Rybrevant Combo Improves Survival in EGFR-Mutated, Advanced NSCLC

Findings from the MARIPOSA trial showed that Rybrevant plus Leclaza outperformed Tagrisso for certain patients with lung cancer.

Frontline treatment with Rybrevant (amivantamab) plus Leclaza (lazertinib), compared with Tagrisso (osimertinib) alone, appeared to demonstrate superior efficacy in patients with previously untreated or Tagrisso-pretreated, EGFR-mutated, advanced non–small-cell lung cancer (NSCLC), according to results from the phase 3 MARIPOSA trial.

“Treatment with [Rybrevant] (plus) [Leclaza] offers the added benefit of preserving chemotherapy for use in later lines of therapy,” the researchers wrote in the study published in The New England Journal of Medicine.

After a median follow-up of 22 months, the median progression-free survival (the length of time during and after treatment that a patient lives with the disease, but it does not get worse) was significantly longer among patients treated with Rybrevant plus Leclaza, compared with Tagrisso alone (23.7 months versus 16.6 months, respectively). As a result, treatment with the combination regimen led to a 30% reduced risk for disease progression or death. Of note, the median progression-free survival in the Leclaza group was 18.5 months.

Further, at 18 months following treatment with both the combination therapy and Tagrisso alone, 60% and 48% of patients, respectively, were alive and free from disease; however, these rates decreased to 48% and 34% at the two-year mark.

In total, 86% of patients in the Rybrevant- Leclaza group experienced an objective response, which included a complete or partial response to treatment, compared with 85% of patients in the Tagrisso arm. Among the patients who demonstrated a confirmed response following treatment with Rybrevant plus Leclaza (336 patients) and Tagrisso alone (314 patients), the median durations of response were 25.8 months and 16.8 months, respectively.

According to an interim analysis planned by the researchers, treatment with the combination reduced the risk for death by 20%. At 18 months following treatment, 82% of those in the Rybrevant-plus- Leclaza arm and 79% of those in the Tagrisso group were alive, compared with 74% and 69%, respectively, at 24 months post-therapy. At this interim analysis, however, median overall survival (the length of time from the start of treatment that a patient is still alive with their disease) could not be estimated in either treatment group.

The researchers noted that the most common reasons for treatment discontinuation of the combination regimen, compared with Tagrisso, were progressive disease (20% versus 36%, respectively) and side effects (20% versus 12%).

In total, 49% of patients in the combination arm and 33% in the Tagrisso monotherapy arm experienced a serious side effect. The most common grade 3 or higher side effects, considered severe or medically significant, from Rybrevant plus Leclaza included rash (15%), paronychia (infection of the tissue adjacent to a nail; 11%), dermatitis (8%), pulmonary embolism (8%) and infusion-related reactions (6%).

“The discontinuation of all agents due to treatment-related (side effects) in the [Rybrevant- Leclaza] group was infrequent, which suggests that most patients can continue receiving treatment,” the researchers wrote.

Prior to this trial, the combination of Rybrevant, an EGFR-MET bispecific antibody, and Leclaza, a third-generation EGFR tyrosine kinase inhibitor (TKI), was evaluated in patients whose disease had progressed during or after treatment with Tagrisso. Here, clinically meaningful and durable antitumor activity was shown.

“Although most patients with EGFR-mutated advanced NSCLC have an initial response to treatment with third-generation EGFR-TKIs, real-world survival estimates show that only 19% of patients are alive after five years,” the researchers explained. “There is a continuous need to improve clinical outcomes with first-line treatment beyond those seen with EGFR-TKI monotherapy, given that 25% of patients die before receiving second-line therapy.”

Therefore, in the international, randomized, phase 3 MARIPOSA trial, researchers aimed to assess the efficacy and safety of Rybrevant plus Leclaza, compared with Tagrisso, as a first-line therapy in patients with EGFR-mutated locally advanced or metastatic NSCLC.

Patients were randomly assigned to one of three treatment groups, with one arm consisting of patients who received the Rybrevant– Leclaza regimen (429 patients), the second arm including those given Tagrisso alone (429 patients), and a third arm looking at Leclaza monotherapy (216 patients) so that the researchers could evaluate the drug’s components contributing to the combination treatment arm, they wrote.

“A comparison of [Leclaza] with [Tagrisso] will be informative,” the researchers added.

Progression-free survival served as the primary end point of the study. Secondary end points included objective response, duration of response to therapy and safety.

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