Treatment Approaches for NSCLC With Concurrent KRAS/STK11 or KRAS/KEAP-1 Mutations


Meghan J. Mooradian, MD, discusses how she makes NSCLC treatment decisions based on concurrent mutations.


Martin Dietrich, MD, PhD: I think this is one of the questions you probably get in your second opinion clinics when you look at mutational reports. Obviously, STK11, KEAP1, and TP53 may not be as readily present on the front page. How do you do this in your clinic? How do you look at them? How do you relay the effects? What are your approaches for the management of those co-occurring mutations?

Meghan J. Mooradian, MD: I think it brings us back to that initial point, the importance of broad-based molecular testing. It is understanding that we need to ensure we have the full genomic landscapes so that way we know not only does this patient have KRAS, but they have KRAS with this driver, which puts them at a disadvantage in respect to having that durable response from chemoimmunotherapy.

Like you, prior to the CheckMate 9LA and POSEIDON trials, I didn’t withhold PD-1 with chemotherapy. I almost uniformly always used that doublet approach for patients who are eligible. But I went into it understandably with some pessimism. But now based on POSEIDON and the retrospective data we’re armed with, I will often think about using that dual ICI [immune checkpoint inhibitor] approach with chemotherapy.

You point out a very important topic that as thoracic oncologists, we’re still a bit reticent to use CTLA-4. But borrowing from our colleagues in the melanoma world, in the renal cell carcinoma world, we know that we can use these drugs effectively both in an academic center and in the community. We just have to be cognizant that we are going to be in a position where we may be dealing with higher rates of immune-related adverse events. But even in POSEIDON when they looked at the difference between the durvalumab, tremelimumab, chemotherapy arm and durvalumab, chemotherapy, there was a minimal increase in the rates of immune-related adverse events and serious grade 3 and 4 toxicity in general.

Potentially, that’s because of the abbreviated course of dupilumab. I think one important differing point between 9LA and POSEIDON is the duration of CTLA-4 use. POSEIDON focuses on the 4 doses of tremelimumab, that CTLA-4 inhibitor, during the induction phase with 1 additional dose at week 16. Whereas in both 9LA and CheckMate 227, we continued with CTLA-4. I think that’s still an unanswered question in the thoracic world. Is there a benefit to ongoing CTLA-4 inhibition up front? Is that 1 additional dose really enough to kickstart that immune response? I think that’s still yet to be determined. Both are very intriguing options for this patient population.

For myself, I do enjoy the ability to give the 4 cycles of chemotherapy that POSEIDON offers, which is a bit different from 9LA, noting that it can take time for that immune response to become relevant. Additional cytotoxic chemotherapy allows the immune system hopefully to have enough time to escalate. I guess the counter could be that it potentially diminishes an immune response. We haven’t seen that to date when we’re using regimens like KEYNOTE-189.

Transcript edited for clarity.

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