Clinical trials landscape¶
TL;DR — The active colorectal trial landscape is organized around actionability rather than new cytotoxic drugs: ctDNA-guided adjuvant decisions, rectal organ preservation, earlier biomarker combinations, immunotherapy for MMR-proficient disease and expanded local therapy. All NCT statuses below were retrieved live from ClinicalTrials.gov v2 on 2026-08-30. The key design problem is that prognostic enrichment is easier than therapeutic rescue: ctDNA-positive patients recur more often, but escalation has not reliably erased that risk (Tie 2025, PMID 41115959). OPRA and dostarlimab show organ preservation is feasible in selected biology/response settings, while phase III studies now test duration, radiation and systemic combinations (Verheij 2024, PMID 37883738; Cercek 2025, PMID 40293177). BREAKWATER, CheckMate 8HW and CodeBreaK 300 have already moved targeted/immune combinations earlier (Kopetz 2025, PMID 39863775; André 2025, PMID 39874977; Fakih 2023, PMID 37870968). Trial reading must distinguish registry status, published cohort, primary endpoint and actual practice-changing evidence.
Registry method¶
ClinicalTrials.gov v2 was queried live with colorectal-cancer condition plus 15 topic searches: ctDNA/adjuvant, CIRCULATE, DYNAMIC, OPRA, dostarlimab, TNT, CheckMate 8HW, BREAKWATER, MOUNTAINEER, KRAS G12C, liver transplant, ablation, MSS immunotherapy, blood screening and early-onset disease. The union contained 445 unique NCT records.
Status definitions used here are registry values:
| Registry status | Interpretation |
|---|---|
| Recruiting | Enrollment open at ≥1 site |
| Active, not recruiting | Ongoing follow-up/intervention; enrollment closed |
| Not yet recruiting | Registered but enrollment not open |
| Completed | Study activities completed; results may still be unpublished |
| Unknown | Last known status not recently verified by sponsor |
| Terminated/withdrawn | Stopped after/before enrollment; reason must be inspected |
Registry status does not establish efficacy. A completed trial without results is not positive evidence.
ctDNA and molecular residual disease¶
| NCT | Phase/status (2026-08-30) | Population/question |
|---|---|---|
| NCT04089631 | Phase III; unknown | Stage II colon adjuvant decisions from ctDNA |
| NCT07340567 | Phase III; active, not recruiting | Blood-test personalization after stage III surgery |
| NCT06197425 | Phase III; recruiting | Chemotherapy for ctDNA-positive stage III after surgery/adjuvant therapy |
| NCT07227636 | Phase II; recruiting | Botensilimab/balstilimab for ctDNA-positive CRC after surgery/chemotherapy |
| NCT07562659 | Phase II; recruiting | Plasma-methylation ctDNA guidance in stage I/low-risk stage II |
| NCT07188025 | Phase III; recruiting | ctDNA-based adjuvant therapy in high-risk rectal cancer |
DYNAMIC stage II established that one ctDNA strategy reduced chemotherapy from 28% to 15% with noninferior 2-year recurrence-free survival (Tie 2022, PMID 35657320). Five-year follow-up supports durable de-escalation (Tie 2025, PMID 40055522).
DYNAMIC-III is the caution: risk-adapted escalation did not automatically overcome ctDNA-positive biology, so ongoing trials must test an intervention, not only a marker (Tie 2025, PMID 41115959).
CIRCULATE-style platforms separate observational prognostic discovery from randomized de-escalation/escalation (Taniguchi 2021, PMID 33931919). Critical endpoints include DFS/OS, chemotherapy exposure, quality of life and false-negative recurrence.
Rectal organ preservation¶
| NCT | Phase/status | Core question |
|---|---|---|
| NCT02008656 | Phase II; active, not recruiting | Induction vs consolidation around chemoradiation with TME/NOM (OPRA design) |
| NCT04246684 | Phase III; active, not recruiting | Short-course RT vs chemoradiation, then chemotherapy and preservation |
| NCT06991465 | Phase II; recruiting | Hypofractionated pelvic RT organ-preservation pathway (Hypo-OPRA) |
| NCT05723562 | Phase II; active, not recruiting | Dostarlimab in untreated dMMR/MSI-H locally advanced rectal cancer |
| NCT06640049 | Phase II; active, not recruiting | Dostarlimab in Chinese dMMR/MSI-H rectal cancer |
| NCT07740720 | Phase III; not yet recruiting | Duration of dostarlimab in dMMR/MSI-H rectal cancer |
OPRA 5-year TME-free survival was 39% after induction versus 54% after consolidation, with similar DFS, moving organ preservation from retrospective practice into a prospective response-adapted design (Verheij 2024, PMID 37883738).
The initial dostarlimab study reported clinical complete response in all 12 treated dMMR rectal patients, but single-arm, small-cohort evidence requires durability and external validation (Cercek 2022, PMID 35660797). Expanded follow-up retains a high complete-response signal (Cercek 2025, PMID 40293177).
Organ-preservation trials should report:
- sustained organ preservation, not cCR alone;
- local regrowth timing and salvage R0 rate;
- distant recurrence and DFS/OS;
- bowel, sexual and urinary function;
- surveillance burden and adherence;
- permanent stoma and treatment-related death.
dMMR metastatic immunotherapy¶
| NCT | Phase/status | Question |
|---|---|---|
| NCT04008030 | Phase III; active, not recruiting | Nivolumab, nivolumab–ipilimumab or chemotherapy in dMMR/MSI-H mCRC |
CheckMate 8HW demonstrated superior PFS for nivolumab–ipilimumab versus chemotherapy and versus nivolumab alone, establishing dual-checkpoint efficacy with greater toxicity (André 2024, PMID 39602630; André 2025, PMID 39874977).
Remaining questions are not whether checkpoint therapy works in dMMR, but who needs dual therapy, optimal duration, management after complete response and sequencing after resistance.
BRAF V600E¶
| NCT | Phase/status | Question |
|---|---|---|
| NCT04607421 | Phase III; active, not recruiting | Encorafenib–cetuximab ± chemotherapy in untreated BRAF V600E mCRC (BREAKWATER) |
BREAKWATER showed first-line encorafenib–cetuximab–mFOLFOX6 improved response and PFS versus standard care (Kopetz 2025, PMID 39863775), shifting trials toward maintenance, duration, resistance and metastasis-directed integration.
BEACON remains the post-prior-therapy anchor with median OS 9.3 versus 5.9 months (Tabernero 2021, PMID 33503393).
HER2¶
| NCT | Phase/status | Question |
|---|---|---|
| NCT03043313 | Phase II; completed | Tucatinib–trastuzumab in HER2-positive mCRC (MOUNTAINEER) |
MOUNTAINEER reported a 38.1% confirmed response rate (95% CI 27.7–49.3) in cohorts A and B (Strickler 2023, PMID 37142372). The frontier is earlier-line combination and resolving heterogeneous HER2 definitions.
KRAS G12C¶
| NCT | Phase/status | Question |
|---|---|---|
| NCT05198934 | Phase III; completed | Sotorasib–panitumumab vs investigator choice (CodeBreaK 300) |
| NCT06252649 | Phase III; recruiting | First-line sotorasib–panitumumab–FOLFIRI vs FOLFIRI ± bevacizumab |
CodeBreaK 300 improved median PFS to 5.6 versus 2.2 months with high-dose combination; response was 26.4% versus 0% (Fakih 2023, PMID 37870968). Moving the combination first line tests whether earlier use improves survival or merely changes sequence.
MMR-proficient/MSS immunotherapy¶
| NCT | Phase/status | Biological strategy |
|---|---|---|
| NCT06733038 | Phase III; recruiting | FOLFOXIRI–bevacizumab ± atezolizumab in pMMR immune-score-selected mCRC |
| NCT06558773 | Phase II; recruiting | Glycosphingolipid-synthetase inhibition + checkpoint and/or regorafenib |
MSS colorectal cancer is the largest immunotherapy failure space. Rational trials should predefine immune niche, liver-metastasis burden and on-treatment pharmacodynamics rather than pool all MSS disease (Ganesh 2019, PMID 30886395).
Liver metastases may create systemic immune suppression; trials should stratify liver versus lung/peritoneal distribution.
Liver metastases: local treatment and transplant¶
| NCT | Phase/status | Question |
|---|---|---|
| NCT05129787 | Not applicable; active, not recruiting | Ablation versus resection of liver metastases |
| NCT06185556 | Phase II/III; recruiting | Irreversible electroporation versus SBRT for perivascular/peribiliary lesions |
| NCT05863195 | Phase III; recruiting | Hepatic-artery pump chemotherapy + systemic therapy vs systemic therapy |
| NCT03803436 | Phase II; unknown | Liver transplantation in selected unresectable liver-only disease |
| NCT03494946 | Not applicable; recruiting | Transplantation compared with chemotherapy |
| NCT04161092 | Not applicable; active, not recruiting | Swedish transplant study |
| NCT02864485 | Not applicable; recruiting | Living-donor transplant for unresectable liver metastases |
The field needs randomized local-treatment evidence because observational selection is extreme. EORTC 40983 improved PFS but not OS with perioperative FOLFOX (Nordlinger 2013, PMID 24120480), and New EPOC showed a plausible targeted addition can worsen outcome (Bridgewater 2020, PMID 32014119).
SECA-II reported 5-year OS 83% but 3-year DFS 35% in highly selected transplant recipients; expanded criteria produced median OS 18 months (Dueland 2020, PMID 31188200; Smedman 2020, PMID 32333527). Registry trials must include graft opportunity cost and donor outcomes.
Survivorship and early-onset trials¶
| NCT | Status | Question |
|---|---|---|
| NCT07018869 | Recruiting, phase III | Educational website to improve survivor follow-up |
| NCT04812912 | Recruiting | Reproductive and sexual health in early-onset CRC |
| NCT06202183 | Recruiting, not applicable | Exercise–microbiome intervention during chemotherapy in young-onset CRC |
| NCT06342401 | Recruiting | Early-onset colorectal-cancer detection |
| NCT04715074 | Completed | Community intervention to increase early-onset awareness |
These trials address outcomes underrepresented in drug studies: fertility, sexual health, care coordination, activity and diagnostic delay. Early-onset reviews identify decades of survivorship as a distinct burden even without age-specific tumor therapy (Spaander 2023, PMID 37105987).
Why colorectal trials fail¶
| Failure mode | Example | Prevention |
|---|---|---|
| Prognostic marker mistaken for treatment target | ctDNA-positive escalation | Randomize the action |
| Surrogate not validated | Response without survival/function | Co-primary patient-important outcomes |
| Molecular dilution | All MSS pooled | Biology-defined eligibility |
| Site heterogeneity | Liver and lung disease pooled | Stratify metastatic niche |
| Cross-over/post-progression noise | OS diluted | Prespecified estimands and sequence capture |
| Expert-center selection | Watch-and-wait/transplant | External pragmatic validation |
| Registry staleness | “Unknown” status | Date-stamped live checks |
Open questions¶
- Which intervention improves survival after postoperative ctDNA positivity? (Tie 2025, PMID 41115959)
- How short can dostarlimab treatment be while preserving durable rectal cCR? (NCT07740720)
- Can immune-score selection rescue checkpoint therapy in pMMR disease? (NCT06733038)
- Is ablation noninferior to resection for small resectable liver lesions? (NCT05129787)
- Does transplant improve OS versus modern systemic/local therapy under fair graft-allocation rules? (NCT03494946)
- Can early-onset detection trials reduce late stage without excessive low-risk colonoscopy? (NCT06342401)
Related pages¶
- Biomarkers and liquid biopsy — MRD trial logic.
- Localized rectal cancer — organ-preservation evidence.
- Precision oncology — target-specific trial results.
- Liver and lung metastasis — local-treatment evidence.
- Patient experience and advocacy — patient-important endpoints.
References¶
- Tie J, et al. Circulating tumor DNA-guided adjuvant therapy in locally advanced colon cancer: the randomized phase 2/3 DYNAMIC-III trial. Nat Med. 2025;31(12):4291-4300. PMID 41115959
- Verheij FS, et al. Long-Term Results of Organ Preservation in Patients With Rectal Adenocarcinoma Treated With Total Neoadjuvant Therapy: The Randomized Phase II OPRA Trial. J Clin Oncol. 2024;42(5):500-506. PMID 37883738
- Cercek A, et al. Nonoperative Management of Mismatch Repair-Deficient Tumors. N Engl J Med. 2025;392(23):2297-2308. PMID 40293177
- Kopetz S, et al. Encorafenib, cetuximab and chemotherapy in BRAF-mutant colorectal cancer: a randomized phase 3 trial. Nat Med. 2025;31(3):901-908. PMID 39863775
- André T, et al. Nivolumab plus ipilimumab versus nivolumab in microsatellite instability-high metastatic colorectal cancer (CheckMate 8HW): a randomised, open-label, phase 3 trial. Lancet. 2025;405(10476):383-395. PMID 39874977
- Fakih MG, et al. Sotorasib plus Panitumumab in Refractory Colorectal Cancer with Mutated KRAS G12C. N Engl J Med. 2023;389(23):2125-2139. PMID 37870968
- Tie J, et al. Circulating Tumor DNA Analysis Guiding Adjuvant Therapy in Stage II Colon Cancer. N Engl J Med. 2022;386(24):2261-2272. PMID 35657320
- Tie J, et al. Circulating tumor DNA analysis guiding adjuvant therapy in stage II colon cancer: 5-year outcomes of the randomized DYNAMIC trial. Nat Med. 2025;31(5):1509-1518. PMID 40055522
- Taniguchi H, et al. CIRCULATE-Japan: Circulating tumor DNA-guided adaptive platform trials to refine adjuvant therapy for colorectal cancer. Cancer Sci. 2021;112(7):2915-2920. PMID 33931919
- Cercek A, et al. PD-1 Blockade in Mismatch Repair-Deficient, Locally Advanced Rectal Cancer. N Engl J Med. 2022;386(25):2363-2376. PMID 35660797
- Andre T, et al. Nivolumab plus Ipilimumab in Microsatellite-Instability-High Metastatic Colorectal Cancer. N Engl J Med. 2024;391(21):2014-2026. PMID 39602630
- Tabernero J, et al. Encorafenib Plus Cetuximab as a New Standard of Care for Previously Treated BRAF V600E-Mutant Metastatic Colorectal Cancer: Updated Survival Results and Subgroup Analyses from the BEACON Study. J Clin Oncol. 2021;39(4):273-284. PMID 33503393
- Strickler JH, et al. Tucatinib plus trastuzumab for chemotherapy-refractory, HER2-positive, RAS wild-type unresectable or metastatic colorectal cancer (MOUNTAINEER): a multicentre, open-label, phase 2 study. Lancet Oncol. 2023;24(5):496-508. PMID 37142372
- Ganesh K, et al. Immunotherapy in colorectal cancer: rationale, challenges and potential. Nat Rev Gastroenterol Hepatol. 2019;16(6):361-375. PMID 30886395
- Nordlinger B, et al. Perioperative FOLFOX4 chemotherapy and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC 40983): long-term results of a randomised, controlled, phase 3 trial. Lancet Oncol. 2013;14(12):1208-15. PMID 24120480
- Bridgewater JA, et al. Systemic chemotherapy with or without cetuximab in patients with resectable colorectal liver metastasis (New EPOC): long-term results of a multicentre, randomised, controlled, phase 3 trial. Lancet Oncol. 2020;21(3):398-411. PMID 32014119
- Dueland S, et al. Survival Following Liver Transplantation for Patients With Nonresectable Liver-only Colorectal Metastases. Ann Surg. 2020;271(2):212-218. PMID 31188200
- Smedman TM, et al. Liver transplantation for unresectable colorectal liver metastases in patients and donors with extended criteria (SECA-II arm D study). BJS Open. 2020;4(3):467-477. PMID 32333527
- Spaander MCW, et al. Young-onset colorectal cancer. Nat Rev Dis Primers. 2023;9(1):21. PMID 37105987