Amivantamab-Based Regimens Show Anticancer Activity in EGFR-Mutated Advanced NSCLC

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Widely anticipated findings from the MARIPOSA1 and MARIPOSA-22 trials were presented at the European Society for Medical Oncology (ESMO) Congress 2023, showing potentially improved outcomes with regimens incorporating the bispecific antibody amivantamab-vmjw for patients with advanced non–small cell lung cancer (NSCL) and epidermal growth factor receptor (EGFR) mutations. The studies were conducted in the first-line and second-line settings, respectively, and with and without the addition of the EGFR tyrosine kinase inhibitor lazertinib and chemotherapy.

Byoung Chul Cho, MD, PhD, of Yonsei University College of Medicine, Seoul, South Korea, who presented the findings from MARIPOSA, noted the third-generation EGFR tyrosine kinase inhibitor osimertinib is the current first-line standard of care, “yet resistance and disease progression are nearly inevitable,” he said. Secondary EGFR and MET alterations may account for 25% to 50% of tumor resistance, he added.

Byoung Chul Cho, MD, PhD

Byoung Chul Cho, MD, PhD

Amivantamab is an EGFR-MET–targeted bispecific antibody with immune cell–directing activity against a wide range of EGFR and MET alterations. Lazertinib is a third-generation EGFR tyrosine kinase inhibitor with penetration into the central nervous system (CNS) and a safety profile well suited for combining it with other agents, according to Dr. Cho. “Combining amivantamab with lazertinib should proactively address resistance and improve clinical outcomes with the addition of chemotherapy,” he maintained.

Amivantamab received accelerated approval from the U.S. Food and Drug Administration for advanced or metastatic NSCLC with EGFR exon 20 insertion mutations. The MARIPOSA studies evaluated its benefit in classical EGFR-mutated disease. In MARIPOSA, amivantamab plus lazertinib significantly reduced the risk of disease progression or death by 30% as a first-line treatment. In MARIPOSA-2, as a second-line treatment after osimertinib, amivantamab plus chemotherapy reduced this risk by 52%, whereas amivantamab plus lazertinib and chemotherapy reduced the risk by 56%, investigators reported.


The phase III MARIPOSA trial enrolled 1,074 patients with treatment-naive EGFR-mutated advanced or metastatic NSCLC (more than 40% with a history of brain metastases). They were randomly assigned to receive amivantamab plus lazertinib, osimertinib alone, or lazertinib alone.1

“We are thrilled to say the study met its primary endpoint of progression-free survival by blinded independent central review,” Dr. Cho said. “We saw consistent benefit in patients with and without brain metastases, more durable responses, and a favorable trend in overall survival at the early interim assessment…. Amivantamab plus lazertinib represents a new first-line standard of care in patients with EGFR-mutant advanced non–small cell lung cancer.”

At a median follow-up of 22 months, median progression-free survival was 23.7 months with amivantamab plus lazertinib vs 16.6 months with omisertinib (hazard ratio [HR] = 0.70; P < .001). At 24 months, 48% vs 34%, respectively, were progression-free, and benefit was seen across all predefined subgroups. Lazertinib monotherapy also demonstrated “meaningful clinical activity” based on a median progression-free survival of 18.5 months. “This indicates lazertinib is a wonderful combination partner for amivantamab,” Dr. Cho said.

“Unlike previous studies in EGFR-mutant lung cancer, MARIPOSA required serial brain MRIs in all patients, which might have led to more frequent detection of CNS disease progression. Therefore, we wanted to know what the median progression-free survival would be when it is measured in a similar way as previous studies, and we did this by looking at the extracranial progression-free survival where CNS-alone first disease progression was censored,” he explained.

In this analysis, amivantamab plus lazertinib led to a 9-month improvement in progression-free survival, based on a median of 27.5 months vs 18.5 months with osimertinib (HR = 0.68; P < .001). Benefit was consistent (HR = 0.69) for subsets with and without brain metastases.

Response rates were the same—86% with the combination and 85% with osimertinib—but the combination yielded more complete responses (7% vs 4%) and a longer median duration of response (25.8 months vs 16.8 months). Progression-free survival after first subsequent therapy was also improved with the combination (HR = 0.75; P = .03), and early overall survival data showed a favorable trend (HR = 0.80; P = .11), he reported.

Treatment-related adverse events grade ≥ 3 occurred in 73% with the combination vs 43% with osimertinib, with subsequent death in 8% and 7% and treatment discontinuation in 10% and 3%, respectively. EGFR- and MET-related adverse events were higher with the combination, but diarrhea was more common with osimertinib. Rates of interstitial lung disease or pneumonitis remained low at about 3% per arm. Venous thromboembolism, mostly grade 1 or 2, was more common with the combination, mostly in the first 4 months. “Prophylactic dose anticoagulation is now recommended for the first 4 months of treatment in ongoing trials of amivantamab plus lazertinib,” Dr. Cho added.


MARIPOSA-2 evaluated amivantamab plus chemotherapy with and without lazertinib in 657 patients who experienced disease progression on osimertinib, and progression-free survival benefits were reported for both regimens, compared with chemotherapy alone.2 These results met the study’s dual endpoints of improved progression-free survival with both amivantamab regimens by blinded independent review.

“At a median follow-up of 8.7 months, amivantamab plus chemotherapy and amivantamab plus lazertinib and chemotherapy reduced the risk of disease progression or death by 52% and 56%, respectively,” said Antonio Passaro, MD, PhD, of the European Institute of Oncology, Milan, Italy. “These regimens are the first to demonstrate improved progression-free survival vs chemotherapy in EGFR-mutated advanced NSCLC after disease progression on osimertinib. MARIPOSA-2 sets a new landmark in osimertinib-resistant NSCLC.”

Antonio Passaro, MD, PhD

Antonio Passaro, MD, PhD

Based on the results of this trial, a supplemental biologics application has been submitted to the U.S. Food and Drug Administration for the use of amivantamab plus chemotherapy in this setting.

Compared with a median progression-free survival of 4.2 months with chemotherapy alone, median progression-free survival was 6.3 months with amivantamab plus chemotherapy (HR = 0.48; P < .001) and 8.3 months with amivantamab plus lazertinib and chemotherapy (HR = 0.44; P < .001). For both regimens, benefit was consistent across subgroups. The findings were concurrently published in Annals of Oncology.3

More than a 40% reduction in the risk of intracranial disease progression was achieved in both amivantamab-containing arms, suggestive of antitumor CNS effects, he said. Median intracranial progression-free survival was 12.5 months with amivantamab plus chemotherapy (HR = 0.55; P = .001) and 12.8 months with amivantamab plus lazertinib and chemotherapy, compared with 8.3 months with chemotherapy alone (HR = 0.58; P < .001). Reduction in risk was even greater in the subset of patients with a history of brain metastases and no prior brain radiotherapy.

The objective response rate was 64% with amivantamab plus chemotherapy and 63% with amivantamab plus lazertinib and chemotherapy compared with 36% with chemotherapy alone (P < .001 for both). There were six complete responses (2%) to amivantamab plus lazertinib and chemotherapy, and the median duration of response was longer for both experimental groups. In addition, the odds of achieving an objective response was approximately three times higher for the amivantamab-containing arms than for chemotherapy. Importantly, the percent of patients with progressive disease as their best response was 20% with chemotherapy, compared with 5% and 8% with the amivantamab-containing regimens.

Interim analysis of overall survival showed hazard ratios of 0.77 (95% confidence interval [CI] = 0.49–1.21) with amivantamab plus chemotherapy and 0.96 (95% CI = 0.67–1.35) with amivantamab plus lazertinib and chemotherapy.

Patients in the amivantamab arms had higher rates of grade ≥ 3 adverse events and required more dose modifications. Based on undue hematologic toxicity with amivantamab plus lazertinib and chemotherapy—specifically grade ≥ 3 neutropenia (55%), thrombocytopenia (37%), and leukopenia (27%)—the protocol was revised to start lazertinib after carboplatin is completed. “The modified regimen may reduce these rates. Those data will be reported after longer follow-up,” he said.

Dr. Passaro also indicated that subcutaneous amivantamab is in clinical trials “and should improve convenience and quality of life” for patients. 

DISCLOSURE: Dr. Cho reported financial relationships with Abion, BeiGene, Novartis, AstraZeneca, Boehringer Ingelheim, Roche, BMS, CJ, CureLogen, Cyrus Therapeutics, Ono, Onegene Biotechnology, Yuhan, Pfizer, Eli Lilly, GI-Cell, Guardant Health, HK Inno-N, Imnewrun Biosciences, Janssen, Takeda, MSD, Kanaph Therapeutic, Bridgebio Therapeutics, Cyrus Therapeutics, Oscotec, Medpacto, Blueprint Medicines, RandBio, Hanmi, Interpark Bio Convergence Corp, J INTS BIO, TheraCanVac, Gencurix, Champions Oncology, Crown Bioscience, Imagen, MOGAM Institute, LG Chem, GI Innovation, AbbVie, AstraZeneca, Bayer, CJ Blossom Park, Dizal Pharma, Genexine, Novartis, Nuvalent, Oncternal, Regeneron, Dong-A ST, Yuhan, ImmuneOncia, Illumina, Therapex, JINTSbio, CHA Bundang Medical Center, and DAAN Biotherapeutics. Dr. Passaro reported financial relationships with AstraZeneca, Bristol Myers Squibb, Eli Lilly, Janssen, Pfizer, Roche, Bayer, Boehringer Ingelheim, Merck Sharp & Dohme, Mundipharma, Daiichi Sankyo, and Medscape.


1. Cho BC, Felip E, Spira AI, et al: Amvantamab plus lazertinib vs osimertinib as first-line treatment in patients with EGFR-mutated, advanced non-small cell lung cancer: Primary results from MARIPOSA, a phase III, global, randomized, controlled trial. ESMO Congress 2023. Abstract LBA14. Presented October 23, 2023.

2. Passaro A, Cho BC, Wang Y, et al: Amivantamab plus chemotherapy (with or without lazertinib) vs chemotherapy in EGFR-mutated advanced NSCLC after progression on osimertinib: MARIPOSA-2, a phase III, global, randomized, controlled trial. ESMO Congress 2023. Abstract LBA15. Presented October 23, 2023.

3. Passaro A, Wang J, Wang Y, et al: Amivantamab plus chemotherapy with and without lazertinib in EGFR-mutant advanced NSCLC after disease progression on osimertinib: Primary results from the phase III MARIPOSA-2 study. Ann Oncol. October 23, 2023 (early release online).

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Zofia Piotrowska, MD, of the Massachusetts General Hospital/Harvard Medical School, Boston, noted that MARIPOSA and MARIPOSA-2 are “two well-designed, randomized phase III trials, each meeting its primary endpoints and representing important advances for patients with EGFR-mutant lung cancer.”...