Combination Shows Promise in Post-Osimertinib Lung Cancer

More than a third of lung cancers that progressed on osimertinib (Tagrisso) responded to combined targeting of EGFR, a subgroup analysis of an early clinical trial showed.

Results in 45 patients showed one complete response and 12 partial responses to the bispecific antibody amivantamab (Rybrevant) targeting EGFR and MET and the third-generation EGFR tyrosine kinase inhibitor (TKI) lazertinib. An additional 16 patients had stable disease, resulting in a clinical benefit rate of 64%. A majority of responses lasted 6 months or longer. The overall response rate increased to 47% in patients with EGFR/MET-based resistance.

Biomarker analysis yielded mixed results with next generation sequencing (NGS), but immunohistochemistry (IHC) identified a higher proportion of responding patients, reported Byoung Chul Cho, MD, of Yonsei Cancer Center in Seoul, at the American Society of Clinical Oncology (ASCO) virtual meeting.

“CHRYSALIS-2^a, a phase I/Ib study, will seek to validate these biomarkers prospectively in a new cohort requiring tumor biopsy at entry among post-osimertinib, EGFR-mutated non-small cell lung cancer (NSCLC),” said Cho.

A key takeaway from the study is that objective response was driven by the mechanism of resistance, said ASCO invited discussant Nicolas Girard, MD, PhD, of the Curie Institute in Paris.

“The overall response rate (ORR) was 47% in the EGFR/MET-based resistance group, but looking deeper at the data, we have a 75% response rate in purely MET-driven resistance mechanism and only 27% in purely EGFR resistance mechanism,” said Girard. “The group of patients without EGFR-MET-based resistance is heterogeneous. We have no response in EGFR/MET-independent resistance patients.”

Preliminary evidence suggests duration of response may be prolonged, Girard continued. PFS data remain immature, given the number of ongoing responses. Duration of response by resistance mechanism also should be analyzed and reported.

Amivantamab previously demonstrated clinical activity in NSCLC associated with a wide range of EGFR mutations, said Cho. Lazertinib demonstrated efficacy in NSCLC associated with activating EGFR mutations, T790M resistance mutation, and central nervous system (CNS) disease. Low rates of EGFR-related toxicity have been reported to date, and the drug has a favorable cardiovascular profile.

“The safety profile of lazertinib supported evaluation of combination therapy with other anti-EGFR molecules,” he said.

Cho reported updated results from a prospective evaluation of the amivantamab-lazertinib combination in patients with osimertinib-relapsed NSCLC, EGFR mutations (exon 19 deletion or L858R), and no intervening chemotherapy. Resistance mutations or amplifications in EGFR/MET were identified by NGS analysis of circulating tumor DNA or tumor tissue. IHC staining for EGFR and MET expression was explored for biomarker potential.

The patients’ treatment history included a median of two prior lines of therapy. Three-fourths of the patients had prior exposure to first- or second-generation TKIs, and all had received osimertinib. Two-thirds of the patients had exon 19 deletion as the primary mutation.

The combination therapy led to an ORR of 36% in the 45 patients. The median duration of response (DOR) was 9.6 months, and median PFS was 4.9 months. Cho reported that 69% of responses lasted 6 months or longer.

NGS identified 17 patients with EGFR– or MET-based resistance. In that subgroup, eight (47%) objective responses occurred. Median DOR was 10.4 months, CBR was 82%, and median PFS was 6.7 months. In contrast, responses occurred in eight of 28 (29%) patients without EGFR/MET-based resistance. Median DOR was 8.3 months, CBR 54%, and median PFS 4.1 months.

Tumor tissue for IHC analysis was available for 20 patients, including 10 patients who had objective responses. The results showed that nine of 10 responding patients tested positive for EGFR/MET expression. The IHC-positive group had a median DOR of 9.7 months, CBR of 100%, and median PFS of 12.5 months.

The combination therapy led to no unexpected adverse events (AEs), most of which were grade 1/2. The most common AEs were infusion-related reactions (78%), rash (78%), and paronychia (49%). Grade ≥3 treatment-related AEs occurred in 16% of patients. Cho said 4% of patients discontinued because of AEs, and 18% required dose reductions.

During a discussion that followed the presentation, multiple attendees in the virtual audience questioned the need for the EGFR inhibitor and asked Cho whether single-agent amivantamab might have worked just as well.

“In the CHRYSALIS phase I study, we retrospectively analyzed amivantamab monotherapy versus combination therapy, and we observed a numerically higher response rate and progression-free survival [PFS], without enhanced toxicity compared to amivantamab monotherapy,” said Cho. “Second, given the bispecific nature of the drug, we imagined that amivantamab cannot penetrate the CNS, so a CNS-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 antitumor activity of amivantamab,” Cho noted.