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MSS-CRC novel combinations — synthesis dossier (ADCs, bispecifics, IO combinations)

Headline: ASCO GI 2026 surfaced incremental but not yet practice-changing activity in MSS metastatic CRC across three classes — EGFRxMET bispecifics (OrigAMI-1 amivantamab), PD-1xVEGF bispecifics in CRC follow-on (rilvegostomig and class-mates), and emerging ADCs. None displaces SOC alone; together they sketch the post-regorafenib / TAS-102 landscape for the ~90% of metastatic CRC patients without MSI-H, BRAF-V600E, KRAS-G12C, or HER2 amplification.

At a glance

  • Sponsor / PI / institution: Multi-sponsor synthesis — J&J (amivantamab / OrigAMI-1), AstraZeneca (rilvegostomig PD-1xTIGIT and class), various ADC sponsors
  • NCT ID: NCT05379595 (OrigAMI-1); rilvegostomig CRC cohorts NCT05848739 / related; ADC trials sponsor-specific
  • Phase / arms / N: Phase 1b/2 dose-expansion across cohorts; ~50-200 patients per readout
  • Primary endpoint(s): ORR, DoR, PFS, safety
  • Indication / line: 2L+ MSS metastatic CRC, biomarker subsets (EGFR-amp, MET-amp, post-chemo+anti-EGFR)
  • Comparator: Single-arm vs historical reference
  • Session: Day 1 (Thu Jan 8, 2026), CRC General Session + posters, Moscone West

Headline result

OrigAMI-1 (amivantamab in MSS / EGFR-amp mCRC): durability update post-AACR 2025 confirmed activity in a biomarker-selected MSS subset, with response durability supporting the EGFRxMET bispecific class as a real option in EGFR-amplified or anti-EGFR rechallenge populations. Rilvegostomig and PD-1xTIGIT class: CRC cohort signals remain modest in unselected MSS but show signal in MSS subsets with high TLS / inflamed microenvironment. ADC readouts: HER2-low / TROP2-directed ADC follow-ups extend class read-through from breast and gastric. No single MSS-CRC asset declared the next 2L+ SOC.

Mechanism / class

Three mechanism classes synthesized here: (1) EGFRxMET bispecifics (amivantamab) — co-engage EGFR + MET to block bypass-track resistance; (2) PD-1xVEGF / PD-1xTIGIT bispecifics — combine checkpoint blockade with anti-angiogenic or T-cell co-inhibitory release; (3) ADCs against HER2-low, TROP2, CEACAM5, B7-H3 in MSS CRC.

Class deep dive

Class architecture. Synthesis spans three mechanism families across mostly single-arm Phase 1b/2 dose-expansion cohorts (50-200 patients each). No randomized confirmatory data at this readout — class-level inference is by cross-trial framing against historical regorafenib (~1.5 mo PFS gain in CORRECT) and trifluridine/tipiracil ± bev (SUNLIGHT) benchmarks.

Endpoint definitions. Predominantly investigator-assessed ORR per RECIST 1.1 with confirmation requirement; DoR and PFS as supportive. Some sponsor programs (J&J OrigAMI-1) prespecified central BICR for ORR. ctDNA dynamics increasingly used as pharmacodynamic readout especially in EGFR-amp / anti-EGFR rechallenge populations.

Key subgroup analyses.

  • EGFR-amp (FISH +/NGS) vs non-amp MSS-CRC: OrigAMI-1 amivantamab activity concentrated in EGFR-amplified subset; non-amp signal weaker.
  • Anti-EGFR rechallenge with ctDNA selection (RAS-wt confirmed): an emerging biomarker-enrichment frame across EGFRxMET bispecifics and anti-EGFR ADCs.
  • HER2-low (IHC 1+/2+ FISH-) MSS-CRC: trastuzumab deruxtecan and follow-on TROP2/CEACAM5 ADCs being explored; TBD on cross-trial response rates.
  • Inflamed / high-TLS MSS-CRC tumors: PD-1xVEGF / PD-1xTIGIT bispecifics show signal in inflamed-microenvironment subsets; cold-tumor MSS-CRC unmoved.

Comparator context. SOC 3L+ MSS-CRC remains regorafenib (CORRECT/CONCUR) or TAS-102 + bev (SUNLIGHT, mOS 10.8 vs 7.5 mo) — both modest. No single ASCO GI 2026 MSS-CRC asset displaces the SOC; class momentum is real but pre-pivotal.

FDA / regulatory implications. No filings expected from ASCO GI 2026 MSS-CRC datasets alone. OrigAMI-1 amivantamab and select ADC programs may pursue accelerated approval in biomarker-enriched subsets pending randomized confirmation in 2026-2027. PD-1xVEGF / PD-1xTIGIT class needs Phase 3 confirmation before regulatory engagement in CRC.

Discussant takeaway

CRC discussants framed the MSS-CRC space as still defined by absence — no single class has yet declared itself the post-regorafenib / TAS-102 backbone. Biomarker enrichment (EGFR-amp, HER2-low, MET-amp) is the path forward; all-comer MSS CRC trials remain hard.

Practice-changing verdict

No — incremental. No single MSS-CRC asset at ASCO GI 2026 reaches practice-changing threshold. Class momentum is real for EGFRxMET bispecifics; ADCs and PD-1 bispecifics remain Phase 2 stories needing randomized confirmation.

  • ASCO 2026 — OrigAMI-1 durability + MSS-CRC ADC randomized data expected at May GI track
  • AACR 2026 — bispecific / ADC mechanism sessions
  • ESMO 2026 — EU MSS-CRC ADC follow-ups expected Oct
  • JPM 2026 — J&J / AZ / ADC sponsor framing

Sources