COMMENTARY

KEYNOTE-189 Establishes New Lung Cancer Standard of Care

H. Jack West, MD; Hossein Borghaei, DO

Disclosures

May 11, 2018

H. Jack West, MD: Hello. I am Jack West, medical director of the Thoracic Oncology Program at the Swedish Cancer Institute, in Seattle. Welcome to Medscape Oncology Insights. Joining me today is Hossein Borghaei, chief of the Thoracic Medical Oncology Program at Fox Chase Cancer Center in Philadelphia. Welcome.

Hossein Borghaei, DO: Thank you.

West: We just attended the 2018 American Association for Cancer Research (AACR) meeting, and unusual for a meeting that is more of a showcase for early clinical and preclinical work, major clinical studies were presented in the plenary session devoted entirely to lung cancer. I want to focus first and foremost on the KEYNOTE-189 study, which I think is going to have real clinical implications.[1]

In this trial for patients with advanced nonsquamous, non–small cell lung cancer with any level of PD-L1 expression, patients could not have EGFR mutations or ALK rearrangements. A little over 600 patients were randomized 2:1 to receive either chemotherapy, cisplatin or carboplatin, with pemetrexed. Two thirds of patients received pembrolizumab and one third received placebo.

Overall survival was the primary endpoint, and we knew it was positive from a press release a couple of months ago, but we did not know whether it was clinically significant. It turns out it was hugely significant, with a hazard ratio of 0.49 in the overall intent-to-treat population. This is essentially a doubling of survival across the entire time course reported.

Leena Gandhi, lead author of the study that was presented at AACR and published at the same time in the New England Journal of Medicine, also noted that in the subsets of patients (zero or less than 1% PD-L1 expression, 1%-49%, or PD-L1 50% or greater), all benefited significantly in terms of overall survival.

The results were similar for progression-free survival and response rate, namely huge differences in the general population favoring the pembrolizumab arm, with real—but not as impressive—differences in the lowest PD-L1 subgroup, more benefits in the 1%-49% group, and the most benefit in the 50% or greater group.

For toxicity, we saw a little more nephritis than we might have expected. We have had carboplatin and pemetrexed plus pembrolizumab as an FDA-approved option since May 2017, based on the trial you were very much involved in, KEYNOTE-021 cohort G, but approval has not yet had a big impact.[2,3,4] People have been more reserved because the overall survival benefit was not as clear and it was a randomized phase 2. What do you see as the impact of this study, in terms of adoption of this regimen?

Borghaei: I want to emphasize two things. First, KEYNOTE-189 did not have any patients with molecularly driven tumors; we need to keep that in mind. Second, nobody with any evidence of brain metastases was allowed in the trial. We have to be careful with those two subpopulations.

I think the reason KEYNOTE-021 cohort G was not accepted right away, as you suggest, was that it was a randomized phase 2, the survival data were not quite as clear, and we really did not know how the different subgroups of patients, based on the PD-L1 expression, truly did.

We were all waiting for additional information, which KEYNOTE-189 has provided. I think this study establishes this regimen as the standard of care because of the significant overall survival advantage, practically in all of the subgroups of patients, and the fact that responses were better in all subgroups. I agree with you that the PD-L1 negatives did not have as much of a benefit, but it was still better than standard chemotherapy.

For the nonsquamous histology, KEYNOTE-189 becomes a de facto standard of care, such that if I am designing another clinical trial in this patient population, this is going to be my control. The key thing to study is how to improve on these results. There are lingering questions: What is going to happen to patients who have EGFR mutations or ALK translocations? Do they have as much of a benefit from this? Can we do a study to look at that?

What is the real long-term benefit from all of this? By that, I mean that we have data now from earlier immuno-oncology drugs that there is a 5-year survival benefit for a very small subpopulation. Are we likely to see that 5-year survival improving significantly, or to any extent, with the addition of chemo-IO? For me, this really becomes one of the standards of care that I discuss with my patients in the clinic.

West: There was a very significant absolute difference in 1-year survival: nearly 70% in the chemotherapy-pembrolizumab arm versus just under 50% in the chemotherapy-alone arm. The response rate with chemotherapy alone and placebo was 19%. Some people have grumbled that that is disappointing for a control arm these days, especially when it is nonsquamous and in a world where we have second-line immunotherapy.

In this trial, 50% of patients who were eligible crossed over to pembrolizumab. To me, that is a little disappointing when we have immunotherapy available and of proven benefit after chemotherapy. What would you say about the control arm? Is that a real concern or are these differences so substantial that it really washes out?

Borghaei: I am not really concerned about it. From time to time, you get trials like this where the control arm does not seem to do quite as well. We have to keep in mind that this is a randomized study; everybody had the same eligibility and received the same chemotherapy backbone. It is hard to argue that something happened with the chemotherapy in the control arm. Could the hazard ratio be slightly less? Maybe, but the magnitude of benefit is so great that it is really hard to argue that this is not an effective regimen.

West: Again, even if the hazard ratio were 0.57, we would still have the same general conclusions.

Borghaei: As far as 50% not getting an effective drug, I do wonder about that, but multiple different questions come into play. Remember from a trial many, many years ago in the era of platinum-doublet, we learned that up to 35%-40% of patients never make it to second-line therapy.[5] Is that playing a role here? I do not know.

West: Certainly, there are data from not that long ago that we just do not deliver second-line treatment in more than 55% or 60% at most. The problem with that is that was in the docetaxel-based chemotherapy, with modest efficacy and challenging tolerability. Now, we have multiple trials of checkpoint inhibitors that have all consistently shown major survival benefits and good tolerability.[6]

Very few of these patients who were initially eligible for first-line chemoimmunotherapy should be ineligible for subsequent immunotherapy. In my clinic, I would say that over 85%-90%, and as close to 100% as possible, are going to get immunotherapy if eligible.

Borghaei: I agree with that, and I have made that argument at various meetings, but again, when you see data like these, you have to wonder what percentage of the patients who were in the control arm really could not go on. We have never captured that kind of information.

The other part is that we now have some data from KEYNOTE-024 suggesting that for some patients, patients with really high PD-L1, maybe immunotherapy after chemo is not quite as good.[7] Maybe patients should get immunotherapy right off the bat. That is an area that I think requires more investigation and more analysis.

It is possible that something like that is in play when it comes to the crossover in some patients not really getting the active drug. Also, where you do the studies sometimes matters. I mean, was the study done in places where perhaps an active IO agent was not available after chemotherapy? We do not know.

West: Were there any real issues with tolerability or was that pretty much as expected?

Borghaei: Toxicity was what you would expect, except for nephritis, which was a little bit of a surprise because we did not see that in the phase 2 study. Again, clinically, I have not necessarily noticed any increased rate of nephritis, but it is what the study suggests, and I think it is something for investigators and for doctors to keep in mind when they are treating their patients. I do not see any major safety concerns.

West: Great. We are going to do a few subsequent videos on the implications for the specific subgroups, because I think that these different groups, whether they are negative for PD-L1, low, or high, have different options, both now and in the near-term future. I look forward to people following that.

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