Janssen announces positive results from phase 3 MARIPOSA study of Rybrevant in combo with lazertinib versus osimertinib to treat patients with EGFR-mutated NSCLC

The Janssen Pharmaceutical Companies of Johnson & Johnson announced positive topline results from the phase 3 MARIPOSA study evaluating Rybrevant (amivantamab-vmjw), a bispecific antibody targeting epidermal growth factor receptor (EGFR) and mesenchymal-epithelial transition (MET), in combination with lazertinib, an oral third-generation EGFR tyrosine kinase inhibitor (TKI), versus osimertinib as first-line treatment in patients with locally advanced or metastatic EGFR-mutated non-small cell lung cancer (NSCLC).

The pivotal phase 3 MARIPOSA study met its primary endpoint with a statistically significant and clinically meaningful improvement in progression-free survival (PFS) in patients receiving Rybrevant plus lazertinib compared to osimertinib. The combination of Rybrevant and lazertinib demonstrated a safety profile consistent with previously reported data on the combination. A planned interim overall survival (OS) analysis showed a trend favouring the combination of Rybrevant and lazertinib compared to osimertinib. Patients in the study will be followed for subsequent OS analyses, which will determine the statistical and clinical significance of OS.

“Positive topline results from the MARIPOSA study reinforce the potential of the Rybrevant and lazertinib combination in frontline EGFR-mutated non-small cell lung cancer as a future standard of care,” said Peter Lebowitz, M.D., Ph.D., global therapeutic area head, oncology, Janssen Research & Development, LLC. “As a combination targeted regimen, Rybrevant and lazertinib inhibit critical oncogenic driver pathways and activate the immune system to address disease in multiple ways.”

“Patients with treatment-naïve EGFR-mutated non-small cell lung cancer have historically been treated with EGFR TKIs, but these agents invariably lead to resistance and disease progression when used as monotherapy,” said Alexander Spira†, M.D., Ph.D., FACP, director, Virginia Cancer Specialists Research Institute, and study investigator. “These promising data from MARIPOSA underscore the potential for the Rybrevant and lazertinib regimen to advance treatment beyond TKI monotherapy.”

MARIPOSA (NCT04487080), which enrolled 1,074 patients, is a randomized, open-label Phase 3 study evaluating Rybrevant in combination with lazertinib versus osimertinib and versus lazertinib alone in first-line treatment of patients with locally advanced or metastatic NSCLC with EGFR exon 19 deletions (ex19del) or substitution mutations. The primary endpoint of the study is PFS (using RECIST v1.1 guidelines‡) as assessed by blinded independent central review. Secondary endpoints include OS, objective response rate (ORR), duration of response (DoR), intracranial PFS, PFS after first subsequent therapy (PFS2) and time to symptomatic progression.1

MARIPOSA marks the third Rybrevant phase 3 study to readout this year following PAPILLON and MARIPOSA-2. Janssen plans to submit these results for presentation at an upcoming scientific congress, including additional details on select secondary endpoints.

Rybrevant (amivantamab-vmjw), a fully-human bispecific antibody targeting EGFR and MET with immune cell-directing activity, received accelerated approval by the US Food and Drug Administration (FDA) in May 2021 for the treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy. This indication is approved under accelerated approval based on ORR and DoR. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. Rybrevant has also received approval from health authorities in Europe, as well as other markets around the world.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Small Cell Lung Cancer§ prefer next-generation sequencing-based strategies over polymerase chain reaction-based approaches for the detection of EGFR exon 20 insertion variants, and include amivantamab-vmjw (Rybrevant) as a subsequent therapy option with a Category 2A recommendation for patients that have progressed on or after platinum-based chemotherapy with or without immunotherapy and have EGFR exon 20 insertion mutation-positive advanced NSCLC.¶

In addition to the phase 3 MARIPOSA study, Rybrevant is being studied in multiple clinical trials in NSCLC, including:

The phase 3 MARIPOSA-2 (NCT04988295) study assessing the efficacy of Rybrevant (with or without lazertinib) and carboplatin-pemetrexed versus carboplatin-pemetrexed in patients with locally advanced or metastatic EGFR ex19del or L858R substitution NSCLC after disease progression on or after osimertinib. Topline data for this randomized phase 3 study demonstrated statistically significant and clinically meaningful improvement in PFS in patients receiving Rybrevant plus chemotherapy with and without lazertinib versus chemotherapy.

The phase 3 PAPILLON (NCT04538664) study assessing Rybrevant in combination with carboplatin-pemetrexed versus chemotherapy alone in the first-line treatment of patients with advanced or metastatic NSCLC with EGFR exon 20 insertion mutations. Topline data for this randomized phase 3 study demonstrated statistically significant and clinically meaningful improvement in PFS in patients receiving Rybrevant.

The phase 1 CHRYSALIS (NCT02609776) study evaluating Rybrevant in participants with advanced NSCLC.

The phase 1/1b CHRYSALIS-2 (NCT04077463) study evaluating Rybrevant in combination with lazertinib and lazertinib as a monotherapy in patients with advanced NSCLC with EGFR mutations.

The phase 1 PALOMA (NCT04606381) study assessing the feasibility of subcutaneous (SC) administration of amivantamab based on safety and pharmacokinetics and to determine a dose, dose regimen and formulation for amivantamab SC delivery.

The phase 2 PALOMA-2 (NCT05498428) study assessing subcutaneous amivantamab in participants with advanced or metastatic solid tumors including EGFR-mutated NSCLC.

The phase 3 PALOMA-3 (NCT05388669) study assessing lazertinib with subcutaneous amivantamab compared to intravenous amivantamab in participants with EGFR-mutated advanced or metastatic NSCLC.

The phase 1/2 METalmark (NCT05488314) study assessing Rybrevant and capmatinib combination therapy in locally advanced or metastatic NSCLC.

The phase 1/2 PolyDamas (NCT05908734) study assessing Rybrevant and cetrelimab combination therapy in locally advanced or metastatic NSCLC.

The phase 2 SKIPPirr study (NCT05663866) exploring how to decrease the incidence and/or severity of first-dose infusion-related reactions with Rybrevant in combination with lazertinib in relapsed or refractory EGFR-mutated advanced or metastatic NSCLC.

Lazertinib is an oral, third-generation, brain-penetrant EGFR TKI that targets both the T790M mutation and activating EGFR mutations while sparing wild type-EGFR. An analysis of the efficacy and safety of lazertinib from the phase 3 LASER301 (NCT04248829) study was published in The Journal of Clinical Oncology in 2023 and demonstrated lazertinib improved PFS compared to the first generation EGFR TKI gefitinib in all prespecified subgroups, including Asian patients, those with L858R mutations and those with a history of brain metastases. In 2018, Janssen Biotech, Inc., entered into a license and collaboration agreement with Yuhan Corporation for the development of lazertinib.

Worldwide, lung cancer is one of the most common cancers, with NSCLC making up 80 to 85 percent of all lung cancer cases. The main subtypes of NSCLC are adenocarcinoma, squamous cell carcinoma and large cell carcinoma. Among the most common driver mutations in NSCLC are alterations in EGFR, which is a receptor tyrosine kinase controlling cell growth and division. EGFR mutations are present in 10 to 15 per cent of Western patients with NSCLC with adenocarcinoma histology and occur in 40 to 50 per cent of Asian patients. EGFR ex19del or EGFR L858R mutations are the most common EGFR mutations. The five-year survival rate for all people with advanced NSCLC and EGFR mutations treated with EGFR TKIs is less than 20 percent. Patients with EGFR ex19del or L858R mutations have a real-world five-year OS of 19 per cent.

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