Durable responses with amivantamab and lazertinib in chemotherapy-naïve patients with EGFR-mutant NSCLC who relapsed on osimertinib

Updated results of the phase I CHRYSALIS study, evaluating a combination of  amivantamab and lazertinib, indicate durable responses in a population of osimertinib-relapsed non-small cell lung cancer (NSCLC) patients. Furthermore, next-generation sequencing identified that patients with EGFR/MET-based resistance were more likely to respond to this novel treatment modality.

Previously, the combination of the EGFR-MET bispecific antibody amivantamab and the third-generation anti-EGFR tyrosine kinase inhibitor (TKI) lazertinib showed signs of efficacy in both treatment-naïve and osimertinib-relapsed patients with EGFR-mutated non-small cell lung cancer (NSCLC). At ASCO 2021, updated results with this combination were presented in osimertinib-relapsed patients, including an analysis of potential biomarkers of response.

CHRYSALIS phase I study

The CHRYSALIS study evaluates the safety, pharmacokinetics and preliminary efficacy of amivantamab and lazertinib  in patients with advanced NSCLC harboring an EGFR exon 19 deletion or a L858R mutation. Part 1 of the trial enrolled patients without restriction on prior therapy to evaluate escalating dose cohorts of amivantamab (700-1,050 mg, IV once weekly for 28 days; biweekly thereafter) in combination with standard monotherapy dosing of lazertinib (240 mg oral daily). The ongoing Part 2 dose expansion Cohort E is evaluating preliminary efficacy, without biomarker selection, in patients progressing on osimertinib.

In Part 1, the recommended phase II combination dose was the maximally assessed doses of 1,050 mg (1,400 mg, ≥80 kg) amivantamab + 240 mg lazertinib. This dosing regimen was also used to assess safety and efficacy in the osimertinib-relapsed population (n=45). Response was assessed by investigator per RECIST v1.1. Osimertinib-resistance mutations or amplifications in EGFR/MET identified by next-generation sequencing (NGS) in either ctDNA or tumour biopsy (biomarker-positive), were evaluated for enriching response. In total, 44/45 patients were evaluable by ctDNA and 29/45 by tumour NGS. Immunohistochemistry (IHC) staining for EGFR and MET expression was also explored as a potential biomarker for response. The median age of the 45 patients in the cohort was 65 years with approximately half of the patients being female and half being never smokers. Overall, 29% of patients had previously reported brain metastasis and 73% had received prior first- or second-generation TKIs.

After a median follow-up of 11.0 months, the objective response rate (ORR) was reported at 36%. Importantly, these responses proved to be durable, with a median duration of response (DoR) of 9.6 months and 69% of responding patients having a response lasting for at least six months. The clinical benefit rate (CBR) was 64% for a median progression-free survival (PFS) of 4.9 months. The safety profile was consistent with previous experience with the amivantamab plus lazertinib combination with the most common adverse events (AEs) consisting of infusion-related reactions (78%), rash (acneiform dermatitis: 51% and rash: 27%) and paronychia (49%), the majority of which were grade 1-2. The rates of treatment-related AEs of grade ≥3, treatment discontinuation and dose reductions were reported at 16%, 4% and 18%, respectively.

Potential biomarkers for response

In total, 17 out of 45 patients were found to have EGFR/MET-based resistance by NGS. Of these patients, eight (47%) responded to treatment. Interestingly, responses were also observed in three patients harbouring additional EGFR/MET independent resistance mechanisms, such as mTOR and cell cycle alterations. Among these patients, the median DoR was 10.4 months, with a CBR of 82% and a median PFS of 6.7 months. Among the remaining 28 patients who did not have an identified EGFR/MET-based resistance by NGS, the ORR was 29%. Among these 28 patients, 18 had unknown mechanisms of osimertinib-resistance (8 partial responses) with the remaining 10 having a non-EGFR/MET mechanisms of resistance identified (none responded). The median DoR among these patients without an identified EGFR/MET-based resistance was 8.3 months, with a CBR of 54% and a median PFS of 4.1 months.

Switching gears to EGFR/MET expression identified by IHC staining, 20 out of 45 patients had a tumor biopsy that was sufficient for IHC staining after tumor NGS. Of these, ten patients were IHC-positive for EGFR/MET (combined EGFR+MET H score ≥400), with the remainder defined as IHC-negative. Nine out of ten IHC-positive patients responded to treatment, with a median DoR of 9.7 months, a CBR of 100% and a median PFS of 12.5 months. In contrast, the ORR was only 10% in the IHC negative group.

Conclusion

The combination of amivantamab and lazertinib yields durable responses in over a third of chemotherapy-naïve patients with advanced NSCLC who progressed on osimertinib. Interestingly, EGFR and MET-based biomarkers of resistance identified a subgroup of patients that were more likely to respond to this combination, although also a proportion of patients lacking such a resistance marker responded to the therapy.

Reference

Bauml J, et al. Amivantamab in combination with lazertinib for the treatment of osimertinib-relapsed, chemotherapy-naïve EGFR mutant (EGFRm) non-small cell lung cancer (NSCLC) and potential biomarkers for response. Presented at ASCO 2021; Abstract 9006.