Amivantamab/Chemo Sustains Efficacy Despite Osimertinib Resistance in EGFR-Mutated NSCLC

Amivantamab/chemotherapy remained efficacious regardless of the osimertinib resistance mechanism for patients with EGFR-mutated NSCLC.

Amivantamab-vmjw (Rybrevant) plus chemotherapy improved efficacy compared with chemotherapy alone for patients with EGFR-mutated non–small cell lung cancer (NSCLC), according to results from the phase 3 MARIPOSA-2 trial (NCT04988295) assessing osimertinib (Tagrisso) resistance mechanisms, which were presented at the 2025 American Society of Clinical Oncology Annual Meeting.

The basis of the MARIPOSA-2 trial was to assess the efficacy and safety of amivantamab plus chemotherapy with or without lazertinib (Lazcluze) for patients with EGFR-mutated NSCLC after disease progression on or after osimertinib.

For patients with detectable ctDNA at baseline, the median progression-free survival (PFS) in the amivantamab/chemotherapy group (n = 104) was 5.9 months (95% CI, 5.5-8.4) vs 4.2 months (95% CI, 4.0-4.4) in the chemotherapy-alone arm (n = 195; HR, 0.49; 95% CI, 0.36-0.68; P <.0001). The objective response rate (ORR) was 67% (95% CI, 57%-76%) vs 39% (95% CI, 32%-47%), respectively (OR, 3.12; 95% CI, 1.89-5.16; P <.0001).

For patients who were EGFR/MET independent, the median PFS was 5.6 months (95% CI, 4.4-7.2) in the amivantamab arm (n = 39) vs 3.9 months (95% CI, 2.1-5.4) in the chemotherapy-alone arm (n = 41; HR, 0.54; 95% CI, 0.31-0.94; P = .025). The ORR was 64% (95% CI, 47%-79%) vs 37% (95% CI, 22%-53%) in both arms, respectively (OR, 3.10; 95% CI, 1.24-7.71; P = .015).

For patients who were EGFR/MET dependent, the median PFS was 5.5 months (95% CI, 4.3-11.1) in the amivantamab arm (n = 27) vs 4.1 months (95% CI, 3.0-4.4) in the chemotherapy-alone arm (n = 62; HR, 0.57; 95% CI, 0.33-0.99; P = .042). The ORR was 70% (95% CI, 50%-86%) vs 35% (95% CI, 24%-49%; OR, 4.32; 95% CI, 1.63-11.46; P = .003), respectively.

For those with unknown resistance mechanisms, the median PFS was 9.7 months (95% CI, 6.2-not evaluable [NE]) in the amivantamab arm (n = 38) vs 4.2 months (95% CI, 4.0-5.7) in the chemotherapy-alone arm (n = 92; HR, 0.31; 95% CI, 0.17-0.56; P <.001). The ORR was 68% (95% CI, 50%-82%) vs 43% (95% CI, 33%-54%), respectively (OR, 2.72; 95% CI, 1.22-6.09; P = .015).

For patients with a MET amplification, the median PFS was 4.4 months (95% CI, 1.5-5.8) in the amivantamab arm (n = 12) vs 3.1 months (95% CI, 2.2-4.1) in the chemotherapy-alone arm (n = 30; HR, 0.51; 95% CI, 0.24-1.11; P = .078). The ORR was 67% (95% CI, 35%-90%) vs 23% (95% CI, 10%-42%), respectively (OR, 6.57; 95% CI, 1.51-28.54; P = .012).

In patients with secondary EGFR mutations, the median PFS was 5.7 months (95% CI, 4.2-NE) in the amivantamab arm (n = 15) vs 5.0 months (95% CI, 3.2-6.8) in the chemotherapy arm (n = 39; HR, 0.55; 95% CI, 0.26; 95% CI, 0.26-1.19; P = .125). The ORR was 73% (95% CI, 45%-92%) vs 44% (95% CI, 28%-60%), respectively (OR, 3.56; 95% CI, 0.96-13.16; P = .057).

“Amivantamab/chemotherapy improved median PFS and ORR vs chemotherapy across baseline subgroups, including those associated with known or unknown mechanisms, as identified with ctDNA NGS [next-generation sequencing] analysis,” Raffaele Califano, MD, a consultant in medical oncology at The Christie and University Hospital of South Manchester in England, and coauthors wrote in the poster. “Amivantamab/chemotherapy was efficacious regardless of the type of osimertinib resistance mechanism.”

The trial randomly assigned 657 patients 2:2:1 to amivantamab/lazertinib (n = 263), chemotherapy (n = 263), or amivantamab/chemotherapy (n = 131). The focus of the presentation was on the amivantamab/chemotherapy and chemotherapy-alone arms.

Patients were eligible for treatment if they had locally advanced or metastatic NSCLC, documented EGFR exon 19 deletion or L858R substitutions, progression on or after osimertinib monotherapy, and an ECOG performance status of 0 or 1.

Resistance mechanisms that were analyzed included TP53 comutation, MET amplification, secondary EGFR mutations, EGFR/MET independent, EGFR/MET dependent, or unknown.

The diagnostic test was ctDNA NGS. Blood samples were collected at baseline. The analysis of the ctDNA was done with Guardant360 CDx or PredicineCARE NGS assay, followed by blood samples collected again at the end of treatment.

Reference

Califano R, Passaro A, Tan JL, et al. Amivantamab plus chemotherapy vs chemotherapy in EGFR-mutant advanced NSCLC after disease progression on osimertinib: outcomes by osimertinib resistance mechanisms in MARIPOSA-2. Presented at the 2025 American Society of Clinical Oncology Annual Meeting, May 30-June 3, 2025; Chicago, IL. doi:10.1200/JCO.2025.43.16_suppl.8639