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Topline results from the Phase III MARIPOSA trial (NCT04487080) show the combination of Rybrevant (amivantamab-vmjw) plus Lazcluze (lazertinib) produced a statistically significant improvement in overall survival (OS) in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletions (ex19del) or L858R substitution mutations.1,2 The combination was found to extend median survival by over one year compared to the current standard of care Tagrisso (osimertinib).
“The combination of these two agents previously demonstrated an improvement in progression-free survival, but this does not always capture the impact on the entire treatment course. Evaluation of overall survival can better demonstrate the benefit of a first-line treatment regimen,” Stephen Liu, MD, associate professor of Medicine at Georgetown University School of Medicine, director of Thoracic Oncology and head of Developmental Therapeutics at the Lombardi Comprehensive Cancer Center, said in a press release. “Seeing this increase in overall survival in a trial with mature data is powerful and reaffirms that first-line treatment with Rybrevant and Lazcluze can lead to better patient outcomes.”1
Rybrevant is a bispecific antibody that targets EGFR and MET with immune cell-directing activity, whereas Lazcluze is a kinase inhibitor. The therapy is indicated for the treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations whose disease progressed on or after platinum-based chemotherapy. It is also used as first-line treatment for patients with NSCLC in combination with chemotherapy (carboplatin and pemetrexed.3
The combination was approved in September 2024 in combination with carboplatin and pemetrexed to treat locally advanced or metastatic EGFR mutated NSCLC for patients with exon 19 deletions or L858R substitution mutations and whose disease has progressed after EGFR tyrosine kinase inhibitor therapy.4
Trial Design
The international, randomized MARIPOSA trial enrolled 1074 patients with locally advanced or metastatic NSCLC with EGFR ex19del or substitution mutations. Patients were randomly assigned in a 2:2:1 ratio to receive Rybrevant with Lazcluze (n=429) in an open-label fashion, Tagrisso (n=429) in a blinded fashion, or Lazcluze in a blinded fashion (n=216) to evaluate how it contributes to the treatment components. The trial’s primary endpoint is progression-free survival (PFS) in the Rybrevant with Lazcluze cohort as compared to the Tagrisso cohort, assessed by blinded independent central review.5 Secondary endpoints included OS, objective response rate, duration of response (DOR), second PFS, and intracranial PFS.
Rybrevant with Lazcluze achieved the final pre-specified secondary endpoint of OS by showing clinically meaningful and statistically significant improved OS compared to Tagrisso.
Data released in June 2024 show the combination achieved the primary endpoint, with median PFS at 23.7 months with Rybrevant plus Leclaza compared to 16.6 months with Tagrisso (hazard ratio for disease progression or death, 0.70; 95% confidence interval [CI], 0.58 to 0.85; P<0.001). Rybrevant with Leclaza produced an objective response in 86% of patients (95% CI, 83 to 89) vs. 85% of patients (95% CI, 81 to 88) administered Tagrisso.
Among 336 patients who achieved a confirmed response in the Rybrevant plus Leclaza combination group and 314 who achieved a confirmed response in the Tagrisso group, median DOR was 25.8 months with Rybrevant plus Leclaza (95% CI, 20.1 to could not be estimated) vs. 16.8 months (95% CI, 14.8 to 18.5) with Tagrisso.
The predominant adverse events (AEs) reported in the trial were EGFR-related toxic effects, with incidence of discontinuation for treatment-related AEs of 10% in the Rybrevant plus Leclaza cohort compared to 3% with Tagrisso.1
“These new findings reinforce the clinically meaningful impact this chemotherapy-free regimen can have for patients worldwide with non-small cell lung cancer and represent the first overall survival benefit over the current standard of care,” Yusri Elsayed, MD, MHSc, PhD, global therapeutic area head, Oncology, Johnson & Johnson Innovative Medicine, said in the release. “With less than 20% of patients living beyond five years, an incredible unmet need remains for EGFR-positive lung cancer. These MARIPOSA results show Rybrevant plus Lazcluze can extend survival beyond the current standard of care, providing patients with more time and hope in their fight against this devastating disease. Extending median overall survival by more than a year would be transformative for these patients.”1
References
1. 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 7, 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
2. 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 7, 2025. https://clinicaltrials.gov/study/NCT04487080
3. Amivantamab-vmjw (Rybrevant) label. Janssen Biotech Inc. Accessed January 7, 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761210s003lbl.pdf.
4. RYBREVANT® (amivantamab-vmjw) plus standard of care approved in the U.S. as first and only targeted regimen to cut risk of disease progression by more than half in second-line EGFR-mutated advanced lung cancer. J&J. September 19, 2024. Accessed January 7, 2025. https://www.jnj.com/media-center/press-releases/rybrevant-amivantamab-vmjw-plus-standard-of-care-approved-in-the-u-s-as-first-and-only-targeted-regimen-to-cut-risk-of-disease-progression-by-more-than-half-in-second-line-egfr-mutated-advanced-lung-cancer
5. Cho B, et al. Amivantamab plus Lazertinib in Previously Untreated EGFR-Mutated Advanced NSCLC. N Engl J Med 2024, Published June 26, 2024 DOI: 10.1056/NEJMoa2403614.