Episode 4: The MARIPOSA trial

In this episode of WND in lung cancer, Professor Johan Vansteenkiste from University Hospitals Leuven and Professor Mariana Brandao, a medical oncologist at Institut Jules Bordet in Brussels, explore the MARIPOSA trial.

This phase 3 trial randomized treatment-naïve NSCLC patients with classic EGFR mutations (ex19del or L858R) between SOC osimertinib and lazertinib, another third-generation EGFR TKI with excellent brain penetration, and a third arm combining amivantamab with lazertinib. Amivantamab is a novel EGFR-MET bispecific antibody, aiming to overcome first-line osimertinib resistance by inhibiting both EGFR and MET pathways upfront.

The primary endpoint of the trial, median PFS, increased from 16 months with osimertinib monotherapy to 24 months with the combination (HR 0.70). Notably, these benefits extended across subgroup characteristics, including patients with brain metastasis.

However, the combination of amivantamab and lazertinib presents notable toxicity, with amivantamab inducing rash and paronychia and MET inhibition leading to diarrhoea and oedema, significantly impacting patients’ daily lives.

The positive impact on PFS and a promising trend for OS suggests the potential of this novel combination, despite its side effects. It allows moving away from a uniform approach with osimertinib to tailored escalation strategies for specific patient subsets.

In clinical practice, choices regarding treatment options need to be carefully considered. Should one opt for the convenience of osimertinib monotherapy, combine it with amivantamab and reserve chemotherapy for the second line, or reverse the approach?

This complexity underscores the necessity of open discussions with patients, considering QoL aspects. Implementing such demanding treatment without robust OS data or a clearly defined subgroup demonstrating substantial OS benefits may prove challenging.

Trial designs that initiate with inhibition using osimertinib or lazertinib, escalating with amivantamab or chemotherapy for patients in stable disease or without ctDNA clearance, may offer insight into the preferred approach. This could potentially differentiate patients suitable for chemotherapy or amivantamab based on factors like brain metastasis or exon21 mutations, though numerous considerations remain.

Follow-up on the OS improvement trend and ongoing evaluation of CNS effects are crucial to assess the benefit-risk ratio for patients while understanding patient priorities in QoL.