medwireNews: CHRYSALIS trial findings suggest that the bispecific monoclonal antibody amivantamab could be combined with the third-generation EGFR–tyrosine kinase inhibitor lazertinib for the treatment of patients with metastatic or unresectable non-small-cell lung cancer (NSCLC) with an EGFR exon 19 deletion or L858R mutation.
“Because both amivantamab and lazertinib are active against various resistance mutations and produce low rates of EGFR-related toxicity as a monotherapy, combination of these two agents may have potential to delay or prevent emergence of resistance without increasing toxicity,” explained presenting author Byoung Chul Cho, from Yonsei University College of Medicine in Seoul, South Korea.
He told delegates at the ESMO Virtual Congress 2020 that the dose-escalation phase of the study was performed in 26 patients, establishing a recommended intravenous amivantamab dose of 1050 mg (<80 kg) or 1400 mg (≥80 kg) given weekly in cycle 1 and every 2 weeks thereafter plus oral lazertinib 240 mg/day.
This regimen was given to two expansion cohorts consisting of 45 chemotherapy-naïve patients with osimertinib-resistant disease and 20 treatment-naïve patients.
“The patient characteristics are consistent with EGFR-mutant lung cancer in general,” the presenter said, namely the median age was 61 years, 52% were female, and 55% were nonsmokers. The majority (64%) of patients had an exon 19 deletion and 36% an exon 21 L858R mutation, while 37% had brain metastases at baseline.
Safety analysis after a median 5 months of treatment and 6 months of follow-up did not reveal any dose-limiting toxicity. Treatment-related adverse events leading to dose interruptions, reductions, or discontinuations were seen in 19%, 19%, and 6% of the 91 patients, respectively.
“The combination of amivantamab and lazertinib was safe and well tolerated,” with events predominantly grade 1 or 2 and similar in the two expansion cohorts, Cho summarized. Rash was the most common adverse effect, occurring in 85% of patients for a median of 29 days.
Although grade 1 or 2 infusion-related reactions occurred in 65% of patients on first dose, this did not lead to discontinuation or affect subsequent doses. One patient who initially developed grade 3 treatment-related pneumonitis subsequently died from progressive disease but overall there was a “low incidence” of grade 3 or more severe treatment-related adverse events, such as rash (4%) and hypoalbuminemia (2%).
After a median 4 months, the objective response rate (ORR) for the osimertinib-resistant patients was 36%, including one complete response, and the clinical benefit rate was 60%. The presenter noted that responses occurred in patients who had received osimertinib in the first or second line, and that target lesion regression occurred even in two patients who had previously received lazertinib.
“The majority of patients are still ongoing; however, responses seem to be rapid and durable,” he commented, with biomarker and central nervous system analysis continuing for this cohort.
Moreover, all 20 patients in the treatment-naïve cohort achieved a partial response after a median 1.5 months of treatment, giving an ORR of 100%. All patients are continuing treatment after a median 7 months and the median duration of response is not yet estimable, Cho said.
The presenter concluded that “amivantamab can be safely combined with lazertinib” and that the combination is “efficacious in advanced EGFR-mutant NSCLC.”
He noted that analysis of the mechanism of resistance to amivantamab plus lazertinib is ongoing and that two trials of the combination have now started – the phase 2 CHRYSALIS-2 study in both osimertinib-resistant and chemotherapy-relapsed NSCLC patients, and the phase 3 MARIPOSA trial, in a direct comparison with front-line osimertinib for EGFR-mutated NSCLC.
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