The latest advancements in cancer treatment are offering new hope to patients with advanced non-small cell lung cancer (NSCLC), especially those with specific genetic mutations. This news report focuses on the MARIPOSA-2 study, an extensive global trial that investigates the effectiveness of new treatment combinations for NSCLC patients who have developed resistance to standard therapies. This study represents a significant step in personalized cancer treatment, aiming to improve outcomes for patients with limited options after first-line treatment failure.
The MARIPOSA-2 study specifically targeted NSCLC patients with mutations in the epidermal growth factor receptor (EGFR) gene. These mutations are among the most common actionable genomic alterations in NSCLC, comprising approximately 85%-90% of EGFR mutations. The most common mutations are exon 19 deletions and the L858R substitution mutations. The standard first-line treatment for NSCLC with these mutations is osimertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI). While osimertinib has shown improved progression-free survival (PFS) and overall survival compared to first-generation TKIs, resistance to this drug is a significant challenge, with nearly all patients eventually developing it.
To address this issue, the MARIPOSA-2 trial explored the use of amivantamab, an EGFR-MET bispecific antibody, in combination with chemotherapy. Amivantamab possesses multiple mechanisms of action, including ligand blocking, receptor degradation, and engagement of effector cells. Its unique ability to bind extracellularly allows it to bypass intracellular mutations that contribute to TKI resistance. Amivantamab has demonstrated activity against a wide range of activating and resistance mutations in EGFR-mutated NSCLC, presenting a new avenue for treatment after resistance to osimertinib develops.
Another critical component of the study was lazertinib, a highly selective central nervous system (CNS)-penetrant third-generation TKI. Lazertinib is effective against activating EGFR mutations and T790M resistance. The combination of amivantamab with lazertinib (amivantamab-lazertinib) was theorized to provide a synergistic benefit by simultaneously targeting extracellular and catalytic EGFR domains. This combination has shown clinically meaningful activity in patients with EGFR-mutated NSCLC after disease progression on osimertinib.
The MARIPOSA-2 trial was a global, randomized phase III trial assessing the efficacy and safety of amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy alone in patients with EGFR-mutated advanced NSCLC. The study enrolled 657 patients who were randomized to receive one of these treatment regimens. The trial’s design adhered strictly to the highest ethical standards, following the Declaration of Helsinki and Good Clinical Practice guidelines, with informed consent obtained from each participant.
The results of the MARIPOSA-2 trial were promising and significant. The median PFS was considerably longer for the amivantamab-chemotherapy (6.3 months) and amivantamab-lazertinib-chemotherapy (8.3 months) groups compared to chemotherapy alone (4.2 months). This improvement in PFS was consistent across various patient subgroups, including those with a history of brain metastases and different types of EGFR mutations. The objective response rate was also significantly higher in the amivantamab-containing arms compared to chemotherapy alone.
Notably, the trial also demonstrated an improvement in intracranial PFS with amivantamab combinations, which is crucial for patients with brain metastases, a common complication in advanced NSCLC. However, it’s important to note that the treatments were associated with a higher incidence of adverse events, particularly hematologic and gastrointestinal toxicities, underscoring the need for careful management and monitoring of patients undergoing these treatment regimens.
The MARIPOSA-2 trial marks a significant advancement in the treatment of EGFR-mutated NSCLC, particularly for patients who have developed resistance to osimertinib. The results highlight the potential of amivantamab, both alone and in combination with lazertinib and chemotherapy, to improve outcomes for these patients. This study not only offers new hope for patients with limited treatment options but also underscores the importance of ongoing research and innovation in the fight against cancer. As we continue to unravel the complexities of this disease, such studies pave the way for more effective, personalized treatment strategies that can significantly improve the quality of life and survival rates for cancer patients.
Reference:
Passaro, A., et al. “Amivantamab plus chemotherapy with and without lazertinib in EGFR-mutant advanced NSCLC after disease progression on osimertinib: Primary results from the phase 3 MARIPOSA-2 study.” Annals of Oncology (2023).
