The combination of the EGFR-MET bispecific antibody amivantamab-vmjw and the EGFR tyrosine kinase inhibitor lazertinib continues to demonstrate superior efficacy compared with the kinase inhibitor osimertinib alone in the first-line treatment of EGFR-mutant advanced non–small cell lung cancer (NSCLC). These findings were presented at the International Association for the Study of Lung Cancer (IASLC) 2024 World Conference on Lung Cancer.1 Extended follow-up data from the phase III MARIPOSA study showed 3-year intracranial progression-free survival with the combination was more than double that of osimertinib monotherapy (38% vs 18%).
Shirish M. Gadgeel, MD
Results of the study continued to show promising trends in overall survival favoring the combination therapy, “with survival curves separating early and widening over time,” according to lead study author Shirish M. Gadgeel, MD, a medical oncologist at Henry Ford Cancer Institute/Henry Ford Health, Detroit.
“These data show that amivantamab, with its multitargeted mechanism of action, plus lazertinib showed longer improvement in long-term outcomes vs osimertinib in this patient population,” he added.
As Dr. Gadgeel reported, there is a strong need for improved first-line treatments in EGFR-mutant NSCLC, with current therapies showing a median survival of approximately 3 years and an estimated real-world 5-year survival of less than 20%. Additionally, 25% to 40% of patients do not receive subsequent treatment, he noted, underscoring the importance of more effective initial therapies.
Amivantamab, an EGFR-MET bispecific antibody with immune cell-directing activity, combined with lazertinib, a third-generation EGFR tyrosine kinase inhibitor, had previously demonstrated significantly improved progression-free survival over osimertinib in the first interim analysis of the MARIPOSA study.2 Based on these results, the U.S. Food and Drug Administration (FDA) recently approved this combination for first-line treatment of common EGFR mutation–positive advanced NSCLC.
The MARIPOSA study enrolled 1,074 patients with EGFR mutations (exon 19 deletion or L858R mutation) and advanced NSCLC who were treatment-naive for advanced disease. Patients were randomly assigned in a 2:2:1 ratio to receive amivantamab plus lazertinib, osimertinib, or lazertinib alone. The primary endpoint was progression-free survival as assessed by blinded independent central review.
Improved Intracranial Efficacy
At a median follow-up of 31.1 months, the combination therapy demonstrated improved intracranial progression-free survival (hazard ratio [HR] = 0.82). The 3-year intracranial progression-free survival rate was 38% with amivantamab plus lazertinib vs18% with osimertinib alone. Although intracranial response rates were identical (77%) in both arms, the median intracranial duration of response was not reached for the combination therapy, compared with 24.4 months for osimertinib alone.
Endpoints after disease progression also favored the combination therapy. Time to treatment discontinuation was increased (HR = 0.80), with 40% of patients continuing treatment at 3 years vs 29% with osimertinib. Time to subsequent treatment was also longer, with a median of 30 months for the combination vs 24 months for osimertinib alone.
Of note, there was a trend toward improved overall survival favoring amivantamab plus lazertinib. Although the median survival was not reached with the combination therapy, it was 37.3 months with osimertinib. The 3-year overall survival rate was 61% for the combination therapy compared with 53% for osimertinib alone (HR = 0.77; P = .019).
Dr. Gadgeel emphasized that the MARIPOSA study is ongoing, with a prespecified final overall survival analysis with formal statistical testing to occur in the future. These promising results have led to several ongoing studies building upon the MARIPOSA findings. The COCOON trial is investigating enhanced dermatologic management to address skin toxicities observed with the combination therapy.
“As research continues, the amivantamab-plus-lazertinib combination represents a significant advancement in the treatment of EGFR-mutant advanced NSCLC, potentially offering patients improved long-term outcomes and intracranial efficacy compared to current standards of care,” Dr. Gadgeel concluded.
EXPERT POINT OF VIEW
Marina Chiara Garassino, MD
Discussant of the abstract on the MARIPOSA trial, Marina Chiara Garassino, MD, Professor of Medicine, Biological Sciences Division, University of Chicago Medicine, provided valuable insights into the evolving landscape of first-line therapy for EGFR-mutant non–small cell lung cancer (NSCLC). She addressed three key questions during her discussion.
Are All New EGFR Tyrosine Kinase Inhibitors the Same?
According to Dr. Garassino, recent data on rilertinib and lazertinib compared with osimertinib suggest that in terms of efficacy, “these new tyrosine kinase inhibitors are remarkably similar, with a different toxicity profile.” The median progression-free survival with rilertinib (18.9 months) closely mirrors that of osimertinib (19.3 months) from the FLAURA2 trial. Lazertinib also demonstrated comparable progression-free survival and early survival outcomes to osimertinib, she added.
However, the toxicity profiles differ subtly but importantly. Rilertinib appears to cause less rash and dry skin than osimertinib, whereas lazertinib shows reduced cardiotoxicity and QT prolongation but more skin toxicity. These distinctions in side-effect profiles may prove crucial when considering future combination therapies or treating patients with comorbidities, she noted.
Is There a Superior Combination Strategy?
The FLAURA2 trial (osimertinib plus chemotherapy) and the MARIPOSA study (amivantamab-vmjw plus lazertinib) both showed promising results, according to Dr. Garassino. Hazard ratios for progression-free survival were 0.62 and 0.70, respectively, with median progression-free survival reaching 29.1 months in FLAURA2 and 23.7 months in MARIPOSA. “Both trials are showing encouraging trends in overall survival, with similar hazard ratios (0.75 vs 0.77 for FLAURA2 vs MARIPOSA, respectively) at comparable follow-up times,” shared Dr. Garassino.
Conditional power calculations suggest a high likelihood (92% for FLAURA2, 80% for MARIPOSA) that both trials will ultimately demonstrate statistically significant overall survival benefits. Intracranial efficacy data, although not directly comparable because of population differences, appear to be more convincing for FLAURA2 in patients with brain metastases.
Which Patients Might Still Benefit From Single-Agent Therapy?
Despite the superiority of combination strategies over single-agent osimertinib, explained Dr. Garassino, subgroup analyses suggest that patients who are circulating tumor DNA (ctDNA)-negative, without co-mutations or brain metastases, might be candidates for single-agent therapy. These patients potentially have long progression-free survival, even without combination treatment, making it worth considering osimertinib monotherapy in such cases, she said.
“As we continue to refine our approach to first-line EGFR-mutant -NSCLC therapy, the goal remains to optimize outcomes while minimizing toxicity for each patient,” Dr. Garassino concluded. “The complexity of these new data underscores the importance of personalized decision-making, considering each patient’s individual characteristics, preferences, and risk factors. Future research should focus on identifying reliable biomarkers to guide treatment selection and further optimize patient outcomes,” she added.
DISCLOSURE: Dr. Gadgeel reported financial relationships with Merck Sharp & Dohme, Rahway, AstraZeneca, Genentech/Roche, Takeda/Ariad, Bristol Myers Squibb, AbbVie, Janssen, Pfizer, Jazz Pharmaceuticals, Blueprint, Mirati Therapeutics, Eisai, GSK, Gilead Sciences, Arcus, Lilly, Bayer, and Regeneron. Dr. Garassino reported financial relationships with AstraZeneca, Abion, MSD International GmbH, Bayer, BMS, Boehringer Ingelheim Italia S.p.A, Celgene, Eli Lilly, Incyte, Nuvation Bio, Novartis, Pfizer, Roche, Takeda, Seattle Genetics, Mirati Therapeutics, Daiichi Sankyo, Regeneron, Merck, Blueprint, Janssen, Sanofi, AbbVie, BeiGenius, Oncohost, Medscape, Gilead Sciences, Io Biotech, and Revolution Medicines.
REFERENCES
1. Gadgeel S, Cho BC, Lu S, et al: Amivantamab plus lazertinib vs osimertinib in first-line EGFR-mutant advanced NSCLC: Longer follow-up of the MARIPOSA study. 2024 World Conference on Lung Cancer. Abstract OA02.03. Presented September 8, 2024.
2. Cho BC, Lu S, Felip E, et al: Amivantamab plus lazertinib in previously untreated EGFR-mutated advanced NSCLC. N Engl J Med. June 26, 2024 (early release online).
