Amivantamab/Lazertinib Combination May Overcome Osimertinib Resistance in Patients With EGFR-Positive NSCLC

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Combination targeting of epidermal growth factor receptor (EGFR) with amivantamab/lazertinib achieved durable responses in more than one-third of chemotherapy-naive patients with EGFR-mutant non–small cell lung cancer (NSCLC) that had progressed on osimertinib, according to a cohort analysis of the CHRYSALIS trial presented at the 2021 ASCO Annual Meeting.1

The study also provided insights into resistance mechanisms in patients previously treated with osimertinib. “Biomarker analysis with next-generation sequencing identified a subgroup of patients more likely to respond to this combination: those with EGFR/MET-based resistance. Immunohistochemistry (IHC) suggests that high EGFR and MET expression may be an alternate way to identify responders to this combination,” said presenting author Byoung Chul Cho, MD, of Yonsei Cancer Center, Seoul, Korea.

Amivantamab is a fully human bispecific antibody targeting EGFR and MET that was recently approved by the U.S. Food and Drug Administration for the frontline treatment of adults with EGFR exon 20 insertion–mutant NSCLC. Lazertinib is a potent third-generation EGFR tyrosine kinase inhibitor with good tolerability.

“[We] targeted two different mechanisms with these two drugs,” Dr. Cho told listeners.

“Despite osimertinib’s efficacy in NSCLC, resistance develops and the mechanisms of resistance to osimertinib are complex. In fact, resistance mechanisms are unknown in 50% of patients, and co-occurrence of multiple mechanisms of resistance have been observed. Following resistance to osimertinib, platinum-based chemotherapy is typically used, but this has limited activity,” Dr. Cho said, explaining part of the rationale for the CHRYSALIS study.

Cohort E Study Details

The ongoing CHRYSALIS study is a first-in-human study of amivantamab as a single agent or in combination with lazertinib or chemotherapy. Dr. Cho reported on Cohort E (amivantamab plus lazertinib), which identified a recommended phase II dose of amivantamab at 1,050 mg for patients < 80 kg and 1,400 mg for those 80 kg or above, administered intravenously weekly during cycle 1 and every 2 weeks thereafter, in combination with oral lazertinib at 240 mg/d.

The dose-expansion phase of Cohort E enrolled 45 patients who progressed on osimertinib but had not received chemotherapy. Biomarker analysis of tumor tissue and circulating tumor DNA was done with next-generation sequencing and IHC for EGFR/MET expression.

Biomarker analysis with next-generation sequencing identified a subgroup of patients more likely to respond to this combination: those with EGFR- or MET-based resistance.
— Byoung Chul Cho, MD

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“The demographics were consistent with EGFR-mutated relapsed NSCLC,” Dr. Cho said. The median age was 65 years (range = 39–85), 56% were female, 44% were Caucasian, 42% were Asian, and 56% were smokers. Twenty-nine percent of patients had previously treated brain metastasis. The median number of prior lines of therapy was 2 (range = 1-4).

At a median follow-up of 11 months and a median treatment duration of 5.6 months, objective response rate was 36% and clinical benefit rate was 64%. The median duration of response was 9.6 months. Median progression-free survival was 4.9 months.

The safety profile of the combination of amivantamab and lazertinib was consistent with previous experience with these agents. Adverse events were observed in all patients in Cohort E. Treatment-related grade 3 or higher adverse events occurred in 16%; 4% discontinued treatment, and 18% required a dose reduction. The most common adverse events of any grade included infusion-related reactions (78%), rash (78%), and paronychia (49%); these events were mainly grades 1 and 2.

Biomarker Analysis

“This is the most exciting part of the presentation,” Dr. Cho said. “We identified EGFR/MET-based resistance.”

Next-generation sequencing identified 17 patients with either EGFR-based resistance (n = 11), MET-based resistance (n = 4), or both (n = 2). Seven patients had co-occurring mutations.

“This reflects the complex and heterogeneous landscape of tumor and osimertinib resistance,” Dr. Cho emphasized.

Patients with EGFR-based mutations (n = 17) had an objective response rate of 47%, a median duration of response of 10.4 months, a clinical benefit rate of 82%, and a median progression-free survival of 6.7 months.

Among 28 patients without EGFR-based resistance, the objective response rate was 29%, the median duration of response was 8.3 months, the clinical benefit rate was 54%, and the median progression-free survival was 4.1 months.

“All eight responders [without EGFR-based resistance] had unknown mechanisms of resistance, which suggests there are predictive markers other than EGFR alterations,” Dr. Cho continued.

Twenty of the 45 patients enrolled in CHRYSALIS Cohort E had sufficient tumor biopsy for IHC staining after next-generation sequencing. Ten were positive for EGFR/MET expression; in this subgroup, there were 10 partial response, and 9 were positive for EGFR/MET expression.

IHC-positive patients had an objective response rate of 90%, clinical benefit rate of 100%, median duration of response of 9.7 months, and median progression-free survival of 12.5 months. The objective response rate was 10% in IHC-negative patients.

In 20 patients with both IHC and genomic data, 5 responders in the IHC-positive subgroup had unknown mechanisms of resistance.

“IHC may identify a patient subgroup with better responses to the combination, regardless of underlying genetic mutations,” Dr. Cho said.

A prospective ongoing trial (CHRYSALIS-2a) will validate these biomarkers in a new cohort requiring tumor biopsy at entry among post-osimertinib, EGFR-mutated NSCLC.

Is the Combination Needed?

During the discussion following Dr. Cho’s presentation, a number of listeners wrote in with a similar question: Why the combination? Wouldn’t single-agent amivantamab have just as good a showing?

His response was: “In the CHRYSALIS phase I study, we retrospectively analyzed amivantamab monotherapy vs combination therapy, and we observed a numerically higher response rate and progression-free survival without enhanced toxicity compared to single-agent amivantamab. Second, given the bispecific nature of the drug, we imagined that amivantamab cannot penetrate the central nervous system, so a central nervous system–protective effect may be provided by lazertinib. Third, amivantamab has immune cell–directing activity in multiple preclinical studies. The combination, compared to amivantamab monotherapy, will induce several chemokine-recruiting immune cells in the tumor microenvironment. This may enhance the antitumor activity of amivantamab.” 


DISCLOSURE: The study was sponsored by Johnson & Johnson. Dr. Cho has served in a leadership role for Gencurix Inc and Interpark Bio Convergence Corp; holds ownership interests in Bridgebio Therapeutics, Cyrus Therapeutics, Gencurix Inc, Interpark Bio Convergence Corp, KANAPH Therapeutics Inc, and TheraCanVac Inc; has served in a consulting or advisory role for AstraZeneca, Blueprint Medicines, Bristol Myers Squibb, Boehringer Ingelheim, Bridgebio Therapeutics, Cyrus Therapeutics, Eli Lilly, Guardant Health, Janssen, KANAPH Therapeutics Inc, Medpacto, MSD, Novartis, Ono Pharmaceutical, Oscotec Inc, Pfizer, Roche, Takeda, and Yuhan; has received research funding from Abbvie, AstraZeneca, Bayer, Blueprint Medicines, Champions Oncology, Dizal Pharma, Dong-A ST, Eli Lilly, GIInnovation, Interpark Bio Convergence Corp, Janssen, Medpacto, MOGAM Institute, MSD, Novartis, Ono, and Yuhan; holds intellectual property in Champions Oncology; and has held other relationships with DAAN Biotherapeutics.


1. Bauml J, Cho BC, Park K, et al. Amivantamab in combination with lazertinib in the treatment of osimertinib-relapsed, chemotherapy-naïve EGFR mutant non-small cell lung cancer and potential biomarkers for response. 2021 ASCO Annual Meeting. Abstract 9006. Presented June 4, 2021.

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