Cut NSCLC Resistance Rates by 30% with Dual Therapy

The combination of amivantamab and lazertinib reduces the rates of EGFR and MET resistance alternations in non–small cell lung cancer (NSCLC) and could reshape treatment strategies in the second-line setting, explained Danny Nguyen, MD, medical oncologist and hematologist at City of Hope National Medical Center in Duarte, California.

In this interview, he discusses the importance of reducing resistance mechanisms, implications for sequencing therapies, and why rebiopsy and mutation testing remain essential for optimizing long-term disease management and patient outcomes.

This interview has been edited lightly for clarity.

The American Journal of Managed Care® (AJMC®): Broadly setting the stage, what is the importance of having a therapy in the first-line setting that reduces rates of EGFR and MET resistance alterations in NSCLC?

Nguyen: I guess I would take a step back. The standard of care for a long time was single-agent osimertinib, which is still a very appropriate choice for a certain number of patients. From there, we learned that most of these patients will eventually progress at some point. Even osimertinib was designed as targeting a resistance mechanism, T790M. We've used that model, knowing that if we have a therapy that addresses resistance mechanisms and we use it upfront, maybe it helps keep patients on treatment longer and helps prevent those resistance mechanisms from occurring, so that patients will, hopefully, progress later and consequently live longer.

AJMC: Given the significant reduction in acquired EGFR and MET resistance alterations with amivantamab-lazertinib, how does this translate into a change in the standard of care for second-line treatment options and long-term disease management?

Nguyen: As we saw, for instance, with the EGFR resistance mechanisms, patients who progress on osimertinib had more of the C797S mutations, as well as the L718X and G724X mutations. For those patients who happen to have those resistance mechanisms, I know and am involved in some clinical trials designed to try to target those resistance mechanisms. Now that patients are not progressing through those pathways, there are other pathways that it looks like there are a little bit more of, such as HER2 amplifications. [This is] potentially opening up other therapy options in the future.

The MET implications were a lot lower, too, which also seems to have other implications. It seems like patients who progressed on osimertinib within 6 months tended to have higher expressions of MET. We saw less of that with the combination of amivantamab and lazertinib. Maybe that also helps prevent these patients from progressing within 6 months or earlier than expected.

AJMC: On the flip side, the abstract highlights that mutational heterogeneity was significantly increased after osimertinib treatment. What are the clinical implications of this increased heterogeneity for a treating physician, particularly in the context of subsequent lines of therapy?

Nguyen: That's a good question, because really, it’s like a potpourri of things that can happen in patients if and when they progress on osimertinib. It stresses the importance of rebiopsy and retesting for these mutations, because a lot of things can pop up, and then you can try to tailor treatment based on those specific findings.

For instance, if a patient develops a different mutation, you might want to try some targeted therapies that might work in that respect. There is some suggestion of increased TP53 and/or RB1 loss with single-agent osimertinib, which may have implications for small cell transformation. Then you might have to go for treatment down that route.

As opposed to in patients who progress on amivantamab and lazertinib, the decreased heterogeneity will oftentimes let me feel a little bit more confident in maybe lining up my second-line therapy, which would probably be chemotherapy, which still has a very good effectiveness for patients in the second line with EGFR mutations. But I think regardless of whichever pathway that you go, you’re still going to want to retest on progression just to confirm those mutations.