Management of Stage III NSCLC Rapid Recommendation Update

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.