Research Priorities Evolve With Amivantamab's Broader NSCLC Indications

Continuing our discussion with Martin Dietrich, MD, PhD, thoracic oncologist with The US Oncology Network and Cancer Care Centers of Brevard in Orlando, Florida, about the most recent approval for amivantamab in non–small cell lung cancer (NSCLC), here he examines unmet treatment needs for the subset of patients who have exon 19 deletions or exon 21 L858R substitution mutations whose disease has progressed on or after EGFR tyrosine kinase inhibitor (TKI) treatment, whom the newest indication covers, and what should be current research priorities.

Amivantamab currently has 4 approved indications from the FDA, and along with chemotherapy, it is the only Category 1 treatment per National Comprehensive Cancer Network Guidelines for patients with EGFR-mutated NSCLC who are progressing on osimertinib with multiple lesions.

This transcript has been edited for clarity.

Transcript

What unmet treatment needs does this latest approval address?

The versatility of amivantamab is very broad. I mentioned the indication in first-line EGFR exon 19 and 21 in MARIPOSA, first-line EGFR exon 20 in PAPILLON, the post progression in MARIPOSA-2, as well as the CHRYSALIS [NCT02609776] data that had the single-agent indication for EGFR exon 20. So it really tells you that it captures all of the difficult intracellular kinase domain processes that are not as easily approachable by a tyrosine kinase small molecule.

We are seeing, obviously, still concerns about durability. We're still learning about overall survival.Those trials, while they've had very good initial results, are still maturing. We're still trying to see the optimal sequence and trying to refine which patient benefits the most from these therapies. Are there patients that are fine with monotherapy alone? Whenever we add additional therapy combinations, we always expect an increase in side effects.

So we're still learning a lot about the biomarker space, and there's still a lot of improvements and tailoring that can be made for patients to really optimize outcomes. Prospectively, I'm excited about these lessons. I think it has been a priority to take the lessons from MARIPOSA and MARIPOSA-2 back into new clinical trial designs that help us refine the way we give the medication—both in frequency and application route—expecting a subcutaneous injection over the intravenous route that we're currently using.I think we'll be seeing additional insight and protocols with regards to management of skin toxicities.

So there is more to be learned, and I think that's always the beautiful part of a clinical trial. It is a lesson that answers as many questions as it poses, and so a continuous driver, if we take it on, as a continuous learning lesson.

And then prospectively, obviously, a side of amivantamab that we haven't really tackled in our discussion at all is, obviously, we know that CMET is an escape mechanism for post progression on an EGFR TKI in the first-line setting, but CMET plays a role individually in non–small cell lung cancer as well, both through amplification and through intercellular kinase domain alterations, including the MET exon 14 skipping mutation that essentially leads to a decreased turnover on the intracellular side and a decrease in protein reduction by ubiquitous retention.So I think there's still a lot more development to be seen with the amivantamab molecule.

Unfortunately, even though patients are doing better, we're still in the process of now resorting our thoughts not only with regards to who do we select what first-line therapy for, but also what are we going to do when a patient progresses? What therapies do we use in the first line, and then how would this influence second- and third-line treatment for our patients? So always good to have new options, but the complexity is getting higher and higher. It used to be sort of a 1-drug space, and that has certainly been augmented broadly with these new approvals.

Can you discuss what should be research priorities moving forward in patients with EGFR-mutated NSCLC?

In this scenario, we're talking about really the complexity of the EGFR mutation family, and we are having mutations in exon 18, 19, 20, and 21. And while MARIPOSA addresses mutations in exon 19 and 21, the specifically referenced regimen, the PAPILLON regimen, references mutations in EGFR exon 20. It's a very difficult-to-treat subset where we had very limited success obtaining small molecule inhibitors that would mimic the response pattern that we've seen in exon 19 and 21.

So, it's the same receptor, similar mutations, but clinically very, very difficult to treat. And we were having 2 options for treatment in the second-line setting for EGFR exon 20: amivantamab as a monotherapy based on the CHRYSALIS study, and we had for a brief period of time also mobocertinib as a targeted therapy—that has been removed by the FDA. But now we've seen the results of the PAPILLON study, where we combine chemotherapy as the previous first-line standard of care in the EGFR exon 20 population, and adding amivantamab, and we're seeing a doubling in the progression-free survival.

We're seeing very nice and deep responses, with about 60% response rates in this subgroup. This adds to the reach of amivantamab by basically overcoming any intracellular kinase domain alterations by tackling the EGFR receptor from the extracellular side. So, it shows the versatility of the agent, basically reaching any EGFR alteration in this subset of treatment.

We've seen some data published also for the atypical mutations. And again, agnostically and biologically, there's absolutely no reason why amivantamab wouldn't be helpful in this subset, so we're using it. But for EGFR exon 20, it's really the only approved standard-of-care option that is evidence based.