and urban studies at Brown University. Learn more about your ad choices. Visit megaphone.fm/adchoices Support our show by becoming a premium member! https://newbooksnetwork.supportingcast.fm/new-books-network

At the height of the civil rights movement, Charles C. Diggs Jr. (1922-1998) was the consummate power broker. In a political career spanning 1951 to 1980, Diggs, Michigan's first Black member of Congress, was the only federal official to attend the trial of Emmett Till's killers, worked behind the scenes with Martin Luther King Jr., and founded the Congressional Black Caucus. He was also the chief architect of legislation that restored home rule to Washington, DC, and almost single-handedly ignited the American anti-apartheid movement in the 1960s. Drawing on extensive archival research, including Diggs's rarely seen personal papers, FBI documents, and original interviews with family members and political associates, political scientist Marion Orr reveals that Diggs practiced a politics of strategic moderation. Orr argues that this quiet approach was more effective than the militant race politics practiced by Adam Clayton Powell and more appealing than the conservative Chicago-style approach of William Dawson--two of Diggs's better-known Black contemporaries.Vividly written and deeply researched, House of Diggs is the first biography of Congressman Charles C. Diggs Jr., one of the most consequential Black federal legislators in US history. Congressman Diggs was a legislative lion whose unfortunate downfall punctuated his distinguished career and pushed him and his historic accomplishments out of sight. Now, for the first time, House of Diggs restores him to his much-deserved place in the history of American politics. Marion Orr is the Frederick Lippitt Professor of Public Policy and professor of political science and urban studies at Brown University. Learn more about your ad choices. Visit megaphone.fm/adchoices Support our show by becoming a premium member! https://newbooksnetwork.supportingcast.fm/history

At the height of the civil rights movement, Charles C. Diggs Jr. (1922-1998) was the consummate power broker. In a political career spanning 1951 to 1980, Diggs, Michigan's first Black member of Congress, was the only federal official to attend the trial of Emmett Till's killers, worked behind the scenes with Martin Luther King Jr., and founded the Congressional Black Caucus. He was also the chief architect of legislation that restored home rule to Washington, DC, and almost single-handedly ignited the American anti-apartheid movement in the 1960s. Drawing on extensive archival research, including Diggs's rarely seen personal papers, FBI documents, and original interviews with family members and political associates, political scientist Marion Orr reveals that Diggs practiced a politics of strategic moderation. Orr argues that this quiet approach was more effective than the militant race politics practiced by Adam Clayton Powell and more appealing than the conservative Chicago-style approach of William Dawson--two of Diggs's better-known Black contemporaries.Vividly written and deeply researched, House of Diggs is the first biography of Congressman Charles C. Diggs Jr., one of the most consequential Black federal legislators in US history. Congressman Diggs was a legislative lion whose unfortunate downfall punctuated his distinguished career and pushed him and his historic accomplishments out of sight. Now, for the first time, House of Diggs restores him to his much-deserved place in the history of American politics. Marion Orr is the Frederick Lippitt Professor of Public Policy and professor of political science and urban studies at Brown University. Learn more about your ad choices. Visit megaphone.fm/adchoices Support our show by becoming a premium member! https://newbooksnetwork.supportingcast.fm/biography

At the height of the civil rights movement, Charles C. Diggs Jr. (1922-1998) was the consummate power broker. In a political career spanning 1951 to 1980, Diggs, Michigan's first Black member of Congress, was the only federal official to attend the trial of Emmett Till's killers, worked behind the scenes with Martin Luther King Jr., and founded the Congressional Black Caucus. He was also the chief architect of legislation that restored home rule to Washington, DC, and almost single-handedly ignited the American anti-apartheid movement in the 1960s. Drawing on extensive archival research, including Diggs's rarely seen personal papers, FBI documents, and original interviews with family members and political associates, political scientist Marion Orr reveals that Diggs practiced a politics of strategic moderation. Orr argues that this quiet approach was more effective than the militant race politics practiced by Adam Clayton Powell and more appealing than the conservative Chicago-style approach of William Dawson--two of Diggs's better-known Black contemporaries.Vividly written and deeply researched, House of Diggs is the first biography of Congressman Charles C. Diggs Jr., one of the most consequential Black federal legislators in US history. Congressman Diggs was a legislative lion whose unfortunate downfall punctuated his distinguished career and pushed him and his historic accomplishments out of sight. Now, for the first time, House of Diggs restores him to his much-deserved place in the history of American politics. Marion Orr is the Frederick Lippitt Professor of Public Policy and professor of political science and urban studies at Brown University. Learn more about your ad choices. Visit megaphone.fm/adchoices Support our show by becoming a premium member! https://newbooksnetwork.supportingcast.fm/american-studies

Ed and Jeremy took some time from the final hour of Tuesday's BBMS to discuss John Harbaugh's claim that he is still a believer in the Ravens D and DC Zach Orr. He said that while also criticizing the play-calling of OC Todd Monken. Is Harbaugh going too easy on Orr considering the defense's struggles?

Was this the final nail in the Adrian Orr coffin? Can we add Christian Hawkesby and the entire monetary policy committee? After all, it's easy to blame a governor, but it's a committee that votes on what to do with the cash rate. After the famed Q2 finished (remember April, May and June), we come to the next committee decision in July. Orr is gone, Hawkesby is up, and they have just witnessed the previous three months. And what do they do? Nothing. No change. They held. Why? Because they felt things were in hand. They also said the economy would contract 0.3%. Yesterday came the proof that it's hard, when you are actually paid as a so-called expert, to get it more wrong than they did. We all felt it and knew it. Most of us wouldn't have been able to put a number round it like the banks have to, but most of us don't have the data they have access to. But what we all knew was it was bad, it was tight, it was ugly, and it wasn't going in the right direction. But the gap between -0.3% and -0.9% is inexcusable. The same way it is inexcusable to stand there in July and tell us more stimulus wasn't needed. At some point someone has to be held to account. Yes, Orr is gone, but only because he packed a sad. Yes, Quigley is gone, but only because he got found out. No one has actually been held to account for a spectacular failure to do the job. Why are the Monetary Policy Committee members still in work? How many of them are there because of their so-called "expertise" versus being appointed for the so-called “right” reasons? Results count. Facts matter. And here is the issue for the Government: as the poll showed us this week, a lot of New Zealanders blame the Government for the economy. They have been let down in no small part by the Reserve Bank and when the Prime Minister the other week on this show fired off a bit of advice, all the pointy heads wrote op-eds whining about independence. Independence is fine. But not if you're useless. See omnystudio.com/listener for privacy information.

Social media experts with experience at LADbible and Great British Memes are the guests on PRWeek's latest Beyond the Noise podcast.How can brands show that they're culturally-led on social media, without crossing a line or seeming too corporate?PRWeek's latest Beyond the Noise podcast delves into the topic, hearing from George Bacon, founder of GBM Group, and Maya Orr, founder of Big Name on Campus (BNOC).Beyond the Noise looks at some of the biggest issues affecting communications and PR. Download the podcast via Apple, Spotify, or listen on your favourite platform.Bacon has built a network of over 15 million followers across TikTok and Instagram, on pages such as GreatBritishMemes and Thatgirlpage. GBM Group's meme pages have partnered with brands including Uber Eats, Jaffa Cakes, Persil, Warburtons and Bumble on ‘lo-fi' social media ad partnerships.Meanwhile, ex-LADbible and Lidl marcomms pro Orr now runs a ‘values-led' influencer agency, BNOC, which aims to connect brands with influencers whose work is rooted in purpose.Speaking to PRWeek's deputy news editor, Evie Barrett, the pair discuss the most common mistakes they see PR and marketing teams make when trying to help brands seem relatable online.Bacon and Orr share how a business should balance the risks and rewards of an active social media presence, from jumping on big trends to actively participating in comment sections.The duo also give their views on whether there is still a place for more polished, traditional campaigns. Hosted on Acast. See acast.com/privacy for more information.

In this episode of 1819 News: The Podcast, host and CEO Bryan Dawson sits down with Alabama State Sen. Arthur Orr, Chairman of the Education Trust Fund, for an in-depth conversation on the state's educational landscape, political evolution, and pathways to prosperity. Hailing from North Alabama's rapidly growing District 3, encompassing Morgan County and parts of Limestone and Madison Counties, Orr shares his personal journey—from his roots in a family with deep Alabama ties, to his time in the Peace Corps in Nepal, Habitat for Humanity in South Asia, and his legal career before entering politics in 2006. Orr recounts his challenging entry into the Senate during a Democrat-dominated era, the pivotal 2010 Republican takeover, and the ethics reforms that followed high-profile scandals. As chair of the education budget, he addresses Alabama's persistent education challenges, noting a near-doubling of funding since 2017 under Gov. Kay Ivey. Despite criticisms that increased spending hasn't always yielded results, Orr highlights legislative-driven reforms like the Literacy Act (preventing social promotion for non-readers), the Numeracy Act (boosting math scores from 52nd nationally to the 30s), and the Choose Act, which introduces school choice and competition. He praises these initiatives for originating in the legislature rather than the State School Board, emphasizing accountability and measurable progress. The discussion delves into the Alabama Education Association's diminished influence compared to its heyday under Paul Hubbert, and also Orr's views on higher education, including prioritizing in-state students, scrutinizing out-of-state tuition benefits, and enforcing compliance with laws banning divisive concepts (DEI). He warns of funding cuts for non-compliant institutions and critiques leftist biases in university curricula, advocating for meritocracy and race-neutral policies. Orr also touches on controversial topics like the Magic City Acceptance Academy, suggesting oversight by the state charter commission and potential use of the "power of the purse." Finally, he spotlights his "success sequence" bill—now law—teaching middle schoolers three research-backed steps to escape poverty: graduate high school, get a job, and avoid out-of-wedlock children, boasting a 96% success rate. Tune in for an honest, forward-looking dialogue on reforming Alabama's education system, fostering conservative values, and building a brighter future. Whether you're a parent, educator, or policy enthusiast, this episode offers invaluable insights into the decisions shaping the Yellowhammer State.

In this episode of 1819 News: The Podcast, host and CEO Bryan Dawson sits down with Alabama State Sen. Arthur Orr, Chairman of the Education Trust Fund, for an in-depth conversation on the state's educational landscape, political evolution, and pathways to prosperity. Hailing from North Alabama's rapidly growing District 3, encompassing Morgan County and parts of Limestone and Madison Counties, Orr shares his personal journey—from his roots in a family with deep Alabama ties, to his time in the Peace Corps in Nepal, Habitat for Humanity in South Asia, and his legal career before entering politics in 2006. Orr recounts his challenging entry into the Senate during a Democrat-dominated era, the pivotal 2010 Republican takeover, and the ethics reforms that followed high-profile scandals. As chair of the education budget, he addresses Alabama's persistent education challenges, noting a near-doubling of funding since 2017 under Gov. Kay Ivey. Despite criticisms that increased spending hasn't always yielded results, Orr highlights legislative-driven reforms like the Literacy Act (preventing social promotion for non-readers), the Numeracy Act (boosting math scores from 52nd nationally to the 30s), and the Choose Act, which introduces school choice and competition. He praises these initiatives for originating in the legislature rather than the State School Board, emphasizing accountability and measurable progress. The discussion delves into the Alabama Education Association's diminished influence compared to its heyday under Paul Hubbert, and also Orr's views on higher education, including prioritizing in-state students, scrutinizing out-of-state tuition benefits, and enforcing compliance with laws banning divisive concepts (DEI). He warns of funding cuts for non-compliant institutions and critiques leftist biases in university curricula, advocating for meritocracy and race-neutral policies. Orr also touches on controversial topics like the Magic City Acceptance Academy, suggesting oversight by the state charter commission and potential use of the "power of the purse." Finally, he spotlights his "success sequence" bill—now law—teaching middle schoolers three research-backed steps to escape poverty: graduate high school, get a job, and avoid out-of-wedlock children, boasting a 96% success rate. Tune in for an honest, forward-looking dialogue on reforming Alabama's education system, fostering conservative values, and building a brighter future. Whether you're a parent, educator, or policy enthusiast, this episode offers invaluable insights into the decisions shaping the Yellowhammer State.

Copies of text messages just released by Treasury confirm Adrian Orr was likely to be sacked if he didn't resign as Reserve Bank Governor. The process was so advanced, Secretary to the Treasury Iain Rennie warned Finance Minister Nicola Willis she might receive a recommendation from the Reserve Bank board to advise the Governor-General to remove Orr. NZ Herald Wellington business editor Jenee Tibshraeny explained further, LISTEN ABOVESee omnystudio.com/listener for privacy information.

Rhetorical question - why do you think Neil Quigley quit on a Friday night? The key is, he would have been booted if he didn't walk. So it sort of ends a shambolic and shameful period for what should be one of our most esteemed institutions. Between Orr and Quigley (mainly Orr) they have made a joke of the Reserve Bank. What should have happened is simple. When the Government decided, rightly, that the gargantuan amount of money Orr wanted to run his fiefdom was never going to fly Orr should have, in an adult way, stated he disagreed and he disagreed to the point he could not see himself continuing in the job. He would then resign, they would organise a nice, but frugal, farewell morning tea and that would have been that. But what actually happened was Orr chucked his toys, yelled and stamped his feet to the extent that Quigley had to write to Orr. All this was also kept secret until the Official Information Act and the Ombudsman forced their hand and exposed them for the bunch of egotistical babies they are. Quigley was yelling at Treasury, Orr was yelling at Willis, deals were looking to be done, letters and proof was looking to be binned and cheques were being written to make it all go away. Lest we forget, in an irony of ironies, this is the same group of clowns who buried the economy in the hole we are still trying to get ourselves out of years after Covid. So they couldn't do their job, they stuffed the place, then packed a massive sad when their rain shower of funding was getting rectified, started a big tantrum and scrap with various departments and ministers, then tried to cover it all up. Have I missed anything? Oh, Orr vanished with the money, never to be heard from again. To his credit Quigley hung around and made a few public appearances while trying to paint a picture of normality, until the Ombudsman undid him last week and that was that. They really are an embarrassing, shambolic mess. On a side note, it's also why I assume Christian Hawkesby stands zero chance of getting Orr's old job. He is fatally linked to this period of mayhem. We'd be glad to see the back of them, if it wasn't for the fact we are still trying to clean up the mess and every one of us is paying the bill. LISTEN ABOVESee omnystudio.com/listener for privacy information.

The resignation of the Reserve Bank chair Neil Quigley was announced by Finance Minister Nicola Willis last night as happening with "immediate effect". It came after months of close scrutiny over his handling of Adrian Orr's resignation as Governor. Quigley described Orr's resignation, in early March, as a "personal decision" but a series of revelations followed that cast doubt on that. Minister Willis declined to be interviewed on Saturday Morning but in a pre-recorded interview to RNZ last night she said "Mr Quigley chose to tend his resignation. If he had not offered his resignation, I would have asked him for it." RNZ Business Editor Gyles Beckford has the latest.

Reserve Bank board chairman Neil Quigley has resigned “with immediate effect” in the wake of the shambolic handling of Adrian Orr's resignation as Governor. Finance Minister Nicola Willis made the announcement just before 6pm on Friday - the day after the Reserve Bank revealed Orr temporarily stepped down as Governor a week before the public was told he resigned The Finance Minister says she did not ask the Reserve Bank Chair to quit, following news he's resigned with immediate effect. Nicola Willis told Heather du Plessis-Allan that having completed key work streams with the bank, Quigley said the timing was appropriate. Willis says she raised criticism around the board's handling of information relating to the former Governor's exit. LISTEN ABOVESee omnystudio.com/listener for privacy information.

Whether it's the government, international organisations, higher education, or the media, one of the defining dynamics of the social media age is the deteriorating trust in public institutions. It's extraordinary, really. At a time when humans are on the whole wealthier, healthier, and more dominant than at any other time in our species' history, we're more distrustful of the institutions that are supposed to serve us. Saturday Mornings is usually a monetary policy-free zone, and I promise to mostly keep it that way for now. But it was pretty remarkable at the close of play last night to see an announcement from the Finance Minister about the Chair of the Reserve Bank. Neil Quigley had resigned, effective immediately, following further revelations about his handling of former Governor Adrian Orr's departure. Nicola Willis confirmed to Newstalk ZB that if Quigley hadn't offered his resignation, she'd have asked for it. I don't expect everyone to follow all of the Reserve Bank dramas. But the long and short of it is that former Governor Adrian Orr got in a dispute with the government over the bank's funding. It turned into a showdown of sorts, the Reserve Bank Board raised concerns with him about his conduct (some of which he disputed), and after taking leave for a few days he ultimately resigned. But instead of being absolutely transparent about the dispute and what had actually happened, the RBNZ Chair Neil Quigley told media that Orr had resigned for “personal reasons”. If this was just some rando then no harm no foul. But Adrian Orr was the Governor of the Reserve Bank, one of the most powerful public servants in the country. His pen stroke and the decisions of his Monetary Policy Committee could be the difference between thousands or hundreds of thousands of people losing their jobs or homes. Like many journalists, I didn't buy the “personal reasons” explanation and felt we all deserved to know more detail about what had actually happened. Ater all, this wasn't a private company. The Reserve Bank serves us. After Neil Quigley's explanation, and after the Reserve Bank declined for Adrian Orr to be interviewed, I even went to the extreme length of sending him a letter at his home asking him to front. It's something I'd almost never do, but the public deserved an explanation. And it's taken until now and a ruling from the ombudsman for us to get the full story. I think there are lessons in this for all of us who work in jobs that purport to serve the public. In my role, I think about trust a lot. And look, I know this is very different to the Reserve Bank, much lower stakes, but I had the chance to reflect on my own work this week, and tried to lean into the spirit of introspection and openness. I was on a podcast, re_covering, in which Newstalk ZB's Frank Ritchie asks journalists to reflect on a story they covered. I didn't choose one which I'd absolutely nailed. Instead, I reflected on my five years as TVNZ's US Correspondent, and on my surprise at the first election of Donald Trump. As I said on re_covering, the fact so many of us were so shocked by the result (including Trump!) shows I and the rest of the news media covering that election had done a massively insufficient job of reflecting the scale of the anger and dissatisfaction with the status quo in the US. That election changed the world. Ultimately, I hope reflecting on my surprise will make me more sceptical of conventional wisdom, and better at my job today. Humans are fallible. We all make mistakes. But the Reserve Bank episode demonstrates the best thing a public institution can do to protect its reputation is not try and protect its reputation. Just admit when you got things wrong. Admit things that make you look bad. Learn lessons the hard way. Convince the public you have nothing to hide by showing us you have nothing to hide. See omnystudio.com/listener for privacy information.

In the latest blind tasting episode of GuildSomm: Into the Glass, host and Master Sommelier Chris Tanghe chats with Erica Orr, a Washington winemaker and enologist. Erica crafts the wines for her own label, Orr, and also has a lab service providing wine analysis and consulting for other Washington wineries. Chris pours her a white, a rosé, and a red. After Erica tastes the wines blind, she and Chris discuss winemaking cause and effect. Thanks for listening. If you enjoy this episode, please consider leaving us a review, as it helps us connect and grow the GuildSomm community. Cheers! Erica ran analysis on the wines that she and Chris tasted, which you can find on our website. Click over only when you're ready for the wines to be revealed! https://www.guildsomm.com/public_content/features/podcasts/b/guild_podcasts/posts/tasting-with-winemaker-erica-orr  Find out more about Erica's wine lab: https://www.orrwinelab.com Learn about Orr Wines: https://ericaorrwines.com Read our Tasting Study Guide: https://www.guildsomm.com/learn/study/w/study-wiki/2683/tasting Discover more GuildSomm blind tasting resources: https://www.guildsomm.com/learn/blind-tasting/

Dr Tim Orr talks to Mark Powell about how to share the Gospel of Jesus with those of a Muslim faith. Dr. Orr is a scholar of Islam and an Evangelical minister, whose work emphasises the theological, historical, and sociopolitical intersections between Christianity and Islam.

Hunting Jessica Brok, South Africa’s homegrown thriller, hits SterKinekor cinemas today. John Maytham speaks to director Alastair Orr about the making of the film, starring Danica De La Rey Jones as a retired special forces agent navigating dangerous criminals and the African wilderness, and also featuring Hlubi Mboya and Richard Lukunku. Orr shares insights into his filmmaking journey and the film’s upcoming US release. Good Morning Cape Town with Lester Kiewit is a podcast of the CapeTalk breakfast show. This programme is your authentic Cape Town wake-up call. Good Morning Cape Town with Lester Kiewit is informative, enlightening and accessible. The team’s ability to spot & share relevant and unusual stories make the programme inclusive and thought-provoking. Don’t miss the popular World View feature at 7:45am daily. Listen out for #LesterInYourLounge which is an outside broadcast – from the home of a listener in a different part of Cape Town - on the first Wednesday of every month. This show introduces you to interesting Capetonians as well as their favourite communities, habits, local personalities and neighbourhood news. Thank you for listening to a podcast from Good Morning Cape Town with Lester Kiewit. Listen live on Primedia+ weekdays between 06:00 and 09:00 (SA Time) to Good Morning CapeTalk with Lester Kiewit broadcast on CapeTalk https://buff.ly/NnFM3Nk For more from the show go to https://buff.ly/xGkqLbT or find all the catch-up podcasts here https://buff.ly/f9Eeb7i Subscribe to the CapeTalk Daily and Weekly Newsletters https://buff.ly/sbvVZD5 Follow us on social media CapeTalk on Facebook: https://www.facebook.com/CapeTalk CapeTalk on TikTok: https://www.tiktok.com/@capetalk CapeTalk on Instagram: https://www.instagram.com/ CapeTalk on X: https://x.com/CapeTalk CapeTalk on YouTube: https://www.youtube.com/@CapeTalk567 See omnystudio.com/listener for privacy information.

Remember just a few weeks ago how Sir John Key wanted 100 point cut from Reserve Bank? We'll, they've almost given him what he wants. It's easy to be an armchair critic of the boffins down at Number 2 The Terrace - "They should have gone for 50." "Club 25 was too cautious." But markets listen as much to the guff after the big cut announcement as much as they do the actual announcement. Need proof? Already retail banks have started slashing mortgage rates, both variable and fixed. That's on top of the cuts they already made last week, pricing in yesterday's 25. Some of the big ones will, in the coming weeks - I reckon we'll get down to 4.5% on short-term fixed. Look how the currency markets reacted - these guys were surprised. Coming out with what is essentially a triple shot to 2.5% by Christmas sends is sending a strong signal. It's easy to get caught up in the hysteria of calls for double shot all at once, but the bank can have its cake and eat it too. Get businesses and households spending without risking inflation, which is touching cloth on 3%. Yes, they do look through near-term stuff. But there's also heat in the provinces - it's not all about Auckland. And remember the days of Orr where the Reserve Bank hiked the rate quick as a sherpa up Everest before nosediving it back down again? You can achieve the same outcome without risk overcooking things again. It's only six or so weeks till the next call. If they need to do more, they can do more then. There's no doubt we've had a Q2 recovery blip, but we've had promising July manufacturing and improving services data out last week. The message is clear: we're walking back to Everest base camp, not running. And given the over and under cooking that went on under Orr, that's probably the right speed So, I'm with the four in Club 25 with a caveat - for now. See omnystudio.com/listener for privacy information.

“That whole sense of loss reverberated again.” Judy Orr, CEO of Catholic Charities Nashville, lost both of her parents before turning 20. She then faced a different kind of loss when Judy found out she was pregnant with the man she believed she would marry.   However, he told her he wasn't ready.  Judy sought wise counsel from her parish priest. He recommended she see a counselor at Catholic Charities. Judy followed his advice.  Judy's beloved son is now grown. As a single mom, she met and married her husband. They have been married for 39 years and have two more children together.  Judy also serves as the CEO of the nonprofit that helped her: Catholic Charities. Listen to this final mini retreat in a podcast in the “Women of Wisdom” series. Discover how God calls us to help others, just as we have been helped. May we love as God loved us first. Learn more about Catholic Charities Nashville at cctenn.org.

Michael Reddell, who appears on this show a fair bit, has put the Adrian Orr resignation back in the news. He has a source close to the action that, in simple terms, suggests that Orr packed a sad at a couple of meetings, one of which was with Nicola Willis, the chair of the Reserve Bank Neil Quigley wrote to Orr with a list of concerns over that behaviour, and Orr quit. The underlying issue appears to be the fact the Government were determined to cut the Reserve Bank's budget, which ultimately, they were successful in doing. Why? Because like everything else under the Labour Government, too much money was spent, things blew out and the Reserve Bank had wandered off into new and expensive areas they didn't need to be in. The main point being: essentially what we thought happened, did. Adrian Orr has a short fuse, a fairly elevated sense of entitlement and importance, and didn't like what was unfolding – which is fine. He didn't have to like it and if he disliked it so badly, he could walk, which he did. But, and here is where this is important, he held a critical role in all our lives. People in jobs like that need to exemplary. Exemplary in execution and exemplary in person. He wasn't. He was a failure. Which then takes us back to how he got the job: through Grant Robertson. Not only did Robertson appoint Orr, he reappointed him. Bad people make bad decisions, and those bad decisions go on to have consequences. By way of contrast what do you reckon the pressure on Jerome Powell is like right now? Is Powell yelling and packing a sad? Is Powell going to quit in a massive hissy fit and vanish from the face of the earth without a word? I have a dollar with anyone who wants it that the answer is "no". Maybe Orr doesn't give a monkey's. Maybe Orr is that sort of bloke who's so inflated and mesmerised by himself that he is well past any reputational reflection. Maybe Grant is too. But the damage still sits in our bank accounts and rates bills and economic funk to this day. The bloke who stuffed the joint, packed a sad and stormed out, never to be heard from again. It's a sad indictment on a role and influence that should have been handled a great deal more elegantly and with a mile more professionalism.See omnystudio.com/listener for privacy information.

The Treasury has confirmed concerns were raised about former Reserve Bank Governor Adrian Orr's conduct. Its comment comes as it responds to an allegation there was more to Orr's departure than the public has been led to believe. NZ Herald Wellington business editor Jenee Tibshraeny speculates further. LISTEN ABOVESee omnystudio.com/listener for privacy information.

AlabamaBoth US senators call on Trump to change rule re: federal contractsAPLS tells libraries to comply with Trump executive order or funds are cutBirmingham pastor Rich Lusk honors the life of John MacArthurState senator Orr working on bill restricting SNAP money for food not candyImmigration agents locate Mexican restaurant owner wanted for fraudFederal Trial delayed in Mobile after lawyer uses false info from AIFormer US senator Jeff Sessions inducted into AL Lawyer Hall of HonorNationalRescissions package from DOGE being debated in US senateUS attorney general Bondi fires SDNY prosecutor Maureen ComeyPaul Sperry reports WH looking into trove of docs on Russia collusion setupByron Donalds considers Biden decisions null and void based on two staff member pleading the fifth re: Joe's mental cognitionPart 2 of interview with Douglass Mackey, "the Meme guy"

Following the FDA approval of taletrectinib (Ibtrozi) for patients with locally advanced or metastatic ROS1-positive non–small cell lung cancer (NSCLC), CancerNetwork® spoke with Jorge Nieva, MD, about how this regulatory decision may impact the treatment paradigm for this disease. The approval was supported by findings from the phase 2 TRUST-I trial (NCT04395677) and the phase 2 TRUST-II trial (NCT04919811). The total efficacy population included 157 patients who had no prior treatment with a ROS1 tyrosine kinase inhibitor (TKI) and 113 who were previously treated with a ROS1 TKI. Topline results showed an objective response rate (ORR) of 90% (95% CI, 83%-95%) in TRUST-I and 85% (95% CI, 73%-93%) in TRUST-II among patients who had no prior treatment. Of those with pretreated disease, the respective ORRs were 52% (95% CI, 39%-64%) and 62% (95% CI, 46%-75%) in each study population. According to Nieva, an associate professor of clinical medicine at the Keck School of Medicine of the University of Southern California, taletrectinib may offer advantages over other therapies in the ROS1-positive metastatic NSCLC space based on its improved central nervous system (CNS) toxicity profile and “excellent” response and progression-free survival data. He stated that taletrectinib would become the go-to first-line agent in his practice. Additionally, he discussed strategies for mitigating toxicities related to taletrectinib such as nausea and diarrhea, and highlighted the need for additional research to improve immunotherapy options in NSCLC.  “I'm very happy that we have choices for patients, and I'm very happy that we have such a wide variety of drugs, but we still need to do better, and we need to find better ways of using these agents because they're still not cures for the majority of patients,” Nieva stated. “While these drugs can be helpful at debulking tumors, we still need to do a lot more work [to do] on making this a disease of the past for those patients who have it.” Reference FDA approves taletrectinib for ROS1-positive non-small cell lung cancer. News release. FDA. June 11, 2025. Accessed July 8, 2025. https://tinyurl.com/yc4f379m

Un'altra telefonata anonima indica l'auto di Salvatore Pirosu, un amico della famiglia Orrù, come quella in cui la ragazza sarebbe salita la sera della sua scomparsa. L'uomo, interrogato dagli inquirenti, confessa tutto e racconta la sua versione del delitto di Gisella. Una versione che appare piena di incongruenze e lacune e che tira in ballo altre persone, tra cui Licurgo Floris, ma che, nonostante tutto, viene ritenuta attendibile. E mentre in città le voci su presunti traffici di minorenni e festini a luci rosse continuano a circolare, emergono altre morti misteriose che potrebbero essere collegate al delitto di Gisella Orrù.See omnystudio.com/listener for privacy information.

Dr. Diwakar Davar and Dr. Jason Luke discuss novel agents in melanoma and other promising new data in the field of immunotherapy that were presented at the 2025 ASCO Annual Meeting. TRANSCRIPT Dr. Diwakar Davar: Hello. My name is Diwakar Davar, and I am welcoming you to the ASCO Daily News Podcast. I'm an associate professor of medicine and the clinical director of the Melanoma and Skin Cancer Program at the University of Pittsburgh's Hillman Cancer Center. Today, I'm joined by my colleague and good friend, Dr. Jason Luke. Dr. Luke is a professor of medicine. He is also the associate director of clinical research and the director of the Phase 1 IDDC Program at the University of Pittsburgh's Hillman Cancer Center. He and I are going to be discussing some key advancements in melanoma and skin cancers that were presented at the 2025 ASCO Annual Meeting. Our full disclosures are available in the transcript of this episode.  Jason, it is great to have you back on the podcast. Dr. Jason Luke: Thanks again so much for the opportunity, and I'm really looking forward to it. Dr. Diwakar Davar: Perfect. So we will go ahead and start talking a little bit about a couple of key abstracts in both the drug development immunotherapy space and the melanoma space. The first couple of abstracts, the first two, will cover melanoma. So, the first is LBA9500, which was essentially the primary results of RELATIVITY-098. RELATIVITY-098 was a phase 3 trial that compared nivolumab plus relatlimab in a fixed-dose combination against nivolumab alone for the adjuvant treatment of resected high-risk disease. Jason, do you want to maybe give us a brief context of what this is? Dr. Jason Luke: Yeah, it's great, thanks. So as almost all listeners, of course, will be aware, the use of anti–PD-1 immunotherapies really revolutionized melanoma oncology over the last 10 to 15 years. And it has become a standard of care in the adjuvant setting as well. But to review, in patients with stage III melanoma, treatment can be targeted towards BRAF with BRAF and MEK combination therapy, where that's relevant, or anti–PD-1 with nivolumab or pembrolizumab are a standard of care. And more recently, we've had the development of neoadjuvant approaches for palpable stage III disease. And in that space, if patients present, based on two different studies, either pembrolizumab or nivolumab plus ipilimumab can be given prior to surgery for somewhere in the 6- to 9-week range. And so all of these therapies have improved time-to-event endpoints, such as relapse-free or event-free survival. It's worth noting, however, that despite those advances, we've had a couple different trials now that have actually failed in this adjuvant setting, most high profile being the CheckMate-915 study, which looked at nivolumab plus ipilimumab and unfortunately was a negative study. So, with RELATIVITY-047, which was the trial of nivolumab plus relatlimab that showed an improvement in progression-free survival for metastatic disease, there's a lot of interest, and we've been awaiting these data for a long time for RELATIVITY-098, which, of course, is this adjuvant trial of LAG-3 blockade with relatlimab plus nivolumab. Dr. Diwakar Davar: Great. So with that, let's briefly discuss the trial design and the results. So this was a randomized, phase 3, blinded study, so double-blinded, so neither the investigators knew what the patients were getting, nor did the patients know what they were getting. The treatment investigational arm was nivolumab plus relatlimab in the fixed-dose combination. So that's the nivolumab standard fixed dose with relatlimab that was FDA approved in RELATIVITY-047. And the control arm was nivolumab by itself. The duration of treatment was 1 year. The patient population consisted of resected high-risk stage III or IV patients. The primary endpoint was investigator-assessed RFS. Stage and geography were the standard stratifying factors, and they were included, and most of the criteria were balanced across both arms. What we know at this point is that the 2-year RFS rate was 64% and 62% in the nivolumab and nivolumab-combination arms, respectively. The 2-year DMFS rate was similarly equivalent: 76% with nivolumab monotherapy, 73% with the combination. And similar to what you had talked about with CheckMate 915, unfortunately, the addition of LAG-3 did not appear to improve the RFS or DMFS compared to control in this patient population. So, tell us a little bit about your take on this and what do you think might be the reasons why this trial was negative? Dr. Jason Luke: It's really unfortunate that we have this negative phase 3 trial. There had been a lot of hope that the combination of nivolumab with relatlimab would be a better tolerated combination that increased the efficacy. So in the metastatic setting, we do have 047, the study that demonstrated nivolumab plus relatlimab, but now we have this negative trial in the adjuvant setting. And so as to why exactly, I think is a complicated scenario. You know, when we look at the hazard ratios for relapse-free survival, the primary endpoint, as well as the secondary endpoints for distant metastasis-free survival, we see that the hazard ratio is approximately 1. So there's basically no difference. And that really suggests that relatlimab in this setting had no impact whatsoever on therapeutic outcomes in terms of efficacy. Now, it's worth noting that there was a biomarker subanalysis that was presented in conjunction with these data that looked at some immunophenotyping, both from circulating T cells, CD8 T cells, as well as from the tumor microenvironment from patients who were treated, both in the previous metastatic trial, the RELATIVITY-047 study, and now in this adjuvant study in the RELATIVITY-098 study. And to briefly summarize those, what was identified was that T cells in advanced melanoma seemed to have higher expression levels of LAG-3 relative to T cells that are circulating in patients that are in the adjuvant setting. In addition to that, there was a suggestion that the magnitude of increase is greater in the advanced setting versus adjuvant. And the overall summary of this is that the suggested rationale for why this was a negative trial may have been that the target of LAG-3 is not expressed as highly in the adjuvant setting as it is in the metastatic setting. And so while the data that were presented, I think, support this kind of an idea, I am a little bit cautious that this is actually the reason for why the trial was negative, however. I would say we're not really sure yet as to why the trial was negative, but the fact that the hazard ratios for the major endpoints were essentially 1 suggests that there was no impact whatsoever from relatlimab. And this really makes one wonder whether or not building on anti–PD-1 in the adjuvant setting is feasible because anti–PD-1 works so well. You would think that even if the levels of LAG-3 expression were slightly different, you would have seen a trend in one direction or another by adding a second drug, relatlimab, in this scenario. So overall, I think it's an unfortunate circumstance that the trial is negative. Clearly there's going to be no role for relatlimab in the adjuvant setting. I think this really makes one wonder about the utility of LAG-3 blockade and how powerful it really can be. I think it's probably worth pointing out there's another adjuvant trial ongoing now of a different PD-1 and LAG-3 combination, and that's cemiplimab plus fianlimab, a LAG-3 antibody that's being dosed from another trial sponsor at a much higher dose, and perhaps that may make some level of difference. But certainly, these are unfortunate results that will not advance the field beyond where we were at already. Dr. Diwakar Davar: And to your point about third-generation checkpoint factors that were negative, I guess it's probably worth noting that a trial that you were involved with, KeyVibe-010, that evaluated the PD-1 TIGIT co-formulation of vibostolimab, MK-4280A, was also, unfortunately, similarly negative. So, to your point, it's not clear that all these third-generation receptors are necessarily going to have the same impact in the adjuvant setting, even if they, you know, for example, like TIGIT, and they sometimes may not even have an effect at all in the advanced cancer setting. So, we'll see what the HARMONY phase 3 trial, that's the Regeneron cemiplimab/fianlimab versus pembrolizumab control with cemiplimab with fianlimab at two different doses, we'll see how that reads out. But certainly, as you've said, LAG-3 does not, unfortunately, appear to have an impact in the adjuvant setting. So let's move on to LBA9501. This is the primary analysis of EORTC-2139-MG or the Columbus-AD trial. This was a randomized trial of encorafenib and binimetinib, which we will abbreviate as enco-bini going forward, compared to placebo in high-risk stage II setting in melanoma in patients with BRAF V600E or K mutant disease. So Jason, you know, you happen to know one or two things about the resected stage II setting, so maybe contextualize the stage II setting for us based on the trials that you've led, KEYNOTE-716, as well as CheckMate-76K, set us up to talk about Columbus-AD. Dr. Jason Luke: Thanks for that introduction, and certainly stage II disease has been something I've worked a lot on. The rationale for that has been that building off of the activity of anti–PD-1 in metastatic melanoma and then seeing the activity in stage III, like we just talked about, it was a curious circumstance that dating back about 7 to 8 years ago, there was no availability to use anti–PD-1 for high-risk stage II patients, even though the risk of recurrence and death from melanoma in the context of stage IIB and IIC melanoma is in fact similar or actually higher than in stage IIIA or IIIB, where anti–PD-1 was approved. And in that context, a couple of different trials that you alluded to, the Keynote-716 study that I led, as well as the CheckMate 76K trial, evaluated pembrolizumab and nivolumab, respectively, showing an improvement in relapse-free and distant metastasis-free survival, and both of those agents have subsequently been approved for use in the adjuvant setting by the US FDA as well as the European Medicines Agency.  So bringing then to this abstract, throughout melanoma oncology, we've seen that the impact of anti–PD-1 immunotherapy versus BRAF and MEK-targeted therapy have had very similar outcomes on a sort of comparison basis, both in frontline metastatic and then in adjuvant setting. So it was a totally reasonable question to ask: Could we use adjuvant BRAF and MEK inhibitor therapy? And I think all of us expected the answer would be yes. As we get into the discussion of the trial, I think the unfortunate circumstance was that the timing of this clinical trial being delayed somewhat, unfortunately, made it very difficult to accrue the trial, and so we're going to have to try to read through the tea leaves sort of, based on only a partially complete data set. Dr. Diwakar Davar: So, in terms of the results, they wanted to enroll 815 patients, they only enrolled 110. The RFS and DMFS were marginally improved in the treatment arm but certainly not significantly, which is not surprising because the trial had only accrued 16% to 18% of its complete accrual. As such, we really can't abstract from the stage III COMBI-AD data to stage II patients. And certainly in this setting, one would argue that the primary treatment options certainly remain either anti–PD-1 monotherapy, either with pembrolizumab or nivolumab, based on 716 or 76K, or potentially active surveillance for the patients who are not inclined to get treated.  Can you tell us a little bit about how you foresee drug development going forward in this space because, you know, for example, with HARMONY, certainly IIC disease is a part of HARMONY. We will know at least a little bit about that in this space. So what do you think about the stage IIB/C patient population? Is this a patient population in which future combinations are going to be helpful, and how would you think about where we can go forward from here? Dr. Jason Luke: It is an unfortunate circumstance that this trial could not be accrued at the pace that was necessary. I think all of us believe that the results would have been positive if they'd been able to accrue the trial. In the preliminary data set that they did disclose of that 110 patients, you know, it's clear there is a difference at a, you know, a landmark at a year. They showed a 16% difference, and that would be in line with what has been seen in stage III. And so, you know, I think it's really kind of too bad. There's really going to be no regulatory approach for this consideration. So using BRAF and MEK inhibition in stage II is not going to be part of standard practice moving into the future. To your point, though, about where will the field go? I think what we're already realizing is that in the adjuvant setting, we're really overtreating the total population. And so beyond merely staging by AJCC criteria, we need to move to biomarker selection to help inform which patients truly need the treatment. And in that regard, I don't think we've crystallized together as a field as yet, but the kinds of things that people are thinking about are the integration of molecular biomarkers like ctDNA. When it's positive, it can be very helpful, but in melanoma, we found that, unfortunately, the rates are quite low, you know, in the 10% to 15% range in the adjuvant setting. So then another consideration would be factors in the primary tumor, such as gene expression profiling or other considerations.  And so I think the future of adjuvant clinical trials will be an integration of both the standard AJCC staging system as well as some kind of overlaid molecular biomarker that helps to enrich for a higher-risk population of patients because on a high level, when you abstract out, it's just clearly the case that we're rather substantially overtreating the totality of the population, especially given that in all of our adjuvant studies to date for anti–PD-1, we have not yet shown that there's an overall survival advantage. And so some are even arguing perhaps we should even reserve treatment until patients progress. I think that's a complicated subject, and standard of care at this point is to offer adjuvant therapy, but certainly a lot more to do because many patients, you know, unfortunately, still do progress and move on to metastatic disease. Dr. Diwakar Davar: Let's transition to Abstract 2508. So we're moving on from the melanoma to the novel immunotherapy abstracts. And this is a very, very, very fascinating drug. It's IMA203. So Abstract 2508 is a phase 1 clinical update of IMA203. IMA203 is an autologous TCR-T construct targeting PRAME in patients with heavily pretreated PD-1-refractory metastatic melanoma. So Jason, in the PD-1 and CTLA-4-refractory settings, treatment options are either autologous TIL, response rate, you know, ballpark 29% to 31%, oncolytic viral therapy, RP1 with nivolumab, ORR about 30-ish percent. So new options are needed. Can you tell us a little bit about IMA203? Perhaps tell us for the audience, what is the difference between a TCR-T and traditional autologous TIL? And a little bit about this drug, IMA203, and how it distinguishes itself from the competing TIL products in the landscape. Dr. Jason Luke: I'm extremely enthusiastic about IMA203. I think that it really has transformative potential based on these results and hopefully from the phase 3 trial that's open to accrual now. So, what is IMA203? We said it's a TCR-T cell product. So what that means is that T cells are removed from a patient, and then they can be transduced through various technologies, but inserted into those T cells, we can then add a T-cell receptor that's very specific to a single antigen, and in this case, it's PRAME. So that then is contrasted quite a bit from the TIL process, which includes a surgical resection of a tumor where T cells are removed, but they're not specific necessarily to the cancer, and they're grown up in the lab and then given to the patient. They're both adoptive cell transfer products, but they're very different. One is genetically modified, and the other one is not. And so the process for generating a TCR-T cell is that patients are required to have a new biomarker that some may not be familiar with, which is HLA profiling. So the T-cell receptor requires matching to the concomitant HLA for which the peptide is bound in. And so the classic one that is used in most oncology practices is A*02:01 because approximately 48% of Caucasians have A*02:01, and the frequency of HLA in other ethnicities starts to become highly variable. But in patients who are identified to have A*02:01 genotype, we can then remove blood via leukapheresis or an apheresis product, and then insert via lentiviral transduction this T-cell receptor targeting PRAME. Patients are then brought back to the hospital where they can receive lymphodepleting chemotherapy and then receive the reinfusion of the TCR-T cells. Again, in contrast with the TIL process, however, these T cells are extremely potent, and we do not need to give high-dose interleukin-2, which is administered in the context of TIL. Given that process, we have this clinical trial in front of us now, and at ASCO, the update was from the phase 1 study, which was looking at IMA203 in an efficacy population of melanoma patients who were refractory at checkpoint blockade and actually multiple lines of therapy. So here, there were 33 patients and a response rate of approximately 50% was observed in this population of patients, notably with a duration of response approximately a year in that treatment group. And I realize that these were heavily pretreated patients who had a range of very high-risk features. And approximately half the population had uveal melanoma, which people may be aware is a generally speaking more difficult-to-treat subtype of melanoma that metastasizes to the liver, which again has been a site of resistance to cancer immunotherapy. So these results are extremely promising. To summarize them from what I said, it's easier to make TCR-T cells because we can remove blood from the patient to transduce the T cells, and we don't have to put them through surgery. We can then infuse them, and based on these results, it looks like the response rate to IMA203 is a little bit more than double what we expect from lifileucel. And then, whereas with lifileucel or TILs, we have to give high-dose IL-2, here we do not have to give high-dose IL-2. And so that's pretty promising. And a clinical trial is ongoing now called the SUPREME phase 3 clinical trial, which is hoping to validate these results in a randomized global study. Dr. Diwakar Davar: Now, one thing that I wanted to go over with you, because you know this trial particularly well, is what you think of the likelihood of success, and then we'll talk a little bit about the trial design. But in your mind, do you think that this is a trial that has got a reasonable likelihood of success, maybe even a high likelihood of success? And maybe let's contextualize that to say an alternative trial, such as, for example, the TebeAM trial, which is essentially a T-cell bispecific targeting GP100. It's being compared against SOC, investigator's choice control, also in a similarly heavily pretreated patient population. Dr. Jason Luke: So both trials, I think, have a strong chance of success. They are very different kinds of agents. And so the CD3 bispecific that you referred to, tebentafusp, likely has an effect of delaying progression, which in patients with advanced disease could have a value that might manifest as overall survival. With TCR-T cells, by contrast, we see a very high response rate with some of the patients going into very durable long-term benefit. And so I do think that the SUPREME clinical trial has a very high chance of success. It will be the first clinical trial in solid tumor oncology randomizing patients to receive a cell therapy as compared with a standard of care. And within that standard of care control arm, TILs are allowed as a treatment. And so it will also be the first study that will compare TCR-T cells against TILs in a randomized phase 3. But going back to the data that we've seen in the phase 1 trial, what we observe is that the duration of response is really connected to the quality of the response, meaning if you have more than a 50% tumor shrinkage, those patients do very, very well. But even in patients who have less than 50% tumor shrinkage, the median progression-free survival right now is about 4.5 months. And again, as we think about trial design, standard of care options for patients who are in this situation are unfortunately very bad. And the progression-free survival in that population is probably more like 2 months. So this is a trial that has a very high likelihood of being positive because the possibility of long-term response is there, but even for patients who don't get a durable response, they're likely going to benefit more than they would have based on standard chemotherapy or retreatment with an anti–PD-1 agent. Dr. Diwakar Davar: Really, a very important trial to enroll, a trial that is first in many ways. First of a new generation of TCR-T agents, first trial to look at cell therapy in the control arm, a new standard of efficacy, but potentially also if this trial is successful, it will also be a new standard of trial conduct, a new kind of trial, of a set of trials that will be done in the second-line immunotherapy-refractory space. So let's pivot to the last trial that we were going to discuss, which was Abstract 2501. Abstract 2501 is a first-in-human phase 1/2 trial evaluating BNT142, which is the first-in-class mRNA-encoded bispecific targeting Claudin-6 and CD3 in patients with Claudin-positive tumors. We'll talk a little bit about this, but maybe let's start by talking a little bit about Claudin-6. So Claudin-6 is a very interesting new target. It's a target that's highly expressed in GI and ovarian tumors. There are a whole plethora of Claudin-6-targeting agents, including T-cell bispecifics and Claudin-6-directed CAR-Ts that are being developed. But BNT142 is novel. It's a novel lipid nanoparticle LNP-encapsulated mRNA. The mRNA encodes an anti–Claudin-6 CD3 bispecific termed RiboMAB-021. And it then is administered to the patient. The BNT142-encoding mRNA LNPs are taken up by the liver and translated into the active drug. So Jason, tell us a little bit about this agent. Why you think it's novel, if you think it's novel, and let's talk a little bit then about the results. Dr. Jason Luke: So I certainly think this is a novel agent, and I think this is just the first of what will probably become a new paradigm in oncology drug development. And so you alluded to this, but just to rehash it quickly, the drug is encoded as genetic information that's placed in the lipid nanoparticle and then is infused into the patient. And after the lipid nanoparticles are taken up by the liver, which is the most common place that LNPs are usually taken up, that genetic material in the mRNA starts to be translated into the actual protein, and that protein is the drug. So this is in vivo generation, so the patient is making their own drug inside their body. I think it's a really, really interesting approach. So for any drug that could be encoded as a genetic sequence, and in this case, it's a bispecific, as you mentioned, CD3-Claudin-6 engager, this could have a tremendous impact on how we think about pharmacology and novel drug development moving into the future in oncology. So I think it's an extremely interesting drug, the like of which we'll probably see only more moving forward. Dr. Diwakar Davar: Let's maybe briefly talk about the results. You know, the patient population was heavily pretreated, 65 or so patients, mostly ovarian cancer. Two-thirds of the patients were ovarian cancer, the rest were germ cell and lung cancer patients. But let's talk a little bit about the efficacy. The disease control rate was about 58% in the phase 1 population as a whole, but 75% in the ovarian patient population. Now tell us a little bit about the interesting things about the drug in terms of the pharmacokinetics, and also then maybe we can pivot to the clinical activity by dose level. Dr. Jason Luke: Well, so they did present in their presentation at ASCO a proportionality showing that as higher doses were administered, that greater amounts of the drug were being made inside the patient. And so that's an interesting observation, and it's an important one, right? Suggesting that the pharmacology that we classically think of by administering drugs by IV, for example, would still be in play. And that did translate into some level of efficacy, particularly at the higher dose levels. Now, the caveat that I'll make a note of is that disease control rate is an endpoint that I think we have to be careful about because what that really means is sometimes a little bit unclear. Sometimes patients have slowly growing tumors and so on and so forth. And the clinical relevance of disease control, if it doesn't last at least 6 months, I think is probably pretty questionable. So I think these are extremely interesting data, and there's some preliminary sense that getting the dose up is going to matter because the treatment responses were mostly observed at the highest dose levels. There's also a caveat, however, that across the field of CD3 bispecific molecules like this, there's been quite a bit of heterogeneity in terms of the response rate, with some of them only really generating stable disease responses and other ones having more robust responses. And so I think this is a really interesting initial foray into this space. My best understanding is this molecule is not moving forward further after this, but I think that this really does set it up to be able to chase after multiple different drug targets on a CD3 bispecific backbone, both in ovarian cancer, but then basically across all of oncology. Dr. Diwakar Davar: Perfect. This is a very new sort of exciting arena where we're going to be looking at, in many ways, these programmable constructs, whether we're looking at in vivo-generated, in this case, a T-cell bispecific, but we've also got newer drugs where we are essentially giving drugs where people are generating in vivo CAR T, and also potentially even in vivo TCR-T. But certainly lots of new excitement around this entire class of drugs. And so, what we'd like to do at this point in time is switch to essentially the fact that we've got a very, very exciting set of data at ASCO 2025. You've heard from Dr. Luke regarding the advances in both early drug development but also in advanced cutaneous melanoma. And Jason, as always, thank you so much for sharing your very valuable and great, fantastic insights with us on the ASCO Daily News Podcast. Dr. Jason Luke: Well, thanks again for the opportunity. Dr. Diwakar Davar: And thank you to our listeners for taking your time to listen today. You will find the links to the abstracts that we discussed today in the transcript of this episode. And finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Follow today's speakers:    Dr. Diwakar Davar    @diwakardavar    Dr. Jason Luke @jasonlukemd Follow ASCO on social media:     @ASCO on Twitter       ASCO on Bluesky   ASCO on Facebook       ASCO on LinkedIn   Disclosures:     Dr. Diwakar Davar:      Honoraria: Merck, Tesaro, Array BioPharma, Immunocore, Instil Bio, Vedanta Biosciences     Consulting or Advisory Role: Instil Bio, Vedanta Biosciences     Consulting or Advisory Role (Immediate family member): Shionogi     Research Funding: Merck, Checkmate Pharmaceuticals, CellSight Technologies, GSK, Merck, Arvus Biosciences, Arcus Biosciences     Research Funding (Inst.): Zucero Therapeutics     Patents, Royalties, Other Intellectual Property: Application No.: 63/124,231 Title: COMPOSITIONS AND METHODS FOR TREATING CANCER Applicant: University of Pittsburgh–Of the Commonwealth System of Higher Education Inventors: Diwakar Davar Filing Date: December 11, 2020 Country: United States MCC Reference: 10504-059PV1 Your Reference: 05545; and Application No.: 63/208,719 Enteric Microbiotype Signatures of Immune-related Adverse Events and Response in Relation to Anti-PD-1 Immunotherapy     Dr. Jason Luke:     Stock and Other Ownership Interests: Actym Therapeutics, Mavu Pharmaceutical, Pyxis, Alphamab Oncology, Tempest Therapeutics, Kanaph Therapeutics, Onc.AI, Arch Oncology, Stipe, NeoTX     Consulting or Advisory Role: Bristol-Myers Squibb, Merck, EMD Serono, Novartis, 7 Hills Pharma, Janssen, Reflexion Medical, Tempest Therapeutics, Alphamab Oncology, Spring Bank, Abbvie, Astellas Pharma, Bayer, Incyte, Mersana, Partner Therapeutics, Synlogic, Eisai, Werewolf, Ribon Therapeutics, Checkmate Pharmaceuticals, CStone Pharmaceuticals, Nektar, Regeneron, Rubius, Tesaro, Xilio, Xencor, Alnylam, Crown Bioscience, Flame Biosciences, Genentech, Kadmon, KSQ Therapeutics, Immunocore, Inzen, Pfizer, Silicon Therapeutics, TRex Bio, Bright Peak, Onc.AI, STipe, Codiak Biosciences, Day One Therapeutics, Endeavor, Gilead Sciences, Hotspot Therapeutics, SERVIER, STINGthera, Synthekine     Research Funding (Inst.): Merck , Bristol-Myers Squibb, Incyte, Corvus Pharmaceuticals, Abbvie, Macrogenics, Xencor, Array BioPharma, Agios, Astellas Pharma , EMD Serono, Immatics, Kadmon, Moderna Therapeutics, Nektar, Spring bank, Trishula, KAHR Medical, Fstar, Genmab, Ikena Oncology, Numab, Replimmune, Rubius Therapeutics, Synlogic, Takeda, Tizona Therapeutics, Inc., BioNTech AG, Scholar Rock, Next Cure     Patents, Royalties, Other Intellectual Property: Serial #15/612,657 (Cancer Immunotherapy), and Serial #PCT/US18/36052 (Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof)     Travel, Accommodations, Expenses: Bristol-Myers Squibb, Array BioPharma, EMD Serono, Janssen, Merck, Novartis, Reflexion Medical, Mersana, Pyxis, Xilio

Dr. Vamsi Velcheti and Dr. Nate Pennell discuss novel treatment approaches in small cell and non-small cell lung cancer that were featured at the 2025 ASCO Annual Meeting. TRANSCRIPT Dr. Vamsi Velcheti: Hello, I'm Dr. Vamsi Velcheti, your guest host of the ASCO Daily News Podcast. I'm a professor of medicine and chief of hematology and oncology at the Mayo Clinic in Jacksonville, Florida. The 2025 ASCO Annual Meeting featured some exciting advancements in small cell lung cancer, targeted therapies for non-small cell lung cancer, and other novel [treatment] approaches. Today, I'm delighted to be joined by Dr. Nate Pennell to discuss some of the key abstracts that are advancing the lung cancer field. Dr. Pennell is the co-director of the Cleveland Clinic Lung Cancer Program and also the vice chair of clinical research at the Taussig Cancer Institute. Our full disclosures are available in the transcript of this episode. Nate, it's great to have you back on the podcast. Thanks so much for being here. Dr. Nate Pennell: Thanks, Vamsi. Always a pleasure. Dr. Vamsi Velcheti: Let's get started, and I think the first abstract that really caught my attention was Abstract 8516, “The Randomized Trial of Relevance of Time of Day of Immunotherapy for Progression-Free and Overall Survival in Patients With Non-Small Cell Lung Cancer.” What are your thoughts about this, Nate? Dr. Nate Pennell: I agree. I thought this was one of the most discussed abstracts, certainly in the lung cancer session, but I think even outside of lung cancer, it got some discussion. So, just to put this in perspective, there have been a number of publications that have all been remarkably consistent, and not just in lung cancer but across multiple cancer types, that immunotherapy, immune checkpoint inhibitors, are commonly used. And all of them have suggested, when looking at retrospective cohorts, that patients who receive immune checkpoint inhibitors earlier in the day – so in the morning or before the early afternoon – for whatever reason, appear to have better outcomes than those who get it later in the day, and this has been repeated. And I think many people just sort of assumed that this was some sort of strange association and that there was something fundamentally different from a prognostic standpoint in people who came in in the morning to get their treatment versus those who came later in the afternoon, and that was probably the explanation. The authors of this randomized trial actually decided to test this concept. And so, about 210 patients with previously untreated advanced non-small cell lung cancer were randomly assigned to get chemo and immune checkpoint inhibitor – either pembrolizumab or sintilimab – and half of them were randomly assigned to get the treatment before 3 PM in the afternoon, and half of them were assigned to get it after 3 PM in the afternoon. And it almost completely recapitulated what was seen in the retrospective cohorts. So, the median progression-free survival in those who got earlier treatment was 13.2 months versus only 6.5 months in those who got it later in the day. So, really enormous difference with a hazard ratio of 0.43, which was statistically significant. And perhaps even more striking, the median overall survival was not reached in the early group versus 17.8 months in the late group with a hazard ratio of 0.43, also highly statistically significant. Even the response rate was 20% higher in the early patients; 75% response rate compared to 56% in the late-time-of-day patients. So very consistent across all measures of efficacy with pretty good matched characteristics across the different groups. And so, I have to tell you, I don't know what to make of this. I certainly was a skeptic about the retrospective series, but now we have a prospective randomized trial that shows essentially the same thing. So, maybe there is a difference between getting treated in the morning, although I have yet to hear someone give a very good mechanistic explanation as to why this would be. What were your thoughts on this? Dr. Vamsi Velcheti: It's indeed fascinating, Nate, and I actually think this was a very interesting abstract. Really, I was caught off guard looking at the data. I mean, if it were a drug, we would be so excited, right? I mean, with those kind of survival benefits. I don't know. I think circadian rhythm probably has something to do with it, like different cytokine profiles at the time of administration. I mean, who knows? But I think it's a randomized trial, and I think I would expect to see a mad rush for treatment appointments early in the morning given this, and at least I want my patients to come in first thing in the morning. It'll be interesting to see. Dr. Nate Pennell: It's important to point out that in this study, everyone got chemo and immunotherapy. And, at least in our cancer center, most patients who are getting platinum-doublet chemotherapy and immunotherapy actually do get treated earlier in the day already, just because of the length of the infusion appointment that's needed. So it really is oftentimes people getting single-agent immunotherapy who are often getting the later, shorter visits. But if you have a choice, I think it would be very reasonable to have people treated earlier in the day. And I do think most of the impressions that I got from people about this is that they would like to see it reproduced but certainly well worth further investigation. And I personally would like to see more investigation into what the rationale would be for this because I still can't quite figure out, yes, if you got it at, say, you know, 5 PM, that's later in the day and I can understand that maybe your immune system is somewhat less receptive at that point than it would be in the morning. But because these checkpoint inhibitors have such long half-lives, it's still in your system the next morning when your immune system is supposedly more receptive. So I don't quite understand why that would be the case. Well, let's move on to the next study. I would like to hear your thoughts on Abstract 8515, “Plasma-Guided, Adaptive First-Line Chemoimmunotherapy for Non-Small Cell Lung Cancer.” Dr. Vamsi Velcheti: Yeah, this was another abstract that seems to be really interesting in my opinion. I think there's kind of a lot of emphasis lately on ctDNA and MRD-based assays to monitor disease. In the lung cancer space, we haven't had a lot of clinical trials looking at this prospectively, and this was one of those pilot studies where they looked at circulating free DNA (cfDNA)-based response-adaptive strategy for frontline patients who are PD-L1 positive. So, patients started with pembrolizumab monotherapy, and based on plasma molecular response after 2 cycles, those patients without response received early treatment intensification with a platinum doublet. So the approach essentially was to reduce the chemotherapy exposure in patients who respond to immunotherapy. And only about 17.5% of the patients on the trial received chemotherapy based on lack of molecular response. So, in this trial, what they found was patients with the cfDNA response had a markedly improved PFS of 16.4 months versus 4.8 months. So essentially, like, this is a really nice study to set a foundation on which we have to do larger studies to incorporate molecular markers trying to look at cfDNA response to inform treatment strategy, either escalation or de-escalation strategies. So, I thought it was a very interesting study. Dr. Nate Pennell: Yeah. I mean, we always have this question for patients, “Should they get immunotherapy alone or combined with chemo?” and I think this certainly is intriguing, suggesting that there may be ways you can monitor people and perhaps rescue those that aren't going to respond to single agent. I'd like to see a randomized trial against, you know, this strategy, perhaps against everyone getting, say, chemoimmunotherapy or make sure that you're not potentially harming people by doing this strategy. But I agree, it's time to move beyond just observing that cell-free DNA is prognostic and important and start using it to actually guide treatment. Dr. Vamsi Velcheti: Yeah, and I would just caution though, like, you know, I think we need more data, but, however, it's certainly a very interesting piece of data to kind of help inform future trials. So, there was another abstract that caught my attention, and I think this would be a very interesting abstract in the EGFR space. Abstract 8506, "Patritumab Deruxtecan (HER3-DXd) in Resistant EGFR-Mutant Advanced Non-Small Cell Lung Cancer Patients After Third-Generation EGFR TKI," it's the HERTHENA-Lung02 study. What do you think about the results of this study? Dr. Nate Pennell: Yeah, this was, I would say, very widely anticipated and ultimately a little disappointing, despite being a positive trial. So, these are patients with EGFR-mutant non-small cell lung cancer who have progressed after a third-generation EGFR TKI like osimertinib. This is really an area of major unmet need. We do have drugs like amivantamab in this space, but still definitely an area where essentially patients move from having a highly effective oral therapy to being in the realm of chemotherapy as their best option. So, this HER3 antibody-drug conjugate, patritumab deruxtecan, had some good single-arm data for this. And we're sort of hoping this would become an available option for patients. This trial was designed against platinum-doublet chemotherapy in this setting and with a primary endpoint of progression-free survival. And it actually was positive for improved progression-free survival compared to chemo with a hazard ratio of 0.77. But when you look at the medians, you can see that the median PFS was only 5.8 versus 5.4 months. It was really a modest difference between the two arms. And on the interim analysis, it appeared that there will not be a difference in overall survival between the two arms. In fact, the hazard ratio at the interim analysis was 0.98 for the two arms. So based on this, unfortunately, the company that developed the HER3-DXd has withdrawn their application to the FDA for approval of the drug, anticipating that they probably wouldn't get past approval without that overall survival endpoint. So, unfortunately, probably not, at least for the near future, going to be a new option for these patients. Dr. Vamsi Velcheti: Yeah, I think this is a space that's clearly an unmet need, and this was a big disappointment, I should say. I think all of us were going into the meeting anticipating some change in the standard of care here. Dr. Nate Pennell: Yeah, I agree. It was something that I was telling patients, honestly, that I was expecting this to be coming, and so now, definitely a bit of a disappointment. But it happens and, hopefully, it will still find perhaps a role or other drugs with a similar target. Certainly an active area. Well, let's leave the EGFR-mutant space and move into small cell. There were a couple of very impactful studies. And one of them was Abstract 8006, “Lurbinectedin Plus Atezolizumab as First-Line Maintenance Treatment in Patients With Extensive-Stage Small Cell Lung Cancer, Primary Results from the Phase III IMforte Trial.” So, what was your impression of this? Dr. Vamsi Velcheti: Yeah, I think this is definitely an interesting study, and small cell, I remember those days when we had barely any studies of small cell at ASCO, and now we have a lot of exciting developments in the small cell space. It's really good to see. The IMforte trial is essentially like a maintenance lurbinectedin trial with atezolizumab maintenance. And the study was a positive trial. The primary endpoint was a PFS, and the study showed improvement in both PFS and OS with the addition of lurbinectedin to atezolizumab maintenance. And definitely, it's a positive trial, met its primary endpoint, but I always am a little skeptical of adding maintenance cytotoxic therapies here in this setting. In my practice, and I'd like to hear your opinion, Nate, most patients with small cell after 4 cycles of a platinum doublet, they're kind of really beaten up. Adding more cytotoxic therapy in the maintenance space is going to be tough, I think, for a lot of patients. But also, most importantly, I think this rapidly evolving landscape for patients with small cell lung cancer with multiple new, exciting agents, actually like some FDA-approved like tarlatamab, also like a lot of these emerging therapeutics like I-DXd and other ADCs in this space. You kind of wonder, is it really optimal strategy to bring on like another cytotoxic agent right after induction chemotherapy, or do you kind of delay that? Or maybe have like a different strategy in terms of maintenance. I know that the tarlatamab maintenance trial is probably going to read out at some point too. I think it's a little challenging. The hazard ratio is also 0.73. As I said, it's a positive trial, but it's just incremental benefit of adding lurbi. And also on the trial, we need to also pay attention to the post-progression second-line treatments, number of patients who received tarlatamab or any other investigational agents.  So I think it's a lot of questions still. I'm not quite sure I'd be able to embrace this completely. I think a vast majority of my patients might not be eligible anyway for cytotoxic chemotherapy maintenance right away, but yeah, it's tough. Dr. Nate Pennell: Yeah. I would call this a single and not a home run. It definitely is real. It was a real overall survival benefit. Certainly not surprising that a maintenance therapy would improve progression-free survival. We've known that for a long time in small cell, but first to really show an overall survival benefit. But I completely agree with you. I mean, many people are not going to want to continue further cytotoxics after 4 cycles of platinum-doublet chemo. So I would say, for those that are young and healthy and fly through chemo without a lot of toxicity, I think certainly something worth mentioning. The problem with small cell, of course, is that so many people get sick so quickly while on that observation period after first-line chemo that they don't make it to second-line treatment. And so, giving everyone maintenance therapy essentially ensures everyone gets that second-line treatment. But they also lose that potentially precious few months where they feel good and normal and are able to be off of treatment. So, I would say this is something where we're really going to have to kind of sit and have that shared decision-making visit with patients and decide what's meaningful to them. Dr. Vamsi Velcheti: Yeah, I agree. The next abstract that was a Late-Breaking Abstract, 8000, “Overall Survival of Neoadjuvant Nivolumab Plus Chemotherapy in Patients With Resectable Non-Small Cell Lung Cancer in CheckMate-816.” This was a highly anticipated read-out of the OS data from 816. What did you make of this abstract? Dr. Nate Pennell: Yeah, I thought this was great. Of course, CheckMate-816 changed practice a number of years ago when it first reported out. So, this was the first of the neoadjuvant or perioperative chemoimmunotherapy studies in resectable non-small cell lung cancer. So, just to review, this was a phase 3 study for patients with what we would now consider stage II or stage IIIA resectable non-small cell lung cancer. And they received three cycles of either chemotherapy or chemotherapy plus nivolumab, and that was it. That was the whole treatment. No adjuvant treatment was given afterwards. They went to resection. And patients who received the chemoimmunotherapy had a much higher pathologic complete response rate and a much better event-free survival. And based on this, this regimen was approved and, I think, at least in the United States, widely adopted.  Now, since the first presentation of CheckMate 816, there have been a number of perioperative studies that have included an adjuvant component of immunotherapy – KEYNOTE-671, the AEGEAN study – and these also have shown improved outcomes. The KEYNOTE study with pembrolizumab also with an overall survival benefit. And I think people forgot a little bit about CheckMate-816. So, this was the 5-year overall survival final analysis. And it did show a statistically and, I think, clinically meaningful difference in overall survival with the 3 cycles of neoadjuvant chemo-nivo compared to chemo with a hazard ratio of 0.72. The 5-year overall survival of 65% in the chemo-IO group versus 55% with the chemo alone. So a meaningful improvement. And interestingly, that hazard ratio of 0.72 is very similar to what was seen in the peri-operative pembro study that included the adjuvant component. So, very much still relevant for people who think that perhaps the value of those neoadjuvant treatments might be really where most of the impact comes from this type of approach. They also gave us an update on those with pathologic complete response, showing really astronomically good outcomes. If you have a pathologic complete response, which was more than a quarter of patients, the long-term survival was just phenomenal. I mean, 95% alive at 5 years if they were in that group and suggesting that in those patients at least, the adjuvant treatment may not be all that important.  So, I think this was an exciting update and still leaves very much the open question about the importance of continuing immunotherapy after surgery after the neoadjuvant component. Dr. Vamsi Velcheti: Yeah, I completely agree, Nate. I think the million-dollar question is: “Is there like a population of patients who don't have complete response but like maybe close to complete response?” So, would you like still consider stopping adjuvant IO? I probably would not be comfortable, but I think sometimes, you know, we all have patients who are like very apprehensive of continuing treatments. So, I think that we really need more studies, especially for those patients who don't achieve a complete CR. I think trying to find strategies for like de-escalation based on MRD or other risk factors. But we need more trials in that space to inform not just de-escalation, but there are some patients who don't respond at all to a neoadjuvant IO. So, there may be an opportunity for escalating adjuvant therapies. So, it is an interesting space to watch out for. Dr. Nate Pennell: No, absolutely. Moving to KRAS-mutant space, so our very common situation in patients with non-small cell lung cancer, we had the results of Abstract 8500, “First-Line Adagrasib With Pembrolizumab in Patients With Advanced or Metastatic KRASG12C-Mutated Non-Small Cell Lung Cancer” from the phase 2 portion of the KRYSTAL-7 study. Why was this an interesting and important study? Dr. Vamsi Velcheti: First of all, there were attempts to kind of combine KRASG12C inhibitors in the past with immune checkpoint inhibitors, notably sotorasib with pembrolizumab. Unfortunately, those trials have led to like a lot of toxicity, with increased especially liver toxicity, which was a major issue. This is a phase 2 study of adagrasib in combination with pembrolizumab, and this is a study in the frontline setting in patients with the G12C-mutant metastatic non-small cell lung cancer. And across all the PD-L1 groups, the ORR was 44%, and the median PFS was 11 months, comparable to the previous data that we have seen with adagrasib in this setting. So it's not like a major improvement in clinical efficacy. However, I think the toxicity profile that we were seeing was slightly better than the previous trials in combination with sotorasib, but you still have a fair amount of transaminitis even in the study. At this point, this is not ready for clinical primetime. I don't think we should be using sotorasib or adagrasib in the frontline or even in the second line in combination with checkpoint inhibitors. Combining these drugs with checkpoint inhibitors in the clinical practice might lead to adverse outcomes. So, we need to wait for more data like newer-generation G12C inhibitors which are also being studied in combination, so we'll have to kind of wait for more data to emerge in this space. Dr. Nate Pennell: I agree, this is not immediately practice changing. This is really an attempt to try to combine targeted treatment with immune checkpoint inhibitor. And I agree with you that, you know, it does appear to be perhaps a little bit better tolerated than some of the prior combinations that have tried in this space. The outcomes overall were not that impressive, although in the PD-L1 greater than 50%, it did have a better response rate perhaps than you would expect with either drug alone. And I do think that the company is focusing on that population for a future randomized trial, which certainly would inform this question better. But in the meantime, I agree with you, there's a lot of newer drugs that are coming along that potentially may be more active and better tolerated. And so, I'd say for now, interesting but we'll wait and see. Dr. Vamsi Velcheti: Yeah, so now moving back again to small cell. So, there was a Late-Breaking Abstract, 8008. This is a study of tarlatamab versus chemotherapy as second-line treatment for small cell lung cancer. They presented the primary analysis of the phase III DeLLphi-304 study. What do you think about this? Dr. Nate Pennell: Yeah, I thought this was really exciting. This was, I would say, perhaps the most important lung study that was presented. Tarlatamab is, of course, the anti-DLL3 bispecific T-cell engager compound, which is already FDA approved based on a prior single-arm phase II study, which showed a very nice response rate as a single agent in previously treated small cell lung cancer and relatively manageable side effects, although somewhat unique to solid tumor docs in the use of these bispecific drugs in things like cytokine release syndrome and ICANS, the neurologic toxicities. So, this trial was important because tarlatamab was approved, but there were also other chemotherapy drugs approved in the previously treated space. And so, this was a head-to-head second-line competition comparison between tarlatamab and either topotecan, lurbinectedin, or amrubicin in previously treated small cell patients with a primary endpoint of overall survival. So, a very well-designed trial. And it did show, I think, a very impressive improvement in overall survival with a median overall survival in the tarlatamab group of 13.6 months compared to 8.3 months with chemotherapy, hazard ratio of 0.6. And progression-free survival was also longer at 4.2 months versus 3.2 months, hazard ratio of 0.72. In addition to showing improvements in cancer-related symptoms that were improved in tarlatamab compared to chemotherapy, there was actually also significantly lower rates of serious treatment-related adverse events with tarlatamab compared to chemotherapy. So, you do still see the cytokine release syndrome, which is seen in most people but is manageable because these patients are admitted to the hospital for the first two cycles, as well as a significant number of patients with neurologic side effects, the so-called ICANS, which also can be treated with steroids. And so, I think based upon the very significant improvement in outcomes, I would expect that this should become our kind of standard second-line treatment since it seems to be much better than chemo. However, tarlatamab is definitely a new drug that a lot of places are not used to using, and I think a lot of cancer centers, especially ones that aren't tied to a hospital, may have questions about how to deal with the CRS. So, I'm curious your thoughts on that. Dr. Vamsi Velcheti: Yeah, thank you, Nate. And I completely agree. I think the data looked really promising, and I've already been using tarlatamab in the second-line space. The durability of response and overall, having used tarlatamab quite a bit - like, I participated in some of the early trials and also used it as standard of care - tarlatamab has unique challenges in terms of like need for hospitalization for monitoring for the first few treatments and make sure, you know, we monitor those patients for CRS and ICANS. But once you get past that initial administration and monitoring of CRS, these patients have a much better quality of life, they're off chemotherapy, and I think it's really about the logistics of actually administering tarlatamab and coordination with the hospital and administration in the outpatient setting. It's definitely challenging, but I think it definitely can be done and should be done given what we are seeing in terms of clinical efficacy here. Dr. Nate Pennell: I agree. I think hospital systems now are just going to have to find a way to be able to get this on formulary and use it because it clearly seems to be more effective and generally better tolerated by patients. So, should move forward, I think. Finally, there's an abstract I wanted to ask you about, Abstract 8001, which is the “Neoadjuvant osimertinib with or without chemotherapy versus chemotherapy alone in resectable epidermal growth factor receptor-mutated non-small cell lung cancer: The NeoADAURA Study”. And this is one that I think was also fairly highly anticipated. So, what are your thoughts? Dr. Vamsi Velcheti: You know, I wasn't probably surprised with the results, and I believe we were all expecting a positive trial, and we certainly were handed a positive trial here. It's a phase III trial of osimertinib and chemotherapy or osimertinib in the neoadjuvant space followed by surgery, followed by osimertinib. It's a global phase 3 trial and very well conducted, and patients with stage II to stage IIIB were enrolled in the study. And in the trial, patients who had a neoadjuvant osimertinib with or without chemotherapy showed a significant improvement in major pathologic response rates over chemotherapy alone. And the EFS was also positive for osimertinib and chemotherapy, osimertinib monotherapy as well compared to chemotherapy alone. So overall, the study met its primary endpoint, and I think it sheds light on how we manage our patients with early-stage lung cancer. I think osimertinib, we know that osimertinib is already FDA approved in the adjuvant space, but what we didn't really know is how was osimertinib going to work in the neoadjuvant space. And there are always situations, especially for stage III patients, where we are on the fence about, are these patients already close to being metastatic? They have, like, almost all these patients have micrometastatic disease, even if they have stage III. As we saw in the LAURA data, when you look at the control arm, it was like a very short PFS. Chemoradiation does nothing for those patients, and I think these patients have systemic mets, either gross or micrometastatic disease at onset. So, it's really important to incorporate osimertinib early in the treatment course. And I think, especially for the locally advanced patients, I think it's even more important to kind of incorporate osimertinib in the neoadjuvant space and get effective local control with surgery and treat them with adjuvant. I'm curious to hear your thoughts, Nate. Dr. Nate Pennell: I am a believer and have long been a believer in targeted adjuvant treatments, and, you know, it has always bothered me somewhat that we're using our far and away most effective systemic therapy; we wait until after they go through all their pre-op treatments, they go through surgery, then they go through chemotherapy, and then finally months later, they get their osimertinib, and it still clearly improves survival in the adjuvant setting. Why not just start the osimertinib as soon as you know that the patient has EGFR-mutant non-small cell lung cancer, and then you can move on to surgery and adjuvant treatment afterwards? And I think what was remarkable about this study is that all of these patients almost - 90% in each arm - went to surgery. So, you weren't harming them with the neoadjuvant treatment. And clearly better major pathologic response, nodal downstaging, event-free survival was better. But I don't know that this trial is ever going to show an overall survival difference between neoadjuvant versus just surgery and adjuvant treatment, given how effective the drug is in the adjuvant setting. Nonetheless, I think the data is compelling enough to consider this, certainly for our N2-positive, stage IIIA patients or a IIIB who might be otherwise surgical candidates. I think based on this, I would certainly consider that. Dr. Vamsi Velcheti: Yeah, and especially for EGFR, like even for stage IIIB patients, in the light of the LAURA study, those patients who do not do too well with chemoradiation. So you're kind of delaying effective systemic therapy, as you said, waiting for the chemoradiation to finish. So I think probably time to revisit how we kind of manage these locally advanced EGFR patients. Dr. Nate Pennell: Yep, I agree. Dr. Vamsi Velcheti: Nate, thank you so much for sharing your fantastic insights today on the ASCO Daily News Podcast. It's been an exciting ASCO again. You know, we've seen a lot of positive trials impacting our care of non-small cell lung cancer and small cell lung cancer patients. Dr. Nate Pennell: Thanks for inviting me, Vamsi. Always a pleasure to discuss these with you. Dr. Vamsi Velcheti: And thanks to our listeners for your time today. You will find links to all of the abstracts discussed today in the transcript of the episode. Finally, if you value the insights that you hear from the ASCO Daily News Podcast, please take a moment to rate, review, subscribe wherever you get your podcast. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. More on today's speakers:    Dr. Vamsi Velcheti   @VamsiVelcheti    Dr. Nathan Pennell   @n8pennell   Follow ASCO on social media:     @ASCO on Twitter     ASCO on Facebook     ASCO on LinkedIn   ASCO on BlueSky   Disclosures:   Dr. Vamsi Velcheti:   Honoraria: ITeos Therapeutics   Consulting or Advisory Role: Bristol-Myers Squibb, Merck, Foundation Medicine, AstraZeneca/MedImmune, Novartis, Lilly, EMD Serono, GSK, Amgen, Elevation Oncology, Taiho Oncology, Merus   Research Funding (Inst.): Genentech, Trovagene, Eisai, OncoPlex Diagnostics, Alkermes, NantOmics, Genoptix, Altor BioScience, Merck, Bristol-Myers Squibb, Atreca, Heat Biologics, Leap Therapeutics, RSIP Vision, GlaxoSmithKline   Dr. Nathan Pennell:     Consulting or Advisory Role: AstraZeneca, Lilly, Cota Healthcare, Merck, Bristol-Myers Squibb, Genentech, Amgen, G1 Therapeutics, Pfizer, Boehringer Ingelheim, Viosera, Xencor, Mirati Therapeutics, Janssen Oncology, Sanofi/Regeneron    Research Funding (Inst): Genentech, AstraZeneca, Merck, Loxo, Altor BioScience, Spectrum Pharmaceuticals, Bristol-Myers Squibb, Jounce Therapeutics, Mirati Therapeutics, Heat Biologics, WindMIL, Sanofi 

This past weekend, an estimated 5 million folks across the country protested Trump's attack on our rights. And if you asked anyone in the crowd why they showed up—and who they showed up for—they'd likely have an answer. Today, W. Kamau Bell is joined by three activists—Ash Lazarus Orr and Stephen and Hobbes Chukumba—who are showing up for LGBTQIA+ rights. Listen in as they discuss how they're navigating Trump's escalating abuses of power, what trans rights have to do with reproductive and racial justice, and how they're finding joy this Pride month. A note from the At Liberty team: just after recording this episode, we received a ruling on U.S. v. Skrmetti. You can learn more about the decision, and the latest on Orr v. Trump, at aclu.org: https://www.aclu.org/press-releases/transgender-us-passport-holders-granted-temporary-relief-in-challenge-to-trump-gender-marker-policy https://www.aclu.org/press-releases/aclu-lambda-legal-respond-to-supreme-court-ruling-in-u-s-v-skrmetti This episode was executive produced by Jessica Herman Weitz for the ACLU, and W. Kamau Bell, Kelly Rafferty, PhD, and Melissa Hudson Bell, PhD for Who Knows Best Productions. It was recorded at Skyline Studios in Oakland, CA. Our senior executive producer is Sam Riddell. At Liberty is edited and produced by Erica Getto and Myrriah Gossett for Good Get.

Branden Keith Orr is an alleged predator caught in a Polk County, Florida investigation of Takedown with Chris Hansen. Known for working as a lifeguard at Disney World and giving ghost tours, Orr became infamous for fleeing the sting house and being tased by deputies in the yard. As part of Operation Cyber Guardian, the Polk County Sheriff's Office set up a sting house and was “bombarded” with men attempting to meet minors for sex. Orr was one of them, engaging in an explicit chat with a decoy posing as a 14-year-old girl. He quickly escalated the conversation, suggesting they watch a movie, cuddle, make out, and have sex—promising to bring a condom. When the decoy asked if sex would hurt, he replied, “It's not going to hurt for me.” After a 45-minute drive, Orr parked, briefly left, then returned and approached the house—only to suddenly flee. Deputies chased him around the yard and tased him before arresting him. A condom was found in his back pocket. Once detained, he was brought back inside, where Chris interviewed him while officers searched him. Learn more about your ad choices. Visit megaphone.fm/adchoices

AlabamaCongressman Aderholt decries the recent killing of 100 Christians in NigeriaSen. Tuberville says moving FBI training to Redstone Arsenal is a "no brainer"ADEM as new director, Edward Poolos, after Lance Lefleur retired on May 1stthe AL conference for UMC has voted to close down 26 churches in regionProtests were held over weekend, state lawmaker Orr says its all stagedState Sen. Larry Stutts talks about fallout from Covid with trust in expertsNationalPresident Trump and Army military parade went well in Washington DCNo Kings protests result in bystander being shot and killed by securityManhunt in MN ends for gunman who killed state lawmaker and husbandRand Paul says he will be a YES vote on BBB if the debt ceiling is addressedTrump says retaliation from Iran will be bad mistake for themThe exiled Crown prince of Iran pushes for people to overthrow the regime

The Finance Minister made it clear she was unimpressed with the way the RBNZ handled public communication around Adrian Orr's departure. Reserve Bank board chair Neil Quigley recently revealed he 'regretted' the time it took to release information around Orr's surprise resignation. Nicola Willis says the central bank could have provided some clarifying statements more promptly than they did. "As soon as they'd worked through what they could say with the former governor, there was obviously significant public interest in that information. And it would have been in everybody's best interests for them to share that at an earlier junction." LISTEN ABOVESee omnystudio.com/listener for privacy information.

It's hardly a surprise, is it? Adrian looks at what Nicola is offering to run the place, packs a sad, and is off. It's a pathetic end to a tumultuous period in which we, the people who paid him, deserved an awful lot better. The fact this information on the Orr resignation had to be dragged out of the bank by way of the Official Information Act, the rules of which were ignored as the bank failed to meet deadlines, shows you just what sort of place we are dealing with. How you conduct yourself is critical. It's critical to all of us and even more critical the further up the totem pole you are. There's nothing wrong with Adrian quitting if he genuinely believed the money being offered to run the bank wasn't enough. But you do it with some dignity. You quit, you serve out your period, you offer reasons for you quitting and you move on with life. In doing it that way you give us all an insight into what sort of human being you are. And in this case, you might well have been able to give us insight into how your organisation runs, what its thinking is, what the gap is between the bank and the Government and why you might be right, and they might be wrong. It doesn't have to turn into a scrap or a fallout. Just a series of adult ideas as to why people might see things at odds to each other. If Covid taught us nothing else, it taught us the critical role of a central bank and what sort of people run it. The way Adrian ran it is well documented and the general view held by many is widely traversed. But the sudden departure was another insight into why Adrian did things the way he did. He is petulant. You don't leave out of the blue and in silence. You don't bail on hosting an international finance conference having said you were looking forward to it. It's toys and sandpits with Adrian and then obfuscation from the bank when a few simple questions were asked. If you can't conduct yourself, and the bank can't conduct themselves, with any great level of clarity, transparency and professionalism, is it any wonder the economy got run over the way it did? Ol' Adrian won't be missed. But you would have hoped for something a bit more sophisticated on the way out. See omnystudio.com/listener for privacy information.

Ed, Rob, and Jeremy took some time from Thursday's BBMS to recap Chuck Smith's impassioned defense of Zach Orr on Wednesday afternoon. Smith wanted to make it clear that Orr was behind the D's turnaround in 2024 after some fans questioned if it was Dean Pees' doing. Do you believe Orr was robbed of the credit for the defense coming back to life?

I don't enjoy saying what I'm about to say because personally I quite like Neil Quigley, but I think that he needs to quit as the chair of the Reserve Bank - simply because I do not think that we can ever trust a single word that comes out of that man's mouth again as the chair. He has been busted telling not just one, but quite a lot of fibs about Adrian Orr's resignation. So for a start, on the day that Adrian Orr quit, you'll recall Neil Quigley was the one who held the press conference. At the time he said Adrian's resignation was a personal decision. That is clearly not true. Adrian, we now find out, packed a sad, and quit over funding. Neil Quigley also said that there was nothing that the Government had said in the days before that that caused Adrian to quit. Not true. Adrian and Nicola, and actually Neil himself, had a meeting about the funding 9 days before the resignation. Neil Quigley was also asked whether there were any policy conduct or performance issues which are at the centre of this resignation. He said there are no issues of that type that are behind this resignation. Once again, not true. He was asked what happened because: "Reserve Bank governors don't just up and resign" and he said: "There is a time when you think having achieved what you wanted to achieve, that's enough". Once again, not true. That's not why Adrian quit. Adrian quit because he packed a tantrum because he didn't get enough money. Now, I do not know why Neil Quigley decided that he needed to tell porkies in order to defend Adrian Orr. I mean, I get the feeling that he has spent a great deal of his time, unfortunately for him, trying to manage the tantrums of our former toddler governor, and perhaps he just got into a little bit of a pattern of butt covering for the guy. He has suggested that he was constrained in what he could say by Orr's exit agreement. But in that case, you simply say, look, I can't say much because it's an employment agreement. And I think we all will understand that because we're all employees or employers, and we're all constrained by the same law, so we get it. But he didn't choose to do that, did he? He chose to stand there and fib to us, and that means that next time he's up answering some tough questions, I don't know if we're going to trust him, are we? Already, unfortunately for Neil, he's got quite a big black mark against him. He was part of the money printing team with Adrian Orr that stuffed up the economy, and some already think that that is enough reason to call for him to quit. Never mind the fact that he has now been busted telling straight out porkies in public. So if I was Neil Quigley, he's got two options. He can hang in there and see how it goes, or he can quit while he's still ahead - and I would do the latter. LISTEN ABOVESee omnystudio.com/listener for privacy information.

The Finance Minister says the Reserve Bank should have given the reasons behind Governor Adrian Orr's abrupt departure - sooner. It released documents yesterday showing Orr resigned over Government funding being well below the Budget allocation he sought. Nicola Willis criticised the central bank's delay in outlining the reasons. NZ Herald political editor Thomas Coughlan explained further. LISTEN ABOVESee omnystudio.com/listener for privacy information.

A former Reserve Bank economist is calling out his former employers' lack of transparency. The bank today revealed Adrian Orr quit as Governor in March, when the five-year funding for the RBNZ was much less than anticipated. Michael Reddell says the bank waited far too long to say why Orr left so abruptly. "It's just extraordinary - maybe they couldn't tell us the full story on the day, but the new Reserve Bank funding agreement was published on the 16th of April. There's absolutely no excuse at this point for lack of clarity." LISTEN ABOVESee omnystudio.com/listener for privacy information.

Revelation of long-awaited details of Reserve Bank Governor Adrian Orr's March resignation. In February, Orr emailed his board - saying there were significant differences in the funding needed and how much the Government would provide. The bank confirmed its board agreed to a lesser amount of funding and that caused Orr's resignation. NZ Herald political editor Thomas Coughlan says it's unclear why the central bank was so secretive about this matter. LISTEN ABOVESee omnystudio.com/listener for privacy information.

After breaking down some of the boldest and most thought-provoking predictions from Conor Orr, we turn our attention to the hometown team, your Washington Commanders. Orr projects them to finish under their 9.5 win total, and The Rooster isn't letting that slide. He weighs in with his own season outlook and expectations for the team heading into 2025. Plus, we revisit a few more wild picks from Orr's list as the hype for the upcoming NFL season continues to build. Buckle up, football's almost back.

We kick off the show fired up about the Nationals' return, though their matchup with the red-hot Cubs tempers the excitement. The Rooster previews the series, shares predictions, and outlines what the Nats must do to stay competitive. Then it's all about football, starting with Conor Orr's 100 bold predictions for the 2025 NFL season—we break down the wildest and most surprising takes. That leads us to the Washington Commanders, who Orr projects to finish under 9.5 wins. The Rooster pushes back, offering his own outlook for the season. As the NFL hype builds, we revisit more bold picks before closing with breaking NBA news: Tom Thibodeau is out as Knicks head coach. We react and discuss possible replacements. Plus, Commanders GM Josh Harris made headlines on Alex Rodriguez's podcast, hinting at a potential D.C. return—we dig into what that could mean for the franchise and the city.

Live from the tailgate lounge at Chicago Architectural Biennial 6's booth at Expo Chicago, Duncan and Ryan welcome Joey Orr, the newly appointed Deputy Director and Chief Curator of the MCA Chicago. In this densely brilliant and surprisingly hilarious conversation, Orr discusses what it means to steer a contemporary art institution in an era of deep social complexity, political polarization, and shifting museum ethics. We cover everything from the social life of objects to the lore of performance documentation, and even pitch a game show based on the varied memories of Chris Burden's early MCA performance. Orr reflects on social practice, audience authorship, and why curators are public servants—not VIPs. We get deep into what it means to be a meat sack in space, how to radicalize museum engagement, and why reenactments may just be the key to future institutional magic. This is art talk that grinds, gropes, and glows in the dark. No hot dogs, just conceptual fireworks.   Joey Orr – Deputy Director and Chief Curator at MCA Chicago IG: @joeyorr13 Bio: https://joeyorr.com/about/ Chris Burden – Performance artist Wiki: Chris Burden John Cage – Composer and performance artist Wiki: John Cage Resource: John Cage Trust Dick Higgins – Intermedia artist and Fluxus co-founder Wiki: Dick Higgins Alison Knowles – Fluxus artist IG: @alisonknowlesartist Wiki: Alison Knowles Mary Jane Jacob – Curator of public art and socially engaged practice Wiki: Mary Jane Jacob Bio: SAIC Faculty Page Pablo Helguera – Artist and educator working in socially engaged art IG: @pablo_helguera Website: pablohelguera.net Book: Education for Socially Engaged Art Diana Taylor – Performance theorist; author of The Archive and the Repertoire Profile: NYU Performance Studies Book Info: Duke University Press Naomi Beckwith – Curator, formerly at MCA and Guggenheim IG: @naomibx Article: Guggenheim Chief Curator Announcement MCA Chicago (Museum of Contemporary Art) Website: mcachicago.org IG: @mcachicago School of the Art Institute of Chicago (SAIC) Website: saic.edu IG: @saic_news High Museum of Art (Atlanta) Website: high.org IG: @highmuseumofart The Louvre Website: louvre.fr IG: @museelouvre Queens Museum Website: queensmuseum.org IG: @queensmuseum Fluxus – Movement reference MoMA: Fluxus Overview - https://www.moma.org/collection/terms/fluxus#:~:text=Founded%20by%20George%20Maciunas%20and,to%20integrate%20art%20and%20life.    

AlabamaAG Marshall files legal support of law in Ohio similar to AL's VCAP lawState Sen. Orr defends Governor Ivey on rumors of cognitive declineFBI director Kash Patel calls facility at Redstone Arsenal a "crown jewel'An audit of the AL Music Hall of Fame results in director placed on leaveAssociate justice to state Supreme Court, Jay Mitchell, resignsPrimary election dates for 2026 are set for May 19 for both political partiesFirst Uterus transplant patient in AL has given birth to 2nd babyNationalSCOTUS clears way for Trump Admin to deport Venezuelan immigrantsPresident Trump says the recent cancer diagnosis for Joe Biden is very fishyNYC oncologist Dr. David Samadi also questions news of Biden's cancerPresident Trump signs the "Take it Down" bill into law re: AI porn/deepfakesUS attorney charges Democrat Congresswoman for assault at NJ ICE facilityCBS News President Wendy McMahon has suddenly resigned from position

Senior Reporter Brad Johnson sits down with Representative Angelia Orr, a Republican from Itasca, Texas, representing House District 13. They discuss the intense final night of the legislative session, including the passage of Orr's significant House Bill 3749. Orr shares the emotional backstory of the bill related to elective IV therapy safety, which was inspired by a tragic incident in her district. The conversation covers various topics, including the appropriations process, local government challenges, and the dynamics within the Texas House. Representative Orr also reflects on her transition from local to state politics, her work on key committees, and her relationships with colleagues across the aisle.

John Orr was a renowned fire investigator who was also a prolific arsonist, and whose thinly veiled novel helped to convict him. In this episode we hear from the fire captain who first suspected him—and from Orr himself. New episodes every Tuesday.To read more about these cases, visit Crimes of the Times at latimes.comVideo episodes will be available on Spotifyand Youtube.

This is episode 219 — a new Governor has sailed into Table Bay. Sir Philip Edmond Wodehouse, born in 1811, eldest child of Edmond Wodehouse who married his first cousin Lucy, daughter of Philip Wodehouse, uncle Philip to Sir Philip Edmond. How very Victorian. Queen Victoria herself, who married her first cousin Prince Albert—did allow and even encourage cousin marriage, particularly among royalty and the upper classes to consolidate power, property, and lineage. But it also increased the risk of birth defects by 2 percent, and if both parents carry a recessive gene mutation, their child has a 25 percent chance of expressing the disorder. Scientists have a well-worn phrase for this — its called inbreeding. Wodehouse junior entered the Ceylon Civil Service in 1828, and was installed as superintendent of British Honduras between 1851 to 1854. From there he sailed to British Guiana where he served as Governor between 1854 to 1861 — before heading to the Cape in 1862. It's illuminating to touch on Sir Philip Wodehouse's disastrous time in British Guiana. Two years after he took office in the South American country, the Angel Gabriel riots broke out. His implacable opponent was John Sayers Orr, whose nom de guerre was the Angel Gabriel, was half Scottish, half African. Edinburgh's Caledonian Newspaper of the time reported that his mother Mary Ann Orr was a respectable coloured woman and married to a respectable Scot — John Orr senior. Young John Sayer Orr was rabidly anti-papal, hated the Pope and had an anti-Catholic obsession. He took to the Guianese streets with bullhorn in hand, whereupon the distant Glasgow Herald noted he spoke “rampant anti-papist froth and lies..” Between 1850 and 1851 he popped up in Boston, then New York, Bath in Maine, and Manchester in New Hampshire. In 1854 he was hustled off by police in Boston. Apart from the usual racial insults levelled at him, the Boston police report says he had more impudence than brains .. “…who with a three cornered hat and a cockade on his head, and old brass horn .. took advantage of the political excitement .. travelled around the city …tooting his horn … collecting crowds in the streets, delivering what he called his political lectures and passing around the hat for contributions…” Sounds like a modern political influencer, the bullhorn, the disinformation, the extreme rhetoric, not to mention his hat which is literally crowd sourcing. He was arrested at least 20 times for what was called his international harangues tour — where he'd shout confusing messages like “Scorn be those who rob us of our rights — purgatory for popery and the Pope — Freedom to man be he black or white — Rule Britannia…!!” Bizarrely, the resonances to today's crazy politics continued, Orr was associated with the fantastically named Know Nothing Party in America. Wait to hear about this bunch, you'll recognise bits of modern USA. Members of the movement were required to say "I know nothing" whenever they were asked about its specifics by outsiders, and that providing the group with its colloquial name. Before you wonder aloud what relevance all this has, let me quickly point out that the so-called Know Nothing Party had 43 representatives in Congress at the height of its power in the late 1850s. In 1855 this strange 19th Century character pitched up in British Guiana, and Sir Philip Wodehouse had his work cut out. Soon Orr was up to his old tricks, walking about with his bull horn, carrying a flag and a British imperial badge, followed by a group of …. Well .. followers. They were not repeating they Knew Nothing, but attacking the British establishment. We'll also hear about the Angel Gabriel riots. By 1862 Wodehouse who survived a public stoning in Guiana, had arrived in the Cape as Governor. Here he was to face the implacable enemies - the Westerners and the Easterners. Two parts of the Cape that did not get along.

The news of Texas covered today includes:Our Lone Star story of the day: Abilene's state Rep. Stan Lambert demonstrates that he is a man of questionable integrity in House vote over restoring the attorney general's back pay.Other key legislative news needing attention: School choice debate set for tomorrow in the Texas House. Democrats are said to be threatening all HJRs (constitutional amendments) if choice isn't put to a statewide plebiscite. Texas Senators Approve Increasing Public Participation in Judicial Oversight – important bill and it takes away the Texas State Bar, run by leftists, right to appoint two to the committee. What compromising with the Left to get power does: Texas House Set to Honor Former Planned Parenthood President Cecile Richards. Budget, SB1, conferees set: Senate's are Huffman, Creighton, Kolkhorst, Nichols, and Schwertner. House's are Bonnen, Gonzales, Orr, Kitzman, and Walle. Our Lone Star story of the day is sponsored by Allied Compliance Services providing the best service in DOT, business and personal drug and alcohol testing since 1995.Sen. Mayes Middleton launches bid for Texas attorney general.Mexico to deliver water to Texas owed under the 1944 treaty.Pure B.S: Trump admin blocked from revoking status of over 500K migrants by federal judge.Listen on the radio, or station stream, at 5pm Central. Click for our radio and streaming affiliates.www.PrattonTexas.com

Anthony and Harrison try to break down the game but the only thing they can get themselves to focus on is that brutal night from referee J.T. Orr, who ejected Luka Doncic for a back-and-forth with a fan. They discuss that, their thoughts on OKC now having seen them a couple times in a few days, and the Nuggets imploding to an insane extent. To learn more about listener data and our privacy practices visit: https://www.audacyinc.com/privacy-policy Learn more about your ad choices. Visit https://podcastchoices.com/adchoices

This was a spectacular game and was shaping up to be one of the absolutely best of the year but nope, J.T. Orr decided it was his time to shine and had one of the most baffling sequences (and overall games) any ref has had this year. To learn more about listener data and our privacy practices visit: https://www.audacyinc.com/privacy-policy Learn more about your ad choices. Visit https://podcastchoices.com/adchoices

John T. Orr is the author of "Analysis of Gunshots in Dealey Plaza." Orr's independent research convinced the FBI to conduct additional testing on JFK evidence as late as 1997. Results were inconclusive, but he suggests that even more testing should be done. On April 17, 1995, John mailed a 72-page report on the final results of my research project to Attorney General Janet Reno. The report proves beyond a reasonable doubt that four shots were fired during the assassination. This episode John is back to discuss an area we briefly mentioned in his first appearance over two years ago which looks more into the mafia connection in the assassination.

Mary Elizabeth Lease was a progressive political activist who fought big business, worked on behalf of the common man, and believed strongly in the importance of third parties in the U.S. political system. But there are also some really problematic parts of her story and ideology. Research: Barnes, Donna A. “Farmers’ Alliance.” Texas State Historical Association. Jan. 1 1995. https://www.tshaonline.org/handbook/entries/farmers-alliance Bauer, Pat. "Farmers’ Alliance". Encyclopedia Britannica, 12 Sep. 2019, https://www.britannica.com/topic/Farmers-Alliance Bentson, Sarah. “Mary Elizabeth Lease.” March 1, 2022. “Bryan’s Cross of Gold and the Partisan Battle over Economic Policy.” University of Virginia, Miller Center. https://millercenter.org/bryans-cross-gold-and-partisan-battle-over-economic-policy#:~:text=On%20this%20day%20in%201896,silver%20standard%20for%20U.S.%20currency “Concerning a Mortgage.” New York Times. Aug. 11, 1896. https://timesmachine.nytimes.com/timesmachine/1896/08/11/103382098.pdf?pdf_redirect=true&ip=0 “Farmers and Laborers.” Daily Kansas People. Aug. 13, 1890. https://www.newspapers.com/image/477977710/?match=1&terms=%22mary%20e.%20lease%22%20divorce “Furor Over Mary Lease.” New York Times. Aug. 11, 1896. https://timesmachine.nytimes.com/timesmachine/1896/08/11/103382074.pdf?pdf_redirect=true&ip=0 Harper, Ida Husted. “THE LIFE AND WORK OF SUSAN B. ANTHONY, Vol. II.” Bowen-Merrill. 1898. Accessed online: https://www.gutenberg.org/files/31125/31125-h/31125-h.htm “Ingalls Knocked Out.” Daily Alta California. Dec. 7, 1890. https://cdnc.ucr.edu/?a=d&d=DAC18901207.2.2.4&e=-------en--20--1--txt-txIN-------- Lease, Mary Elizabeth. “The Problem of Civilization Solved.” 1895. Accessed online: https://digital.lib.niu.edu/islandora/object/niu-gildedage%3A24027/print_object “Mary Lease Dead; Long Dry Agitator.” New York Times. Oct. 30, 1933. https://timesmachine.nytimes.com/timesmachine/1933/10/30/105813706.pdf?pdf_redirect=true&ip=0 “Mrs. Lease Is Not In It.” Akron Evening Times. Jan.5 , 1893. https://www.newspapers.com/image/228089290/?match=1&terms=%22mary%20e.%20lease%22%20supreme%20court McLeRoy, Sherrie S. “Lease, Mary Elizabeth Clyens (1853–1933).” Texas State Historical Association. Handbook of Texas Women. https://www.tshaonline.org/handbook/entries/lease-mary-elizabeth-clyens “Mrs. Mary Lease Removed From Office.” New York Times. July 7, 1895. https://timesmachine.nytimes.com/timesmachine/1895/07/07/105980959.html?pageNumber=1 Orr, Brooke Speer. “The ‘People’s Joan of Arc’: Mary Elizabeth Lease, Gendered Politics and Populist Party Politics in Gilded-Age America (American University Studies Book 14) .” Peter Lang Inc., International Academic Publishers. 2014. Kindle edition. Press, Donald E. “Kansas Conflict: Populist Versus Railroader in the 1890's.” Kansas Historical Quarterlies. Autum, 1977. Vol. 43, No. 3. https://www.kancoll.org/khq/1977/77_3_dpress.htm#Ref42 See omnystudio.com/listener for privacy information.