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Dr. Navneet Singh joins us again, this time to discuss the rapid recommendation update for stage III non-small cell lung cancer, incorporating updated data presented at the 2023 ASCO Annual Meeting. He discusses the new trials that prompted the guideline update and updated recommendations on adjuvant osimertinib for patients with EGFR exon 19 deletion or exon 21 L858R mutation, and the option of neoadjuvant chemoimmunotherapy for patients with stage III NSCLC. Read the update, "Management of Stage III Non-Small Cell Lung Cancer: ASCO Guideline Rapid Recommendation Update" at www.asco.org/thoracic-cancer-guidelines TRANSCRIPT This guideline, clinical tools, and resources are available at www.asco.org/thoracic-cancer-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest disclosures in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.23.01261 Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts.  My name is Brittany Harvey, and today I'm interviewing Dr. Navneet Singh from the Postgraduate Institute of Medical Education and Research in Chandigarh, India, Co-chair on “Management of Stage III Non-Small Cell Lung Cancer: ASCO Guideline Rapid Recommendation Update.”  Thank you for being here, Dr. Singh. Dr. Navneet Singh: Thank you for having me. Brittany Harvey: Then, before we discuss this guideline, I'd just like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Singh, who is joining us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes.  So then, to dive into the content of this guideline, first, Dr. Singh, what prompted this rapid update to the ASCO management of stage III non-small cell lung cancer, which was initially published in 2021? Dr. Navneet Singh: There have been a number of studies that have involved patients with stage III non-small cell lung cancer since the publication of the stage III NSCLC management guidelines. Of note, three trials deserve special recognition and have actually formed the basis for this rapid update. These include the ADAURA trial for use of osimertinib as adjuvant treatment for completely resected stages Ib to IIIa NSCLC and harboring a sensitizing EGFR mutation. The other two trials have explored the use of PD-1 immune checkpoint inhibitor therapy in combination with chemotherapy as neoadjuvant treatment of potentially resectable stages I to III NSCLC. And these are the CheckMate 816 trial with nivolumab and the KEYNOTE-671 trial with pembrolizumab. Brittany Harvey: Great, thank you for that background. So then, based off these three new trials that you just mentioned, what are the updated recommendations issued in this rapid recommendation update? Dr. Navneet Singh: The first updated recommendation is based on the overall survival benefit observed in the ADAURA trial. And this recommendation is that patients with dissected stage III NSCLC and harboring an EGFR exon 19 deletion or an exon 21 L858R mutation should be offered adjuvant osimertinib after platinum-based chemotherapy. The second important update is that in the absence of contraindications, patients with stage III non-small cell lung cancer who are planned for surgical resection should receive a neoadjuvant combination of a platinum doublet chemotherapy, and immunotherapy. Now, both of these are based on high-quality evidence and have a strong strength of recommendation. Brittany Harvey: Understood. I appreciate you reviewing both the level of evidence and the strength of the recommendation for those as well. So then, what should clinicians know as these new recommendations are implemented? Dr. Navneet Singh: Now, it's very important for clinicians involved in the management of lung cancer to realize the importance of biomarker testing, something that was initially believed to have relevance only for metastatic disease. But now, with the availability of data indicating the benefit of immunotherapy and targeted therapy not just in metastatic disease but also in early-stage as well as locally advanced disease, clinicians need to ensure that biomarker testing, especially EGFR mutation and PD-L1 expression by approved and validated methods is performed in all patients with stages I to  III non-small cell lung cancer. This is important to decide and select patients for the appropriate biological therapy, which is either targeted therapy or immunotherapy that can be used in conjunction with or following chemotherapy. I need to clarify here that the spectrum of biomarker testing that is recommended for metastatic disease is much larger than what is currently being advocated for early or locally advanced NSCLC. Brittany Harvey: Great, and I appreciate that clarification. So then you've just described what this guideline means for clinicians, but how does this rapid update impact patients diagnosed with stage III non-small cell lung cancer? Dr. Navneet Singh: Well, for patients with stage III non-small cell lung cancer, all the three trials that form the basis for this rapid update indicate very encouraging developments. The neoadjuvant chemo-immunotherapy approach is now the standard of care for potentially resectable stage III disease, as this combination has been shown to be superior to chemotherapy alone in terms of higher probability of achieving a complete or major pathological tumor response, as well as improving recurrence or event-free survival following surgical resection. Similarly, adjuvant osimertinib for resected stage III NSCLC patients having a sensitizing EGFR mutation has been shown to significantly improve overall survival compared to placebo. It is important to highlight here that osimertinib treatment in stage III NSCLC should be initiated following the completion of adjuvant chemotherapy. Brittany Harvey: Understood. So then this panel works to rapidly update this guideline, turning it around after the ASCO Annual Meeting. But what are the ongoing research developments that the panel is monitoring for future guideline updates? Dr. Navneet Singh: Well, the expert panel is eagerly awaiting overall survival data from the neoadjuvant chemo-immunotherapy trials. We have several unanswered questions which ongoing research will attempt to answer. And some of these questions include number one, whether adjuvant immunotherapy is beneficial for patients who have already received neoadjuvant chemo-immunotherapy, and if so, what is the optimal duration for the same? Second, is the three-year adjuvant osimertinib duration appropriate? Can lesser duration of treatment suffice for a subgroup of patients? And if so, it would lead to a reduction in both treatment costs as well as a reduction in potential treatment-related adverse effects. On the other hand, other patients in whom stopping at three years may not be warranted, and should patients with exon 19 deletion be treated differently from those with exon 21 L858R mutation? Third, does a similar adjuvant targeted therapy approach be warranted for ALK-rearranged NSCLC that has been surgically resected? And fourth, are there specific subgroups of patients undergoing neoadjuvant treatment in whom immunotherapy as a neoadjuvant treatment may not be effective? Examples are those with EGFR mutations or ALK rearrangements, or even those with no PD-L1 expression. Brittany Harvey: Absolutely. We'll look forward to finding the answer to those questions for future guideline updates. So I want to thank you so much for your work to rapidly update this guideline and thank you for your time today, Dr. Singh. Dr. Navneet Singh: Pleasure. Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/thoracic-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in the Apple App Store or the Google Play Store.  If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. 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.  

Dr Herbst discusses the FDA approval of adjuvant pembrolizumab in non–small cell lung cancer, key efficacy and safety data from the KEYNOTE-091 trial, and future research efforts that may further improve outcomes in this population.

Featuring a roundtable discussion with Drs Joshua Bauml, Nathan A Pennell and Lecia V Sequist, including the following topics: Expert perspectives on new online formats of continuing medical education programs (0:00) Case: A woman in her early 80s with Stage IIIB non-small-cell lung carcinoma (NSCLC) and an EGFR exon 21 mutation — Zanetta S Lamar, MD (7:07) Clinical implications of the Phase III ADAURA trial evaluating adjuvant osimertinib for patients with completely resected Stage IB to IIIA NSCLC and an EGFR mutation (16:18) Case: A woman in her late 30s with Stage IIIB adenocarcinoma of the lung positive for ROS1 alteration and PD-L1 expression — Spencer Henick Bachow, MD (23:42) Case: A woman in her late 70s with extensive-stage small-cell lung cancer — Namrata I Peswani, MD (28:19) Case: A man in his late 70s with NSCLC who develops recurrent mediastinal disease and pleural effusion — Ranju Gupta, MD (31:02) Case: A woman in her early 60s with metastatic NSCLC and discordant BRAF mutation test results — Syed Farhan Zafar, MD (39:07) CME information and select publications

This JCO Podcast provides observations and commentary on the JCO article “Erlotinib Versus Gemcitabine Plus Cisplatin as Neoadjuvant Treatment for Stage IIIA-N2 EGFR-Mutant NSCLC (EMERGING-CTONG 1103): A Randomized Phase II Study” by Zhong et al. My name is Tony Mok, and I am a Professor of Clinical Oncology at the Chinese University of Hong Kong in the Prince of Wales Hospital in Hong Kong. My oncologic specialty is Medical Oncology.   With the advent of molecular targeted therapy, patients harboring driver oncogenes may now survive longer and better than before, and EGFR mutation is the prime example of such achievement. However, evidence for “cure” of patients with metastatic EGFR mutation positive lung cancer remains scanty. In contrast, It may be more reasonable to first attempt cure of patients with earlier stage disease using molecular targeted therapy. CTONG 1103, published in this issue of Journal of Clinical Oncology, is the first randomized study comparing neoadjuvant erlotinib with chemotherapy for patients with stage IIIA EGFR mutation positive lung cancer.   CTONG 1103, the report that accompanies this podcast, is not an easy study to conduct. Between December 2011 and December 2017, investigators from 17 centers across China managed to screen 386 patients with stage IIIA non-small cell lung cancer (NSCLC) and identified only 72 (which is about 19%) eligible EGFR mutation positive patients. They were randomized to receive either erlotinib 150mg daily for 42 days or two cycles of chemotherapy using gemcitabine and cisplatin as neo-adjuvant therapy. After neoadjuvant therapy, 73% of the erlotinib arm, and 63% of the chemotherapy arm, received curative surgery, including two patients in erlotinib arm who received pneumonectomy. The primary endpoint of this study is tumor response rate, which is 54.1% for erlotinib and 34.3% for chemotherapy. However, the odds ratio of 2.26 for tumor response rate was not statistically significant. Two other important and impactful endpoints include major pathological response and progression free survival (PFS). Major pathological response is defined as less than 10% residual viable tumor cell and it occurred only in 10.7% of patients who received erlotinib and none with the chemotherapy. But on the other hand, PFS was significantly better with erlotinib arm, reporting median of 21.5 month comparing with 11.4 months with chemotherapy arm.   In reference to the primary endpoint of tumor response rate, we should conclude that CTONG 1103 is a negative study. Zhong et al has reasonably estimated the sample size based on a presumptive response rate of 70% in the erlotinib arm and 36% in the chemotherapy arm.  The reported response rate at 54.1% with erlotinib in this study has significantly fallen short of the expected rate of 70%, which was actually the widely accepted response rate in patients with stage IV disease. The authors selected to offer 42 days of neo-adjuvant erlotinib in order to match the two cycles of neo-adjuvant chemotherapy. While there is no biologic reason to explain the low response rate in earlier stage disease, the shorter duration of treatment may contribute to the relatively lower response rate. The other important outcome is the major pathological response of 10.7% with neo-adjuvant erlotinib, which is supposed to be a surrogate for overall survival. Hellman et al were among the first groups to suggest the predictive power of major pathological response for neo-adjuvant chemotherapy for patients with early stage lung cancer. The lower than expected major pathological response may be considered a surrogate indicator for overall survival but it is more important to wait for the mature survival outcomes.   A negative study can still be impactful. This study has established the feasibility of neo-adjuvant EGFR TKI for patients with potentially resectable EGFR mutation positive lung cancer. The first single arm phase II study on pre-operative gefitinib published in 2009 in the Journal of Clinical Oncology enrolled 36 patients but only 6 harbored the activating EGFR mutations. Tumor response was observed in 4 patients and all were positive for the mutations. Another single arm study published in 2018 in the journal The Oncologist enrolled 19 patients with EGFR mutation positive stage IIIA NSCLC and treated with neoadjuvant erlotinib for 56 days. Tumor response rate was 42.1% and resection rate was 68.4%. Only 5 of the 14 patients (35.7%) with surgical resection had documented pathologic downstaging from N2 to N0/N1 disease. The median PFS and OS was 11.2 and 51.6 months respectively. CTONG 1103 is the first and only randomized comparative study that confirmed the feasibility and efficacy of neo-adjuvant EGFR TKI. Tumor response rate is higher than chemotherapy by 20% although not statistically significant, but toxicity profile is better, which is an established fact from multiple phase III studies on advanced stage disease. The resection rates were similar between the two arms but it was unclear how many of the enrolled patients had unresectable disease prior to neo-adjuvant therapy. Key objectives of neo-adjuvant therapy are to down-stage tumor/nodal disease and to improve resectability. This randomized study may potentially document if erlotinib is more capable of converting unresectable stage IIIA disease to being resectable, however, this data is not currently available.   The authors of the current study have also reported improvement in progression free survival, but we cannot conclude that the improvement is solely due to the neo-adjuvant therapy. As per study protocol, patients from neo-adjuvant EGFR TKI arm did receive 12 months of erlotinib as adjuvant therapy while the chemotherapy arm received only 2 more cycles of similar treatment. Considering the duration of therapy, the adjuvant erlotinib may in fact  contribute more to prolongation of progression free survival than the neo-adjuvant therapy. In 2017 in the journal Lancet Oncology, the same group of investigators have reported a randomized phase III study comparing adjuvant gefitinib with chemotherapy and the median disease free survival was 28.7 months and 18.0 months, respectively. All patients enrolled in this study had resectable lung cancer with over 60% of patients having N2 disease, and the authors had concluded on the potential survival advantage of adjuvant EGFR TKI. Thus, the improvement in progression free survival should be explained by both neo-adjuvant and adjuvant erlotinib.   In summary, CTONG 1103 is a negative study but it has significant impact on management of stage IIIA EGFR mutation positive lung cancer. With high screening failure rate at 80%, it took the authors 6 years to enroll 72 patients. This study will remain the only randomized study on this patient group for a long time as similar  large scale phase III trials of this strategy will be unlikely. Clinicians are obligated to share and explain CTONG 1103 to patient with stage IIIA EGFR mutation positive lung cancer. For patients with resectable disease at presentation, the benefit of neo-adjuvant EGFR TKI may be debatable. But for patients with un-resectable stage IIIA disease, neo-adjuvant EGFR TKI may potentially downstage the disease status and facilitate resection.     This concludes this JCO podcast. Thank you for listening.

Dr. Mark Socinski, University of Pittsburgh Medical Center, compares the use of chemotherapy to chemo/radiation in the preoperative setting in stage IIIA lung cancer.

Dr. Mark Socinski, University of Pittsburgh Medical Center, compares the use of chemotherapy to chemo/radiation in the preoperative setting in stage IIIA lung cancer.

Dr. Mark Socinski, University of Pittsburgh Medical Center, compares the use of chemotherapy to chemo/radiation in the preoperative setting in stage IIIA lung cancer.

Dr. Mark Socinski, University of Pittsburgh Medical Center, describes the primary treatment options for stage IIIA NSCLC, including chemoradiation and surgery, and discusses trial evidence for each approach.

Dr. Mark Socinski, University of Pittsburgh Medical Center, describes the primary treatment options for stage IIIA NSCLC, including chemoradiation and surgery, and discusses trial evidence for each approach.

Dr. Mark Socinski, University of Pittsburgh Medical Center, describes the primary treatment options for stage IIIA NSCLC, including chemoradiation and surgery, and discusses trial evidence for each approach.

Dr. David Gerber, University of Texas-Southwestern, reviews a Swiss study comparing tri-modality therapy with chemoradiation followed by surgery to chemo followed by surgery for stage IIIA NSCLC.

Dr. David Gerber, University of Texas-Southwestern, reviews a Swiss study comparing tri-modality therapy with chemoradiation followed by surgery to chemo followed by surgery for stage IIIA NSCLC.

Dr. David Gerber, University of Texas-Southwestern, reviews a Swiss study comparing tri-modality therapy with chemoradiation followed by surgery to chemo followed by surgery for stage IIIA NSCLC.

Dr. David Gerber, University of Texas-Southwestern, reviews a Swiss study comparing tri-modality therapy with chemoradiation followed by surgery to chemo followed by surgery for stage IIIA NSCLC.

Dr. David Gerber, University of Texas-Southwestern, reviews a Swiss study comparing tri-modality therapy with chemoradiation followed by surgery to chemo followed by surgery for stage IIIA NSCLC.

Dr. David Gerber, University of Texas-Southwestern, reviews a Swiss study comparing tri-modality therapy with chemoradiation followed by surgery to chemo followed by surgery for stage IIIA NSCLC.

This slide presentation by medical oncologist and lung cancer expert Dr. Jack West covers the most common management strategies for stage IIIA N2 node-positive NSCLC, with a particular focus on a comparison of preoperative treatment followed by surgery vs. chemo and radiation without surgery.