Targeted therapies are improving outcomes for patients with mutated lung cancer progressing on standard chemotherapy, but a precision-guided approach is essential. Recent data presented at the ESMO Congress 2024 in Barcelona shed light on overcoming resistance mechanisms and optimizing treatments for EGFR-mutant advanced non-small cell lung cancer (NSCLC). Studies focused on combinations like osimertinib plus chemotherapy and amivantamab plus lazertinib are expanding the understanding of resistance and treatment options.
Amivantamab Plus Lazertinib: Impact on Resistance Mechanisms
The phase III MARIPOSA study compared resistance mechanisms in EGFR-mutated advanced NSCLC patients treated with amivantamab plus lazertinib versus osimertinib. The analysis, involving 858 patients, revealed that amivantamab and lazertinib significantly reduced the likelihood of MET amplification, secondary EGFR resistance mutations, and small-cell transformation (LBA55). Dr. Natasha Leighl noted the unexpected reduction in small-cell transformation, suggesting it may uncover drivers of this transformation and identify future treatments. These results contrast with the FLAURA2 study, where resistance mechanisms were similar between osimertinib plus chemotherapy and osimertinib alone.
MARIPOSA-2: Amivantamab Plus Chemotherapy Post-Osimertinib
Previous MARIPOSA-2 study results showed improved progression-free survival (PFS, HR 0.48) and a trend toward overall survival (OS) benefit with amivantamab plus chemotherapy. The latest analysis presented at ESMO Congress 2024 (LBA54) demonstrated a deepening survival benefit, though it did not reach the pre-specified significance threshold. At a median follow-up of 18.1 months, OS in patients receiving amivantamab plus chemotherapy was 17.7 months compared to 15.3 months with chemotherapy alone (HR 0.73; p=0.039). PFS after the first subsequent therapy was significantly longer with amivantamab plus chemotherapy (median 16.0 months versus 11.6 months; HR 0.64; p=0.002). According to Dr. Leighl, these results strengthen amivantamab plus chemotherapy's position as the most effective regimen post-osimertinib progression, pending final OS analysis and clarification of its role after first-line combinations beyond osimertinib alone.
Zipalertinib Shows Promise After Amivantamab Failure
Data from the REZILIENT1 phase IIb study highlighted the anti-tumor activity of zipalertinib, an irreversible and selective EGFR TKI, in patients with EGFR exon 20 insertion-mutated NSCLC who had progressed on amivantamab (Abstract 1254MO). In 30 evaluable patients, zipalertinib showed a 40% confirmed objective response rate, with the median duration of response not yet estimable. This activity mirrors the initial 41% response rate observed with zipalertinib in patients previously treated with platinum-based chemotherapy. The rates of dose reductions and discontinuations were low, and toxicity was manageable. Dr. Leighl emphasized zipalertinib's marked activity even after amivantamab failure, along with its favorable toxicity profile and CNS activity, making it a promising option for this patient population.
Personalizing Treatment Approaches
These findings offer hope for patients with EGFR-resistant NSCLC. As the number of targeted agents and combinations grows, the challenge lies in personalizing first-line and subsequent treatment approaches. Considerations include balancing efficacy and toxicity, front-line combinations versus sequential approaches, and maximizing benefit through biomarker-guided strategies. This new evidence contributes to an evidence-based approach to personalized, effective care for patients.
