Next-Gen Strategies for Resistance in EGFR-Mutated Lung Cancer

In the conclusion to our interview with Joshua K. Sabari, MD, which focused on the first-line approval of amivantamab (Ami; Rybrevant; Johnson & Johnson) plus lazertinib (Lazcluze, Janssen Biotech), he discusses Ami’s promise in patients who have EGFR-mutation positive non–small cell lung cancer (NSCLC) and looks ahead to potential uses that could help to overcome treatment resistance.

To revisit part 1 and part 2 of this interview, please visit these links:

• Novel Mechanisms Set FDA-Approved Amivantamab-Lazertinib Combom Apart in NSCLC
• Balancing Benefits and Risks of Amivantamab

This transcript has been lightly edited for clarity.

Transcript

What are some top ongoing challenges in treating NSCLC?

I think what's interesting is that amivantamab [Ami] seems to have broad activity, not just in the common EGFR mutations, but across all EGFR mutations, including exon 20 and including the uncommon, or historically atypical, we now call them the PaC mutations, the PαC helix mutations, in this population. More broadly than EGFR-mutation–positive lung cancer, this is a therapy that is being looked at in other diseases, other histologies, primarily colorectal cancers, and other histologies as well. But it's an exciting opportunity. It's the first frontline indication for amivantamab in combination with lazertinib—again, building upon what is a standard of care, a third-generation EGFR TKI [tyrosine kinase inhibitor].

I think focusing specifically on EGFR, we've sort of plateaued in the sense of developing our fourth-gen inhibitors. We need to start thinking more broadly to encompass resistance. We know that MET amplification is common, occurring in 10% to 12% of patients. We know that C797S is also occurring in about 8% to 10%—it's a point mutation in exon 20. And we also know that we have such a broad range of heterogeneous alterations as resistance in the second-plus-line setting.

I think we need to better understand resistance mechanisms, particularly resistance mechanisms against amivantamab, the EGFR MET bispecific, and in understanding those resistance mechanisms, we'll then be able to sort of develop and design our next-generation therapeutics. So, despite Ami and lazertinib being a phenomenal treatment option for patients in the frontline setting, I think we're going to build upon that as well. So, exciting opportunities with EGFR and met ADCs [antibody drug conjugates] as well as EGFR and CD3 T-cell engagers in the EGFR population space as well.

I think one of the holy grails in the EGFR-mutant space has been the lack of immune response in this population, and I think with amivantamab, especially with the FC portion of the bispecific antibody, we're starting to see some immune activation. And I think that's where the next generation of inhibitors are going to go.