European Approval Sought for Frontline Amivantamab Plus Lazertinib in EGFR+ NSCLC


The EMA is evaluating a Type II extension of indication application for the approval of first-line amivantamab plus lazertinib in EGFR-mutated NSCLC.

Lung Cancer -

Lung Cancer -

A Type II extension of indication application seeking approval of amivantamab-vmjw (Rybrevant) plus lazertinib in 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 has been submitted to the European Medicines Agency (EMA).1

Findings from the phase 3 MARIPOSA study (NCT04487080) showed that at a median follow-up of 22.0 months, the median progression-free survival (PFS) with amivantamab plus lazertinib (n = 429) was 23.7 months (95% CI, 18.1-27.7) by blinded independent central review (BICR) compared with 16.6 months (95% CI, 14.8-18.5) with osimertinib (Tagrisso; n = 429), translating to a 30% reduction in the risk of disease progression or death (HR, 0.70; 95% CI, 0.58-0.85; P < .001).2 The respective PFS rates at 24 months with the doublet and the monotherapy were 48% and 34%.

“Today’s submission is testament to our steadfast dedication to advancing innovative therapies for those who need them most, now and in the future,” Kiran Patel, MD, vice president of Clinical Development in Solid Tumors at Janssen Research & Development, LLC, stated in a press release.1 “Pending approval, this novel combination of amivantamab and lazertinib has the potential to transform first-line treatment for patients with EGFR-mutated NSCLC.”

In MARIPOSA, patients with locally advanced or metastatic NSCLC harboring EGFR exon 19 deletions or L858R substitution mutations and an ECOG performance status of 0 or 1 (n = 1074) were randomized 2:2:1 to receive amivantamab at 1050 mg weekly or 1400 mg weekly if 80 kg or greater for the first 4 weeks and then every 2 weeks plus lazertinib at 240 mg daily (open-label), osimertinib at 80 mg daily (blinded), or lazertinib monotherapy at 240 mg daily (blinded). Patients were stratified by EGFR mutation (exon 19 deletions vs L858R substitution mutations), history of brain metastases (yes vs no), and Asian race (yes vs no).

PFS by BICR and RECIST v1.1 criteria served as the trial’s primary end point. Key secondary end points comprised overall survival (OS), objective response rate (ORR), duration of response (DOR), PFS after first subsequent treatment, symptomatic PFS, intracranial PFS, and safety.

Across the treatment arms, the median patient age was 63.3 years (range, 25-88) and 62% were female. Slightly more than half of patients were Asian (58.7%), and most patients had adenocarcinoma (97.3%) and an ECOG performance status of 1 (65.7%). Moreover, 40.3% of patients had a history of brain metastases, and approximately one-third of patients had a history of smoking. Regarding EGFR mutations, most patients had exon 19 deletion (60.3%) and the remaining 40% had L8582 substitutions.

Additional findings presented during the 2023 ESMO Congress revealed an improvement in extracranial PFS with the doublet vs the monotherapy, at a median of 27.5 months (95% CI, 22.1-not evaluable [NE]) vs 13.0 months (95% CI, 12.2-16.4), respectively (HR, 0.68; 95% CI, 0.56-0.83; P < .001). Amivantamab plus lazertinib produced a PFS benefit over osimertinib that was consistent regardless of whether brain metastases were present. In those with a history of brain metastases, the doublet (n = 178) led to a median PFS of 18.3 months (95% CI, 16.6-23.7) compared with 13.0 months (95% CI, 12.2-16.4) with the monotherapy (n = 172; HR, 0.69; 95% CI, 0.53-0.92). In those without a history of these metastases, the median PFS was 27.5 months (95% CI, 22.1-NE) with amivantamab/lazertinib (n = 251) vs 19.9 months (95% CI, 16.6-33.9) with osimertinib (n = 257; HR, 0.69; 95% CI, 0.53-0.89).

In all patients, the doublet induced an ORR of 86% (95% CI, 83%-89%) by BICR compared with 85% (95% CI, 81%-88%) with osimertinib; respective confirmed ORRs were 80% (95% CI, 76%-84%) and 76% (95% CI, 71%-80%). The median DOR with the doublet was 25.8 months (95% CI, 20.1-NE) vs 16.8 months (95% CI, 14.8-18.5) with the monotherapy.

In the doublet and monotherapy arms, 98 and 137 patients, respectively, initiated subsequent treatment. The most common first subsequent treatment received by those in the doublet arm was an EGFR TKI monotherapy (49%) followed by chemotherapy alone (33%); in the osimertinib arm, most patients received chemotherapy alone (39%) or a single-agent EGFR TKI (27%). Amivantamab plus lazertinib resulted in a 25% reduction in the risk of second disease progression or death vs osimertinib (HR, 0.75; 95% CI, 0.58-0.98; P = .03).

Interim data regarding OS revealed a trend that favored the doublet over the monotherapy, with a HR of 0.80 (95% CI, 0.61-1.05; P = .11). The estimated OS rate at 12 months with amivantamab/lazertinib was 74% vs 69% with osimertinib.

Any-grade adverse effects (AEs) were experienced by 100% of those who received amivantamab/lazertinib vs 99% of those given osimertinib, with grade 3 or higher AEs reported in 75% and 43% of patients, respectively. Moreover, 49% of those in the doublet arm vs 33% of those in the monotherapy arm experienced serious AEs. AEs resulted in interruption, reduction, or discontinuation for 83%, 59%, and 35% of patients, respectively in the amivantamab plus lazertinib arm; in the osimertinib arm, these respective rates were 39%, 5%, and 14%, respectively. Eight percent of those on the doublet arm experienced AEs that led to death vs 7% of those on the monotherapy arm.

The majority of AEs experienced with amivantamab plus lazertinib were grade 1 or 2. In the doublet arm, the most common AEs experienced were (grade 1/2, 57%; grade ≥3, 11%), rash (46%; 15%), diarrhea (27%; 2%), dermatitis acneiform (21%; 8%), stomatitis (28%; 1%), pruritus (23%; 0.5%), hypoalbuminemia (43%; 5%), peripheral edema (34%; 2%), infusion-related reaction (57%; 6%), increased alanine aminotransferase (31%; 5%), constipation (29%; 0%), increased aspartate aminotransferase (25%; 3%), COVID-19 (24%; 2%), reduced appetite (24%; 1%), anemia (19%; 4%), nausea (20%; 1%), hypocalcemia (19%; 2%), and cough (15%; 0%).

In December 2023, a marketing authorization application seeking the approval of amivantamab plus lazertinib, for an equivalent frontline combination indication, was submitted to the EMA.3 In the same month, a supplemental biologics license application and new drug application seeking approval of amivantamab plus lazertinib in the same indication were submitted to the FDA.4 The applications were also supported by MARIPOSA data.


  1. Janssen submits Type II extension of indication application to the European Medicines Agency seeking approval of Rybrevant (amivantamab), in combination with lazertinib, for first-line treatment of patients with EGFR-mutated non-small cell lung cancer. News release. The Janssen Pharmaceutical Companies of Johnson & Johnson. February 8, 2024. Accessed February 8, 2024.
  2. Cho BC, Felip E, Spira AI, et al. LBA14 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. Janssen submits marketing authorisation application to the European Mediciens Agency seeking approval of lazertinib, in combination with Rybrevant (amivantamab), for the first-line treatment of patients with EGFR-mutated non-small cell lung cancer. News release. The Janssen Pharmaceutical Companies of Johnson & Johnson. December 21, 2023. Accessed February 8, 2024.
  4. Johnson & Johnson submits supplemental biologics license application and new drug application to U.S. FDA seeking approval of RYBREVANT (amivantamab-vmjw) plus lazertinib for the treatment of patients with EGFR-mutated non-small cell lung cancer (NSCLC). News release. Johnson & Johnson. December 21, 2023. Accessed February 8, 2024.
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