BRAF wild-type metastatic colorectal cancer, chemorefractory & 1L¶

Abstract: 3548 (poster) · Session: Gastrointestinal Cancer — Colorectal and Anal poster session, ASCO Annual Meeting (May 29 – Jun 2, 2026, Chicago) · Presenter: Janssen/J&J OrigAMI-1 investigators · Embargo: per ASCO

At a glance¶

Sponsor: Janssen Research & Development / Johnson & Johnson
PI / presenter: OrigAMI-1 study investigators (Janssen/J&J)
NCT ID: NCT05379595
Phase: 1b/2
Design: Open-label, multicenter, multi-cohort. Monotherapy cohorts (left-sided anti-EGFR–naïve, left-sided anti-EGFR–pretreated, right-sided) plus combination cohorts of amivantamab + FOLFOX or FOLFIRI. Enriched for KRAS/NRAS/BRAF and EGFR-ectodomain wild-type, no ERBB2/HER2 amplification.
N: 94 (monotherapy, chemorefractory cohort, JCO publication); combination cohorts reported separately
Primary endpoint(s): Objective response rate (ORR) by RECIST; safety. Secondary: duration of response (DOR), PFS, biomarker correlates.
Comparator: None (single-arm, phase 1b/2)
Indication: RAS/BRAF wild-type metastatic colorectal cancer (mCRC)
Line: Chemorefractory (monotherapy, median 2 prior lines) and first-/second-line (combination cohorts)

Headline result¶

The OrigAMI-1 data presented at the 2026 ASCO Annual Meeting (abstract 3548) is a biomarker analysis across tumor subtypes in RAS/BRAF wild-type mCRC, supporting the EGFR–MET mechanism of amivantamab. Reported translational findings: amivantamab treatment downregulated EGFR and cell-cycle pathway signatures and upregulated immune signatures — significant increases in dendritic-cell signature (P<.005) and T-cell–inflamed signature (P<.05) in paired baseline vs C3D1 tumor samples, plus increased cytolytic/NK-mediated cytotoxicity scores; higher baseline EGFR-ligand (AREG/EREG) expression correlated with benefit (in cohort A, AREG-high vs -low PFS 9.1 vs 4.5 months, P=.0076). The underlying efficacy (reported in the JCO publication and at ASCO GI 2026, not the Annual Meeting): monotherapy ORR was 29% (left-sided, anti-EGFR–naïve), 19% (left-sided, anti-EGFR–pretreated), and 22% (right-sided) across N=94 chemorefractory patients (median 2 prior lines). In the chemotherapy-combination cohorts, first-line ORR was ~73% with durable responses beyond 16 months, and ~49% ORR overall per J&J topline (ASCO GI 2026, abstract 166).

Mechanism / class¶

Amivantamab (RYBREVANT) is a bispecific antibody targeting EGFR and MET with immune-cell–directing (Fc) activity. FDA-approved across EGFR-mutant NSCLC settings (exon 20 insertions; in combination with chemotherapy and with lazertinib). In mCRC it is investigational; OrigAMI-1 is the proof-of-concept phase 1b/2, with phase 3 confirmatory studies ongoing (OrigAMI-2 in 1L left-sided RAS/BRAF WT, OrigAMI-3 with FOLFIRI in previously treated disease).

Practice-changing?¶

Pending. OrigAMI-1 is a single-arm phase 1b/2 generating hypothesis-level efficacy and supportive translational/biomarker data; the ASCO 2026 Annual Meeting contribution (abstract 3548) is a biomarker poster, not a randomized efficacy readout. The durable first-line combination responses and biomarker rationale support the ongoing randomized phase 3 OrigAMI-2/-3 trials, which will determine whether amivantamab displaces first-generation anti-EGFR antibodies (cetuximab) in RAS/BRAF wild-type mCRC.

Cross-links¶

Other ASCO 2026 trials: see ../index.md for GI / colorectal trials
AACR 2026: ../../aacr-2026/index.md

Sources¶

ASCO Meeting Library (OrigAMI-1 abstract record): https://www.asco.org/abstracts-presentations/241913
JCO (OrigAMI-1 monotherapy primary results): https://ascopubs.org/doi/10.1200/JCO-25-02187
J&J ASCO 2026 press release ("more than 20 studies at ASCO 2026," lists OrigAMI-1 biomarker poster #3548): https://www.jnj.com/media-center/press-releases/johnson-johnson-ushers-in-the-next-wave-of-innovation-in-cancer-care-with-more-than-20-clinical-and-real-world-studies-at-asco-2026
J&J ASCO GI 2026 release (combination efficacy, abstract 166): https://www.jnj.com/media-center/press-releases/rybrevant-amivantamab-vmjw-longer-term-results-show-promising-and-durable-responses-in-difficult-to-treat-colorectal-cancer
Targeted Oncology (OrigAMI-1 biomarker / EGFR-inhibitor shift): https://www.targetedonc.com/view/new-origami-1-data-signal-shift-beyond-first-gen-egfr-inhibitors-in-metastatic-crc
The ASCO Post (amivantamab in chemorefractory RAS/BRAF WT mCRC): https://ascopost.com/news/april-2026/amivantamab-in-chemorefractory-rasbraf-wild-type-metastatic-colorectal-cancer/
ClinicalTrials.gov: https://clinicaltrials.gov/study/NCT05379595