COMMENTARY

Yes or No to Chemo-IO Combo in High PD-L1 NSCLC Patients?

H. Jack West, MD; Hossein Borghaei, DO

Disclosures

May 16, 2018

H. Jack West, MD: Hello. I'm Jack West, medical director of the thoracic oncology program at Swedish Cancer Institute in Seattle. Welcome to Medscape Oncology Insights. Joining me today is Hossein Borghaei, chief of thoracic medical oncology at Fox Chase Cancer Center in Philadelphia. Thanks, Hoss.

Hossein Borghaei, DO: Thank you.

West: Let's talk about the KEYNOTE-189 trial presented in the plenary session at the American Association for Cancer Research (AACR) meeting[1] and simultaneously published in the New England Journal of Medicine. This very important study has clear clinical implications. The phase 3 trial tests the concept of chemotherapy plus immunotherapy versus chemotherapy alone in nonsquamous, non–small cell lung cancer. Carboplatin and pemetrexed in combination with pembrolizumab was approved by the US Food and Drug Administration in May 2017, in the wake of the very favorable results from the phase 2 KEYNOTE-21G study.[2,3] This study, which included 123 patients, looked good for this regimen but [did not have] a clear survival benefit.

KEYNOTE-189 included over 600 patients with nonsquamous, non–small cell lung cancer who had any level of PD-L1 expression, no EGFR mutation or ALK rearrangement, and no brain metastasis. Patients were randomized 2:1 to cisplatin or carboplatin, with pemetrexed as the backbone in both arms. Two thirds of patients received pembrolizumab; one third received placebo. The trial was highly positive for a difference in survival in the entire population. Progression-free survival and response rate were also quite a bit better.

Tolerability was what we expected, a little more toxicity in the chemo-immunotherapy arm. Leena Gandhi, lead author, who presented the study at the AACR Plenary, highlighted the differences among the different groups, specifically whether they had PD-L1 less than 1%, 1%-49%, or 50% or greater. The greatest benefit was in patients with high PD-L1. This is a subgroup of patients where we already test; and if we find high PD-L1 [expression], even though we have the triplet available, most oncologists—both thoracic specialists and general oncologists alike— have tended to favor monotherapy with pembrolizumab. That option still exists.

There were great results with the addition of pembrolizumab to chemotherapy, but in the discussion at the AACR meeting, Roy Herbst highlighted the side-by-side curves of KEYNOTE-024 and the -189 subgroup.[1,4] One-year survival is about 70% with monotherapy and 73% in the subgroup with high PD-L1 with chemotherapy added.

What do you say to this issue where you have competing potential standards and they're comparable? Perhaps the chemotherapy arm looks a little better, but you have toxicity with it.

Borghaei: In my clinic, if I see somebody with 50% PD-L1 expression, my preference is to use pembrolizumab, because we don't have any data to clearly tell us that chemotherapy adds that much to pembrolizumab alone for this particular patient population. In the cross-trial comparison, there's a little bit of a difference—70%-73%—but I believe that the data are not as supportive of adding chemotherapy in this particular group. The point that I'd like to highlight is that the PFS in the subgroup was really good. If I'm faced with a patient who has a huge burden of disease and they're losing a couple of pounds a week, they have night sweats and fever, and I need to gain some level of control over their tumors sooner rather than later, results from KEYNOTE-189 tell me that if I add chemotherapy to pembrolizumab, I can avoid the rapid progression in somebody who could be in trouble, and perhaps continue to maintain some level of benefit from four to six cycles of chemotherapy with some maintenance. There might be a role for the addition of chemotherapy to pembrolizumab; but as far as I'm concerned, it would be a narrow patient population in need of immediate cytoreduction. Other than that, I would probably stick with pembrolizumab alone.

West: For much of the past year, the results from KEYNOTE-021 cohort G have not been universally embraced, because it was a smaller trial and overall survival was not as clearly compelling.[5] Many of us have used [chemotherapy plus pembrolizumab] primarily in patients where we worried we wouldn't get that second shot on goal if we sequenced things. If you weren't sure they'd be eligible for subsequent treatment, you would give [pembrolizumab plus chemotherapy] up front. Now, even in your high-PD-L1 patients, if you feel like you need to just have that extra little edge, that's a group [where you can use this]. Otherwise, for patients who you feel have the performance status and not a rapidly escalating disease, would you suggest monotherapy?

Borghaei: I would definitely say that's my choice at this time.

One of the great appeals of immunotherapy was to be able to avoid chemotherapy.

West: Initially, one of the great appeals of immunotherapy as a concept was to be able to avoid chemotherapy. Yes, for the people who need [chemotherapy], of course; but most of my patients would prefer to avoid it if they possibly can.

Borghaei: Absolutely. I agree with you. I am seeing one or two patients every couple of months who come in and say, "I'll take anything you've got, but I don't want chemotherapy." That's a recent phenomenon because of the popularity of the immuno-oncology drugs.

West: The other issue is that if you start on chemo-immunotherapy, most patients are going to get maintenance with pemetrexed and pembrolizumab. I suspect that in most of those patients, one of those is doing the heavy lifting and the other is more along for the ride. It's a shame if you're giving people the risk of cumulative toxicities, as well as the costs, and you don't know which of these drugs is really doing the job.

Borghaei: I agree, and again, these trials have definitely taken us a step ahead. As with any good research, you answer some questions, but you still have some unanswered questions. Hopefully, subsequent studies can better refine and define the patient population that would benefit from it. Taken together, this is a major advancement.

West: Absolutely. You're right. At the upcoming ASCO meeting, we're going to get more information from the KEYNOTE-042 trial that will include patients with PD-L1 greater than 50.[6] We already have data on pembrolizumab monotherapy versus chemotherapy for them. More information is good, and as you know, we're going to be looking at future studies that help clarify the benefits of chemo-immunotherapy versus potentially monotherapy with pembrolizumab. We will examine that question for the next few years.

We will be covering the question of other subgroups with lower PD-L1, and even those with no PD-L1 expression, in a couple of subsequent videos. Thank you for joining me.

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