Oncology · Clinical trials
Colorectal Cancer Clinical Trials
Approved therapies, the pivotal-trial endpoints they were judged on, the magnitude of benefit — and the drugs that failed their endpoints, and why.
Indication overview
About colorectal cancer — and why its trials are hard
Colorectal cancer (CRC) is among the most common cancers worldwide, arising from the colon or rectum and often driven by mutations in APC, TP53, KRAS/NRAS and BRAF. Treatment is highly molecularly stratified: RAS status governs anti-EGFR eligibility, BRAF V600E defines a poor-prognosis subset, and mismatch-repair deficiency (dMMR/MSI-H, roughly 4-5% of metastatic cases) predicts immunotherapy benefit. Trials are hard for several reasons. The disease is biologically heterogeneous, so a drug effective in RAS wild-type left-sided tumors may be inert or harmful in RAS-mutant right-sided disease, demanding biomarker-enriched enrollment. Backbone chemotherapy (FOLFOX, FOLFIRI) is already effective, raising the bar for add-on agents. Most metastatic patients are microsatellite stable and immunologically 'cold,' so checkpoint inhibitors largely fail outside MSI-H. Overall survival endpoints require large samples and long follow-up because many later lines of therapy dilute treatment effects, complicating attribution of benefit.
Approved therapies & pivotal evidence
What's been approved — and by how much it moved the endpoint
| Drug (brand) | Approved | Setting | Pivotal trial | Primary endpoint | Magnitude of benefit |
|---|---|---|---|---|---|
| Bevacizumab (Avastin) | 2004 | First-line metastatic, added to chemotherapy | AVF2107g | Overall survival | Median OS 20.3 vs 15.6 months (HR 0.66) |
| Cetuximab (Erbitux) | 2004 (RAS wild-type combo 2012) | RAS wild-type metastatic, +FOLFIRI first-line | CRYSTAL | Progression-free / overall survival | KRAS wild-type median OS 23.5 vs 20.0 months (HR 0.80) |
| Regorafenib (Stivarga) | 2012 | Refractory metastatic (chemo-refractory) | CORRECT | Overall survival | Median OS 6.4 vs 5.0 months (HR 0.77) |
| Trifluridine/tipiracil (Lonsurf) | 2015 | Refractory metastatic after standard therapies | RECOURSE | Overall survival | Median OS 7.1 vs 5.3 months (HR 0.68) |
| Pembrolizumab (Keytruda) | 2020 | First-line MSI-H/dMMR metastatic | KEYNOTE-177 | Progression-free survival | Median PFS 16.5 vs 8.2 months (HR 0.60) |
| Sotorasib + panitumumab (Lumakras + Vectibix) | 2025 | KRAS G12C-mutated metastatic, previously treated | CodeBreaK 300 | Progression-free survival | Improved PFS vs standard care (HR ~0.49) (unverified) |
Where trials have failed
Drugs that missed their endpoint — and what contributed
The most instructive lessons in colorectal cancer development come from programmes that failed the endpoint that mattered.
| Drug / trial | Endpoint outcome | What contributed |
|---|---|---|
| Cetuximab (adjuvant) — N0147 | Adding cetuximab to FOLFOX did not improve disease-free survival in resected stage III colon cancer, even in KRAS wild-type patients | Anti-EGFR benefit seen in metastatic disease did not translate to the micrometastatic adjuvant setting; possible antagonism with oxaliplatin |
| Atezolizumab — IMblaze370 | Atezolizumab +/- cobimetinib failed to improve overall survival versus regorafenib in refractory metastatic CRC | Microsatellite-stable tumors are immunologically cold; MEK-inhibitor priming did not overcome checkpoint resistance |
Choosing the right endpoint
Primary endpoints that matter in colorectal cancer trials
- Overall survival (OS) — Gold-standard regulatory endpoint but diluted by multiple subsequent lines of therapy in CRC
- Progression-free survival (PFS) — Common primary endpoint; basis for KEYNOTE-177 approval in MSI-H disease
- Disease-free survival (DFS) — Primary endpoint in adjuvant trials of resected stage II/III disease
- Objective response rate (ORR) — Supports accelerated approvals, especially in biomarker-defined subsets
- pCR / pathologic response — Emerging endpoint in neoadjuvant and organ-preservation (dMMR) strategies
How iNGENū runs colorectal cancer trials
Physician-led design, built for FDA submission
Endpoint & biomarker strategy
Board-certified specialists design endpoints and patient selection aligned to current FDA guidance for this indication.
FDA-ready data
Built to ICH-GCP and 21 CFR 312.120, with direct FDA submission — data accepted by the FDA, EMA and MHRA.
Faster, lower-cost delivery
~4-week ethics via the TGA CTN scheme, up to 43.5% R&D rebate, and 80–90% below US CRO cost.
Request a fixed-milestone proposal and a tailored endpoint & feasibility summary for this indication.
Frequently asked questions
Colorectal Cancer clinical trials — FAQs
Why does RAS mutation status matter so much in colorectal cancer?
Which colorectal cancer patients benefit from immunotherapy?
What is the role of chemotherapy backbones like FOLFOX and FOLFIRI?
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