Does Immunotherapy Have a Role in EGFR-Mutant Lung Cancer?

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 are Joshua Bauml, assistant professor at the University of Pennsylvania, and Sandip Patel, assistant professor at UC San Diego. Welcome, Josh and Sandip; thanks so much for joining us.

Along with immunotherapy, there are also a few other things to talk about from the 2018 annual meeting of the American Society of Clinical Oncology (ASCO). In the field of lung cancer, one is targeted therapies and specifically treatments for EGFR mutation-positive lung cancer, which is segregated out from the immunotherapy approach that we usually think about in the first-line [setting].

In the past year, we've seen osimertinib emerge as a standard of care, if not the [only] standard of care, for first-line treatment on the basis of the FLAURA trial,^[1] which showed an approximately 19-month progression-free survival. [Osimertinib] has activity in the central nervous system (CNS) and good tolerability, but at this ASCO 2018 meeting, there are some competing ideas. One of the biggest controversies is around the possibilities for sequencing while still having osimertinib available, at least for a subset of patients who are T790M-positive at progression, and particularly perhaps for second-generation ALK inhibitors.

Dacomitinib is one of those, and we saw some results last year from the ARCHER 1050 trial presented by Tony Mok, MD, with results subsequently published in Lancet Oncology^[2] that showed a significant improvement in progression-free survival to a median of about 15 months, and much better than [that with] gefitinib. However, this was in a population that excluded patients with CNS metastases, and toxicity has been an issue.

Now, at this year's ASCO meeting, Dr Mok is speaking again to review the data, and of course, the toxicity issues are still there and the progression-free survival (PFS) benefit is also there; however, now there is also a borderline significant overall survival benefit.^[3] The question is, is this enough to bubble up and disrupt the potential role of osimertinib?

At the same time, there's a Japanese study^[4] presenting further follow-up of a study of erlotinib versus erlotinib and bevacizumab in more than 200 patients [that demonstrated] significant benefit and PFS, though not an improvement in overall survival.

But neither of these burns the bridge of osimertinib. So how do you each see the role of sequencing, versus starting with osimertinib, given the potential alternatives available?

Sandip Patel, MD: In my practice, I use osimertinib front-line as standard of care for patients, because of all the advantages you mentioned. We have overall survival data that look very provocative; it has CNS penetration, which is a major problem for patients with EGFR-mutated non-small cell lung cancer; and the tolerability is much improved compared with first-generation and third-generation EGFR inhibitors. One aspect of these drugs is that they are so effective that patients are on them for a very long time, and so the toxicity aspect cannot be underemphasized. And so as patients are on these agents longer, I think the toxicity advantage of osimertinib compared with dacomitinib actually becomes more pronounced in that setting.

West: It's a great point. With dacomitinib, two thirds of the patients [on trial] required a dose reduction. We are hoping to have these patients on treatment for more than a year, and potentially [multiple] years, and so even grade 1 or 2 toxicities (eg, rash and diarrhea) become, if not prohibitive, quality-of-life–reducing. So it's very important to consider balancing tolerability and the efficacy for a chronic long-term therapy.

Joshua Bauml, MD: One of the things that also needs to be emphasized is that in the presentation last year on the dacomitinib versus gefitinib study, the benefit was predominantly among patients in Asia, and the incremental benefit in North America was essentially absent. I don't know why that would be, but if I've got a drug that is more toxic with borderline improvement in overall survival, it's not terribly appealing when we know that the efficacy in North America was limited.

West: Let's talk about the role of immunotherapy in these patients. Historically—and this is based on limited data—[in] consistent subset analyses from second-line trials of various checkpoint inhibitors versus docetaxel, the EGFR mutation-positive patients don't have a benefit, and our party line has largely been to deprioritize [immunotherapy] and relegate it to a later treatment, if at all. On the other hand, the IMpower150 trial, which gave chemotherapy combined with bevacizumab and atezolizumab, showed a benefit that was really quite robust in the patients with an EGFR mutation.

Also, if you pooled in the ALK-positive patients, there was a benefit. However, it was especially true for the EGFR mutation-positive patients, [and] this was in patients who had received and progressed on an EGFR inhibitor initially. At this meeting, we've also seen some data testing pembrolizumab as a first-line therapy in EGFR mutation-positive patients, even with high PD-L1 expression, which was frankly quite concerning for lack of efficacy.^[5] Putting this all together, how do you [plan on] using immunotherapy in your EGFR mutation-positive patients?

Bauml: The study that you're referencing with pembrolizumab first-line is one of the most important studies here, because it asked, and answered, an important question. People are very excited about immunotherapy, but what it clearly showed was that the toxicity is substantial when we use it first-line, and that the toxicity is extended because the functional half-life of these PD1 inhibitors is much longer than the drug being in the body. The T cells are activated, and it can be prolonged, so there were patients who had a much higher [adverse event] rate; there was a fatal pneumonitis with erlotinib, which is not something we would expect.

In terms of the immunotherapy [data] from the IMpower150 trial, I think that there's interest in the use of vascular endothelial growth factor (VEGF) [inhibitors] in this space. My personal belief is that the reason that it was positive for EGFR patients is that they were included. The other studies excluded them specifically. There are ongoing studies that are evaluating carboplatin-pemetrexed-pembrolizumab and other chemotherapy-immunotherapy (chemo-IO) combinations among patients with an EGFR mutation, but I think at this point, my answer is that PD1 monotherapy is not a great idea; chemo-IO is reasonable, though currently the only regimen that has data is not US Food and Drug Administration (FDA)-approved.

West: We don't really know how much of it is the bevacizumab contribution versus immunotherapy, but [can perhaps] presume it's going to be extrapolated into other settings.

Bauml: The fact that the study that you mentioned with prolonged follow-up for erlotinib-bevacizumab didn't show an overall survival benefit makes me think that bevacizumab is not the drug that's making the difference here. I think that there is activity for chemo-IO, and that it's a reasonable approach in these patients after failure of TKI.

West: Sandip, any other thoughts?

Patel: I completely agree. Hard stop, if you have an EGFR mutation, your best therapies are EGFR-targeting TKIs. Immunotherapy has no current role.

West: So for all of the enthusiasm around immunotherapy, we need to ground ourselves—targeted therapies for patients with driver mutations are the first-line treatment.

Patel: And our targeted therapies have gotten better, and so there should be a lot of enthusiasm to continue in that development. One point of interest, while we're talking about combination therapy, is something I'm sure patients are going to ask us a lot about: the erlotinib-metformin combination study.^[6]

West: Right. That trial suggested a benefit even extending to overall survival, but it was not a large study, and it had some limitations. Do you have some concerns about that?

Patel: It's very early. A lot of us were excited by the initial Japanese experience with the beta study for erlotinib-bevacizumab with a marked PFS improvement, but a negative overall survival. I think there are concerns about erlotinib-metformin along similar lines in a larger study. This was a smaller study. Even though it's positive for overall survival, when we think about financial and medical toxicity, metformin [may be] much more tolerable from that standpoint, but I think it's too early to suggest this routinely. It was one of the more interesting abstracts, along with the use of osimertinib in the atypical EGFR mutations, where we saw substantial benefit with reduced toxicity, compared with some of the other EGFR inhibitors that have been studied in this space, in particular afatinib.^[7]

West: So there was some evolution [in our understanding], but I agree. The metformin story is now one to watch; it has certainly risen in visibility and some credibility, but needs to be validated in a broader setting.

Josh and Sandip, thank you so much for joining me. It was a great discussion, with lots of work ongoing. This is Jack West for Medscape Oncology, and I look forward to our next discussion.

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