Clinical Summary

• Design/Population: CHRYSALIS-2 Cohort C evaluated first-line amivantamab plus lazertinib in 49 patients with atypical EGFR-mutated advanced non–small cell lung cancer (NSCLC), a population representing approximately 5% to 10% of EGFR-mutated lung cancers and historically associated with limited benefit from available EGFR-targeted therapies.
• Key Outcomes: The combination achieved a previously reported overall response rate of 57% and median progression-free survival of 19.5 months. With extended follow-up, median overall survival was 41 months. 
• Clinical Relevance: These findings suggest that amivantamab plus lazertinib may provide meaningful long-term survival benefit in patients with atypical EGFR-mutated NSCLC, a population with historically poor outcomes. 

Joel Neal, MD, discusses updated results from CHRYSALIS-2 Cohort C evaluating first-line amivantamab plus lazertinib in patients with atypical EGFR-mutated advanced NSCLC. The study evaluated the activity of the EGFR-MET bispecific antibody amivantamab in combination with the third-generation EGFR TKI lazertinib in 49 treatment-naive patients.

Updated results demonstrated a median overall survival of 41 months, building on previously reported outcomes that included an overall response rate of 57% and median progression-free survival of 19.5 months. Adverse events were consistent with prior studies of amivantamab and lazertinib and were primarily related to EGFR and MET inhibition, although the use of subcutaneous amivantamab and enhanced supportive care strategies has reduced treatment-related toxicities. No clinical or molecular factors, including mutation subtype, age, race, or baseline brain metastases, were associated with longer treatment duration. These findings support amivantamab plus lazertinib as a promising first-line treatment option for atypical EGFR-mutated NSCLC and are reflected in recent updates to ASCO treatment guidelines.

Dr Neal presented these findings at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Illinois. 

Transcript:

I’m Joel Neal from Stanford Medicine in California. At ASCO, we presented the updated results of CHRYSALIS-2 Cohort C. This cohort of a trial with amivantamab and lazertinib was focused specifically on patients with atypical EGFR-mutant lung cancer.

Atypical EGFR-mutant lung cancer comprises somewhere around 5% to 10% of all EGFR-mutant lung cancer. But unlike classical mutations like exon 19 deletions and L858R mutations, this has been much more resistant to treatment.

Drugs that are available include afatinib, which is FDA-approved for this indication, but with an overall survival of less than 2 years. Osimertinib, a third-generation EGFR TKI, has also been used in this setting off-label, but again, looks like it has an overall survival probably in the modest range of less than 2 years.

So in this study, we used 2 drugs: amivantamab, which is an EGFR-MET bispecific antibody. It targets the extracellular domain of EGFR as well as MET, which could be involved in acquired resistance to tyrosine kinase inhibitors. In addition, we used lazertinib, which is a third-generation tyrosine kinase inhibitor, very similar to osimertinib. This combination is currently approved in the frontline setting for classical EGFR-mutant lung cancer based on the MARIPOSA study. Here, we’re wondering, what is the activity in atypical EGFR-mutant lung cancer in the frontline setting? 

So we looked at 49 patients. In results that we previously published in the Journal of Clinical Oncology, the overall response rate among the 49 previously untreated patients with amivantamab and lazertinib was 57%, which is clinically meaningful, as well as a progression-free survival of 19.5 months.

That was with shorter follow-up, but now, with the extended follow-up, we were able to estimate median overall survival, which we found was 41 months, almost 3.5 years. We thought this was actually quite impressive, given the current landscape of other treatment options in this disease, and similar to what we’re seeing in EGFR-mutant lung cancer with classical mutations.

We looked at side effects, and we found that adverse events were consistent with previous trials of amivantamab and lazertinib, mostly due to EGFR inhibition, including skin rash and diarrhea, as well as MET inhibition. There were also infusion-related reactions, which are one of the known side effects of intravenous amivantamab.

It’s notable, though, that in current formulations of amivantamab, which are subcutaneous, infusion-related reactions are really not seen anymore and that the skin reactions are much improved with the use of enhanced supportive care methods, including increased use of emollients and prophylactic antibiotics. We’ve seen data from both the COCOON study and other data at ASCO being presented in poster format from the COPERNICUS study of enhanced supportive care to try and prevent these reactions, with much lower incidences of adverse events.

So we were particularly interested in figuring out what factors are associated with longer time on treatment that may also predict better overall survival in response to this therapy. What we found was that at 2 years, 39% of patients remained on treatment at 2 years and beyond. The reasons for discontinuation among those who discontinued were mostly disease progression, followed by adverse events from drugs, followed by patient choice.

So we looked at clinical factors that were associated with longer time on treatment. We didn’t see an association with age, didn’t see an association with Asian race versus non-Asian race, and didn’t see an association with brain metastases at baseline versus not. Then we were even more interested in looking at the exact type of atypical mutation because we can classify these into classical-like mutations, which respond fairly well to third-generation EGFR TKIs, and PACC-like mutations, which typically don’t respond to the currently available EGFR inhibitors.

We did not notice an association with longer times on treatment with regard to whether they were classical-like or PACC-like, nor with the presence of TP53 mutations, which were associated with lower progression-free survival.

So when we put these data into context, when we look at afatinib and osimertinib as the currently available options, it looks like amivantamab and lazertinib, based on this 49-patient study, is another potential first-line option. I think it’s worth noting that the ASCO guidelines for treatment of EGFR-mutant lung cancer were actually updated a few days ago to reflect amivantamab and lazertinib as a third treatment option for this patient population.

Source:

Neal JW, Cho BC, Wang Y, Wu L, Felip E, Cui J, et al. Overall survival of first-line amivantamab plus lazertinib in atypical EGFR-mutated advanced non-small cell lung cancer (NSCLC): Updated results from the CHRYSALIS-2 study. Presented at the ASCO Annual Meeting. 2026. Abstract 8514.