Amivantamab plus FOLFOX or FOLFIRI in <i>RAS/BRAF</i> wild-type metastatic colorectal cancer: Long-term follow-up from the phase 1b/2 OrigAMI-1 study.

Abstract

166 Background: Amivantamab (ami) is an EGFR-MET bispecific antibody with immune cell-directing activity that has demonstrated activity across several solid tumor types. In an earlier report, ami plus FOLFOX or FOLFIRI demonstrated rapid and durable antitumor activity among participants (pts) with RAS/BRAF wild-type (WT) metastatic colorectal cancer (mCRC), resulting in their potential eligibility for curative-intent surgery (Pietrantonio ESMO 2024). Here, we present longer follow-up data. Methods: Cohorts D and E of the OrigAMI-1 study (NCT05379595) evaluated ami plus FOLFOX or FOLFIRI in mCRC. Enrolled pts were wild-type for KRAS , NRAS , BRAF , and EGFR ectodomain by central ctDNA testing, without ERBB2 / HER2 amplification. A maximum of one prior systemic line in the metastatic setting was allowed. Prior EGFR inhibitor was exclusionary along with oxaliplatin- or irinotecan-based chemotherapy for cohorts D and E, respectively. Response was assessed by the investigator per RECIST v1.1. Results: As of 28-Jul-2025, median follow-up was 16.0 months (range, 1.2−27.0) for the 43 pts who received either ami-FOLFOX (n=20) or ami-FOLFIRI (n=23). Median age was 62 years; the majority (72%) were male and had left-sided disease (84%). Objective response rate (ORR) was 51% (95% CI, 36−67), with a time to first response of 8.3 weeks (range, 7.3−20.3) and a median duration of response (DoR) of 9.3 months (95% CI, 5.8−14.5). Overall, median progression-free survival (PFS) was 9.2 months (95% CI, 6.4−13.1) and median overall survival (OS) was 19.7 months (95% CI, 16.2−not estimable [NE]). Further, 6 pts underwent curative-intent surgery and were censored upon completion of surgery. There were 11 pts who were previously untreated for metastatic disease. For the 1L subgroup, ORR was 73% (95% CI, 39−94) and median DoR was NE (95% CI, 7.3−NE). Among the remaining 32 pts who received 2L ami-chemo, ORR was 44% (95% CI, 26−62) and median DoR was 7.4 months (95% CI, 5.4−14.5). There were 12 pts (38%) who remained on 2L treatment for &gt;1 year, with 2 pts receiving ami for &gt;2 years as of data cutoff. Among the 30 pts with liver target lesions, intrahepatic ORR was 57% (95% CI, 37−75) and median DoR was 11.4 months (95% CI, 5.6−14.7). Median PFS was 11.3 months (95% CI, 5.9−16.4) and median OS was NE. The safety profile remained consistent with prior reports of ami-FOLFOX and ami-FOLFIRI in this participant population. Treatment-emergent adverse events (AEs) were primarily related to EGFR or MET inhibition and hematologic toxicities. Most common grade ≥3 AE (any ≥10%) was neutropenia. Conclusions: Among pts with RAS/BRAF WT mCRC, ami-FOLFOX and ami-FOLFIRI demonstrated meaningful and durable antitumor activity. Over one-third of pts receiving ami-FOLFOX or ami-FOLFIRI as 2L treatment remained on ami for at least 1 year. Safety profiles were consistent with prior reports and those of the individual agents. Clinical trial information: NCT05379595 .