Clinical Insights on the Role of PD-1/PD-L1 Inhibitors in NSCLC


Martin Dietrich, MD, PhD, describes his approach to using anti-PD-1 therapies in non–small cell lung cancer.


Meghan J. Mooradian, MD: I think we’ve talked a bit about this as well, you’ve touched upon it in terms of what you feel like the role of PD-1 or PD-L1 inhibitors is in patients with these co-occurring mutations. Is there ever a time when you would use PD-1 monotherapy or combination PD-1 and chemotherapy? Or have the data swayed you away from using that for these challenging mutation subtypes?

Martin Dietrich, MD, PhD: Until we had the combination of PD-1, PD-L1, CTLA-4 [inhibitors] available, and certainly now with the confirmatory data from the POSEIDON trial even more so, I would typically use an addition of chemotherapy for these treatments. I was very hesitant to use a single-agent PD-1 outside of a chemotherapy-ineligible kind of setting, unless the PD-L1 levels were high and the marker settings were otherwise favorable. I used to augment this with chemotherapy, but now certainly using CTLA-4 as an additional mechanism. In general terms, when I look at the POSEIDON results, I think for my practice, the use is particularly interesting for CTLA-4s in those who have the lowest expectations for PD-1 responses.

As we go into PD-L1 levels that are low, and in my practice that’s certainly less than 50%, the closer you get to 0%, the more valuable the addition of a checkpoint inhibitor is, utilizing it in a setting of resistance mutations. Especially in the nonsquamous setting, the data in POSEIDON were very striking, where we almost see a 4-fold increase in progression-free survival for STK11-mutated subtypes. I think this is where the intensification is necessary. We look at those mutations in a PD-1 centric world as obstacles for positive treatment outcomes, but it may just be our target that may be interfering with the presence of these mutations.

If we think about combination immunotherapy, and I know there has been a lot of discussion in the lung cancer field and other disease spaces, I’m always impressed with how accepting, for example, the melanoma experts are for combination immunotherapies. We know those are not overall revolutionized settings, where we can expect 30% to 40% improvement in survival, but it’s a gradual improvement. I think if we look at the subgroups where the need is the most dire, where PD-1 outcomes are the least improved over their respective standard of care backbones, I do think we see meaningful improvements here. If I were to think of a patient for whom the POSEIDON regimen is most suited, I would certainly think of the PD-L1 negatives very similarly.

They are confirmatory data, remember, this is the third prospective phase 3 trial we have with a positive outcome for a CTLA-4, PD-1/PD-L1–based regimen in non–small cell lung cancer. But it’s the first one where we see in a staggered way the standard of care of chemotherapy vs chemotherapy, PD-L1, and chemotherapy, PD-L1, CTLA-4.

These mutations certainly sway me to be more accepting of the respective adverse effects. These subgroup analyses, while in need of prospective validation, certainly stand on enough data to be accepted for treatment. As I said, I don’t withhold PD-1 because I think these mutations are less susceptible, but I double down on immunotherapy approaches. This is one of the subgroups where I have the highest expectations of improved responses for treatment.

Transcript edited for clarity.

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