RYBREVANT® (amivantamab) with chemotherapy approved by European Commission for first-line treatment of advanced NSCLC with EGFR exon 20 insertion mutations

On June 28, 2024, Janssen-Cilag International NV, part of Johnson & Johnson, announced that the European Commission (EC) has approved a Type II variation for the drug RYBREVANT® (amivantamab). This approval allows the use of RYBREVANT® in combination with chemotherapy (carboplatin and pemetrexed) for the first-line treatment of adult patients with advanced non-small cell lung cancer (NSCLC) characterized by epidermal growth factor receptor (EGFR) exon 20 insertion mutations.

Professor Nicolas Girard, a trial investigator and Head of Medical Oncology at Institut Curie, emphasized the significance of this approval. Girard noted that patients with NSCLC carrying EGFR exon 20 insertion mutations face a dire need for effective treatments due to the poor prognosis and high disease burden associated with these mutations. The new combination treatment involving amivantamab and chemotherapy is expected to set a new standard of care, potentially enhancing both clinical efficacy and quality of life for these patients.

EGFR exon 20 insertion mutations are the third most common type of activating EGFR mutations and are linked with very low real-world five-year survival rates, sometimes as low as eight percent. This underscores the importance of developing targeted therapies that address the unique challenges posed by these mutations. Henar Hevia, Ph.D., Senior Director at Johnson & Johnson, highlighted the company's commitment to personalized medicine, particularly in advancing treatments that are optimized for individual patient characteristics. He welcomed the approval as a critical step forward for patients with EGFR exon 20 insertion-mutated NSCLC, who now have the opportunity to benefit from amivantamab plus chemotherapy as a first-line treatment.

The expanded approval for amivantamab is based on compelling data from the Phase 3 PAPILLON study. This study compared the combination of amivantamab with chemotherapy to chemotherapy alone in patients with advanced or metastatic NSCLC with EGFR exon 20 insertion mutations. The study met its primary endpoint, showing significant improvement in progression-free survival (PFS) for patients receiving the combination treatment. Specifically, the results demonstrated a 60 percent reduction in the risk of disease progression or death compared to chemotherapy alone. Additionally, interim overall survival (OS) analysis indicated a favorable trend for the combination therapy, although it did not reach statistical significance at the time of the report.

The safety profile of the combination treatment was consistent with the known safety profiles of the individual drugs involved. Rates of treatment-related discontinuation were low, and while the overall rates of adverse events (AEs) and serious adverse events (SAEs) were similar between treatment groups, the combination therapy did result in a higher incidence of Grade ≥3 AEs. Notably, EGFR and MET-related AEs were more common with the combination therapy but were primarily of low severity. Chemotherapy-related hematologic and gastrointestinal toxicities were comparable between the two groups, except for an increased rate of transient neutropenia in the combination treatment group. Pneumonitis was observed in a small percentage of patients receiving the combination therapy.

Following this approval by the EC, the conditional marketing authorization granted to amivantamab in December 2021 has been converted to a standard marketing authorization. Dr. Kiran Patel, Vice President of Clinical Development for Solid Tumors at Johnson & Johnson, reiterated the company's dedication to advancing treatments for EGFR-mutated NSCLC, focusing on precision medicine approaches that target earlier stages of the disease. This approval marks a significant milestone in improving care for these patients.

The PAPILLON study was a randomized, open-label Phase 3 trial evaluating the efficacy and safety of amivantamab combined with chemotherapy compared to chemotherapy alone in newly diagnosed advanced or metastatic NSCLC patients with EGFR exon 20 insertion mutations. The primary endpoint was PFS, assessed by blinded independent central review, with secondary endpoints including overall response rate, duration of response, time to subsequent therapy, and overall survival. Patients initially receiving chemotherapy alone were allowed to switch to amivantamab monotherapy upon disease progression.

Amivantamab is a fully-human bispecific antibody targeting both EGFR and MET pathways, designed to combat tumors with specific EGFR and MET mutations. The EC had previously granted conditional marketing authorization for amivantamab for use in adults with advanced NSCLC harboring EGFR exon 20 insertion mutations after the failure of platinum-based therapy. This recent approval is expected to significantly impact the treatment landscape for NSCLC patients with these specific genetic mutations.