Colorectal cancer is the third most common cancer in the US and remains a major area of clinical research, particularly for metastatic disease and emerging targeted therapy approaches. The field has evolved through immunotherapy in microsatellite instability-high (MSI-H) tumors, KRAS G12C inhibitors, HER2-targeted therapies in colorectal cancer, and combinations addressing previously untargetable mutations. For patients with colorectal cancer, clinical trials for colorectal cancer can provide access to advanced therapies for treatment-resistant disease and emerging approaches in earlier stages. This guide covers how to find colorectal cancer trials, the active research areas in 2026, eligibility considerations, and resources for enrollment.
Categories of colorectal cancer trials
Active colorectal cancer trials in 2026 include:
KRAS G12C inhibitors: Sotorasib and adagrasib have established activity in colorectal cancer (less effective than in lung cancer but meaningful), with newer KRAS inhibitors and combination approaches in development.
Immunotherapy combinations: Beyond MSI-H tumors where checkpoint inhibitors are effective, trials test immunotherapy combinations in microsatellite stable (MSS) tumors using novel mechanisms — TIM-3, LAG-3, TIGIT, and combinations with other agents.
HER2-targeted therapy: About 3-5% of colorectal cancers have HER2 amplification or overexpression, with trials testing trastuzumab deruxtecan (Enhertu), tucatinib combinations, and other HER2 approaches.
BRAF V600E-mutant disease: The triplet of encorafenib + cetuximab + binimetinib established activity; trials test next-line options and combinations with immunotherapy.
Adjuvant therapy in early-stage disease: Studies testing whether intensified or de-escalated chemotherapy regimens improve outcomes in stage II-III colon cancer.
Circulating tumor DNA (ctDNA)-guided treatment: Trials using ctDNA detection to guide adjuvant therapy decisions, potentially identifying which patients benefit from chemotherapy after surgery.
Rectal cancer: Total neoadjuvant therapy approaches and watch-and-wait protocols for patients with complete clinical response.
Where to find colorectal cancer trials
Resources for colorectal cancer trial searches:
- ClinicalTrials.gov
- National Cancer Institute clinical trial search
- Colorectal Cancer Alliance — patient resources and trial matching
- Fight Colorectal Cancer — advocacy and trial information
- NCI-Designated Cancer Centers
- Major academic medical centers with GI oncology programs (MSKCC, MD Anderson, Dana-Farber, Mayo, etc.)
Comprehensive molecular testing of the tumor is essential for matching with appropriate targeted therapy and immunotherapy trials.
Molecular testing for trial matching
Key molecular features that affect colorectal cancer trial eligibility:
- Microsatellite status: MSI-H or MMR-deficient tumors (~5% of metastatic colorectal cancer) are eligible for immunotherapy approaches; MSS tumors require different strategies
- RAS mutation status: KRAS, NRAS mutations affect EGFR-targeted therapy eligibility and qualify for KRAS G12C inhibitors specifically
- BRAF V600E: About 8-10% of metastatic colorectal cancer; eligible for triplet therapy
- HER2 status: 3-5% of metastatic disease; eligible for HER2-targeted approaches
- NTRK fusion: Rare (<1%) but actionable with TRK inhibitors
- Tumor mutational burden: High TMB may predict immunotherapy response
Most patients with metastatic colorectal cancer should have comprehensive genomic profiling at diagnosis or progression. Major academic centers offer this testing as standard care.
Typical eligibility for colorectal cancer trials
Common inclusion criteria:
- Confirmed colorectal cancer diagnosis (colon or rectal)
- Stage matching the trial’s target population
- Specific molecular profile (for targeted therapy trials)
- Performance status (ECOG 0-2 typically)
- Adequate organ function
- Measurable disease (for response-based trials in metastatic disease)
- Specific prior therapy history
Common exclusion criteria:
- Other active cancers
- Recent major bowel obstruction or perforation
- Active uncontrolled inflammatory bowel disease
- Pregnancy
- Significant cardiac disease
- Active autoimmune disease (for immunotherapy trials)
Trials in metastatic disease
Patients with metastatic colorectal cancer often have multiple trial options:
First-line trials: Test new combinations or sequencing strategies vs current standard of FOLFOX/FOLFIRI plus targeted therapy.
Second and third-line trials: Test novel mechanisms after standard chemotherapy. KRAS G12C inhibitors, BRAF triplet variations, immunotherapy combinations in MSS disease.
Refractory disease trials: Test salvage approaches in patients who’ve exhausted standard options. Often Phase 1 or early Phase 2 with novel mechanisms.
For metastatic colorectal cancer, comprehensive molecular profiling and access to NCI-Designated Cancer Centers expand trial options substantially.
Adjuvant therapy trials
Trials in stage II-III colon cancer test whether modifications to standard adjuvant chemotherapy improve cure rates:
- Duration of adjuvant chemotherapy (3 vs 6 months — IDEA collaboration established 3 months as adequate for low-risk stage III)
- ctDNA-guided adjuvant therapy (DYNAMIC, COBRA, and other trials testing whether ctDNA detection guides treatment intensity)
- Adjuvant immunotherapy in MSI-H disease
- De-escalation in low-risk disease
Patients with stage II-III colorectal cancer should discuss adjuvant trial options with their oncologist post-surgery.
Rectal cancer trials
Rectal cancer treatment has evolved significantly. Active research areas:
Total neoadjuvant therapy (TNT): Giving all chemotherapy and radiation before surgery rather than splitting between pre and post-surgery. PRODIGE-23, RAPIDO, and others established TNT approaches.
Watch-and-wait protocols: Patients with complete clinical response after neoadjuvant therapy avoid surgery, monitored intensively for regrowth. The OPRA trial established watch-and-wait as a viable option for selected patients.
Immunotherapy in MSI-H rectal cancer: The dostarlimab MSK trial showed remarkable complete response rates (100% in initial cohort) in MSI-H rectal cancer with neoadjuvant immunotherapy alone — among the most striking results in recent oncology.
What participation involves
Colorectal cancer trials typically involve:
- Comprehensive baseline workup including CT/PET imaging, labs, ECG, tumor biopsy with molecular profiling
- Treatment with the experimental therapy in cycles every 2-4 weeks
- Imaging assessments every 6-12 weeks
- Lab monitoring for toxicities
- Sometimes ctDNA monitoring
- Long-term follow-up
For metastatic disease, treatment continues until progression. For adjuvant trials, treatment is time-limited followed by years of follow-up.
Frequently Asked Questions
Do I need molecular testing for colorectal cancer trials?
Strongly recommended for metastatic disease. Microsatellite status, RAS, BRAF, HER2, and tumor mutational burden affect trial eligibility. Most academic centers perform comprehensive testing as standard care.
Are MSI-H colorectal cancer trials different from MSS trials?
Yes. MSI-H tumors respond to immunotherapy and have specific trials testing immunotherapy combinations and approaches. MSS tumors require different strategies; immunotherapy alone is less effective in MSS disease.
What’s the watch-and-wait approach for rectal cancer?
Patients with complete clinical response after neoadjuvant chemoradiation can be monitored intensively rather than proceeding to surgery. This avoids surgical morbidity but requires close surveillance for regrowth. Established trials are ongoing to refine this approach.
Can I participate in adjuvant trials after colon surgery?
Yes. Adjuvant trials enroll patients post-surgery to test modifications to standard chemotherapy. Discuss options with your oncologist before starting standard adjuvant therapy.
Are colorectal cancer screening trials available?
Yes. Trials test new screening modalities (blood-based tests, novel imaging) and approaches to improve screening uptake. The USPSTF screening recommendations are based partly on ongoing research.
The bottom line on colorectal cancer trials
Colorectal cancer trials cover the full spectrum from prevention and screening through adjuvant therapy and metastatic disease. Molecular profiling is essential for matching with mutation-specific and immunotherapy trials. For patients with metastatic disease, particularly those with treatment-resistant cancer or rare molecular subtypes, trials often offer access to advanced therapies. Adjuvant trials test approaches to improve cure rates after surgery. Rectal cancer trials are exploring less-invasive approaches with watch-and-wait protocols and neoadjuvant immunotherapy in selected patients. Discuss trial options with your oncologist as part of comprehensive treatment planning.