Rybrevant Combo Improves Lung Cancer Outcomes After Tagrisso Failure

Rybrevant plus chemotherapy improved response and delayed disease growth for patients with EGFR-mutated lung cancer after Tagrisso treatment.

Among patients with EGFR-mutated non–small cell lung cancer (NSCLC), Rybrevant (amivantamab-vmjw) plus chemotherapy improved efficacy compared with chemotherapy alone according to results from the phase 3 MARIPOSA-2 trial assessing Tagrisso (osimertinib) resistance mechanisms, as 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 Rybrevant plus chemotherapy with or without Lazcluze (lazertinib) for patients with EGFR-mutated NSCLC after disease progression on or after Tagrisso.

For patients with detectable ctDNA at baseline, the median progression-free survival (PFS) in the Rybrevant/chemotherapy group (104 patients) was 5.9 months versus 4.2 months in the chemotherapy alone arm (195 patients). The objective response rate (ORR) was 67% versus 39%, respectively.

For patients who were EGFR/MET independent, the median PFS was 5.6 months in the Rybrevant arm (39 patients) versus 3.9 months in the chemotherapy arm (41 patients). The ORR was 64% versus 37% between both arms, respectively.

For patients who were EGFR/MET-dependent, the median PFS was 5.5 months in the Rybrevant arm (27 patients) versus 4.1 months in the chemotherapy arm (62 patients). The ORR between either arm was 70% versus 35%.

For those with unknown resistance mechanisms, the median PFS was 9.7 months in the Rybrevant arm (38 patients) versus 4.2 months in the chemotherapy arm (92 patients). The ORR was 68% versus 43%, respectively.

For patients who had a MET amplification, the median PFS was 4.4 months in the Rybrevant arm (12 patients) versus 3.1 months in the chemotherapy arm (30 patients). The ORR was 67% versus 23%, respectively.

In patients with secondary EGFR mutations, the median PFS was 5.7 months in the Rybrevant arm (15 patients) versus 5 months in the chemotherapy arm (39 patients). The ORR was 73% versus 44%, respectively.

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

The trial randomly assigned 657 patients 2:2:1 to either Rybrevant/Lazcluze (263 patients), chemotherapy (263 patients), or Rybrevant/chemotherapy (131 patients). The focus of the presentation was in the Rybrevant/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, progressed on or after Tagrisso monotherapy, and had an ECOG performance score of 0 or 1.

Resistance mechanisms that were analyzed included TP53 co-mutation, 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 Guardant 360 CDx or PredicineCARE NGS assay, followed by blood samples collected again at the end of treatment.

Reference:

“Amivantamab plus chemotherapy versus chemotherapy in EGFR-mutant advanced NSCLC after disease progression on Tagrisso: Outcomes by Tagrisso resistance mechanisms in MARIPOSA-2” by Dr. Raffaele Califano, et al., presented at the 2025 American Society of Clinical Oncology Annual Meeting.

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