Dr Daniel: “This Is Exactly How the Accelerated Approval Process Is Supposed to Work”

Davey Daniel, MD, is an oncologist with Tennessee Oncology in Chattanooga, who recently was a co-author on a paper presented at the 2021 annual meeting of the American Society of Clinical Oncology that costs for participation in clinical trials in the Oncology Care Model were actually cheaper than regular care. Daniel spoke with The American Journal of Managed Care® (AJMC®) about the withdrawal of indications in small cell lung cancer (SCLC) for the PD-1 inhibitors, pembrolizumab and nivolumab, and the implications.

AJMC®: In the past year, we saw the voluntary withdrawal of indications in small cell lung cancer for 2 PD-1 inhibitors, after the FDA moved to deal with dangling approvals. What are your thoughts on how this process played out?

Daniel: I think a lot of us were not surprised at the withdrawal of these indications. It’s actually how the accelerated approval process is supposed to work. If you think about it, the approval for both pembrolizumab and nivolumab was based on very early but hopeful data. So, using surrogate endpoints and when the subsequent trials fail to show a meaningful improvement, it is appropriate for the approvals to be withdrawn. As we think about it in this setting, most patients with extensive stage small cell [lung cancer] will have exposure to immunotherapy in the first line. So, these approvals for subsequent lines of therapy with immunotherapy won’t really affect most patients’ care within small cell. I think this is actually hopeful. This is exactly how the accelerated approval process is supposed to work.

AJMC®: From your perspective as someone actively involved in the clinical trial process, will the FDA hearings in April result in any changes?

Daniel: I was reassured because the meetings in April, I think, confirmed that what’s being done is working. If you think about it, there are a few key things we need to make sure of, that it really is a true area of unmet need. If you have a crowded landscape with multiple drugs available, it does not make sense to have an accelerated approval in that setting. But you want it in a landscape where there are very few other options, but a good signal that there could be a valuable response. But if subsequent trials fail to confirm that benefit, it’s important that we make corrections. I think this is exactly how we want it to work.

AJMC®: Can you discuss the importance of the ADRIATIC trial in addressing unmet need in limited stage small cell lung cancer? And what about the use durvalumab plus chemoradiation in non-small cell lung cancer offers encouragement in this area?

Daniel: Limited stage small cell [lung cancer] is very frustrating. You get this meaningful response, a dramatic response initially, but often 6 months, 12 months, 18 months down the road we’re dealing with a recurrent disease. If you think about it, it’s not much different from what we saw in stage 3 lung cancer, non-small cell lung cancer, previously where good, perhaps not as brisk of response as we see in small cell, but an encouraging response leads us to be disappointed just 18 months later with progression. Now that we have—based on CASPIAN and IMpower133—evidence that immunotherapy has meaningful use in small cell, it is time to bring it up and evaluate it in the limited stage setting. We still don’t have clear markers in extensive stage of which patients derive the most meaningful benefit. But we do know that based on the PACIFIC trial in non-small cell that across most patient populations that immunotherapy following concurrent chemotherapy and radiation had benefit.

AJMC®: What kinds of questions do physicians and patients have about immunotherapy in extensive stage lung cancer relative to other treatment options?

Daniel: I think for physicians, we’re still sorting out whether the benefit you receive from immunotherapy in small cell is similar to what we see in other populations. You look at CASPIAN and IMpower133, we saw a small improvement in progression-free survival. It wasn’t a huge number of really durable responses. We saw a slight improvement. You don’t often see these responses lasting for years, as we saw some in the non-small cell population. We still have to also figure out, is there a marker for response for which patients are more likely to respond? Tumor mutation burden, PD-L1 do not seem to be good markers for response. So, we need to understand is there a decent biomarker for these? That’s where we need to really learn whether we can stratify small cell into other categories.

AJMC®: Can you discuss the importance of the stratification of subtypes in small cell lung cancer?

Daniel: Currently, small cell is small cell, and we don’t have great ways of dividing it out. Based on some recent data out of MD Anderson, we may be able to profile patients and divide them into 4 categories. One that’s more of an immunoresponsive group and 3 other groups based on genetic profiling, not necessarily driver genes, but a group of genes that predict, perhaps, responses to some treatments. I still think we’re laying the groundwork there. They’ll have to do confirmatory trials. But I think that was where we were in non-small cell years ago, looking for subpopulations that we can really target therapy towards. It’s very encouraging to have these subgroups identified. And now the hardware comes in confirming whether it really does predict response or not.

AJMC®: Are there other developments in the use of biomarkers in small cell lung cancer that you find encouraging?

Daniel: We’ve yet to identify clear biomarkers in small cell that are going to dictate responses currently in clinic. It’s important that we know that we continue in any trials for small cell to look for meaningful biomarkers. And in those, based on the current work out of MD Anderson, to identify whether we can investigate whether these groups they’ve identified based on their genetic profiling, whether it really does predict response or not. But currently, we still have to wait for other testing.