Amivantamab Plus Lazertinib Improves PFS Irrespective of Risk in EGFR-Mutant NSCLC

The combination of amivantamab-vmjw (Rybrevant) and lazertinib (Leclaza) led to a significant improvement in progression-free survival (PFS) vs osimertinib (Tagrisso) as frontline therapy in patients with high-risk, EGFR-mutant advanced non–small cell lung cancer (NSCLC), according to findings from a secondary analysis of the phase 3 MARIPOSA trial (NCT04487080) that were presented at the 2024 ASCO Annual Meeting.

“Multiple features such as brain or liver metastases at baseline TP53 co-mutations, and EGFR ctDNA shedding are common in patients with advanced EGFR mutations and are associated with poor prognosis,” study author Enriqueta Felip, MD, PhD, head of the Thoracic and Head and Neck Cancer Unit at Vall d’Hebron Hospital in Barcelona, Spain, said during a presentation of the findings.

This analysis of MARIPOSA included data from 858 patients with treatment-naïve EGFR-mutant (exon 19 deletion or L858R) advanced NSCLC. The majority (89%) had at least one high-risk feature, such as brain or liver metastases, TP53 co-mutations, or detectable ctDNA. Patients were randomized 1:1 to receive amivantamab plus lazeritinib (n = 429) or osimertinib (n = 429).

Findings showed that the PFS in the amivantamab/lazeritinib arm, as determined by blinded independent committee review, was 23.7 months (95% CI, 19.1-27.7), whereas it was 16.6 months in the osimertinib arm (95% CI, 14.8-18.5; HR = 0.70; P < .01). This equated to a 30% reduction in the risk of disease progression or death, and a median PFS improvement of 7.1 months.

Baseline ctDNA for next-generation sequencing analysis of pathogeneic alterations was available for 636 patients: 320 in the amivantamab/lazertinib group and 316 in the osimertinib group.

Among patients with a TP53 co-mutation, the median PFS was 18.2 months in the combination group (n=149), and 12.9 months in the osimertinib group (n=144; HR, 0.65, p=0.002). Patients whose disease was TP53 wildtype (n = 117 and 130 in the combination and single-agent groups, respectively) did not have a significant difference in median PFS, though data showed a trend favoring amivantamab/lazertinib, with a median PFS of 22.1 months, compared to 19.9 months (HR = 0.75; P = .11).

In patients with ddPCR-detectable ctDNA at baseline, median PFS was significantly longer in the amivantamab/lazertinib arm (n = 231) compared to the osimertinib arm (n = 240), at 20.3 months and 14.8 months, respectively (HR = 0.68; P = .002). At baseline, 69% and 71% of patients in the amivantamab/lazertinib arms, respectively, had detectable EGFR-mutant ctDNA, whereas these percentages decreased to 15% in each group at week 9.

The drug duo also proved superior in patients with ctDNA clearance at cycle 3 day 1, with median PFS durations 24 months (n = 163) vs 16.5 months (n = 180), respectively (HR = 0.64; P = .004), and for patients who did not clear ctDNA, at 16.5 (n = 29) vs 9.1 months (n = 32), respectively (HR = 0.49; P = .015).

For patients with brain metastases at baseline, amivantamab/lazertinib also led to improved outcomes. Median PFS for this group was 18.3 months for those given the combination (95% CI, 16.6-23.7) and 13 months (95% CI, 12.2-16.4) for those given osimertinib (HR = 0.69; P = .010). This, according to the researchers, is consistent with the prior PFS benefit observed with amivantamab plus lazertinib in patients with a history of brain metastases.

Regarding liver metastases, at a median follow-up of 22 months, the median PFS was 18.2 months (95% CI, 13.1-NE) and 11 months (95% CI, 7.4-12.8; HR = 0.58; P = .017) in the amivantamab/lazertinib groups, respectively.

“High-risk features occur commonly in first line EGFR-mutant [NSCLC] and carry a poor prognosis,” Felip said. “Amivantamab plus lazertinib produces superior PFS outcomes in patients with high-risk features and represents a promising new standard of care treatment option in first line EGFR-mutant [NSCLC].”

Reference

Felib E, Chul Cho B, Gutérrez V, et al. Amivantamab plus lazertinib vs osimertinib in first-line EGFR-mutant advanced non-small cell lung cancer (NSCLC) with biomarkers of high-risk disease: A secondary analysis from the phase 3 MARIPOSA study. J Clin Oncol. 2024;42(suppl 16):8504. doi:10.1200/JCO.2024.42.16_suppl.8504