Immunotherapy in NSCLC With Concurrent KRAS/STK11 or KRAS/KEAP-1 Mutations


Takeaways from the CheckMate 9LA, CheckMate 227, and POSEIDON trials focused on immunotherapy in non–small cell lung cancer.


Meghan J. Mooradian, MD: Bouncing back to you, are there other takeaway points that you see when you’re thinking between the CheckMate 9LA and POSEIDON trial regimens? Or anything further about the data that intrigues you?

Martin Dietrich, MD, PhD: I do want to say, I’ve always been an early adopter of CTLA-4. We’ve seen some data in CheckMate 227 early that were kind of buried underneath a lot of the noise around the clinical trial design and the realignment of end points. The interesting data in Part 1b of 227 were very clearly telling me that we’re seeing activity for CTLA-4. Obviously, this has never found full adoption. I think one of the very reassuring features is, and I’m not sure if this is related to the dosing schedule or the potency of the agent on the CTLA-4 receptor, but we do see a safety profile with tremelimumab that is quite reassuring. I’m very interested in hearing your thoughts on the dosing scheduling. Obviously, it’s a unique way of positioning it. As you know from the different CTLA-4, PD-1 combinations with nivolumab and ipilimumab, we’ve seen 4 induction cycles in renal cell [carcinoma] and melanoma to intermittent dosing in the lung cancer space. I don’t know what the exact answer is.

My experience is that most CTLA-4 responses happened quite early, and typically after 2 to 3 infusions we see the maximum effect. This is also in reality the median number of doses given in the clinical trials and in the real-world setting. There’s a recent approval for tremelimumab in hepatocellular carcinoma, where 1 cycle of tremelimumab up front was sufficient. I think there’s going to be a lot of debate around how these 2 mechanisms synergize in a way of improving outcomes. Be that as it may, the way the protocol stands shows me that these negative prognostications by biomarker assessment individually and combined seem to be quite responsive to CTLA-4. In all honesty, I think this is a message that’s relatively consistent between POSEIDON, 227, and 9LA, that PD-L1 is losing its importance as a biomarker. It seems to be an equalizer of responses in immunotherapy. I think it’s very reassuring to see that there is an impact on other resistance markers, like STK11 and KEAP1.

I think the main message that I take home is, we must get used to the fact that our panels are getting bigger and more complex to interpret. I don’t think there’s a reason to not look at molecular panels for each non–small cell lung cancer case, either through an outside review in a reference laboratory, or even an in-house molecular tumor board if you have it. It’s getting more and more complicated. If I think about the future of genetic testing and tissue testing, I think this is going to get more and more interesting. Now that we’re entering an era of combinations with antibody-drug conjugates and other targeted therapies, I think the need for tissue and tissue analysis is only going to be growing. I think the idea of replacing our needs with liquid biopsy is going to be rebalanced by an increasing need of our surface markers.

I do think this is still going to be one of the biggest gaps in improving lung cancer care. If you think about this in general terms, we’re seeing about 70% of patients receiving next-generation sequencing completed prior to initiation of first-line therapy…in the general oncology population that’s about the number that is pretty reproducible across different systems. I think this is an immediate opportunity for improvement. Again, for those of us who haven’t trained in molecular genetics, I think these multiplexed immunotherapy assessments are going to be more and more challenging. It’s no longer a KEYNOTE-189, one-size-fits-all kind of world. I think this has gotten a lot more complex, and POSEIDON has just added to the discovery of these complexities, not only as a problem but also with sort of a solution. I’m not saying it’s ideal yet, but certainly another step in the right direction.

Transcript edited for clarity.

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