Amivantamab plus chemotherapy vs chemotherapy in <i>EGFR</i> -mutant advanced NSCLC after disease progression on osimertinib: Outcomes by osimertinib resistance mechanisms in MARIPOSA-2.

Abstract

8639 Background: Amivantamab (ami), an EGFR-MET bispecific antibody with immune cell–directing activity, combined with chemotherapy (chemo) is approved for patients with EGFR -mutant advanced NSCLC after disease progression on an EGFR TKI. In the phase 3 MARIPOSA-2 study (NCT04988295), ami-chemo significantly improved progression-free survival (PFS) vs chemo after disease progression on osimertinib (osi; HR, 0.48; P &lt;0.001). Nearly all patients develop resistance after osi, most commonly MET amplifications ( MET amp) and EGFR resistance mutations (Chmielecki Nat Commun 2023; Besse Ann Oncol 2024; Yang JTO 2024). We evaluated outcomes by baseline osi resistance mechanisms in MARIPOSA-2. Methods: MARIPOSA-2 enrolled participants (pts) with EGFR -mutant (Ex19del or L858R) advanced NSCLC whose disease progressed on osi; ~1/3 received osi as 2L therapy. This analysis included pts randomized to ami-chemo (n=131) or chemo (n=263). Pathogenic alterations were identified by next-generation sequencing (NGS) of blood circulating tumor DNA (ctDNA) with Guardant360 CDx or PredicineCARE assay. Results: Baseline ctDNA for NGS analysis of pathogenic alterations was available for 341 pts (87%; ami-chemo, n=120; chemo, n=221). Characteristic of post-osi resistance, the most commonly detected baseline alterations for ami-chemo vs chemo were MET amp (10% vs 14%) and secondary EGFR (C797X, L718X, G724X, L792X, G796X) resistance mutations (13% vs 18%). Ami-chemo improved median PFS (mPFS) vs chemo among pts with MET amp (HR, 0.51; P =0.078) and secondary EGFR mutations (HR, 0.55; P =0.125; Table). Furthermore, ami-chemo significantly prolonged mPFS vs chemo for pts with EGFR / MET independent (HR, 0.54; P =0.025) and unknown (HR, 0.31; P &lt;0.001) resistance mechanisms. Conclusions: Ami-chemo improved mPFS vs chemo across baseline resistance subgroups, including EGFR/MET dependent, independent, and unknown resistance. Ami-chemo is an important treatment option, regardless of baseline osi resistance mechanism, for pts with EGFR -mutant advanced NSCLC after progression on an EGFR TKI. Clinical trial information: NCT04988295 . Ami-chemo, chemo (n) Ami-chemo vs chemo, mPFS (mo) HR (95% CI); P value Detectable baseline ctDNA 104, 195 5.9 vs 4.2 0.49 (0.36–0.68);&lt;0.001 TP53 co-mutation 59, 127 5.6 vs 4.1 0.63 (0.44–0.92); 0.014 MET amp present 12, 30 4.4 vs 3.1 0.51 (0.24–1.11); 0.078 Secondary EGFR resistance mutations present 15, 39 5.7 vs 5.0 0.55 (0.26–1.19); 0.125 Secondary EGFR resistance mutations absent 89, 156 6.2 vs 4.2 0.47 (0.34–0.67);&lt;0.001 EGFR/MET dependent 27, 62 5.5 vs 4.1 0.57 (0.33-0.99); 0.042 EGFR/MET independent 39, 41 5.6 vs 3.9 0.54 (0.31–0.94); 0.025 Unknown 38, 92 9.7 vs 4.2 0.31 (0.17–0.56);&lt;0.001 Independent + unknown 77, 133 7.0 vs 4.2 0.47 (0.32–0.68);&lt;0.001