COMMENTARY

KEYNOTE-189: Chemotherapy Plus Immunotherapy Now a Viable Option for PD-L1 Low Expression Non-Small Cell Lung Cancer

H. Jack West, MD;   Hossein Borghaei, DO

Disclosures

May 17, 2018

H. Jack West, MD: Hello. I am 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. Welcome, Hoss.

Hossein Borghaei, DO: Thank you.

KEYNOTE-189 and KEYNOTE-012

West: Since the presentation at the American Association for Cancer Research (AACR) meeting, we have been talking about the KEYNOTE-189 study[1] and its clinical implications which, I think, are many. KEYNOTE-189 was a phase 3 study that helped clarify some of the residual questions around chemo/immune-oncology (IO) therapy for nonsquamous, non–small cell lung cancer (NSCLC).

Since May 2017, oncologists have had US Food and Drug Administration (FDA) approval for carboplatin/pemetrexed and pembrolizumab in patients with nonsquamous NSCLC regardless of PDL-1 expression, based on the KEYNOTE-021G randomized phase 2 study[2] that you were involved with. That study evaluated 123 patients, and overall survival (OS) was not clearly, compellingly different, at least in the early iterations of the results. People have not totally embraced [those results] and wanted to see the results of a large phase 3 study.

KEYNOTE-189 also enrolled patients with nonsquamous EGFR and ALK wild-type NSCLC and no brain metastases. This study was across the spectrum of PD-L1—patients had none to lots. Two thirds of the patients received platinum chemotherapy (cisplatin or carboplatin) with pemetrexed and pembrolizumab; the other third received the same choice of chemotherapy and pemetrexed with placebo. The trial was highly positive for OS as well as other efficacy endpoints. The hazard ratio (HR) for OS was 0.49 with a difference at 1 year in OS of about 20%—from over 49% in the control arm to nearly 70% in the chemo-immunotherapy arm. Clearly, this was a very significant result. Leena Gandhi, who presented at AACR and was first author of the concurrent New England Journal of Medicine publication, highlighted differences between the three different PDL-1 expression subgroups. The groups, each consisting of about a third of patients, were < 1% PD-L1 expression, 1%-to 49%, and > 50%.

We have talked in passing about the high-PDL-1 group who have two competing options of pembrolizumab monotherapy or the combination. Let's talk about the 1%-49% group who are covered by the FDA approval now. In the KEYNOTE-189 study, they had a difference favoring the pembrolizumab arm that was not as great as in the highest PD-L1 group but was still highly significant across the different endpoints. For OS, the HR was 0.55. PFS was very different and response rate was more than double.

Awaiting KEYNOTE-042

West: We will also soon have the results of the KEYNOTE-042 trial; it is going to be presented at a plenary session at the American Society of Clinical Oncology (ASCO) meeting. This study was a lot like KEYNOTE-024[3] in that it was for patients with either squamous or nonsquamous NSCLC who had PDL-1 of ≥ 1%. In KEYNOTE-024 it was 50%. KEYNOTE-042 is comparing pembrolizumab monotherapy versus chemo doublet. We know, from a press release, that it is positive for OS. We have not seen the data and we do not know how much of that is going to be propelled by the high-PDL-1 group versus the lower group.

What do you think is going to happen—both now and after KEYNOTE-042 is presented at the plenary presentation—to the group of patients who might be in the same boat of choosing chemo-immunotherapy or pembrolizumab monotherapy?

Borghaei: Again, who knows what KEYNOTE-042 really has in terms of the data. We must wait and see. One thing that is established right now is that chemo/IO therapy for PD-L1 negatives or moderate expressers is a very viable option.

Let's say that we see the KEYNOTE-042 study and we still have a scenario where single-agent pembrolizumab can still be effective in terms of improvement in OS, PFS, and all of that compared with standard chemotherapy. Then we are at a place where we were not too long ago, when we were looking at this triple combination and saying, "Which one of my patients could really benefit from the triple combination?" As you have said many times, we only get one shot on the goal, and we really do not want to see a rapid progression. If KEYNOTE-042 is really that positive, do we use the chemo combination with IO in that setting and reserve single-agent drug for all of the other patients?

Or are we going to say that KEYNOTE-042 is good, and the press release is fine, but I really like the response of PFS that I am getting in the PD-L1 "zeros" and the PD-L1 moderate expressers with the chemo combination, because there, especially for the moderate expressers, the PFS curve really favors the addition of chemotherapy. If you argue that in the PD-L1-negative subgroup of KEYNOTE-189, the PFS curve is not really all that impressive and the improvement in terms of the median numbers is just about a month over chemotherapy, you might say, "I am getting the same benefit from pembrolizumab alone and perhaps I want to consider that"—again, if the data support that.

Given the fact that we do not know what the KEYNOTE-042 presentation is going to say, and like you, I have the same concerns—that the benefit could be mostly driven by the 50-percenters—I would favor the use of a chemo/IO for the moderate group at this time. I am still a little bit hesitant about the PD-L1 negatives. Again, if I have somebody who I think is in trouble and needs more cytoreduction, knowing I might have one shot at goal, I think having the KEYNOTE-189 triple combination gives me the comfort level that I am doing whatever I can for that patient.

In the absence of that, if I am worried about toxicity or reactivating an autoimmune disease, I might still consider standard chemotherapy or perhaps another option, such as an IO/IO regimen, down the road for the PD-L1-negative groups. Not knowing what KEYNOTE-042 looks like makes it difficult to make a call on this right now.

West: I was previously reserving the triplet for the minority of my patients with the fastest-growing disease or marginal performance status if I was not confident that they could get to second line without coming to clinic in a wheelchair. That is the group where I would want to push it all up front. I'm now inclined to be more liberal on the basis of KEYNOTE-189's very compelling improvement in all of the efficacy endpoints. Not just in the 50% and higher group, but also the 1%- 49% group. For me, this is the group for which KEYNOTE-042 is going to be most helpful.

We already know a lot about the high PD-L1 group. We know that pembrolizumab is going to be very effective for them and that chemo is more of a secondary consideration. It is much less clear to me whether pembrolizumab is really going to be enough to hang your hat on in the lower-PD-L1 group. We will have to see how the subsets break out. That will be available to us in the next several weeks, so we will have more to talk about then.

Thank you very much for the discussion, Hoss. Thank you, the audience, for joining us. This is Jack West for Medscape.

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