The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has recommended granting marketing authorization for lazertinib (Lazcluze; Janssen Biotech Inc) in combination with amivantamab (Rybrevant; Janssen Biotech Inc) for the first-line treatment of individuals with advanced non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) exon 19 deletions (ex19del) or exon 21 L858R (L858R) substitution mutations. The CHMP also recommended approval of a type II extension of indication for amivantamab to treat the same patient population.
Lung cancer remains the leading cause of cancer death worldwide, with approximately 2.4 million new cases and 1.8 million deaths in 2022. In Europe, an estimated 484,306 individuals were diagnosed with lung cancer in 2022, with NSCLC accounting for 85% of these cases. EGFR mutations are common drivers in NSCLC, with EGFR ex19del and EGFR exon 21 L858R being the most prevalent. Patients with these mutations treated with EGFR TKIs have a less than 20% 5-year survival rate. Furthermore, 25% to 32% of individuals treated with osimertinib, the current first-line standard of care, do not survive long enough to receive second-line treatment.
Mechanism of Action
Amivantamab, a fully human EGFR-MET bispecific antibody, targets tumors with activating and resistance EGFR mutations and MET mutations and amplifications, while also engaging the immune system. Lazertinib is an oral, third-generation, brain-penetrant EGFR TKI that targets the T790M mutation and activating EGFR mutations, while sparing wild-type EGFR.
Clinical Efficacy
The marketing authorization and type II extension were based on the Phase 3 MARIPOSA study (NCT04487080), which evaluated amivantamab combined with lazertinib versus osimertinib as a first-line treatment for individuals with advanced or metastatic NSCLC with EGFR ex19del or exon 21 L858R substitution mutations. The study met its primary endpoint of progression-free survival, demonstrating that the combination therapy reduced the risk of disease progression or death by 30% compared with osimertinib. Additionally, amivantamab plus lazertinib showed a 9-month improvement in median duration of response compared to osimertinib.
Safety Profile
The safety profile of amivantamab plus lazertinib primarily included grade 1 or grade 2 adverse events. The most common treatment-emergent adverse reactions were paronychia, infusion-related reactions, and rash. Rash, paronychia, and dermatitis acneiform were the most common grade 3 or higher treatment-emergent adverse reactions.
