Chemo-Immunotherapy in NSCLC: The KEYNOTE-189 Trial

Alexander Drilon, MD:The rationale for adding chemotherapy to immune therapy is complex but can basically be broken down to the fact that chemotherapy drugs can, in a way, modulate the immune system. And so, the purpose of adding chemotherapy to immune therapy is to hopefully boost the likelihood of immune therapy acting to augment the immune system, making tumors visible to the immune system and the immune system attacking these cancers and getting rid of them.

Justin Gainor, MD:Over the past 6 months, we’ve had some really exciting data emerge on the role of chemotherapy-plus-immunotherapy combinations. And we’ve seen now 3 randomized controlled studies showing overall survival improvements with the addition of PD-1 or PD-L1 inhibition to standard chemotherapy in non—small cell lung cancer. I think the most important of these studies was KEYNOTE-189. This was a randomized phase III study that compared platinum/pemetrexed versus platinum/pemetrexed plus pembrolizumab. And in the study, the triplet combination resulted in improvement in both progression-free survival as well as overall survival. And an important part of that study is that with respect to overall survival, there was an improvement in every strata of PD-L1 expression, so greater than 50%, 1% to 49%, as well as in less than 1%.

So, the way I’ve approached the KEYNOTE-189 data is that for patients who have 50% or greater PD-L1 expression, I think you could give either pembrolizumab monotherapy or the triplet combination. And what distinguishes the 2 for me are, what are the patient’s comorbidities? What are their sites of disease? How aggressive is the disease behaving? What’s the patient’s preferences with regards to chemotherapy? All of these things would factor into a decision about pembrolizumab monotherapy versus a triplet combination. I’ve generally erred toward monotherapy in that setting while we wait for further data looking at long-term outcomes of the 2 different approaches.

For patients who have a PD-L1 expression score of less than 50%, I do think that the triplet of carboplatin/pemetrexed and pembrolizumab is a standard of care now for patients with less than 50% PD-L1 expression. I should note that this is all nonsquamous histology. That was studied in the KEYNOTE-189 study.

And finally, for patients with squamous histology, at ASCO this past year, we saw 2 studies, both of which showed that the addition of PD-1 pathway inhibition to chemotherapy resulted in improvements in progression-free survival and, in one study, an improvement in overall study. And that one study was KEYNOTE-407. With the addition of pembrolizumab to carboplatin/paclitaxel, it resulted in improvement in both PFS and overall survival. Again, we’re seeing that the addition of PD-1 blockade to standard histology—based chemotherapy is becoming a standard of care in the United States, particularly for patients with PD-L1 expression less than 50%.

Alexander Drilon, MD:Thankfully, in this trial, we’ve seen a signal for response, not just in patients whose cancers are highly PD-L1 expressing, meaning 50% or greater, but the trial also included patients whose tumor proportion scores of their cancer fell below that cutoff. So, I think that it’s a good strategy to consider chemotherapy plus immune therapy for patients who may not fall into that specific bucket or you might think about using pembrolizumab alone. So, in someone that has a score of 1% to 49%, I would consider giving the combination, and in practice we have seen very good results when all 3 drugs are given.

Transcript edited for clarity.