First-Line Amivantamab Plus Lazertinib Wins EU Approval for EGFR+ Advanced NSCLC

The European Commission (EC) has approved lazertinib (Lazcluze) in combination with amivantamab-vmjw (Rybrevant) for the first-line treatment of adult patients with advanced non–small cell lung cancer (NSCLC) harboring EGFR exon 19 deletions or exon 21 L858R substitution mutations.1

The regulatory decision was supported by data from the phase 3 MARIPOSA trial (NCT04487080), which showed that at a median follow-up of 22.0 months, patients treated with amivantamab plus lazertinib (n = 429) experienced a median progression-free survival (PFS) of 23.7 vs 16.6 months for those given osimertinib alone (n = 429; HR, 0.70; 95% CI, 0.58-0.85; P < .001).2,3

Updated findings presented at the 2024 IASLC World Conference on Lung Cancer showed that, at a median follow-up of 31.1 months, a favorable overall survival (OS) trend was observed for the combination vs osimertinib alone (HR, 0.77; 95% CI, 0.61-0.96; P = .019).3 Previously, in January 2025, Johnson & Johnson announced that clinically meaningful and statistically significant improvement in OS was observed for the combination vs osimertinib with a median OS improvement expected to exceed 1 year.4

“This chemotherapy-free regimen has already demonstrated significant PFS improvements, and new topline data suggests it is expected to extend life by a median of 1 year or more in patients with untreated EGFR-mutated NSCLC vs the current standard of care, osimertinib,” Antonio Passaro, MD, PhD, medical oncologist of the Division of Thoracic Oncology at the European Institute of Oncology in Milan, Italy, stated in a news release.1 “These results mark a significant step forward in the treatment of EGFR-mutated NSCLC. Extending life expectancy is a critical indicator of a treatment’s impact. The MARIPOSA study reaffirms the potential of first-line treatment with this combination therapy to redefine the standard of care and offer clinically meaningful improvements in outcomes for patients.”

In August 2024, the FDA approved amivantamab in combination with lazertinib for the first-line treatment of adult patients with locally advanced or metastatic NSCLC harboring EGFR exon 19 deletions or exon 21 L858R substitution mutations, as detected by an FDA-approved test.5 This approval was also supported by data from MARIPOSA.

The MARIPOSA trial included patients with locally advanced or metastatic NSCLC who had not received prior treatment in the advanced setting.3 A documented EGFR exon 19 deletion or exon 21 L858R substitution mutation was required for enrollment. Patients also needed to have an ECOG performance status of 0 or 1.

Patients (n = 1074) were randomly assigned 2:2:1 to receive open-label amivantamab plus lazertinib (n = 429); blinded osimertinib alone (n = 429); or blinded lazertinib alone (n = 216). Stratification factors included EGFR mutation type (exon 19 deletion vs exon 21 L858R substitution mutation), race (Asian vs other), and history of brain metastases (yes vs no).

Blinded independent central review–assessed PFS per RECIST 1.1 criteria for amivantamab plus lazertinib vs osimertinib served as the trial’s primary end point. Secondary end points included intracranial PFS, duration of response, and overall response rate; time to treatment discontinuation; time to subsequent therapy; time to second progression; and OS.

Safety data from MARIPOSA showed that the most common any-grade treatment-emergent adverse effects (TEAEs) with the combination included paronychia (68%), infusion-related reactions (63%), and rash (62%).1 The most frequent grade 3 or higher TEAEs consisted of rash (15%), paronychia (11%), dermatitis acneiform (8%) and pulmonary embolism (8%).

Patients treated with amivantamab plus lazertinib experienced higher rates of EGFR- and MET-related AEs and venous thromboembolism; however, rates of diarrhea were higher for osimertinib. Treatment-related AEs led to the discontinuation of all study treatment in 10% of patients in the combination arm. Interstitial lung disease/pneumonitis occurred in 3% of patients in both the combination and osimertinib arms.

References

1. European Commission approves Lazcluze (lazertinib) in combination with Rybrevant (amivantamab) for the first-line treatment of patients with EGFR-mutated advanced non-small cell lung cancer. News release. Johnson & Johnson. January 21, 2025. Accessed January 21, 2025. https://www.jnj.com/media-center/press-releases/european-commission-approves-lazcluze-lazertinib-in-combination-with-rybrevant-amivantamab-for-the-first-line-treatment-of-patients-with-egfr-mutated-advanced-non-small-cell-lung-cancer
2. Cho BC, Lu S, Felip E, et al. Amivantamab plus lazertinib in previously untreated EGFR-mutated advanced NSCLC. N Engl J Med. 2024;391(16):1486-1498. doi:10.1056/NEJMoa2403614
3. Gadgeel S, Cho BC, Lu S, et al. Amivantamab plus lazertinib vs osimertinib in first-line EGFR-mutant advanced NSCLC: longer follow-up of the MARIPOSA study. Presented at: 2024 IASLC World Conference on Lung Cancer; September 7-10, 2024; San Diego, CA. Abstract OA02.03.
4. Rybrevant (amivantamab-vmjw) plus Lazcluze (lazertinib) shows statistically significant and clinically meaningful improvement in overall survival versus osimertinib. News release. Johnson & Johnson. January 7, 2025. Accessed January 21, 2025. https://www.jnj.com/media-center/press-releases/rybrevant-amivantamab-vmjw-plus-lazcluze-lazertinib-shows-statistically-significant-and-clinically-meaningful-improvement-in-overall-survival-versus-osimertinib
5. FDA approves lazertinib with amivantamab-vmjw for non-small lung cancer. FDA. August 19, 2024. Accessed January 21, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-lazertinib-amivantamab-vmjw-non-small-lung-cancer