Episode 6: The MARIPOSA-2 trial

In this episode of WND on lung cancer, Professor Johan Vansteenkiste from University Hospitals Leuven and Professor Mariana Brandao, medical oncologist at Institut Jules Bordet in Brussels, will discuss the significant advancements in the EGFR field that have occurred over the past year, with the findings of the MARIPOSA-2 trial adding to this progression.

This trial involved patients who had experienced progression on osimertinib. Upon progression, they were randomly assigned to one of three treatment arms: standard platinum-based chemotherapy (chem), platinum-based chemotherapy plus amivantamab (ami-chem), and quadruplet therapy combining chemotherapy, amivantamab, and lazertinib (ami-laz-chem). Ami, a bispecific antibody targeting EGFR and MET to MET amplification, is a common driver of resistance, and laz is a TKI similar to osimertinib but with CNS penetration.

The trial’s significance lies in addressing the poor prognosis associated with osimertinib resistance. Median PFS on chem alone is a mere four months, underscoring the disease’s aggressiveness upon osimertinib resistance. The addition of ami extends PFS to 6-8 months, with an HR of 0.44 for ami-chem and 0.48 for ami-laz-chem. However, significant toxicities necessitated a regimen change, delaying ami-laz administration until after completion of chem.

Despite the trial’s positive outcome, the combined toxicity of chemotherapy and EGFR/MET inhibition and the complex administration schedule burdens patients. Yet, given chemotherapy’s poor prognosis alone, incorporating ami may establish a new SOC, albeit with considerations regarding the addition of laz.

The combination of ami-laz-chemo does not suggest any additional benefit from adding a third-generation TKI after the failure of an earlier third-generation TKI. Based on similar HR outcomes, experts tend to favour triplet therapy due to concerns about the toxicity of the quadruplet treatment and the potential for unforeseen side effects in real-world clinical settings.

When comparing MARIPOSA and MARIPOSA-2, the latter is preferred. While there’s a trend in OS benefit when combining laz-ami in the first line, the data remains inconclusive. Osimertinib is a convenient drug, and starting with it before transitioning to ami-chemo may offer a promising strategy. This speculation presents the additional advantage of initially reducing the treatment burden for the patient with a daily oral intake of osimertinib at home, followed by a more intensive treatment regimen with increased side effects when necessary, thereby striking a balance between heightened toxicity and benefits.