Amivantamab-lazertinib bests osimertinib in head-to-head trial on lung cancer

In the phase III MARIPOSA trial, the amivantamab-lazertinib cocktail outdid osimertinib as first-line (1L) treatment for EGFR-mutated, advanced non-small cell lung cancer (NSCLC).

“The study met its primary endpoint … Amivantamab-lazertinib significantly improved progression-free survival (PFS) in this patient population,” said Dr Byoung Chul Cho from the Yonsei University College of Medicine, Seoul, Republic of Korea, at ESMO 2023.

The combination regimen reduced the risk of progression or death by 30 percent (hazard ratio [HR], 0.70; p<0.001) and improved median PFS by 7.1 months (23.7 vs 16.6 months) vs osimertinib at a median follow-up of 22 months. [ESMO 2023, abstract LBA14]

The Kaplan-Meier curves separated early, with the gap widening over time. The 24-month PFS rate was higher with the cocktail than with osimertinib (48 percent vs 34 percent).

Amivantamab-lazertinib also cut the risk of extracranial progression or death (HR, 0.68; p<0.001) and improved median extracranial PFS (27.5 vs 18.5 months). “We conducted serial brain MRIs on all patients, which is not routinely done in EGFR-mutant NSCLC trials. Both median PFS estimates increase if CNS*-only first progressions are censored, but a consistent benefit was observed,” Cho noted.

There was also a consistent PFS benefit with or without brain metastases (HRs, 0.69 for both). Median PFS with amivantamab-lazertinib was 18.3 and 27.5 months for those with and without brain metastases, respectively. The corresponding values for osimertinib were 13.0 and 19.9 months.

Current SoC issues: Resistance, progression

The third-generation EGFR TKI** osimertinib is the current standard of care (SoC) for 1L NSCLC treatment; however, resistance and disease progression are almost inevitable. [J Natl Compr Canc Netw 2022;20:497-530]

Amivantamab, an EGFR-MET bispecific antibody, is active against a wide range of EGFR and MET alterations, while lazertinib is a highly selective CNS-penetrant, third-generation EGFR TKI with a safety profile that is suitable for combination therapies, Cho noted. “Combining [these two agents] should proactively address resistance and improve clinical outcomes without adding chemotherapy.”

A total of 1,074 patients (median age 63 years, 62 percent female, 59 percent Asian) with treatment-naïve, locally advanced or metastatic NSCLC were randomized 2:2:1 to a combination of amivantamab 1,050 mg (weekly for the first 4 weeks then Q2W) and lazertinib 240 mg daily, osimertinib alone 80 mg daily, or lazertinib monotherapy. Forty-one percent had a history of brain metastases.

Other outcomes

Objective response rates were similar between the experimental and osimertinib arms (86 percent vs 85 percent), but the former had a higher rate of complete response than the latter (7 percent vs 4 percent). At data cutoff, 62 percent of patients on the combo regimen had ongoing responses; with osimertinib, the corresponding rate was 48 percent.

Amivantamab-lazertinib improved median duration of response by 9 months (25.8 vs 16.8 months), suggesting a longer time to resistance and progression.

Early overall survival data showed a trend favouring the cocktail over osimertinib (HR, 0.80; p=0.11).

The experimental arm had higher rates of grade ≥3 adverse events (AEs; 75 percent vs 43 percent) and serious AEs (49 percent vs 33 percent), as well as any AEs leading to treatment interruptions (83 percent vs 39 percent), reductions (59 percent vs 5 percent), and discontinuations of any agent (35 percent vs 14 percent).

Ten percent of patients on amivantamab-lazertinib reported treatment-related AEs (TRAEs) that led to discontinuation of all agents, as opposed to 3 percent in the osimertinib arm.

Nonetheless, the safety profile of the combo regimen aligned with prior reports and most AEs were low-grade. Despite the higher rate of any venous thromboembolism with the cocktail vs osimertinib (37 percent vs 9 percent), most were grade 2 in severity (25 percent vs 6 percent).

A new SoC

Apart from the PFS advantage, amivantamab-lazertinib demonstrated consistent benefit regardless of presence or absence of brain metastases, yielded more durable responses, and had a favourable OS trend on interim analysis than osimertinib. Most AEs were low-grade and discontinuation rate due to TRAEs was low.

“Therefore, amivantamab-lazertinib represents a new SoC in patients with 1L, EGFR-mutant advanced NSCLC,” Cho concluded.