Frontline Treatment Decisions for Stage IV NSCLC

Considerations for selecting frontline therapy for metastatic non–small cell lung cancer based on various new data and treatment approvals in the field of immunotherapy.

Mark A. Socinski, MD: I want to bring Chaitali into the discussion. We’ve just had excellent reviews of all these trials that we now have FDA approvals for, but it gets complicated a little in terms of choice of therapy. I just want to get your perspective and then put it in context. We’ve kind of alluded to patients who have a high symptom burden, high tumor burden versus those—we see so many patients diagnosed with what I would refer to as low-volume, relatively asymptomatic stage IV disease. Do you view them differently in your choices in terms of how you incorporate all of this data?

Chaitali Nangia, MD: Absolutely. When we are in this zone when you have chemotherapy, chemotherapy–I/O [immuno-oncology] combinations as options for you, and I/O–I/O combinations, patient and disease factors completely weigh in. If you have, for example, an individual who isn’t chemotherapy amenable or who has the chemosensitivity, then that’s the one that I might consider a chemotherapy-free I/O–I/O combination. At the same time, if you have bulky disease, then that’s the one—symptomatic, painful. As Sandip mentioned, I would definitely go with chemotherapy–I/O combination. At the same time, if I have very low-volume disease, oligometastatic disease, PD-L1 is high, that’s the one I’ll go with a single-agent I/O. Which single-agent I/O? We have three, and I’m not partial to one. Any of those would be a good combination. Then you start teasing out information. As we just saw from ASCO [American Society of Clinical Oncology Annual Meeting] 2021, if you have squamous histology, and PD-L1 is low or less than one percent, then that’s when you want to consider the ipilimumab-nivolumab combination. If you have somebody with stable CNS [central nervous system] metastasis, at least based on evidence, you can consider cemiplimab if PD-L1 is higher than 50%. You start looking into the data to help you. But ultimately, the patient factors and disease factors both weigh in.

Mark A. Socinski, MD: You raise a good point, and I want to transition to talking a little more about PD-L1 in a bit more granularity. But let me ask Sandip and maybe Roy [Herbst]. We saw a presentation by the FDA group at ASCO this year looking at this group of one to 49% and looking at the use of I/O monotherapy. Of course, we do have an indication for pembrolizumab in that subset of patients versus chemotherapy–I/O. This was an analysis of phase 3 trials that had been done. The take-home message that I took from that was that chemotherapy–I/O is the standard of care in that population. I’ve been reluctant to use monotherapy in this population, but I want to get your perspective, Sandip, on that analysis.

Sandip P. Patel, MD: I completely agree. If we look back to the KEYNOTE-042 presentation, which was a couple of ASCOs ago as a plenary, we saw the 1% to 49% data looked quite similar to the FDA analysis. To me, it was practice reinforcing that for a patient within the PD-L1 strata of 1% to 49%, that a combination approach—whether that’s chemotherapy plus PD-1 inhibitor, chemotherapy–PD-1 inhibitor–antiangiogenic inhibitor, CTLA4 inhibitor—makes sense. In terms of the active clinical trials in this area, TIGIT-based combinations with PD-1 are very reasonable. But the bottom line that I took away from KEYNOTE-042 and the most recent presentation from the FDA is that patients with PD-L1 1% to 49% are best served by a combinatorial strategy. What that best combination is in 2022 and 2023, we still probably won’t know. But the idea is that it should be some combination, so try to maximize the benefit for these patients.

Mark A. Socinski, MD: I agree. In my opinion, that combination, at least until we prove otherwise, should be chemotherapy in that population too.


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