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Lung cancer remains a leading cause of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) being the most common type. Advances in targeted therapies have significantly improved outcomes for patients with specific genetic mutations, such as EGFR. Dr. Enriqueta Felip and colleagues at the ASCO Annual Meeting will present a secondary analysis of the Phase 3 MARIPOSA study, comparing the efficacy of amivantamab plus lazertinib versus osimertinib in first-line treatment for EGFR-mutant advanced NSCLC, particularly in patients with high-risk disease biomarkers.

Non-small cell lung cancer (NSCLC) encompasses several subtypes, with adenocarcinoma being the most prevalent. EGFR mutations are common in NSCLC, particularly among non-smokers. Osimertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI), has been the standard first-line therapy for EGFR-mutant NSCLC. However, resistance inevitably develops, necessitating novel therapeutic combinations to enhance efficacy and delay progression.

Amivantamab is a bispecific antibody targeting both EGFR and MET, designed to engage the immune system in attacking cancer cells. Lazertinib is a CNS-penetrant, third-generation EGFR TKI. The combination aims to provide a robust therapeutic effect by simultaneously targeting multiple pathways involved in tumor growth and resistance mechanisms.

The MARIPOSA study (NCT04487080) is a global, randomized, open-label Phase 3 trial evaluating the efficacy and safety of amivantamab plus lazertinib (ami+laz) versus osimertinib (osi) in treatment-naive patients with EGFR-mutant advanced NSCLC. The study’s primary endpoint is progression-free survival (PFS), with secondary endpoints including overall survival (OS), objective response rate (ORR), and safety. 

The analysis included 858 patients randomized equally to receive ami+laz or osi. The study specifically assessed outcomes in high-risk subgroups, such as those with TP53 co-mutations, detectable circulating tumor DNA (ctDNA), and baseline brain or liver metastases. These factors are known to confer a poorer prognosis and are critical in evaluating the efficacy of new treatment combinations.

The secondary analysis of the MARIPOSA study reveals significant findings:

  • Progression-Free Survival (PFS): Patients receiving ami+laz showed a statistically significant improvement in median PFS compared to those receiving osi, particularly in high-risk subgroups. For instance, among patients with TP53 co-mutations, the median PFS was 18.2 months for ami+laz versus 12.9 months for osi (HR 0.65, p=0.003).
  • Circulating Tumor DNA (ctDNA): The study highlighted the prognostic value of ctDNA clearance. Patients with detectable ctDNA at baseline who cleared ctDNA by Cycle 3 Day 1 had significantly longer PFS with ami+laz compared to osi (24.0 vs. 16.5 months, HR 0.64, p=0.004).
  • Brain and Liver Metastases: Ami+laz also demonstrated superior efficacy in patients with baseline liver metastases, with a median PFS of 18.2 months compared to 11.0 months for osi (HR 0.58, p=0.017).

The findings from this study are important for several reasons:

  1. Enhanced Treatment Efficacy: The combination of amivantamab and lazertinib significantly improves PFS for high-risk EGFR-mutant NSCLC patients, offering a promising alternative to osimertinib.
  2. Targeting Resistance Mechanisms: This combination addresses multiple resistance pathways by simultaneously targeting EGFR and MET, potentially delaying disease progression and improving patient outcomes.
  3. Prognostic Biomarkers: The study underscores the importance of biomarkers like TP53 mutations and ctDNA clearance in predicting treatment response, guiding more personalized therapy approaches.

This study presents compelling evidence supporting the combination of amivantamab and lazertinib as a superior first-line treatment for EGFR-mutant advanced NSCLC, particularly in patients with high-risk disease biomarkers. This study highlights the transformative potential of novel targeted therapies in lung cancer treatment, paving the way for more personalized and effective treatment strategies. Integrating these findings into clinical practice will improve lung cancer patients’ survival and quality of life worldwide as research advances. The insights from this study represent a significant step forward in the quest to optimize NSCLC treatment, offering new hope and better outcomes for patients facing this challenging disease.

References:

  1. Felip E, et al. J Clin Oncol 42, 2024 (suppl 16; abstr 8504)
  2. A Study of Amivantamab and Lazertinib Combination Therapy Versus Osimertinib in Locally Advanced or Metastatic Non-Small Cell Lung Cancer (MARIPOSA)
Zachary Moore

Author Zachary Moore

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