NCT07702032 — Petosemtamab (EGFR×LGR5 bispecific) + chemotherapy vs cetuximab + chemotherapy in RAS/BRAF wild-type CRC
NCT07722494 — IBI363 (PD-1/IL-2α bispecific) + bevacizumab in advanced CRC
Current Clinical Trial Landscape
Active research areas in 2026:
Immunotherapy for MSS/pMMR tumors (234 trials) — the biggest challenge in CRC: making "cold" tumors respond to immunotherapy via bispecifics, HDACi combos, and novel IO agents
MSI-H/dMMR organ preservation (133 trials) — checkpoint immunotherapy alone achieving complete responses, enabling surgery avoidance for rectal cancer
KRAS-targeted therapy (71 trials) — G12C inhibitors moving to first-line, pan-RAS and G12D inhibitors expanding to the most common CRC mutations
ctDNA-guided adjuvant therapy — multiple Phase 3 trials using liquid biopsy to decide who needs chemo after surgery
ADCs (40 trials) and T-cell engagers entering CRC for the first time
Standard of care:MSI-H/dMMR metastatic: Pembrolizumab or nivolumab+ipilimumab first-line. MSS/pMMR metastatic (RAS/BRAF wild-type, left-sided): FOLFOX or FOLFIRI + cetuximab. MSS/pMMR (right-sided or RAS-mutant): FOLFOX or FOLFIRI + bevacizumab. BRAF V600E: Encorafenib + cetuximab (± binimetinib). KRAS G12C: Sotorasib + panitumumab. HER2+: Tucatinib + trastuzumab. Stage III adjuvant: CAPOX (3 or 6 months) or FOLFOX. Locally advanced rectal: Neoadjuvant chemoradiation → surgery (dMMR: immunotherapy may replace chemoradiation).
Key Biomarkers for Trial Eligibility
Colorectal cancer treatment is highly biomarker-driven. These determine your trial options:
Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR) — present in ~15% of early-stage and ~5% of metastatic CRC. Responds dramatically to checkpoint immunotherapy. dMMR rectal cancer patients may achieve complete response with immunotherapy alone, avoiding surgery entirely.
RAS status (KRAS/NRAS) — mutated in ~50% of CRC. KRAS G12C (~3-4%) has FDA-approved targeted therapy (sotorasib + panitumumab). G12D (~12%) and G12V (~8%) have emerging inhibitors. RAS wild-type patients benefit from anti-EGFR therapy.
BRAF V600E — present in ~8-10%. Aggressive biology, poor prognosis with standard chemo. Encorafenib + cetuximab is FDA-approved. Multiple combination trials recruiting.
HER2 amplification — present in ~3-5% (higher in RAS wild-type). Tucatinib + trastuzumab approved. T-DXd and new ADC trials recruiting.
Tumor sidedness — left-sided (splenic flexure to rectum) vs right-sided (cecum to transverse). Left-sided tumors respond better to anti-EGFR therapy. Right-sided tumors are more often MSI-H and BRAF-mutant.
ctDNA (circulating tumor DNA) — increasingly used post-surgery to detect minimal residual disease. ctDNA-positive patients benefit from adjuvant chemo; ctDNA-negative may safely skip it. Multiple Phase 3 trials are testing this approach.
Know your MSI/MMR status and mutations? Get matched to colorectal cancer trials in minutes.
Checkpoint immunotherapy is transforming treatment for this subset. Trials push IO earlier and explore organ preservation:
Neoadjuvant / organ preservation (rectal):
NCT03051464 - No Surgery Trial: dose-escalation strategies for dMMR rectal cancer (Phase 2/3)
NCT06229041 - TNTi: Total neoadjuvant treatment ± immunotherapy for high-risk locally advanced rectal cancer (Phase 3)
Adjuvant / Neoadjuvant (MSI-H/dMMR specific):
NCT07412613 - Neoadjuvant/adjuvant cadonilimab (AK104) in MSI-H/dMMR resectable colorectal cancer (Phase 3, PD-1 × CTLA-4 bispecific peri-operative)
NCT05236972 - PACE: PD-1 antibody for dMMR/MSI-H stage III colon cancer (Phase 3)
NCT06520683 - Adjuvant PD-1 blockade for high-risk stage II dMMR/MSI-H CRC (Phase 3)
MSS / pMMR — Immunotherapy Combinations (the "cold tumor" challenge)
Most CRCs are MSS and don't respond to IO alone. Trials combine IO with targeted agents, bispecifics, or novel immunomodulators. For the broader bispecific checkpoint inhibitor landscape (ivonescimab, cadonilimab, rilvegostomig) across cancer types, see the Bispecific Checkpoint Inhibitors mechanism hub.
NCT07228832 - Ivonescimab or Bevacizumab + FOLFOX in first-line metastatic CRC (Phase 3, head-to-head PD-1/VEGF bispecific vs anti-VEGF backbone)
NCT07221357 - Pumitamig (bispecific) + Chemo vs Bevacizumab + Chemo in mCRC (Phase 3)
KRAS G12C inhibitors are approved for previously-treated metastatic CRC: adagrasib (Krazati) + cetuximab (FDA Jun 2024 per KRYSTAL-1 + KRYSTAL-10) and sotorasib + panitumumab (FDA Jan 2025 per CodeBreaK 300). New frontiers: first-line combos, G12D targeting, and pan-RAS RAS(ON) inhibitors like daraxonrasib. For a cross-cancer view of the KRAS inhibitor class (sotorasib, adagrasib, calderasib, daraxonrasib, zoldonrasib) across NSCLC + CRC + pancreatic, see the KRAS Inhibitors mechanism hub.
HER2-positive metastatic colorectal cancer (HER2+ mCRC) — HER2 amplification occurs in ~3-5% of mCRC, enriched in RAS/BRAF wild-type, left-sided tumors. First-line and second-line treatment sequencing in HER2+ mCRC (2026): the standard first anti-HER2 option is tucatinib + trastuzumab (FDA-approved 2023, MOUNTAINEER); the trial wave is now testing (1) HER2 doublets/ADCs moving into the first-line setting and (2) next-generation HER2 bispecific antibodies and ADCs for the second-line / refractory setting. HER2 status (IHC/ISH) is the gating biomarker. See the HER2 ADCs mechanism hub for the cross-cancer view of these agents.
First-line HER2+ mCRC (Phase 3):
NCT05253651 - Tucatinib + Trastuzumab + mFOLFOX6 vs SOC (MOUNTAINEER-03) — moving the approved tucatinib + trastuzumab doublet into the 1L chemo backbone (Phase 3, recruiting)
NCT07384377 - JSKN003 (HER2 bispecific ADC) vs physician's choice in HER2-positive CRC (Phase 3)
NCT05786716 - Trastuzumab combination (DETERMINE Arm 04) — rare-HER2+ basket including CRC (Phase 2/3, recruiting)
Antibody-Drug Conjugates (~40 trials)
CRC has been a late ADC entrant relative to breast/lung — 2026 brings the first Phase 3 of a CEACAM5-directed ADC in metastatic CRC, and a c-MET ADC entry:
NCT07549412 - Precemtabart Tocentecan (M9140, CEACAM5 ADC) ± Bevacizumab vs Trifluridine/Tipiracil + Bevacizumab in previously-treated metastatic CRC (Phase 3, the first CEACAM5 ADC to enter Phase 3 in CRC; CEACAM5 is expressed in ~85% of CRC)
NCT07525206 - Telisotuzumab Adizutecan + Bevacizumab vs SOC + Bevacizumab (Phase 3, c-MET ADC entering CRC; new mechanism class for the disease)
Trials by Treatment Setting
Neoadjuvant / Perioperative
NCT06017583 - Neoadjuvant chemo + PD-1 + SIB-IMRT for locally advanced rectal cancer (Phase 3)
NCT05194878 - Neoadjuvant FOLFOXIRI vs immediate surgery for stage II-III colon cancer (Phase 3)
NCT07070622 - OPLAR: Organ preservation for low rectal cancer after neoadjuvant chemo (Phase 3)
NCT06205485 - Neoadjuvant chemotherapy + excision + observation vs chemoradiotherapy for rectal cancer (Phase 3, activated 2026-06-10 — second organ-preservation Phase 3 joining OPLAR NCT07070622; tests whether upfront chemo + local excision can spare TME surgery in select responders)
Adjuvant (ctDNA-Guided)
Circulating tumor DNA is reshaping adjuvant treatment decisions:
NCT05174169 - Adjuvant chemo based on residual disease evaluation (Phase 3)
NCT06642844 - Bevacizumab-based chemotherapy adapted to bevacizumab pharmacokinetics in 1L unresectable metastatic CRC (Phase 3, activated 2026-06-17 — dose-personalization strategy for bevacizumab based on individual PK, testing whether PK-adaptive dosing improves efficacy vs standard weight-based dosing in the 1L mCRC bev + chemo backbone)
Novel Approaches
ADCs (~40 trials): Sacituzumab govitecan, new TROP2 and CEACAM5-targeted ADCs entering CRC for the first time (precemtabart tocentecan / M9140 Phase 3, NCT07549412)
How do I find colorectal cancer clinical trials for my biomarkers?
Enter your colorectal cancer details into ClinTrialFinder — including MSI/MMR status, KRAS/NRAS/BRAF mutations, HER2 amplification, tumor sidedness, and prior treatments. The AI matches you with trials based on your specific profile in minutes. No login required.
What colorectal cancer trials are currently recruiting?
There are 1,130 recruiting interventional CRC trials in August 2026 including 127 Phase 3 studies. Immunotherapy for MSS tumors (~234, including new Phase 3s: ivonescimab vs bevacizumab + FOLFOX NCT07228832), MSI-H/dMMR-specific organ preservation and adjuvant trials (~133, including neoadjuvant cadonilimab NCT07412613), EGFR-targeted and EGFR/MET bispecifics (~132), KRAS G12C and pan-RAS inhibitors (~71, including calderasib MK-1084 KANDEL Phase 3 NCT06997497 and daraxonrasib pan-RAS RAS(ON) — see KRAS Inhibitors hub), BRAF V600E-targeted (~59), HER2-targeted (~38, see HER2 ADCs hub), ADCs (~40, including first-Phase-3-CEACAM5-ADC precemtabart tocentecan NCT07549412 and telisotuzumab adizutecan c-MET ADC NCT07525206), and ctDNA-guided adjuvant trials.
What is the difference between MSI-H and MSS colorectal cancer for clinical trials?
MSI-H/dMMR tumors (~15% of early-stage, ~5% of metastatic CRC) respond dramatically to checkpoint immunotherapy — pembrolizumab alone can be first-line treatment. MSS/pMMR tumors (~85-95%) don't respond to standard immunotherapy, which is why the biggest area of research is finding ways to make MSS tumors respond. Knowing your MSI/MMR status is the most important biomarker for determining your trial options.
What is ctDNA-guided adjuvant therapy?
After surgery for stage II-III colorectal cancer, a blood test (liquid biopsy) can detect tiny amounts of circulating tumor DNA (ctDNA). If ctDNA is positive, it means microscopic cancer remains and adjuvant chemotherapy is likely beneficial. If ctDNA is negative, you may safely skip chemotherapy and its side effects. Multiple Phase 3 trials are testing this approach — it could spare thousands of patients from unnecessary chemo.
What are the first-line and second-line treatment options for HER2-positive metastatic colorectal cancer in trials?
HER2 amplification occurs in ~3-5% of metastatic CRC (enriched in RAS/BRAF wild-type, left-sided tumors). The standard first anti-HER2 option is tucatinib + trastuzumab (FDA-approved 2023, MOUNTAINEER). In 2026 trials, first-line HER2+ mCRC studies move HER2 therapy earlier — tucatinib + trastuzumab + mFOLFOX6 (MOUNTAINEER-03, NCT05253651) plus HER2 bispecific ADCs JSKN003 (NCT07384377) and TQB2102 (NCT07483684), all Phase 3. For the second-line / refractory setting, next-generation HER2 bispecific antibodies and ADCs are recruiting: zanidatamab (NCT06695845, NCT07243938, NCT07631871), KN026 (NCT05985707), trastuzumab rezetecan (NCT07631884), TQB2930 (NCT07653685), dual EGFR/HER2 blockade (NCT07059338), and the DETERMINE trastuzumab basket (NCT05786716). HER2 status by IHC/ISH is the gating biomarker. See the full HER2-Amplified section above, organized by treatment line.
Find Colorectal Cancer Trials Matched to Your Situation
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This page is for information only and is not medical advice. ClinTrialFinder helps you find clinical trials that may match your situation, but enrollment decisions and treatment choices should always be made with your oncologist or healthcare team. Trial eligibility, recruitment status, and treatment details can change — verify directly with the trial sponsor or on ClinicalTrials.gov before acting on any information here.
