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

• Main Authors: Passaro, A., Wang, J., Wang, Y., Lee, S. -H., Melosky, B., Shih, J. -Y., Azuma, K., Juan-Vidal, O., Cobo, M., Felip, E., Girard, N., Cortot, A. B., Califano, R., Cappuzzo, F., Owen, S., Popat, S., Tan, J. -l., Salinas, J., Tomasini, P., Gentzler, R. D., William, W. N., Reckamp, K. L., Takahashi, T., Ganguly, S., Kowalski, D. M., Bearz, A., MacKean, M., Barala, P., Bourla, A. B., Girvin, A., Greger, J., Millington, D., Withelder, M., Xie, J., Sun, T., Shah, S., Diorio, B., Knoblauch, R. E., Bauml, J. M., Campelo, R. G., Cho, B. C., Investigators, MARIPOSA-2
• Format: Article
• Published: Elsevier 2024
• Subjects: R Medicine (General)
• Online Access: http://eprints.um.edu.my/45788/; https://doi.org/10.1016/j.annonc.2023.10.117
• Institution: Universiti Malaya

Background: Amivantamab plus carboplatin-pemetrexed (chemotherapy) with and without lazertinib demonstrated antitumor activity in patients with refractory epidermal growth factor receptor (EGFR)-mutated advanced non-smallcell lung cancer (NSCLC) in phase I studies. These combinations were evaluated in a global phase III trial. Patients and methods: A total of 657 patients with EGFR-mutated (exon 19 deletions or L858R) locally advanced or metastatic NSCLC after disease progression on osimertinib were randomized 2 : 2 : 1 to receive amivantamab - lazertinib-chemotherapy, chemotherapy, or amivantamab-chemotherapy. The dual primary endpoints were progression-free survival (PFS) of amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy. During the study, hematologic toxicities observed in the amivantamab-lazertinib-chemotherapy arm necessitated a regimen change to start lazertinib after carboplatin completion. Results: All baseline characteristics were well balanced across the three arms, including by history of brain metastases and prior brain radiation. PFS was significantly longer for amivantamab-chemotherapy and amivantamab-lazertinib - chemotherapy versus chemotherapy hazard ratio (HR) for disease progression or death 0.48 and 0.44, respectively; P < 0.001 for both; median of 6.3 and 8.3 versus 4.2 months, respectively]. Consistent PFS results were seen by investigator assessment (HR for disease progression or death 0.41 and 0.38 for amivantamab -chemotherapy and amivantamab-lazertinib-chemotherapy, respectively; P < 0.001 for both; median of 8.2 and 8.3 versus 4.2 months, respectively). Objective response rate was significantly higher for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy (64% and 63% versus 36%, respectively; P < 0.001 for both). Median intracranial PFS was 12.5 and 12.8 versus 8.3 months for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy (HR for intracranial disease progression or death 0.55 and 0.58, respectively). Predominant adverse events (AEs) in the amivantamab-containing regimens were hematologic, EGFR-, and MET -related toxicities. Amivantamab-chemotherapy had lower rates of hematologic AEs than amivantamab-lazertinib-chemotherapy. Conclusions: Amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy improved PFS and intracranial PFS versus chemotherapy in a population with limited options after disease progression on osimertinib. Longer follow-up is needed for the modified amivantamab-lazertinib-chemotherapy regimen.