Colorectal Cancer Clinical Trial Landscape

Why colorectal cancer trial monitoring matters

Colorectal cancer is one of the most active therapeutic areas in GI oncology, with hundreds of trials on ClinicalTrials.gov spanning early-stage adjuvant therapy, locally advanced disease, and metastatic colorectal cancer (mCRC). Precision oncology has transformed the field — MSI-H tumors, KRAS G12C mutations, BRAF V600E, and HER2 amplification have all become actionable targets with dedicated clinical programs.

Key signals that CRC professionals track:

• New Phase 2/3 programs for mCRC patients with KRAS G12C mutations — now an active area after NSCLC success
• MSI-H / dMMR colorectal cancer immunotherapy combinations and head-to-head trials
• BRAF V600E CRC programs — a distinct biology from melanoma BRAF requiring CRC-specific trials
• HER2-amplified CRC programs as the field catches up to breast/gastric HER2 targeting
• Adjuvant therapy trials and ctDNA-guided treatment de-escalation studies
• ADC (antibody-drug conjugate) programs entering CRC as the modality expands from breast cancer

Active Phase 3 colorectal cancer trials (2026)

64 Phase 3 CRC programs are active or in startup. Key studies spanning novel immunotherapy, EGFR bispecifics, HER2, KRAS, BRAF, and ctDNA-guided therapy:

The MSS immunotherapy problem — and 2026 strategies to solve it

Microsatellite stable (MSS) CRC constitutes roughly 96% of metastatic cases and has been largely resistant to checkpoint immunotherapy. Three distinct strategies dominate the 2026 Phase 2/3 landscape:

CCR8 antibodies (regulatory T-cell depletion)

CCR8 is highly expressed on intratumoral regulatory T cells (Tregs) in CRC, making it a target for selective depletion without systemic immune toxicity. BMS pumitamig (BMS-986340) is in Phase 3 in combination with chemotherapy. Early Phase 1/2 data showed objective responses in MSS patients — a population that historically fails PD-1 monotherapy. Pumitamig holds FDA Fast Track designation.

PD-1 × VEGF bispecific antibodies

Ivonescimab (Summit Therapeutics/Akeso) simultaneously blocks PD-1 and VEGF on a single molecule. VEGF suppresses dendritic cell maturation and promotes immunosuppressive myeloid cell recruitment; co-blockade with PD-1 may restore immune function in the MSS microenvironment. Summit's Phase 3 (NCT07228832) tests ivonescimab plus FOLFOX against bevacizumab plus FOLFOX in first-line MSS mCRC — the first head-to-head test of this concept in a pivotal trial.

Botensilimab + balstilimab (enhanced CTLA-4)

Botensilimab is an Fc-enhanced CTLA-4 antibody with superior Treg depletion and innate immune engagement vs ipilimumab. Combined with balstilimab (anti-PD-1), it showed 28% ORR in heavily pretreated MSS CRC — a clinically meaningful signal where PD-1 monotherapy yields <1% response. The Canadian Cancer Trials Group Phase 3 (NCT07152821) tests this combination vs best supportive care in chemo-refractory patients.

KRAS inhibitors in colorectal cancer: G12C approval and the expanding pipeline

KRAS mutations occur in approximately 45% of CRC, making this the highest-priority precision oncology target in the indication. The 2024 approval of sotorasib plus panitumumab for KRAS G12C mCRC (CodeBreaK 300) was the first KRAS-targeted approval in CRC. In 2026, the landscape expands significantly:

• CodeBreaK 301 (NCT06252649, Amgen): Phase 3 testing sotorasib + panitumumab + FOLFIRI vs FOLFIRI ± bevacizumab in second-line KRAS G12C mCRC — extending the CodeBreaK 300 approval to a triplet combination in the 2L setting
• Revolution Medicines RAS(ON) inhibitors: Zoldonrasib (RMC-6291) and RMC-6236 in combination with ivonescimab in RAS-mutant CRC (NCT07397338), targeting all common KRAS mutations in their active GTP-bound state — a pan-RAS approach that could address G12D, G12V, and other non-G12C mutations
• KRAS G12D inhibitors: Multiple programs (MRTX1133 analogs, HRS-4642) in Phase 1 dose-escalation with CRC cohorts — G12D is the most common KRAS mutation in CRC (~12%) and has no approved therapy
• KRAS G12C second-generation: Overcoming acquired resistance to sotorasib using next-gen allosteric inhibitors and SOS1 inhibitor combinations — resistance emerges through KRAS amplification, secondary RAS mutations, and EGFR bypass

ctDNA-guided adjuvant therapy: the next frontier in Stage II/III CRC

Circulating tumor DNA testing after curative resection identifies patients with residual microscopic disease — the population most likely to relapse. Multiple Phase 3 trials are using ctDNA positivity to assign or withhold adjuvant chemotherapy:

• NRG Oncology (NCT05174169): Personalizing adjuvant chemotherapy in Stage III colon cancer based on post-surgical ctDNA
• UNICANCER (NCT07340567): ctDNA variation guiding de-escalation or switch decisions after first-line mCRC therapy
• University Hospital Rouen (NCT06446557): ctDNA-guided treatment optimization in resected CRC

Amivantamab (EGFR+MET bispecific) — two Phase 3 programs in CRC

Amivantamab (Janssen) is a bispecific antibody that simultaneously targets EGFR and MET, two co-expressed drivers in RAS/BRAF wild-type metastatic CRC. Following its approvals in NSCLC (PAPILLON, MARIPOSA), Johnson & Johnson has opened two concurrent Phase 3 trials in mCRC:

• 1st-line (NCT06662786): Amivantamab + mFOLFOX6 or FOLFIRI vs cetuximab + chemotherapy in previously untreated RAS/BRAF wild-type mCRC — directly competing against the standard-of-care cetuximab backbone
• 2nd-line (NCT06750094): Amivantamab + FOLFIRI vs cetuximab or bevacizumab + FOLFIRI in RAS/BRAF wild-type mCRC after first-line progression

The dual EGFR+MET targeting rationale in CRC is that MET amplification is a known resistance mechanism to anti-EGFR therapy (cetuximab/panitumumab). Simultaneously blocking both may prevent and overcome that resistance. Both trials are recruiting in 2026 — among the most significant new competitive threats to the established cetuximab/panitumumab franchise.

BRAF V600E colorectal cancer: encorafenib approved, DETERMINE expands

BRAF V600E mutations occur in approximately 8–10% of mCRC and confer poor prognosis with standard chemotherapy. The 2022 approval of encorafenib + cetuximab (BEACON CRC) established targeted therapy as standard of care. The Phase 3 landscape is expanding in 2026:

• Encorafenib + cetuximab (approved, BEACON CRC): Now the standard 2nd/3rd-line backbone; multiple combinations are being studied on top of this approved doublet
• DETERMINE basket trial (NCT07440290, Cancer Research UK): Randomized Phase 2/3 testing dabrafenib + trametinib (BRAF+MEK inhibition) in BRAF V600E CRC as a chemotherapy-free targeted approach — testing whether MEK co-inhibition adds to BRAF blockade alone
• Atezolizumab + cobimetinib + vemurafenib (NCI): Triple combination testing whether MEK+BRAF+PD-L1 can convert the immunosuppressed BRAF V600E microenvironment

BRAF V600E CRC is a distinct subtype from BRAF V600E melanoma — the feedback loop through EGFR makes BRAF inhibitor monotherapy largely ineffective, requiring EGFR co-blockade, MEK inhibition, or novel combinations. Multiple Phase 3 programs are now testing alternatives to the encorafenib+cetuximab backbone.

HER2-targeted therapy: the 4% CRC opportunity now entering Phase 3

HER2 amplification occurs in approximately 4% of CRC (typically RAS/BRAF wild-type, left-sided). After Phase 2 proof-of-concept from MOUNTAINEER (tucatinib+trastuzumab) and DESTINY-CRC02 (T-DXd), both programs have advanced to Phase 3:

• MOUNTAINEER-03 (NCT05253651, Seagen/Pfizer): Tucatinib + trastuzumab + mFOLFOX6 vs standard of care in HER2+ mCRC — a randomized Phase 3 validating the tucatinib combination at scale
• JSKN003 (NCT07384377, JMT-Bio): HER2 ADC vs physician choice in HER2+ advanced CRC — testing a novel HER2-directed antibody-drug conjugate vs standard therapy
• T-DXd (trastuzumab deruxtecan, DESTINY-CRC02): Phase 2 data showing 37.8% ORR in HER2+ mCRC — Phase 3 planning anticipated

What DataLookout monitors for colorectal cancer

DataLookout pulls directly from the ClinicalTrials.gov API every day. For a colorectal cancer watch profile, you can configure:

• Condition keywords: "colorectal cancer", "colon cancer", "rectal cancer", "CRC", "mCRC", "colorectal carcinoma", "colorectal neoplasm"
• Biomarker/mechanism keywords: "MSI-H", "dMMR", "KRAS G12C", "BRAF V600E", "HER2 colorectal", "NRAS", "microsatellite instability", "ctDNA colorectal"
• Phase filter: Phase 2 proof-of-concept, Phase 3 pivotal, or all phases
• Sponsor filter: Industry-sponsored programs for competitive intelligence, or all sponsors
• Status filter: Recruiting only, all active studies, or any status

What DataLookout adds to ClinicalTrials.gov

ClinicalTrials.gov RSS feeds tell you that a study record was updated. DataLookout compares each record against the previous day across 12 tracked fields and tells you which one changed, with the old and new values, for every Colorectal Cancer trial on your watchlist. Each change is classified as critical, notable, or minor, so a trial flipping from recruiting to suspended does not read the same as a contact-details edit.

Who uses colorectal cancer trial monitoring

GI oncology pharma BD teams

Business development teams at GI-focused pharmaceutical and biotech companies track the CRC pipeline to identify licensing, co-development, and acquisition opportunities. With precision oncology creating multiple distinct CRC sub-populations (MSI-H, KRAS G12C, BRAF V600E, HER2+), each representing a separate competitive landscape, real-time trial awareness is essential for strategic positioning.

Oncology investors and biotech analysts

Investors covering GI oncology track trial registrations as leading indicators of pipeline value. A Phase 3 initiation for a KRAS G12C CRC program or a new ADC entering Phase 2 can precede a significant valuation event by 12–18 months. Daily monitoring ensures no catalyst is missed.

Medical affairs at established CRC companies

Medical affairs professionals at companies with approved CRC therapies track competitors' programs to anticipate new competitive entries, label expansions, and evolving biomarker-based treatment sequencing. This shapes KOL engagement, medical education priorities, and advisory board topics.

Gastroenterology-focused CROs and research networks

CROs and academic research networks in GI oncology track new CRC trial registrations to identify programs entering active recruitment — and the sponsors who will need site networks, patient identification algorithms, and data management for complex biomarker-selected trials.

Frequently asked questions