Early-Stage Non–Small Cell Lung Cancer: Answers to Frequently Asked Questions With Jamie E. Chaft, MD

In this video, Dr. Jamie E. Chaft, Associate Attending Physician at Memorial Sloan Kettering Cancer Center, answers questions asked by the audience during her CME/NCPD–approved activity with i3 Health, Leveraging the Growing Arsenal of Therapies for Early-Stage Non–Small Cell Lung Cancer (NSCLC), chaired by Dr. Helena Yu. Dr. Chaft shares insights into emerging roles of measurable residual disease (MRD) in lung cancer, the significance of the recent approval of alectinib for ALK-positive disease, treatment considerations for older versus younger patients, important research updates at the American Society of Clinical Oncology (ASCO) Annual Meeting, and more!  

This interview is also available as a podcast. Click here to listen!

Q: How will MRD be used in non–small cell lung cancer in the future?

Jamie E. Chaft, MD: I’m as excited about MRD, or minimal residual disease, as anyone, but just where we were many years ago, when chemotherapy didn’t eradicate disease, we didn’t really have anything to offer. Now we have immunotherapy, and we’re using immunotherapy, but if the disease isn’t eradicated with preoperative chemo- and immunotherapy, we don’t yet have another drug to give. So, I anticipate MRD being tested more frequently, but until we have more effective drugs in our arsenal for the treatment of advanced disease, I’m not sure how we’re going to intervene upon a positive MRD assay after we’ve already given our best drugs. On the contrary, where I hope to see MRD integrate is in therapeutic de-escalation. Perhaps we can stop that immunotherapy after surgery in patients who have cleared their circulating tumor DNA versus prescribing the completion of the year of therapy.

Last week’s approval of alectinib absolutely changes the standard of care. Adjuvant alectinib is approved for the treatment of resected ALK-positive disease. The study was a bit odd in its design as it was randomized. Patients with ALK-positive disease that was resected were randomized to chemotherapy versus alectinib, whereas in the clinic, we still feel that chemotherapy has a role. In practice, I would give patients adjuvant chemotherapy followed by alectinib, which was studied for two years, although, again, I feel particularly for higher-stage disease such as resected stage III, that they likely need a longer duration of therapy.

Q: Are there any specific considerations for an older, frailer patient receiving neoadjuvant therapy?

Dr. Chaft: An older, frailer patient receiving neoadjuvant therapy—I worry a lot about their ability to get to the operating room (OR), so I pick up the phone and call the surgeon and make them confirm that the patient is medically operable, because if they’re older and frail, they’re likely to be a bit frailer after that induction therapy. So, you want to make sure they’ve actually had cardiopulmonary exercise testing and preoperative cardiac testing and they’re truly an operative candidate, because if they’re not an operative candidate, they’re better served by chemoradiation. Other considerations are their functional reserve, and are you going to make them anemic? What’s their renal function? Are we giving them the best agents? But if the patient has resectable and operable disease of a stage appropriate for therapy, still proceeding with that neoadjuvant therapy is appropriate. Give them that stress test, a physiologic stress test before surgery, and just understand they may need a little bit longer to recover before they get to surgery.

Q: For the last case study you presented, could you explain again what you’d like to know before beginning neoadjuvant therapy since the tumor was so large?

Dr. Chaft: So, for a young patient, I always want to try to get them to the operating room. Giving chemoradiation to a young patient, even if you cure their cancer, leaves them with the sequela of radiotherapy, which includes accelerated cardiovascular disease; for a young woman, risk of breast cancer; and the like, so I would really like to know in that patient if they have an epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) alteration, and honestly, I’d like to know the whole next-generation sequencing panel if we can get it in time. There are ongoing studies of targeted therapies for other oncogene driver mutations. There are no FDA-approved neoadjuvant targeted therapies, although I will admit that I use them off-label in this setting in combination with chemotherapy when I can get them approved.

The more important reason to know the genotype, which I didn’t bring up throughout the talk, if they have an EGFR alteration and they’ve received preoperative chemoimmunotherapy is if you go to give them that adjuvant osimertinib and they have a markedly increased risk of developing pneumonitis. We do our best to avoid immunotherapy at all costs in patients with EGFR-driven tumors, as they are most effectively treated by adjuvant osimertinib and there’s an overlapping toxicity. You could say, “Listen, they had surgery, it’s been two months,” but these programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) drugs are still in the system in terms of their efficacy for many months after surgery, so you really run the risk of harming that patient if you’ve given them preoperative immunotherapy and hope to give them postoperative osimertinib.

Q: Do you recommend repeat biomarker testing, and if so, when?

Dr. Chaft: If you have a good preoperative sample and next-generation sequencing (NGS) has been done, then I don’t feel a need to repeat it. If perhaps the tumor content was low in that endobronchial ultrasound (EBUS) specimen and you really didn’t see any alterations, perhaps you’ll use a surgical specimen to repeat it and make sure you know what’s happening in that tumor. The only other time I repeat biomarker testing is at the time of acquired resistance to a targeted therapy.

Q: Are there any abstracts at ASCO that will be important for early-stage non–small cell lung cancer?

Dr. Chaft: Of course. There’s lots of good stuff at ASCO in the early-stage setting, most of which is data updates. I don’t think there’s anything notably new for early-stage lung cancer that’s resectable. We will see data at ASCO on the use of osimertinib in EGFR-driven disease after chemoradiation. I believe it’s in the plenary. There’ll be additional data on neoadjuvant EGFR-directed therapy presented at World Lung in the Fall.

About Dr. Chaft

Jamie E. Chaft, MD, is an Associate Attending Physician at Memorial Sloan Kettering Cancer Center. Dr. Chaft’s expertise extends to precision medicine, where she pioneers innovative approaches tailored to individual patient needs. Her leadership in advancing thoracic oncology has earned her recognition both nationally and internationally, making her an invaluable asset to the medical community and a beacon of hope for patients and their families facing cancer diagnoses.

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