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

H. Jack West, MD: Hiya. I am Jack West, medical director of the Thoracic Oncology Program at Swedish Most cancers Institute in Seattle. Welcome to Medscape Oncology Insights. Becoming a member of me as we speak are Joshua Bauml, assistant professor on the College of Pennsylvania, and Sandip Patel, assistant professor at UC San Diego. Welcome, Josh and Sandip; thanks a lot for becoming a member of us.
Together with immunotherapy, there are additionally just a few different issues to speak about from the 2018 annual assembly of the American Society of Scientific Oncology (ASCO). Within the subject of lung most cancers, one is focused therapies and particularly therapies for EGFR mutation-positive lung most cancers, which is segregated out from the immunotherapy method that we normally take into consideration within the first-line [setting].

Prior to now 12 months, we have seen osimertinib emerge as a typical of care, if not the [only] normal of care, for first-line therapy on the idea of the FLAURA trial,[1] which confirmed an roughly 19-month progression-free survival. [Osimertinib] has exercise within the central nervous system (CNS) and good tolerability, however at this ASCO 2018 assembly, there are some competing concepts. One of many largest controversies is across the potentialities for sequencing whereas nonetheless having osimertinib out there, at the very least for a subset of sufferers who’re T790M-positive at development, and significantly maybe for second-generation ALK inhibitors.
Dacomitinib is a type of, and we noticed some outcomes final 12 months from the ARCHER 1050 trial introduced by Tony Mok, MD, with outcomes subsequently printed in Lancet Oncology[2] that confirmed a major enchancment in progression-free survival to a median of about 15 months, and significantly better than [that with] gefitinib. Nonetheless, this was in a inhabitants that excluded sufferers with CNS metastases, and toxicity has been a problem.

Now, at this 12 months’s ASCO assembly, Dr Mok is talking once more to evaluation the information, and naturally, the toxicity points are nonetheless there and the progression-free survival (PFS) profit can also be there; nevertheless, now there may be additionally a borderline important total survival profit.[3] The query is, is that this sufficient to bubble up and disrupt the potential position of osimertinib?

On the identical time, there is a Japanese examine[4] presenting additional follow-up of a examine of erlotinib versus erlotinib and bevacizumab in additional than 200 sufferers [that demonstrated] important profit and PFS, although not an enchancment in total survival.
However neither of those burns the bridge of osimertinib. So how do you every see the position of sequencing, versus beginning with osimertinib, given the potential alternate options out there?
Sandip Patel, MD: In my apply, I exploit osimertinib front-line as normal of look after sufferers, due to all the benefits you talked about. We now have total survival knowledge that look very provocative; it has CNS penetration, which is a serious downside for sufferers with EGFR-mutated non-small cell lung most cancers; and the tolerability is way improved in contrast with first-generation and third-generation EGFR inhibitors. One facet of those medication is that they’re so efficient that sufferers are on them for a really very long time, and so the toxicity facet can’t be underemphasized. And in order sufferers are on these brokers longer, I believe the toxicity benefit of osimertinib in contrast with dacomitinib truly turns into extra pronounced in that setting.

West: It is a terrific level. With dacomitinib, two thirds of the sufferers [on trial] required a dose discount. We hope to have these sufferers on therapy for greater than a 12 months, and doubtlessly [multiple] years, and so even grade 1 or 2 toxicities (eg, rash and diarrhea) turn out to be, if not prohibitive, quality-of-life–lowering. So it is essential to think about balancing tolerability and the efficacy for a power long-term remedy.
Joshua Bauml, MD: One of many issues that additionally must be emphasised is that within the presentation final 12 months on the dacomitinib versus gefitinib examine, the profit was predominantly amongst sufferers in Asia, and the incremental profit in North America was primarily absent. I do not know why that may be, but when I’ve acquired a drug that’s extra poisonous with borderline enchancment in total survival, it isn’t terribly interesting after we know that the efficacy in North America was restricted.
West: Let’s discuss in regards to the position of immunotherapy in these sufferers. Traditionally—and that is based mostly on restricted knowledge—[in] constant subset analyses from second-line trials of assorted checkpoint inhibitors versus docetaxel, the EGFR mutation-positive sufferers haven’t got a profit, and our social gathering line has largely been to deprioritize [immunotherapy] and relegate it to a later therapy, if in any respect. Then again, the IMpower150 trial, which gave chemotherapy mixed with bevacizumab and atezolizumab, confirmed a profit that was actually fairly sturdy within the sufferers with an EGFR mutation.
Additionally, for those who pooled within the ALK-positive sufferers, there was a profit. Nonetheless, it was very true for the EGFR mutation-positive sufferers, [and] this was in sufferers who had acquired and progressed on an EGFR inhibitor initially. At this assembly, we have additionally seen some knowledge testing pembrolizumab as a first-line remedy in EGFR mutation-positive sufferers, even with excessive PD-L1 expression, which was frankly fairly regarding for lack of efficacy.[5] Placing this all collectively, how do you [plan on] utilizing immunotherapy in your EGFR mutation-positive sufferers?

Bauml: The examine that you simply’re referencing with pembrolizumab first-line is without doubt one of the most vital research right here, as a result of it requested, and answered, an vital query. Individuals are very enthusiastic about immunotherapy, however what it clearly confirmed was that the toxicity is substantial after we use it first-line, and that the toxicity is prolonged as a result of the useful half-life of those PD1 inhibitors is for much longer than the drug being within the physique. The T cells are activated, and it may be extended, so there have been sufferers who had a a lot increased [adverse event] price; there was a deadly pneumonitis with erlotinib, which isn’t one thing we’d count on.

When it comes to the immunotherapy [data] from the IMpower150 trial, I believe that there is curiosity in using vascular endothelial progress issue (VEGF) [inhibitors] on this house. My private perception is that the rationale that it was optimistic for EGFR sufferers is that they had been included. The opposite research excluded them particularly. There are ongoing research which might be evaluating carboplatin-pemetrexed-pembrolizumab and different chemotherapy-immunotherapy (chemo-IO) mixtures amongst sufferers with an EGFR mutation, however I believe at this level, my reply is that PD1 monotherapy just isn’t a terrific thought; chemo-IO is affordable, although presently the one routine that has knowledge just isn’t US Meals and Drug Administration (FDA)-approved.

West: We do not actually understand how a lot of it’s the bevacizumab contribution versus immunotherapy, however [can perhaps] presume it should be extrapolated into different settings.

Bauml: The truth that the examine that you simply talked about with extended follow-up for erlotinib-bevacizumab did not present an total survival profit makes me suppose that bevacizumab just isn’t the drug that is making the distinction right here. I believe that there’s exercise for chemo-IO, and that it is a cheap method in these sufferers after failure of TKI.

West: Sandip, every other ideas?

Patel: I fully agree. Exhausting cease, in case you have an EGFR mutation, your greatest therapies are EGFR-targeting TKIs. Immunotherapy has no present position.

West: So for the entire enthusiasm round immunotherapy, we have to floor ourselves—focused therapies for sufferers with driver mutations are the first-line therapy.

Patel: And our focused therapies have gotten higher, and so there ought to be plenty of enthusiasm to proceed in that growth. One focal point, whereas we’re speaking about mixture remedy, is one thing I am positive sufferers are going to ask us rather a lot about: the erlotinib-metformin mixture examine.[6]

West: Proper. That trial prompt a profit even extending to total survival, but it surely was not a big examine, and it had some limitations. Do you may have some considerations about that?

Patel: It is very early. Plenty of us had been excited by the preliminary Japanese expertise with the beta examine for erlotinib-bevacizumab with a marked PFS enchancment, however a adverse total survival. I believe there are considerations about erlotinib-metformin alongside related traces in a bigger examine. This was a smaller examine. Though it is optimistic for total survival, after we take into consideration monetary and medical toxicity, metformin [may be] far more tolerable from that standpoint, however I believe it is too early to counsel this routinely. It was one of many extra fascinating abstracts, together with using osimertinib within the atypical EGFR mutations, the place we noticed substantial profit with decreased toxicity, in contrast with a few of the different EGFR inhibitors which were studied on this house, specifically afatinib.[7]

West: So there was some evolution [in our understanding], however I agree. The metformin story is now one to observe; it has definitely risen in visibility and a few credibility, however must be validated in a broader setting.

Josh and Sandip, thanks a lot for becoming a member of me. It was a terrific dialogue, with a lot of work ongoing. That is Jack West for Medscape Oncology, and I sit up for our subsequent dialogue.


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