Time to 'Rethink' Immunotherapy for Molecularly Driven NSCLC

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.

West: One concept that we have come to an early conclusion on has been immunotherapy in patients with EGFR mutations or ALK rearrangements. Based on the early work with monotherapy in the second-line setting, we have seen that the subgroup of patients with EGFR mutations is the only subgroup that does not benefit relative to docetaxel in essentially all of the studies. A recent meta-analysis by Dr Lee and colleagues in JAMA Oncology^[1] showed this. I would say that this is also corroborated by our anecdotal experiences and from talking with other folks who see and treat a lot of patients with driver mutations—not just EGFR, but ALK. There is a suggestion that the results may not be as good in never-smokers, but that has not been teased out.

Many of us have relegated immunotherapies to the last things we try and dismiss them as not likely to help. Yet, new data should make us rethink that. Specifically, we had an early presentation in late 2017 on the IMpower150 trial^[2] by Dr Martin Reck and colleagues at the European Society for Medical Oncology (ESMO) 2017 immunology/immuno-oncology (IO) meeting. Then at American Association for Cancer Research (AACR) 2018, we saw a presentation by Dr Socinski and colleagues^[3] that largely spoke to the data we had already seen but had more to say about the potential value of immunotherapy in combination with chemo and bevacizumab.

IMpower150 Trial

West: The IMpower150 trial evaluated about 1200 patients with nonsquamous, non–small cell lung cancer (NSCLC) with no requisite level of PD-L1 expression. Unlike the other trials in the first-line setting, this trial did allow patients with an EGFR mutation or ALK rearrangement, but they were to have received and progressed on targeted therapy already. The control arm was carboplatin/paclitaxel/bevacizumab. The first comparator was carboplatin/paclitaxel/bevacizumab with atezolizumab, and then a secondary and less discussed comparator was carboplatin/paclitaxel with atezolizumab (omitting the bevacizumab).

We have seen results thus far on carboplatin/paclitaxel/bevacizumab with or without atezolizumab. The study showed a significant improvement in progression-free survival (PFS) (hazard ratio [HR] of 0.62) in that broader population.^[2] We've heard from the press release that it's also positive now for overall survival. We have other studies on chemo and immunotherapy—this one has bevacizumab—showing an improvement, but is this trial really that different?

What was different was that in the subset of patients with an EGFR mutation or ALK rearrangement, the HR was 0.59.^[3] It's every bit as good, and even numerically slightly better, as that seen in the broader population. We do not know yet whether it's the atezolizumab and the chemo or the bevacizumab that is more significant here, but for whatever reason, this is our first bit of evidence that should cause us to take a moment and pause. Dr Socinski presented curves that showed quite impressive differences in the patients with EGFR mutations and less so—but still not negligible—with ALK.

What do you take from this? Are you optimistic that there is something different about chemo-immunotherapy that makes it a better choice? We're going to have a lot of patients in the next few years who are progressing on their second, third, and so on, targeted therapies. So, what do you do next? Should we be considering bevacizumab as a critical component? What are you going to do now and what do you think the next few years will lead us to?

Will IMpower150 Change Practice?

Borghaei: It was really impressive to see the data from IMpower150, both the initial presentation and the follow-up at AACR by Dr Socinski. I think this [treatment strategy] is a very viable option for patients who have exhausted the tyrosine kinase inhibitor (TKI) options. What we do now with patients after they have exhausted all of the TKIs is go to standard platinum doublet chemotherapy. Yes, it works in this patient population and we have good data, but we have not seen HRs like the ones that we saw from IMpower150 with standard platinum doublet chemotherapy.

Whether it is the impact of bevacizumab given along with an IO agent that is making this regimen so much better remains to be teased out. We need a separate cohort of patients who are just getting the IO plus [anti–vascular endothelial growth factor antibody] and no chemotherapy to sort of see where the data lie. Now, if I have a patient in the clinic who has exhausted a lot of the TKI options and I'm considering either a clinical trial or platinum doublet only, it gives me a bit more confidence to say, "We have a regimen. It's quadruple therapy but the HR for PFS is really good and there could be a survival advantage to it."

I thought the data were very impressive. It is the first time I've seen something like that in the general patient population with these molecularly driven tumors. It's hard to argue with the meta-analysis of all of the phase 3 studies in the second-line setting looking at the role of single-agent IO. I would still say that single-agent IO in all-comers with this subset of patients might not be appropriate.

West: Forever?

Borghaei: At least until we have a little more information. If we talk about the publication in Lancet Oncology, with durvalumab,^[4] and look at the patient population that had either high or low PD-L1 expression, you see that the benefit is mostly with ones that have really high expression of PD-L1. There again, we have a selection mechanism. I'm not sure I'm comfortable with the idea of IO alone in the third line, or whatever, in everybody with an ALK- or EGFR-mutated tumor post-TKI. But I think if I have a [process for] patient selection, based on PD-L1, or if I have the option of a four-drug regimen that gives me such a good HR of PFS, then I think that is a slightly different question.

West: We may be able to tease out something on the bevacizumab contribution. I hope we get some information on how the patients did in arm A [of IMpower150] who had an EGFR mutation or ALK rearrangement. If it was very good for those patients who did not get bevacizumab but did get atezolizumab, then we can conclude that chemo-immunotherapy is important and it's not just hinging on the bevacizumab.

Borghaei: I agree.

What About KEYNOTE-189?

West: It's interesting. Some people will be inclined to use the now increasingly supported approach of KEYNOTE-189^[5] of a platinum/pemetrexed/pembrolizumab, which is a group in which the driver mutation patients were excluded. I'm afraid that is going to be a bit of the "streetlamp effect," where the drunk loses his keys in the dark alley but chooses to look in the well-lit street because the lights are better. I have some hesitation about extrapolating from a regimen that was studied to a different regimen that was not studied.

Borghaei: I absolutely agree with you. If I'm going to use anything in that patient population, I'll be using the IMpower150 and not the KEYNOTE-189, because there are absolutely no data about that.

West: What we can say, at least, is that this has opened up a field that was previously kind of closing down. There was not much enthusiasm. All of a sudden, we have stepped back and there is now a lot more research looking at the potential utility. I think some docs are going to be quite inclined to consider the combination approach instead of relegating it to late line in hopes of conferring the same kind of benefits with immunotherapy that we have seen in the broader population.

Borghaei: I think that's appropriate. You go where the data go. We did not have the data before, but now we do. We adjust clinical practice based on what is available.

West: For all of the excitement about immunotherapy, it's important to underscore that this does not mean that we should supplant the primary targeted therapy where the response rates are still 70%-80%, often last a very long time, and are well tolerated. This does not mean that we should be replacing that therapy with chemo-immunotherapy, but rather follow [with it].

Borghaei: I absolutely agree with that. Targeted therapy comes first.

West: Hoss, thanks so much for joining me. A great discussion, as always.

Borghaei: Thank you.

West: Thank you, the audience, for joining us today. This is Jack West for Medscape.

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