European Commission Approves Lazertinib Plus Amivantamab in First-Line EGFR-Mutated NSCLC

The European Commission has approved a type II variation extended indication for lazertinib (Lazcluze) plus amivantamab (Rybrevant) for the frontline 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 decisions were supported by findings from the phase 3 MARIPOSA trial (NCT04487080), which met its primary end point of improved progression-free survival (PFS). At a median follow-up of 22 months, patients with locally advanced or metastatic NSCLC with EGFR exon 19 deletion or exon 21 L858R substitution mutations who received amivantamab plus lazertinib (n = 429) achieved a median PFS of 23.7 months (95% CI, 19.1-27.7) vs 16.6 months (95% CI, 14.8-18.5) among those treated with osimertinib (Tagrisso) monotherapy (n = 429; HR, 0.70; 95% CI, 0.58-0.85; P < .001).2

“For people living with advanced NSCLC harboring EGFR mutations, new treatment options are urgently needed in the first-line setting,” Enriqueta Felip, MD, PhD, head of the thoracic cancer unit at Vall d’Hebron University Hospital in Barcelona, Spain, stated in a news release. “The amivantamab and lazertinib combination has shown significant PFS improvements in patients with previously untreated EGFR-mutated advanced NSCLC, including those with brain metastases, compared to osimertinib monotherapy. This approval by the European Commission offers the potential to broaden first-line treatment options and provide a new standard of care for eligible patients.”

MARIPOSA enrolled adult patients with newly diagnosed, treatment-naive locally advanced or metastatic NSCLC that was not amenable to curative therapy including surgical resection or chemoradiation.3 To be eligible for the study, patients also needed to have exon 19 deletions or exon 21 L858R substitution as detected by an FDA-approved test, submit unstained tumor tissue for EGFR mutation analysis, have any prior toxicities from anticancer therapy resolved to grade 1 or baseline level, and have at least 1 measurable lesion per RECIST 1.1 criteria.

Eligible patients were randomly assigned 2:2:1 to receive amivantamab plus lazertinib, osimertinib plus placebo, or lazertinib plus placebo.2,3 Amivantamab was administered intravenously at a dose of 1050 mg for patients with a body weight of less than 80 kg and at 1400 mg for those with a body weight of at least 80 kg once weekly in cycle 1 with a split dose on days 1 and 2 and then every 2 weeks in subsequent cycles. Lazertinib was administered at a dose of 240 mg orally once daily and osimertinib was given at a dose of 80 mg orally once daily.

The primary end point was PFS per RECIST 1.1 criteria assessed by blinded independent central review.1 Secondary end points included overall survival (OS), overall response rate (ORR), duration of response (DOR), second PFS (PFS2), and intracranial PFS. 2 

Additional findings from the study showed that the ORRs in the combination and osimertinib arms were 86% (95% CI, 83%-89%) vs 85% (95% CI, 81%-88%), respectively. The median DORs were 25.8 months (95% CI, 20.1-not estimable [NE]) vs 16.8 months (95% CI, 14.8-18.5), respectively. There was also a trend in favor of the combination reported in terms of PFS2 (HR, 0.75; 95% CI, 0.58-0.98).

Long-term follow-up data presented during the 2024 IASLC World Conference on Lung Cancer revealed that, at a median follow-up of 31.1 months, 61% of patients who received the combination were still alive compared with 53% of patients who received osimertinib monotherapy.1 The median OS was NE vs 37.3 months, respectively (HR, 0.77; 95% CI, 0.61-0.96; nominal P = .019).

In terms of safety, most adverse effects (AEs) reported with amivantamab in combination with lazertinib were grade 1 or 2 in severity; the safety profile of the combination was consistent with previously reported data from phase 1 and 2 studies.1 The most common any-grade treatment-emergent AEs (TEAEs) with the combination included paronychia (68%), infusion-related reactions (63%), and rash (62%). Common grade 3 or higher TEAEs included rash (15%), paronychia (11%) and dermatitis acneiform (8%). The rate of discontinuation of all study treatments was 10%.

A decision by the European Commission regarding lazertinib for the corresponding combination regimen is pending after a positive opinion from the European Medicines Agency’s Committee for Medicinal Products for Human Use in November 2024.4

“This approval marks significant progress for those living with the devastating impact of EGFR-mutated NSCLC, who too often face a poor prognosis and limited treatment options,” Henar Hevia, PhD, senior director and EMEA Therapeutic Area Lead of Oncology at Johnson & Johnson, added in the news release.1 “The combination of amivantamab and lazertinib exemplifies the potential of targeted precision medicine, offering a tailored approach that addresses the underlying genetic drivers of the disease, and avoids or delays the need for chemotherapy.”

References

1. European Commission approves RYBREVANT (amivantamab) in combination with LAZCLUZE(lazertinib) for the first-line treatment of patients with EGFR-mutated advanced non-small cell lung cancer. News release. Johnson & Johnson. December 30, 2024. Accessed January 2, 2025. https://www.jnj.com/media-center/press-releases/european-commission-approves-rybrevant-amivantamab-in-combination-with-lazcluze-lazertinib-for-the-first-line-treatment-of-patients-with-egfr-mutated-advanced-non-small-cell-lung-cancer
2. Cho BC, Felip E, Spira AI, et al. Amivantamab plus lazertinib vs osimertinib as first-line treatment in patients with EGFR-mutated, advanced non-small cell lung cancer (NSCLC): primary results from MARIPOSA, a phase III, global, randomized, controlled trial. Ann Oncol. 2023;34(suppl 2):S1306. doi:10.1016/j.annonc.2023.10.062
3. A study of amivantamab and lazertinib combination therapy versus osimertinib in locally advanced or metastatic non-small cell lung cancer (MARIPOSA). ClinicalTrials.gov. Updated December 9, 2024. Accessed January 2, 2025. https://clinicaltrials.gov/study/NCT04487080
4. CHMP recommends RYBREVANT (amivantamab) in combination with LAZCLUZE (lazertinib) for the first-line treatment of patients with EGFR-mutated advanced non-small cell lung cancer. News release. Johnson & Johnson. November 15, 2024. Accessed January 2, 2025. https://innovativemedicine.jnj.com/emea/chmp-recommends-rybrevant-amivantamab-in-combination-with-lazcluze-lazertinib-for-the-first-line-treatment-of-patients-with-egfr-mutated-advanced-non-small-cell-lung-cancer