Dual EGFR targeting with amivantamab-vmjw (Rybrevant) plus lazertinib (Leclaza) led to durable responses in more than one-third of chemotherapy-naïve patients with EGFR-positive non–small-cell lung cancer (NSCLC) whose disease had progressed on osimertinib (Tagrisso) therapy, according to a cohort analysis of the CHRYSALIS trial. The results from this analysis were presented at the American Society of Clinical Oncology 2021 virtual annual meeting. The study also provided important insights into resistance mechanisms in patients previously treated with osimertinib.
Amivantamab is a fully human bispecific antibody targeting EGFR and MET that was recently approved by the FDA 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 2 different mechanisms with these 2 drugs,” said lead investigator Byoung Chul Cho, MD, PhD, Associate Professor, Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea. “Biomarker analysis with next generation sequencing [NGS] identified a subgroup of patients more likely to respond to this combination, ie, 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,” he added.
Dr Cho explained that although osimertinib is effective in the treatment of NSCLC, patients typically develop resistance to the drug, and these mechanisms of resistance are “complex.”
“Following resistance to osimertinib, platinum-based chemotherapy is typically used but this has limited activity,” he said.
CHRYSALIS Cohort E
Dr Cho presented results from cohort E (amivantamab plus lazertinib) of the CHRYSALIS study—the first in-human study of amivantamab as single agent or in combination with lazertinib or chemotherapy. The recommended phase 1 dose of amivantamab was weight-based: 1050 mg for patients <80 kg and 1400 mg for those ≥80 kg administered intravenously weekly during cycle 1 and every 2 weeks thereafter, in combination with 240 mg/day of oral lazertinib.
The dose-expansion phase of cohort E enrolled 45 patients whose disease progressed on osimertinib treatment but had not been previously treated with chemotherapy. Biomarker analysis of tumor tissue and circulating tumor DNA was conducted with NGS and IHC for EGFR/MET expression.
At baseline, median age was 65 years (range, 39-85), 56% were female, 44% were Caucasian, 42% were Asian, and 56% were smokers. Of the enrolled patients, 29% had previously treated brain metastasis. The median number of previous lines of therapy was 2 (range, 1-4).
At a median follow-up of 11 months, objective response rate (ORR) was 36% and clinical benefit rate was 64%. Median treatment duration was 5.6 months, and median duration of response (DOR) was 9.6 months. Median progression-free survival was 4.9 months. More than two-thirds (69%) of responders had a DOR of ≥6 months.
The safety profile of the combination of amivantamab and lazertinib was consistent with previous reports of both drugs. All patients experienced an adverse event (AE). Treatment-related grade ≥3 AEs occurred in 16% of patients; 4% discontinued treatment and 18% required a dose reduction. The most common AEs of any grade included infusion-related reactions (78%), rash (78%), and paronychia (49%); these events were mainly grades 1 and 2.
Resistance Mechanisms Identified
“This is the most exciting part of the presentation,” Dr Cho said. “We identified EGFR/MET-based resistance. Our findings reflect the complex and heterogeneous landscape of tumor and osimertinib resistance.”
“A major challenge in NSCLC is what happens when osimertinib resistance develops. A key takeaway point from this study is that the efficacy is driven by resistance mechanism,” stated formal discussant Nicolas Girard, MD, PhD, Professor, Respiratory Medicine, Versailles Saint Quentin University, and Head of the Curie-Montsouris Thorax Institute, Paris, France.
NGS testing 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.
Patients with EGFR/MET-based mutations (N = 17) had an ORR of 47%, median DOR was 10.4 months, clinical benefit rate was 82%, and median PFS was 6.7 months.
Among 28 patients without EGFR/MET-based resistance, ORR was 29%, median DOR was 8.3 months, clinical benefit rate was 54%, and median PFS was 4.1 months.
“All 8 responders [without EGFR/MET-based resistance] had unknown mechanisms of resistance, which suggests there are predictive markers other than EGFR alterations,” Dr Cho stated.
Twenty of the 45 patients enrolled in CHRYSALIS cohort E had sufficient tumor biopsy for IHC staining after NGS. Of these, 10 were IHC-positive for EGFR/MET expression; in this subgroup, there were 10 partial responsees and 9 were positive for EGFR/MET expression. IHC-positive patients had an ORR of 90%, clinical benefit rate of 100%, median DOR of 9.7 months, and median PFS of 12.5 months. ORR 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. These biomarkers will be validated in the prospective phase 1/1b CHRYSALIS-2a trial in a new cohort of post-osimertinib, EGFR-mutated NSCLC requiring tumor biopsy at entry.