Resistance to osimertinib treatment presents with diverse and polyclonal mechanisms, with EGFR and MET alterations contributing to approximately 25%-50% of cases. However, platinum-based chemotherapy yields unfavorable outcomes. Amivantamab, an EGFR-MET bispecific antibody with immune cell-directed capabilities, is effective against a wide spectrum of EGFR and MET alterations. Coupled with lazertinib, a highly selective, CNS-penetrant third-generation EGFR tyrosine kinase inhibitor, the addition of amivantamab to platinum-based chemotherapy, with or without lazertinib, could potentially address osimertinib-based resistance.

At a median follow-up of 8.7 months, RYBREVANT, when combined with chemotherapy, significantly reduced the risk of disease progression or mortality by 52%, and when coupled with chemotherapy and lazertinib, this risk reduction was even more substantial at 56%, in comparison to chemotherapy as a standalone treatment. This remarkable improvement in progression-free survival (PFS) was observed consistently across various patient subgroups, encompassing factors such as age, gender, race, history of brain metastasis, smoking history, and the number of prior osimertinib treatments. Furthermore, the addition of RYBREVANT to chemotherapy yielded an impressive overall response rate (ORR) of 64%, and when paired with chemotherapy and lazertinib, the ORR remained high in stark contrast to the ORR achieved with chemotherapy as a sole intervention.

The findings from the MARIPOSA-2 study mark the first instance where combination therapies involving RYBREVANT have shown potential activity in the brain, a critical aspect given that nearly 30% of patients with this disease develop brain metastases. Specifically, when RYBREVANT was combined with chemotherapy, it resulted in a 45% risk reduction for intracranial progression or mortality, and when coupled with chemotherapy and lazertinib, this risk reduction remained significant at 42%, in contrast to chemotherapy alone. Initial interim data on overall survival (OS) suggest a potential benefit favoring RYBREVANT in combination with chemotherapy, compared to chemotherapy as a standalone treatment. However, there was no observable difference in OS at the interim analysis for the combination of RYBREVANT with chemotherapy and lazertinib in comparison to chemotherapy alone.

The duration of treatment was notably extended in the arms that included amivantamab compared to chemotherapy. However, the amivantamab-containing arms exhibited higher frequencies of Grade ≥3 adverse events (AEs) and required dose modifications more frequently compared to the chemotherapy group, with the highest incidence observed in the amivantamab-lazertinib-chemotherapy arm. Although AEs leading to death were infrequent, discontinuations of all treatment agents due to AEs occurred at rates of 2%, 8%, and 10% in chemotherapy, amivantamab-chemotherapy, and amivantamab-lazertinib-chemotherapy arms, respectively.

The amivantamab-containing regimens were associated with increased rates of EGFR- and MET-related AEs. Notably, neutropenia and thrombocytopenia were primarily observed during the first treatment cycle, with low rates of febrile neutropenia and grade 3-4 bleeding. Venous thromboembolism (VTE) incidence was highest in the amivantamab-lazertinib-chemotherapy arm, although no grade 5 VTE events were reported, and discontinuations due to VTE were infrequent. The occurrence of interstitial lung disease (ILD) was low in all treatment arms, with rates of less than 3%.

KOL insights:– “The promising results from the MARIPOSA-2 study show that by combining RYBREVANT with chemotherapy, both with and without lazertinib, patients achieved longer progression-free survival compared with chemotherapy alone. The efficacy seen across the two RYBREVANT regimens suggests that this treatment combination may address the diverse and often varied resistance that can occur in the post-osimertinib setting” – Medical Onclologist, European Institute of Oncology, Italy

Conclusion: The amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy combinations substantially improved progression-free survival (PFS) with over a 50% reduction in disease progression or mortality compared to chemotherapy alone. These regimens consistently benefited PFS across subgroups, displayed higher response rates, and extended response duration. They also demonstrated longer intracranial PFS, potentially indicating central nervous system anti-tumor effects. Initial data favored amivantamab-chemotherapy in overall survival. However, amivantamab-lazertinib-chemotherapy showed higher hematologic adverse event rates, leading to a modified dosing schedule. Notably, both regimens are the first to enhance PFS in advanced EGFR-mutated lung cancer post-osimertinib progression.

NSCLC is increasingly becoming a biomarker-driven market. EGFR is one of the profitable biomarker segments, with blockbuster therapies such as TAGRISSO. DelveInsight estimates that the total incident cases of EGFR NSCLC in the US was ~26,000 in 2022. The majority of the cases fall under EGFR exon 19 deletions followed by Exon 21 L858R substitution.

EGFR NSCLC by Subtypes

For more insight into the patient's burden/epidemiology, treatment, and changing market landscape-related advancements, refer to the Epidermal Growth Factor Receptor-Non Small Cell Lung Cancer (EGFR-NSCLC) Market Insight and Market Forecast and Non-Small Cell Lung Cancer Market Insight, and Market Forecast