MARIPOSA-2 Trial

Design - Phase 3, randomized, open-label: 657 patients with EGFR-mutated (ex19del/L858R) advanced NSCLC after progression on osimertinib, across three arms - amivantamab + carboplatin/pemetrexed, amivantamab + lazertinib + chemotherapy, and chemotherapy alone.

PFS - Amivantamab + chemotherapy: median PFS 6.3 vs 4.2 months vs chemotherapy alone (HR 0.48; 95% CI 0.36-0.64; p<0.0001) - a 52% risk reduction, consistent across all prespecified subgroups including brain metastases. Triplet (+ lazertinib): median PFS 8.3 vs 4.2 months (HR 0.44; 95% CI 0.35-0.56; p<0.001).

Overall survival - At the prespecified second interim analysis (ESMO 2024 update), amivantamab + chemotherapy showed a favorable OS trend (stratified HR 0.73; 95% CI 0.54-0.99) that did not reach statistical significance; follow-up is ongoing. Time to symptomatic progression significantly improved: median 16.0 vs 11.8 months (HR 0.73; p=0.026).

Safety - Serious AEs 32% with amivantamab + chemo vs 20% with chemo alone; the triplet had a higher serious AE rate (52%) and more hematologic toxicity. VTE was more frequent in amivantamab arms but mostly grade 1-2, with discontinuation due to VTE <=1%; ILD/pneumonitis <=3% across amivantamab arms.

Regulatory / sponsor - FDA approved Rybrevant (amivantamab) + carboplatin/pemetrexed on September 19, 2024 for EGFR ex19del/L858R NSCLC after progression on an EGFR TKI; the lazertinib triplet is not approved in this setting. Sponsor: Janssen (Johnson & Johnson).

Compiled and reviewed by the KOL Pulse research team, led by Brian Shields, Founder, KOL Pulse. Last updated August 19, 2026.

Progression-Free Survival (PFS)

Amivantamab + chemotherapy demonstrated a median PFS of 6.3 months (95% CI: 5.6-8.4) vs. 4.2 months (95% CI: 4.0-4.4) for chemotherapy alone (HR 0.48; 95% CI: 0.36-0.64; P<0.0001), representing a 52% reduction in the risk of disease progression or death. The triplet arm (amivantamab + lazertinib + chemo) showed median PFS of 8.3 months vs. 4.2 months (HR 0.44; 95% CI: 0.35-0.56; P<0.001), a 56% risk reduction. PFS benefit was consistent across all prespecified subgroups.

Overall Survival (OS)

At the prespecified second interim analysis with 85% of deaths needed for the final analysis, amivantamab + chemotherapy showed a favorable trend toward improved overall survival (stratified OS HR 0.73; 95% CI: 0.54-0.99), but this did not reach statistical significance. Time to symptomatic progression was significantly improved: median 16.0 months (95% CI: 12.7-19.4) vs. 11.8 months (95% CI: 8.9-13.6) for chemotherapy (HR 0.73; 95% CI: 0.55-0.96; P=0.026). OS follow-up is ongoing.

Safety & Tolerability

The most common adverse events (>=20%) with amivantamab + chemo were rash, infusion-related reactions, fatigue, nail toxicity, nausea, constipation, edema, stomatitis, decreased appetite, musculoskeletal pain, vomiting, and COVID-19 infection. Serious AEs occurred in 32% with amivantamab + chemo vs. 20% with chemo alone. The triplet (+ lazertinib) had higher serious AE rate of 52% and increased hematologic toxicity. VTE rates were higher in amivantamab arms but mostly Grade 1-2, with no Grade 5 events and discontinuation due to VTE in ≤1%. ILD/pneumonitis incidence was ≤3% across amivantamab arms. Treatment-related death rates were low and comparable across all arms.

Clinical Implications

MARIPOSA-2 established amivantamab + chemotherapy as the new standard of care for EGFR-mutated NSCLC after progression on osimertinib, addressing a critical unmet need where platinum-based chemotherapy was previously the only option. The amivantamab doublet (without lazertinib) received FDA approval based on a favorable benefit-risk profile, as the triplet added toxicity without clearly superior efficacy. Key clinical debates include the role of the triplet versus doublet, competition with ivonescimab + chemo (HARMONi-A), optimal management of VTE risk, and whether intracranial PFS improvements translate to meaningful CNS disease control.

What is the MARIPOSA-2 trial?

MARIPOSA-2 is a Phase 3, randomized, open-label trial (NCT04988295) in 657 patients with EGFR-mutated (exon 19 deletion or L858R) advanced NSCLC whose disease progressed on or after osimertinib. It compared amivantamab (Rybrevant) plus carboplatin/pemetrexed, and amivantamab plus lazertinib plus chemotherapy, against chemotherapy alone. The sponsor is Janssen (Johnson & Johnson).

What did MARIPOSA-2 show?

Amivantamab plus chemotherapy reduced the risk of disease progression or death by 52% versus chemotherapy alone: median PFS 6.3 vs 4.2 months (HR 0.48; 95% CI 0.36-0.64; p<0.0001), with consistent benefit across all prespecified subgroups including patients with brain metastases. The triplet with lazertinib showed median PFS 8.3 vs 4.2 months (HR 0.44) but added toxicity.

Is Rybrevant (amivantamab) FDA approved based on MARIPOSA-2?

Yes - for the doublet only. On September 19, 2024 the FDA approved amivantamab-vmjw (Rybrevant) with carboplatin and pemetrexed for adults with locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R mutations whose disease progressed on or after an EGFR TKI. The triplet regimen with lazertinib is not approved in this setting.

What is the safety profile of amivantamab plus chemotherapy in MARIPOSA-2?

The most common adverse events (>=20%) included rash, infusion-related reactions, fatigue, nail toxicity, nausea, and constipation. Serious AEs occurred in 32% with amivantamab + chemotherapy vs 20% with chemotherapy alone. VTE rates were higher in amivantamab arms but mostly grade 1-2 with no grade 5 events, and ILD/pneumonitis incidence was <=3%.

Why is MARIPOSA-2 important?

MARIPOSA-2 established amivantamab plus chemotherapy as a new standard of care for EGFR-mutated NSCLC after progression on osimertinib - a setting where platinum-based chemotherapy was previously the only option. It is the first targeted regimen to significantly improve PFS versus chemotherapy alone in the post-osimertinib setting.