MARIPOSA update: Amivantamab-lazertinib may extend survival beyond 4 years in EGFRm NSCLC

In the protocol-specified final overall survival (OS) analysis of the phase III MARIPOSA trial, treatment with amivantamab plus lazertinib significantly reduced the risk of death in individuals with previously untreated EGFR-mutant (EGFRm) advanced non-small cell lung cancer (NSCLC).

“After a median follow-up of 37.8 months, first-line amivantamab plus lazertinib led to a statistically significant and clinically meaningful reduction in mortality vs osimertinib in [this patient setting],” said Dr James Chih-Hsin Yang from the National Taiwan University Hospital, Taipei, Taiwan, at ELCC 2025.

Median OS was not reached in the combination arm vs 36.7 months with osimertinib. A comparison between arms yielded a hazard ratio (HR) of 0.75 (95 percent confidence interval [CI], 0.61–0.92) and a p-value of <0.005. [ELCC 2025, abstract 4O]

“The Kaplan-Meier OS curves continued to widen over time … Based on an exponential distribution assumption of OS in both arms, the improvement in median OS is projected to exceed 1 year,” Yang said.

Sixty percent of participants on amivantamab plus lazertinib were alive at 3 years as opposed to 51 percent in the osimertinib arm. This benefit persisted at 42 months with 56 percent and 44 percent survival rates, respectively.

Furthermore, the OS benefit with amivantamab plus lazertinib was generally consistent across predefined subgroups, with the most profound benefits seen among patients <65 years (HR, 0.53) and those ≥80 kg (HR, 0.62).

These results build on the favourable OS trend reported for the combo regimen vs osimertinib at the second interim analysis. [ESMO 2024, abstract LBA54]

Other endpoints

Overall, nearly three-quarters (74 percent) of participants received second-line treatment, the most common being chemotherapy-based regimens (56 percent in the combo arm and 67 percent in the osimertinib arm). “This finding implies that a long-term treatment plan after first-line amivantamab plus lazertinib is feasible,” said Yang.

The combination treatment also provided a clinically meaningful improvement in intracranial progression-free survival (icPFS; median 25.4 vs 22.2 months; HR, 0.79, 95 percent CI, 0.61–1.02; p=0.07). The 3-year landmark icPFS was twice as high with the combo regimen vs the comparator (36 percent vs 18 percent). Yang noted that this finding is particularly relevant, as central nervous system progression is always a concern in this patient population, with substantial impact on survival and quality of life (QoL).

Intracranial duration of response was also longer with amivantamab plus lazertinib vs osimertinib (median 35.7 vs 29.6 months), as was time to symptomatic progression (TTSP; median 43.6 vs 29.3 months; HR, 0.69, 95 percent CI, 0.57–0.83; p<0.001).

According to Yang, symptomatic progression is a patient-relevant endpoint measuring the time from randomization to the onset of new/worsening lung cancer symptoms, signalling the need for a change in therapy, clinical intervention, or death, based on investigator discretion.

The TTSP finding shows that the combo regimen significantly delayed the onset or worsening of lung cancer symptoms by a median of >14 months. Half of the combo regimen recipients were free of symptomatic progression at 3 years; only a third of those on osimertinib were able to achieve this endpoint.

Safety profile

The safety profile aligned with that reported in the primary analysis, and adverse events (AEs) were mostly low-grade and EGFR- and MET-related. [N Engl J Med 2024;391:1489-1498; Spira, et al, NACLC 2023]

“Most first-onset AEs occur early (0–4 months), with longer-term follow-up showing no new safety signals and indicating that long-term treatment is feasible,” Yang noted. The most common first-onset AEs were rash and paronychia. Of note, 21 percent of participants with rash were already on prescribed antibiotics at study initiation.

“[However,] early and long-lasting toxicities require aggressive management and impact patients’ daily QoL during the best period of the disease course (ie, the period wherein the disease is very well-controlled),” pointed out discussant Dr Maurice Perol from the Léon Bérard Cancer Centre, Lyon, France. “The daily management of dermatologic toxicity with this combination is a constraint for the patient … We do not have any data about the duration of toxicity.”

Nonetheless, Yang cited evidence supporting prophylactic interventions that can reduce the incidence of key AEs, such as dermatologic AEs, infusion-related reactions, and venous thromboembolism. [ELCC 2025, abstract 10MO; J Thorac Oncol 2025:S1556-0864(25)00051-6; Scott, et al, ASCO 2024] “If prophylactic measures are taken … we can prolong the use of this regimen. This is important because OS has changed.”

Practice-changing superior OS

In MARIPOSA, 1,074 individuals with treatment-naïve, locally advanced or metastatic NSCLC were randomized 2:2:1 to receive open-label amivantamab plus lazertinib, blinded osimertinib, or blinded lazertinib. Amivantamab was administered intravenously at a dose of 1,050 mg (1,400 mg if ≥80 kg) weekly for the first 4 weeks and Q2W weeks thereafter. Lazertinib was given orally daily, as was osimertinib, at the respective doses of 240 mg and 80 mg.

The median age in the combination arm was 64 years, and about two-thirds of patients were women. In the osimertinib arm, the median age was 63 years, and 59 percent were women. Across both arms, nearly all patients had the adenocarcinoma subtype, and 60 percent had the Ex19del mutation.

Amivantamab plus lazertinib has received the nod for first-line treatment of EGFRm advanced NSCLC by the US FDA and EMA. [https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-lazertinib-amivantamab-vmjw-non-small-lung-cancer; https://www.ema.europa.eu/en/medicines/human/EPAR/lazcluze, accessed 6 May 2025] As amivantamab-based regimens for second-line treatment were still not approved during enrolment, crossover was not permitted.

“Fifteen years ago, OS with gefitinib was 20 months. With the third-generation osimertinib, OS improved to more than 3 years,” said Yang.

“Today, we are delighted to share that amivantamab – a special bispecific antibody against EGFR and MET – [in combination with lazertinib], has changed the practice, potentially extending median survival beyond 4 years,” he concluded.

Considerations

However, as the OS improvement was based on an exponential distribution assumption, Perol noted that the amivantamab plus lazertinib upfront regimen provides an absolute 3-year benefit of 9 percent.

“[The study highlights] the importance of frontline treatment and the lower impact of subsequent lines of treatment on survival. It also shows that preventing or delaying the emergence of acquired resistance is more effective than trying to overcome it,” he said.

Perol added that the benefit/risk ratio of the combination regimen must take into account the treatment objectives shared with the patient. “[It is] very important to discuss a patient’s priorities in terms of treatment objectives. This is clearly a shared decision-making process.”