Amivantamab improved progression-free survival (PFS) over osimertinib in the first-line setting and after progression on osimertinib in EGFR-mutated advanced NSCLC, according to MARIPOSA and MARIPOSA-2 results, presented at ESMO Congress 2023, held October 20-24, 2023, virtually and in Madrid, Spain.

EGFR mutations are present in up to half of nonsquamous advanced NSCLC and the current standard of care in the first line is osimertinib, a tyrosine kinase inhibitor (TKI). However, “resistance and disease progression are nearly inevitable,” explained Byoung Chul Cho, MD, PhD, Yonsei Cancer Center, Yonsei University College of Medicine in Seoul, Republic of Korea, during the presentation of MARIPOSA, which evaluated combining amivantamab, an EGFR-MET bispecific antibody, with lazertinib, a highly selective, central nervous system (CNS)–penetrant TKI.

MARIPOSA enrolled patients with locally advanced or metastatic NSCLC who were treatment-naïve for advanced disease and had a documented EGFR mutation. A total of 1074 patients were randomized in a 2:2:1 fashion to receive either amivantamab plus lazertinib (n = 429), osimertinib (n = 429), or lazertinib (n = 216). The lazertinib monotherapy arm was included to assess the contribution of the components of the combination therapy.

The majority of patients were female (64% on combination, 59% on osimertinib, 63% on lazertinib) and Asian (58%, 59%, and 59%, respectively). Approximately 40% of patients had a history of brain metastases.

At the data cutoff on August 11, 2023, amivantamab plus lazertinib was shown to reduce the risk of progression or death by 30% (HR, 0.70; 95% CI, 0.58-0.85; P < .001). The median follow-up was 22.0 months and the median PFS was 23.7 months for the combination therapy compared with 16.6 months for osimertinib. The median PFS for the lazertinib monotherapy was 18.5 months.

Because MARIPOSA required serial brain MRIs on all patients, which is not normally done for similar trials in EGFR-mutated NSCLC, the investigators also looked at median PFS when censoring CNS-only first progressions. The risk of extracranial progression or death was reduced by 32% for patients on the combination compared with osimertinib (HR, 0.68; 95 CI, 0.56-0.83; P < .001). The median PFS was 27.5 months for amivantamab plus lazertinib compared with 18.5 months for osimertinib.

The PFS benefit was seen across all subgroups. There was similar benefit for patients regardless of history of brain metastases with a 31% reduction in risk (HR, 0.69). The median PFS for the combination in patients with a history of brain metastases was 18.3 months compared with 13.0 months. The median PFS for patients without a history of brain metastases was 27.5 months compared with 19.9 months.

The objective response rate was similar between the 2 groups (86% for the combination vs 85% for osimertinib), but 7% of patients on the combination had a complete response vs 4% on osimertinib. In addition, 62% of patients on amivantamab plus lazertinib had ongoing responses compared with 48% of patients on osimertinib.

The median duration of response was 9 months longer for the combination, with a median of 25.8 months vs 18.8 months on osimertinib. Early survival data showed a small trend favoring amivantamab plus lazertinib over osimertinib, but this is based on only an interim analysis of data.

The combination demonstrated greater toxicity, however. Grade 3 or higher adverse events (AEs) occurred in 75% of patients on amivantamab plus lazertinib compared with 43% of patients on osimertinib. In addition, treatment-related AEs leading to discontinuations of all agents occurred in 10% of patients treated with the combination compared with 3% on osimertinib.

Overall, the PFS was significantly higher and the discontinuations of treatment based on treatment-related AEs were infrequent, Cho concluded.

“Based on the MARIPOSA study, amivantamab plus lazertinib represents a new standard of care in patients with first-line EGFR-mutant advanced NSCLC,” he said.

The presentation was followed up the results of MARIPOSA-2, which evaluated amivantamab plus chemotherapy, with or without lazertinib, vs chemotherapy alone in patients with EGFR-mutated advanced NSCLC who have progressed after treatment with osimertinib. The results were presented by Antonio Passaro, MD, Division of Thoracic Oncology, European Institute of Oncology, in Milan, Italy.

The study sought to understand if the combination of amivantamab and a platinum-based chemotherapy, with or without lazertinib, could address osimertinib-based resistance. Outcomes on just chemotherapy after osimertinib resistance are currently poor, he explained.

MARIPOSA-2 had much of the same key eligibility criteria as MARIPOSA with the addition that patients had to have progressed on or after osimertinib monotherapy as the most recent line of treatment. A total of 657 patients were randomized 2:2:1 to receive either amivantamab, lazertinib, and chemotherapy (n = 263); chemotherapy (n = 263); or amivantamab plus chemotherapy (n = 131). Patients in this trial also underwent serial brain MRIs.

There was 1 change to the trial after it started. The amivantamab-lazertinib-chemotherapy arm had increased hematologic toxicities, so lazertinib was started after completion of chemotherapy, and an extension cohort was started with new patients to evaluate the safety and efficacy of the modified regimen. Of the 263 patients in the triple therapy arm, 166 received lazertinib concurrently and 92 received it after.

At a median follow-up of 8.7 months, amivantamab plus chemotherapy had reduced risk of progression or death by 52% (HR, 0.48; 95% CI, 0.36-0.64; P < .001) and the triple therapy had reduced by 56% (HR, 0.44; 95% CI, 0.35-0.56; P < .001). The median PFS was 6.3 months for amivantamab plus chemotherapy, 8.3 months for amivantamab-lazertinib-chemotherapy, and 4.2 months for chemotherapy alone.

The PFS benefit of both amivantamab regimens was consistent across subgroups regardless of age, sex, and presence of brain metastases.

The amivantamab regimens also showed a statistical increase in response with an objective response rate of 64% for amivantamab plus chemotherapy and 63% for amivantamab-lazertinib-chemotherapy vs 36% for chemotherapy alone. Median duration of response was also significantly longer: 6.9 months for amivantamab plus chemotherapy, 9.4 months for amivantamab-lazertinib-chemotherapy, and 5.6 months for chemotherapy alone.

At 1 year, 53% and 40% of patients on amivantamab plus chemotherapy and amivantamab-lazertinib-chemotherapy, respectively, with a history of brain metastases and no prior brain radiotherapy were progression free compared with 26% on chemotherapy.

Early survival data show a positive trend in favor of amivantamab plus chemotherapy over chemotherapy (HR, 0.77; 95% CI, 0.49-1.21), but no benefit for the triple therapy (HR, 0.96; 95% CI, 0.67-1.35). The triple therapy includes all patients on the regimen, including those who had been on lazertinib concurrently. More follow-up is needed to understand the impact of the dose modification of moving lazertinib after carboplatin, Passaro explained.

Similar to MARIPOSA, the amivantamab regimens had higher rates of grade 3 or higher AEs and dose modifications compared with the control. These rates were higher in the amivantamab-lazertinib-chemotherapy arm. The modified regimen may reduce rates, and further data will be reported after a longer follow-up of the modified regimen.

Based on the results seen today, “we can say amivantamab plus chemotherapy is the new standard of care for patients that are progressing after osimertinib,” Passaro concluded.

In an invited discussion after both presentations, Zofia Piotrowska, MD, assistant professor of medicine, Harvard Medical School, and assistant in medicine, Massachusetts General Hospital, wondered where we go now given the results. She noted that it will be important to identify the patients who need the combination therapy and who can avoid the increased burden.

“In conclusion, I think we're making progress,” she said. “Treatment options for patients with EGFR-mutant lung cancer are growing increasingly numerous and complex, and these are very good problems to have.”