Colorectal · CRC

1L mCRC (unselected): mPFS 9.0 vs 6.2 mo (p=0.0003); ORR 50.7% vs 22.3% (p=0.0001); mOS 16.2 vs 14.7 mo (p=0.12, NS); FOLFOX2 (oxaliplatin 85 mg/m2 + LV5FU2) established oxaliplatin superiority in PFS over 5-FU/LV alone

Population: Metastatic CRC, 1L, previously untreated; foundational trial establishing FOLFOX standard.

1L mCRC: IFL vs 5-FU/LV: mPFS 7.0 vs 4.3 mo (p=0.004); ORR 39% vs 21% (p<0.001); mOS 14.8 vs 12.6 mo (p=0.04); irinotecan alone showed no advantage over 5-FU/LV

Population: Metastatic CRC, 1L, previously untreated; established irinotecan-containing chemotherapy as 1L standard.

1L mCRC (unselected): mOS 20.3 vs 15.6 mo (HR 0.66, p<0.001); mPFS 10.6 vs 6.2 mo (HR 0.54, p<0.001); ORR 44.8% vs 34.8% (p=0.004); response duration 10.4 vs 7.1 mo; grade 3 hypertension 11.0% vs 2.3%

Population: Metastatic CRC, 1L, previously untreated; all-comers regardless of RAS status.

1L mCRC: mOS 21.5 mo (arm A) vs 20.6 mo (arm B) (p=0.99); FOLFIRI 1L: RR 56%, mPFS 8.5 mo; FOLFOX6 1L: RR 54%, mPFS 8.0 mo (p=0.26); both sequences yielded equivalent outcomes; FOLFIRI→FOLFOX6 second-line PFS superior (4.2 vs 2.5 mo)

Population: Metastatic CRC, 1L/2L sequential, previously untreated; comparing optimal sequence of FOLFIRI and FOLFOX6.

1L mCRC: FOLFOX vs IFL: mTTP 8.7 vs 6.9 mo (p=0.0014); ORR 45% vs 31% (p=0.002); mOS 19.5 vs 15.0 mo (p=0.0001); IROX: mTTP 6.5 mo, mOS 17.4 mo; FOLFOX significantly superior to IFL on all endpoints

Population: Metastatic CRC, 1L, previously untreated; three-arm comparison establishing FOLFOX superiority over IFL.

1L mCRC (EGFR+, all-comer ITT): mPFS 8.9 vs 8.0 mo (HR 0.85, 95% CI 0.72-0.99, p=0.048); KRAS-wt subgroup: mPFS 9.9 vs 8.7 mo (HR 0.68, p=0.02); mOS 24.9 vs 21.0 mo (HR 0.796, p=0.0093); KRAS-mut: no benefit or trend toward harm

Population: Metastatic CRC, 1L; key efficacy in KRAS wild-type subgroup; foundational trial for the KRAS biomarker paradigm.

1L mCRC (all-comer): primary endpoint ORR cetuximab+FOLFOX4 46% vs FOLFOX4 36% (p=0.064, not significant); KRAS-wt subgroup: ORR 61% vs 37% (p=0.011); mPFS 7.7 vs 7.2 mo (HR 0.57, p=0.0163) favoring cetuximab; KRAS-mut: ORR trend against cetuximab (33% vs 49%)

Population: Metastatic CRC, 1L; primary analysis in all-comers, key subgroup in KRAS wild-type patients.

1L mCRC KRAS-exon-2-wt: mPFS 9.6 vs 8.0 mo (HR 0.80, 95% CI 0.66-0.97, p=0.02); KRAS-wt ORR 55% vs 48%; KRAS-exon-2-mut: mPFS 7.3 vs 8.8 mo (HR 1.29, p=0.02) — panitumumab WORSENED PFS in KRAS-mut; primary endpoint PFS met in KRAS-wt

Population: KRAS wild-type metastatic CRC, 1L, previously untreated; showed harm signal in KRAS-mutant patients.

1L mCRC pan-RAS-wt: panitumumab+FOLFOX4 vs FOLFOX4: mOS 26.0 vs 20.2 mo (HR 0.78, 95% CI 0.62-0.99, p=0.04); mPFS 10.8 vs 9.2 mo (HR 0.72, p=0.004); RAS-mut: mOS 15.6 vs 19.2 mo — panitumumab significantly REDUCED OS in RAS-mut patients (HR 1.25, 95% CI 1.02-1.55, p=0.04)

Population: Metastatic CRC, 1L; subgroup re-analysis extending RAS mutation status beyond KRAS exon 2 to all KRAS/NRAS exons (subgroup re-analysis: RAS-extended).

1L mCRC KRAS-exon-2-wt: primary endpoint ORR cetuximab 62% vs bev 58% (p=0.183, NS); mOS 28.7 vs 25.0 mo (HR 0.77, 95% CI 0.62-0.96, p=0.017) favoring cetuximab; mPFS 10.0 vs 10.3 mo (HR 1.06, NS); depth of response significantly better with cetuximab; discordant PFS/OS pattern

Population: KRAS wild-type (later extended to RAS wild-type) metastatic CRC, 1L, previously untreated.

1L mCRC KRAS-wt exon 2: mPFS panitumumab 10.9 vs bev 10.1 mo (HR 0.87, 95% CI 0.65-1.17, NS); mOS 34.2 vs 24.3 mo (HR 0.62, 95% CI 0.44-0.89, p=0.009); RAS-wt (pan-RAS) subgroup: mOS 41.3 vs 28.9 mo (HR 0.58, p=0.058); PFS NS but OS favors panitumumab in RAS-wt

Population: KRAS wild-type (extended to pan-RAS wild-type) metastatic CRC, 1L, previously untreated.

1L mCRC (unresectable, age ≤75, ECOG 0-2): mPFS 12.1 vs 9.7 mo (HR 0.75, 95% CI 0.62-0.90, p=0.003); ORR 65% vs 53% (p=0.006); mOS 29.8 vs 25.8 mo (HR 0.80, 95% CI 0.65-0.98, p=0.03) in updated analysis (Lancet Oncol 2015); grade 3-4 diarrhea 18.8% vs 10.6%, neurotoxicity 5.0% vs 0.4%

Population: Metastatic CRC, 1L, previously untreated; fit patients (good PS), all RAS/BRAF status.

1L mCRC RAS-wt (pan-RAS, all KRAS/NRAS exons): cetuximab+FOLFIRI vs FOLFIRI: mOS 28.4 vs 20.2 mo (HR 0.69, 95% CI 0.54-0.88); mPFS 11.4 vs 8.4 mo (HR 0.56, 95% CI 0.41-0.76); RAS-mut subgroup: no benefit (mOS 17.7 vs 17.1 mo); extended RAS testing refined the predictive biomarker

Population: Metastatic CRC, 1L; subgroup re-analysis extending RAS mutation status beyond KRAS exon 2 to all KRAS/NRAS exons (subgroup re-analysis: RAS-extended).

1L mCRC updated OS: FOLFOXIRI+bev vs FOLFIRI+bev: mOS 29.8 vs 25.8 mo (HR 0.80, 95% CI 0.65-0.98, p=0.030); BRAF-mut subgroup: mOS 19.0 vs 10.7 mo (HR 0.54); RAS-wt subgroup: mOS 37.1 vs 29.6 mo; RAS-mut subgroup: mOS 22.6 vs 20.6 mo; PFS 12.3 vs 9.7 mo confirmed

Population: Metastatic CRC, 1L, previously untreated; updated OS analysis with RAS/BRAF subgroup data (long-term follow-up), enriched for BRAF-mutant subgroup.

1L mCRC KRAS-wt (exon 2): mOS cetuximab 30.0 vs bevacizumab 29.0 mo (HR 0.88, 95% CI 0.77-1.01, p=0.08, NS); mPFS 10.4 vs 10.8 mo (HR 1.04, NS); ORR 59.6% vs 55.2% (p=0.13, NS); primary endpoint (mOS) not met — no superiority for either biologic

Population: KRAS exon 2 wild-type metastatic CRC, 1L, previously untreated.

Sidedness pooled analysis: Left-sided RAS-wt mCRC: anti-EGFR superior to anti-VEGF (mOS difference ~7 mo); Right-sided RAS-wt: anti-VEGF preferred (anti-EGFR neutral or harmful); Right-sided RAS-wt on anti-EGFR: worse OS than right-sided on anti-VEGF; interaction test significant (p<0.001); provides strongest pooled evidence for sidedness-based biologic selection

Population: RAS wild-type (KRAS exon 2) metastatic CRC, 1L; subgroup re-analysis by primary tumor sidedness from the CALGB 80405 trial (subgroup re-analysis: sidedness).

1L RAS-wt mCRC (all-comer): mOS panitumumab 36.2 vs bev 31.3 mo (HR 0.84, 95% CI 0.72-0.98, p=0.03); left-sided tumors: mOS 37.9 vs 34.3 mo (HR 0.82, p=0.03, pre-specified primary); right-sided: mOS 20.8 vs 23.3 mo (HR 1.09, p=0.72) — no benefit; prospectively validated sidedness interaction

Population: RAS wild-type metastatic CRC, 1L, previously untreated; pre-specified primary analysis in left-sided tumors.

1L mCRC (predominantly MSS, unselected): phase 2 results: mPFS nivolumab arm 9.4 vs control 7.7 mo (HR 0.81, 95% CI 0.57-1.14, p=0.23, NS); mOS 25.7 vs 22.8 mo (HR 0.83, NS); ORR 59% vs 54%; primary PFS endpoint not met in phase 2; phase 3 continuing

Population: Unselected (predominantly MSS/pMMR) metastatic CRC, 1L, previously untreated.

ORR 31.1% (95% CI 20.8–42.9) in 74 pre-treated dMMR/MSI-H mCRC patients (≥1 prior line including fluoropyrimidine and oxaliplatin or irinotecan); disease control ≥12 weeks 69%; median duration of response not reached; 12-month OS 73%; grade 3–4 drug-related AEs: lipase increase 8%, amylase 3%; no treatment-related deaths.

Population: dMMR/MSI-H metastatic CRC, 2L+, previously treated with fluoropyrimidine/oxaliplatin/irinotecan.

Primary cohort (n=119, 76% had ≥2 prior lines): ORR 55% (95% CI 45.2–63.8), disease control ≥12 weeks 80%; at 4-year follow-up (median 50.9 months), ORR increased to 65% (55–73%), complete response rate 13%; median PFS not reached (38.4 months–NE); median OS not reached; grade 3–4 TRAEs 32%; 4-year update confirmed 37 of 44 responders still ongoing.

Population: dMMR/MSI-H metastatic CRC, 2L+, ≥2 prior systemic lines in 76% of patients; 4-year follow-up update.

Cohort A (n=61) ORR 33% (95% CI 21–46%), median OS 31.4 months (21.4–NR); Cohort B (n=63) ORR 33% (22–46%), median OS not reached; median PFS 2.3 and 4.1 months respectively (due to early progressors typical in IO response pattern); grade 3–4 TRAEs: 16% (A), 13% (B).

Population: MSI-H/dMMR metastatic CRC, 2L+ (cohort A ≥3L; cohort B ≥2L), previously treated with fluoropyrimidine/oxaliplatin/irinotecan.

Pembrolizumab vs chemotherapy (5-FU-based ± bev/cet) at 32.4-month follow-up: PFS HR 0.60 (95% CI 0.45–0.80; P=0.0002), median PFS 16.5 vs 8.2 months; ORR 43.8% vs 33.1%; responders with ongoing response at 24 months: 83% (pembro) vs 35% (chemo); OS data immature at primary analysis; grade ≥3 TRAEs: 22% vs 66%.

Population: MSI-H/dMMR metastatic CRC, 1L, centrally confirmed, previously untreated for metastatic disease.

Overall: atezolizumab + FOLFOXIRI+bev vs FOLFOXIRI+bev: median PFS 13.1 vs 11.5 months (HR 0.69 [80% CI 0.56–0.85]; p=0.012); adjusted HR 0.70; dMMR subgroup (n=29): more pronounced benefit; MSS subgroup: modest/non-significant benefit; grade 3–4 neutropenia 42% vs 36%; 2 treatment-related deaths in atezolizumab arm.

Population: Metastatic CRC, 1L, unselected by MMR/MSI status; key subgroup analysis by pMMR/MSS vs dMMR/MSI-H.

Primary 2022 report (n=12): 100% clinical complete response (cCR; 95% CI 74–100%), all avoiding chemoradiotherapy and surgery. Extended 2025 cohort (n=49 rectal + 54 nonrectal dMMR solid tumors): all 49 rectal cancer patients who completed treatment achieved cCR; 37 had sustained cCR at 12 months meeting primary endpoint; recurrence-free survival at 2 years 92% (95% CI 86–99); 95% of patients had grade 1–2 or no AEs.

Population: dMMR stage II or III locally advanced rectal adenocarcinoma, neoadjuvant; organ-preservation intent (no chemoradiotherapy or surgery if cCR achieved).

Nivo+ipi vs chemotherapy in 1L MSI-H/dMMR mCRC: 24-month PFS 72% (95% CI 64–79) vs 14% (6–25); restricted mean survival time 10.6 months longer (95% CI 8.4–12.9); grade ≥3 TRAEs 23% (nivo+ipi) vs 48% (chemo); at 31.5-month median follow-up, PFS significantly better (P<0.001).

Population: MSI-H/dMMR metastatic CRC, 1L (primary analysis), centrally confirmed; also includes any-line comparison.

Timely surgery: 98% (97.5% CI 93–100); pathological response in 109/111 (98%, 95% CI 94–100); major pathological response (≤10% residual): 95%; pathological complete response (0% residual): 68%; no recurrences at median 26-month follow-up; grade 3–4 irAEs: 4%; no discontinuations.

Population: dMMR (mismatch repair-deficient) nonmetastatic locally advanced colon cancer, stage II–III, neoadjuvant immunotherapy before curative resection.

At median follow-up 73.3 months: median OS 77.5 vs 36.7 months (HR 0.73, 95% CI 0.53–0.99); 5-year OS 54.8% vs 44.2%; median PFS 16.5 vs 8.2 months (HR 0.60, 95% CI 0.45–0.79); median duration of response 75.4 months (pembro) vs 10.6 months (chemo); grade ≥3 AEs: 22% vs 67%; effective crossover to PD-(L)1 inhibitor 62%.

Population: MSI-H/dMMR metastatic CRC, 1L, centrally confirmed; 5-year long-term follow-up of KEYNOTE-177 (long-term follow-up).

ORR 30% (95% CI 14–50%), 1 CR + 7 PR; disease control 44% stable disease; no grade 4–5 AEs; grade 3 AEs: fatigue, rash, elevated bilirubin in 22% total; median follow-up 94 weeks; 914 patients screened to find 48 HER2-positive (5% prevalence in KRAS-WT).

Population: HER2-positive (colorectal-specific criteria), KRAS exon 2 wild-type metastatic CRC, 3L+, refractory to standard care including anti-EGFR.

All tumor types (n=55, 17 different tumor types, 4 months to 76 years): ORR 75% (95% CI 61–85) by independent review; at 1 year 71% of responses ongoing; 55% progression-free; median duration of response and PFS not reached at 9.4 months follow-up; 86% of responders continuing treatment or underwent curative surgery; grade 3–4 drug-related AEs: none occurred in >5% of patients; no discontinuations.

Population: NTRK fusion-positive solid tumors (tissue-agnostic), any line, TRK inhibitor naive; CRC subgroup reported separately.

Kopetz 2019 (interim, triplet primary endpoint): triplet vs control: median OS 9.0 vs 5.4 months (HR 0.52, 95% CI 0.39–0.70; P<0.001); ORR 26% vs 2% (P<0.001); doublet (encorafenib+cetuximab) OS 8.4 months (HR 0.60, 95% CI 0.45–0.79; P<0.001). Tabernero 2021 (final analysis): doublet median OS 9.3 months (95% CI 8.0–11.3) vs control 5.9 months (95% CI 5.1–7.1) (HR 0.60 [0.47–0.75]); triplet OS 9.3 months (8.2–10.8); grade ≥3 AEs: triplet 58%, doublet 50%, control 61%.

Population: BRAF V600E-mutant metastatic CRC, 2L (1–2 prior lines), RAS wild-type.

Efficacy-evaluable n=54 (10 different tumor types, 19 histologies): ORR 57% (95% CI 43.2–70.8), 4 CR + 27 PR; median duration of response 10 months (7.1–NE); grade 3–4 AEs: weight increase 10%, anaemia 12%; no treatment-related deaths; CNS efficacy demonstrated (unique vs larotrectinib).

Population: NTRK fusion-positive solid tumors (tissue-agnostic), any line, TRK inhibitor naive; CRC subgroup reported separately.

Cohort A (HER2-positive, n=53): confirmed ORR 45.3% (95% CI 31.6–59.6); median follow-up 27.1 weeks; grade ≥3 AEs: neutropenia 22%, anaemia 14%; ILD/pneumonitis in 5 patients (6%): 2 grade 2, 1 grade 3, 2 grade 5 (treatment-related deaths); cohorts B and C: no responses.

Population: HER2-expressing metastatic CRC, 3L+, RAS and BRAF wild-type; primary efficacy in HER2-positive cohort (IHC 3+ or IHC 2+/ISH+).

Irinotecan + cetuximab + vemurafenib vs irinotecan + cetuximab: PFS HR 0.50 (improved; P value significant per paper); ORR improvement with vemurafenib addition; the triplet demonstrated proof-of-concept for simultaneous BRAF+EGFR+iri targeting, forming the rationale for BEACON CRC.

Population: BRAF V600E-mutant, RAS wild-type metastatic CRC, 2L (1–2 prior regimens).

960mg sotorasib+panitumumab vs standard care: median PFS 5.6 vs 2.2 months (HR 0.49, 95% CI 0.30–0.80; P=0.006); ORR 26.4% (15.3–40.3) vs 0% (0–6.6); 240mg sotorasib+panitu vs standard: PFS HR 0.58 (0.36–0.93; P=0.03), ORR 5.7%; grade ≥3 TRAEs: 35.8% (960mg), 30.2% (240mg), 43.1% (control); skin toxicity and hypomagnesemia most common.

Population: KRAS G12C-mutant chemorefractory metastatic CRC, 3L+ (≥2 prior lines).

Monotherapy (n=44): ORR 19% (95% CI 8–33), median duration of response 4.3 months (2.3–8.3), median PFS 5.6 months (4.1–8.3); combination adagrasib+cetuximab (n=32): ORR 46% (95% CI 28–66), median duration of response 7.6 months (5.7–NE), median PFS 6.9 months (5.4–8.1); grade 3–4 TRAEs: 34% (mono) vs 16% (combo); no grade 5 AEs.

Population: KRAS G12C-mutant metastatic CRC, 3L+ (≥2 prior lines); specific KRAS G12C testing required.

Cohorts A+B combined (n=84): confirmed ORR by BICR 38.1% (95% CI 27.7–49.3), 3 CR + 29 PR; grade ≥3 AEs: hypertension 7%; tucatinib monotherapy (cohort C, n=30): ORR per protocol not primary but lower; no treatment-related deaths; most common AE diarrhoea 64%. First FDA-approved anti-HER2 regimen for mCRC (2023).

Population: HER2-positive, RAS wild-type metastatic CRC, 3L+, chemotherapy-refractory; HER2 by colorectal-specific IHC/FISH criteria.

5.4 mg/kg arm (n=82): ORR by BICR 37.8% (95% CI 27.3–49.2); 6.4 mg/kg arm (n=40): ORR 27.5% (14.6–43.9); activity seen in RAS-mutant and prior anti-HER2-exposed subgroups; grade ≥3 drug-related AEs: 41% (5.4 mg/kg) vs 49% (6.4 mg/kg); ILD events: 8% (5.4 mg/kg, all grade 1–2) vs 13% (6.4 mg/kg, 1 grade 5); 1 treatment-related death (hepatic failure, 5.4 mg/kg arm).

Population: HER2-positive (IHC 3+ or IHC 2+/ISH+) metastatic CRC, 2L+, RAS wild-type or mutant; prior chemotherapy required.

EC+mFOLFOX6 vs standard care (investigator choice): median PFS 12.8 vs 7.1 months (HR 0.53, 95% CI 0.41–0.68; P<0.001); interim OS 30.3 vs 15.1 months (HR 0.49, 95% CI 0.38–0.63; P<0.001); serious AEs during treatment: 46.1% vs 38.9%.

Population: BRAF V600E-mutant, RAS wild-type metastatic CRC, 1L, previously untreated.

2L mCRC (post-fluoropyrimidine+irinotecan): FOLFOX4+bev vs FOLFOX4: mOS 12.9 vs 10.8 mo (HR 0.75, p=0.0011); mPFS 7.3 vs 4.7 mo (HR 0.61, p<0.0001); ORR 22.7% vs 8.6% (p<0.0001); bev monotherapy: mOS 10.2 mo — minimal activity

Population: Metastatic CRC, 2L, bevacizumab-naive, after prior irinotecan-containing chemotherapy.

Chemorefractory mCRC: KRAS-wt subgroup: panitumumab vs BSC mPFS 12.3 vs 7.3 wk (HR 0.45, 95% CI 0.34-0.59, p<0.0001); KRAS-mut subgroup: panitumumab vs BSC mPFS 7.4 vs 7.3 wk (HR 0.99, p=0.96) — no benefit; first randomized evidence establishing KRAS as predictive biomarker

Population: Metastatic CRC, chemotherapy-refractory; landmark subgroup analysis establishing KRAS mutation as predictive biomarker for anti-EGFR non-response.

2L mCRC (post-oxaliplatin): mOS 13.50 vs 12.06 mo (HR 0.817, 95% CI 0.713-0.937, p=0.0032); mPFS 6.90 vs 4.67 mo (HR 0.758, 95% CI 0.661-0.869, p<0.0001); ORR 19.8% vs 11.1% (p=0.0001); benefit consistent in bevacizumab-pretreated subgroup

Population: Metastatic CRC, 2L, after progression on oxaliplatin-containing regimen (including bevacizumab-pretreated patients).

3L+ mCRC (post-all-standard-therapies): mOS 6.4 vs 5.0 mo (HR 0.77, 95% CI 0.64-0.94, p=0.0052); disease control rate 41% vs 15% (p<0.0001); regorafenib 160mg d1-21 q28d; grade 3+ HFSR 17%, fatigue 10%, diarrhea 7%, hypertension 7%

Population: Metastatic CRC, 3L+, refractory to all standard therapies including fluoropyrimidine/oxaliplatin/irinotecan/anti-VEGF/anti-EGFR (KRAS WT).

2L mCRC (post-1L bev+chemo): mOS 11.2 vs 9.8 mo (HR 0.81, 95% CI 0.69-0.94, p=0.0062); mPFS 5.7 vs 4.1 mo (HR 0.68, 95% CI 0.59-0.78, p<0.0001); chemotherapy switch (oxaliplatin↔irinotecan) plus continued bevacizumab at progression

Population: Metastatic CRC, 2L, after progression on first-line bevacizumab-containing chemotherapy.

2L mCRC (post-bev+oxaliplatin+fluoropyrimidine 1L): mOS 13.3 vs 11.7 mo (HR 0.844, 95% CI 0.730-0.976, p=0.0219); mPFS 5.7 vs 4.5 mo (HR 0.793, p=0.0005); consistent benefit across subgroups; grade 3+ neutropenia 38% vs 23%

Population: Metastatic CRC, 2L, after progression on first-line bevacizumab + oxaliplatin-containing regimen.

3L+ mCRC (post-fluoropyrimidine+oxaliplatin+irinotecan±anti-VEGF±anti-EGFR): mOS 7.1 vs 5.3 mo (HR 0.68, 95% CI 0.58-0.81, p<0.001); mPFS 2.0 vs 1.7 mo (HR 0.48, p<0.001); ORR 1.6% vs 0.4%; DCR 44% vs 16% (p<0.001); key toxicities: neutropenia grade 3-4 38%, anemia 18%

Population: Metastatic CRC, 3L+, previously treated with fluoropyrimidine/oxaliplatin/irinotecan ± anti-VEGF ± anti-EGFR (RAS WT).

3L+ mCRC (post-≥2 prior lines including oxaliplatin+irinotecan): mOS fruquintinib 9.3 vs placebo 6.57 mo (HR 0.65, 95% CI 0.51-0.83, p<0.001); mPFS 3.7 vs 1.8 mo (HR 0.26, 95% CI 0.21-0.34, p<0.001); ORR 4.7% vs 0%; DCR 62.2% vs 12.3%; fruquintinib 5mg d1-21 q28d

Population: Metastatic CRC, 3L+, refractory to standard therapy; China-only trial (N=416), 28 Chinese centers.

3L+ MSS mCRC: mOS atezo+cobi 8.87 vs regorafenib 8.51 mo (HR 1.00, 95% CI 0.73-1.38, p=0.99) — no benefit; atezo monotherapy vs regorafenib: mOS 7.10 vs 8.51 mo (HR 1.19, 95% CI 0.83-1.71, p=0.34); ORR atezo+cobi 3% vs regorafenib 2%; primary endpoint not met

Population: MSS/pMMR metastatic CRC, 3L+, chemotherapy-refractory; unselected by biomarker.

3L+ MSS mCRC (regorafenib 80mg + toripalimab PD-1 antibody): ORR 15.2%, DCR 36.4%; mPFS 2.1 mo; mOS 15.5 mo; liver metastases: ORR 8.7% vs lung-only: ORR 100% (3/3); gut microbiome analysis suggests Fusobacterium abundance correlates with response; grade 3 TRAEs 38.5%

Population: MSS/pMMR metastatic CRC, refractory; China-led phase Ib/II trial (N=not specified).

3L+ refractory mCRC (post-TAS-102 and/or regorafenib): mOS fruquintinib 7.4 vs placebo 4.8 mo (HR 0.66, 95% CI 0.55-0.80, p<0.0001); mPFS 3.7 vs 1.8 mo (HR 0.32, 95% CI 0.27-0.39, p<0.0001); ORR 1.5% vs 0%; DCR 55.6% vs 16.1%; benefit consistent regardless of prior regorafenib/TAS-102 exposure

Population: Metastatic CRC, 3L+, refractory to fluoropyrimidine/oxaliplatin/irinotecan ± anti-VEGF ± anti-EGFR (RAS WT); international including China.

3L+ refractory mCRC (≤2 prior chemo regimens): mOS FTD-TPI+bev 10.8 vs FTD-TPI 7.5 mo (HR 0.61, 95% CI 0.49-0.77, p<0.001); mPFS 5.6 vs 2.4 mo (HR 0.44, 95% CI 0.36-0.54, p<0.001); time to PS deterioration 9.3 vs 6.3 mo (HR 0.54); no treatment-related deaths; primary OS endpoint met

Population: Metastatic CRC, 3L+ (≤2 prior lines of therapy for metastatic disease), refractory to standard therapy; unselected by biomarker.

3-year DFS: FOLFOX4 78.2% vs FL 72.9% (HR 0.77, P=0.002); Stage III benefit confirmed; grade 3 sensory neuropathy 12.4% during treatment, declining to 1.1% at 1 year; paradigm-defining trial establishing FOLFOX as adjuvant standard.

Population: Stage II or III colon cancer after curative resection (N=2,246), adjuvant FOLFOX4 vs 5-FU/LV.

Capecitabine non-inferior to bolus FL for DFS (HR upper bound <1.20, P<0.001); relapse-free survival HR 0.86 (P=0.04) favoring capecitabine; fewer adverse events with capecitabine. Established oral capecitabine as equivalent single-agent adjuvant alternative to IV 5-FU/LV.

Population: Stage III colon cancer after curative resection (N=1,987), adjuvant capecitabine vs IV 5-FU/LV.

NEGATIVE: No DFS or OS improvement with irinotecan + FL vs FL alone in stage III colon; toxicity including lethal toxicity significantly higher with irinotecan arm. Irinotecan adjuvant strategy abandoned.

Population: Stage III colon cancer after curative resection (N=1,264), adjuvant irinotecan-containing chemotherapy.

Stage II colorectal cancer: chemotherapy (FL) vs observation: RR death 0.82 (95% CI 0.70-0.95, P=0.008); absolute OS benefit ~3.6% at 5 years (NNT ~28). Small but statistically significant benefit establishing that even stage II patients may derive some benefit from FL, though absolute gain is modest.

Population: Stage II (91%) and low-risk stage III colorectal cancer (N=3,239, predominantly stage II colon cancer), adjuvant fluorouracil vs observation.

NEGATIVE: 5-year DFS irinotecan/LV5FU2 56.7% vs LV5FU2 54.3% (P=.106, not significant); 5-year OS 73.6% vs 71.3% (P=.094). Increased grade 3-4 GI toxicity and neutropenia. Confirms CALGB 89803 finding: irinotecan has no adjuvant colon benefit.

Population: Stage II and III colon cancer; primary efficacy analysis in stage III (N=2,094), adjuvant irinotecan-based chemotherapy.

3-year DFS: XELOX (CAPOX) 70.9% vs FU/FA 66.5% (HR 0.80, P=.0045); 5-year OS: 77.6% vs 74.2% (HR 0.87, P=.15, not significant). Established CAPOX as equivalent alternative to FOLFOX for stage III adjuvant therapy.

Population: Stage III colon cancer after curative resection (N=1,886), adjuvant CAPOX vs bolus FU/LV.

NEGATIVE: 3-year DFS 77.4% (bev+FOLFOX) vs 75.5% (FOLFOX alone), HR 0.89, P=.15. Transient DFS benefit during bevacizumab exposure (HR 0.61 at 15-month landmark) that reverses after cessation (HR 1.22). No recommendation for bevacizumab in adjuvant colon.

Population: Stage II or III colon cancer after curative resection (N=2,672), adjuvant bevacizumab added to mFOLFOX6.

NEGATIVE and HARMFUL: DFS HR bev-FOLFOX4 vs FOLFOX4 = 1.17 (P=0.07, non-significant but numerically worse); OS HR 1.27 (P=0.02) for bev-FOLFOX4, suggesting potential detriment. First adjuvant trial to show possible OS harm from an added agent. Confirmed anti-VEGF has no adjuvant role.

Population: Stage III or high-risk stage II colon cancer after curative resection (N=3,451), adjuvant bevacizumab plus chemotherapy.

NEGATIVE: 3-year DFS KRAS-WT: mFOLFOX6 74.6% vs mFOLFOX6+cetuximab 71.5% (HR 1.21, P=.08); numerically worse with cetuximab. Grade ≥3 AEs 52.3% vs 72.5% (P<.001). No benefit even in KRAS wild-type. Anti-EGFR adjuvant strategy abandoned.

Population: Stage III colon cancer after curative resection (N=2,686); KRAS status determined; primary analysis in KRAS wild-type patients (n=1,863), adjuvant anti-EGFR plus chemotherapy.

10-year OS: FOLFOX4 71.7% vs FL 67.1% (HR 0.85, P=.043) overall; Stage II: no OS benefit (79.5% vs 78.4%, HR 1.00); Stage III: OS benefit confirmed (67.1% vs 59.0%, HR 0.80, P=.016). dMMR is independent favorable prognostic factor. FOLFOX benefit applies regardless of BRAF/MMR status in stage III.

Population: Stage II or III colon cancer after curative resection (N=2,246); 10-year follow-up of the MOSAIC trial (long-term follow-up).

Overall noninferiority of 3 vs 6 months not confirmed (HR 1.07). CAPOX 3 months noninferior (HR 0.95, 95% CI 0.85-1.06); FOLFOX 3 months inferior (HR 1.16). Low-risk (T1-3 N1): 3-year DFS 83.1% vs 83.3% (3 vs 6 mo); High-risk (T4/N2): 6 months superior (64.4% vs 62.7%). Neurotoxicity markedly reduced with 3 months.

Population: Stage III colon cancer after curative resection; pooled analysis of 6 RCTs (N=12,834), comparing 3 vs 6 months adjuvant oxaliplatin-based chemotherapy.

ctDNA-guided management noninferior to standard management for 2-year RFS (93.5% vs 92.4%, absolute difference +1.1%). Adjuvant chemotherapy use reduced from 28% to 15% (RR 1.82). ctDNA-positive patients who received chemotherapy had 3-year RFS 86.4% vs 92.5% for ctDNA-negative patients who did not receive chemotherapy. First RCT validating ctDNA-guided adjuvant decision-making.

Population: Stage II colon cancer after curative resection, ctDNA-guided vs standard adjuvant decision (N=455).

5-year local recurrence: preoperative CRT 6% vs postoperative CRT 13% (P=0.006); 5-year OS: 76% vs 74% (P=0.80, not significant); acute toxicity grade 3-4: 27% vs 40%; long-term toxicity: 14% vs 24%. Sphincter-preservation rates improved with preoperative CRT. Paradigm shift: preoperative CRT becomes standard.

Population: Clinical stage T3, T4 or node-positive rectal cancer (N=823); landmark trial establishing preoperative vs postoperative CRT.

4-year OS: short-course RT 67.2% vs long-course CRT 66.2% (P=0.960); DFS 58.4% vs 55.6% (P=0.820); local recurrence 9.0% vs 14.2% (P=0.170, not significant). Early toxicity higher with CRT. No significant OS or local control difference. Short-course 5×5 Gy shown to be non-inferior alternative.

Population: Clinical T3 or T4 resectable rectal cancer (N=312); comparing short-course vs long-course neoadjuvant radiotherapy strategies.

NEGATIVE for primary endpoint: ypCR 13.9% (Cap 45) vs 19.2% (Capox 50), P=.09. Grade 3-4 toxicity 1% vs 25% (P<.001). Near-complete response rates showed numerical improvement with Capox but not significant for primary endpoint; toxicity significantly higher with oxaliplatin addition. Oxaliplatin should not be added to concurrent CRT.

Population: T3–4 M0 locally advanced rectal cancer (N=598); evaluating intensification of CRT with oxaliplatin.

At 10-year follow-up: adjuvant chemo vs surveillance: OS HR 0.91 (P=0.32, not significant); DFS also not significantly different. Local control improved with preoperative CRT vs RT alone (11.8% vs 22.4% LR at 10 years). Adjuvant chemotherapy after preoperative CRT does NOT improve OS or DFS.

Population: Clinical T3–T4 resectable rectal cancer (N=1,011); 2×2 factorial evaluating role of preoperative and adjuvant chemotherapy with radiotherapy.

3-year DFS: oxaliplatin-intensified regimen 75.9% vs fluorouracil-only 71.2% (HR 0.79, 95% CI 0.64-0.98, P=0.03). Absolute DFS benefit 4.7% at 3 years. pCR rate also improved. Oxaliplatin added to CRT with modified schedule shows DFS benefit unlike ACCORD 12.

Population: Locally advanced rectal cancer (cT3–4 or cN1–2), N=1,236; intensified CRT plus adjuvant oxaliplatin.

2-year local regrowth rate 25.2%; nearly all regrowths (97%) occur within 3 years. Salvage surgery feasible in 88% of regrowths. 5-year OS 85% for watch-and-wait cCR patients. Non-operative management is feasible for selected patients achieving cCR, with intensive surveillance required.

Population: Rectal cancer patients with clinical complete response (cCR) after neoadjuvant treatment (N=880, 47 institutions, 15 countries); registry/observational.

3-year DFS: mFOLFOX6 alone 73.4% vs mFOLFOX6+CRT 75.6% vs 5-FU+CRT 73.7% (P=0.74, no significant difference); pCR rates: mFOLFOX6 alone 6.1% vs mFOLFOX6+CRT 27.5% vs 5-FU+CRT 15.4%. Chemotherapy alone achieves similar DFS as CRT-based approaches in LARC.

Population: Locally advanced rectal cancer cT3–T4 or N+ (N=495), China multicenter; evaluating chemotherapy ± radiation neoadjuvant approaches.

3-year DFS: induction FOLFIRINOX + CRT 75.7% vs CRT alone 68.5% (HR 0.69, P=0.034); pCR 27.5% vs 12.1% (OR 2.76, P<0.0001); 3-year metastasis-free survival 79.0% vs 71.7% (HR 0.64). Induction FOLFIRINOX before CRT improves all endpoints.

Population: Locally advanced rectal cancer cT3–T4 M0 (N=461), neoadjuvant induction TNT approach.

3-year disease-related treatment failure: TNT (short-course 5×5 Gy + 18-week CAPOX/FOLFOX) 23.7% vs standard CRT 30.4% (HR 0.75, P=0.019); pCR 28.4% vs 14.3% (P<0.0001); 3-year OS similar (89.1% vs 88.8%). TNT reduces distant failure; OS benefit not yet demonstrated.

Population: High-risk locally advanced rectal cancer (MRI-defined: cT4a/b, extramural vascular invasion, cN2, involved mesorectal fascia, or lateral lymph nodes), N=920.

3-year organ preservation: consolidation TNT 58% vs induction TNT 43% (HR 0.65, P=0.027); cCR rates 38% vs 24% at time of restaging. Consolidation approach (CRT first, then CAPOX/FOLFOX) achieves higher organ preservation than induction approach (chemo first, then CRT). For patients prioritizing organ preservation, consolidation TNT is preferred sequence.

Population: Stage II–III rectal adenocarcinoma (N=324), candidates for organ preservation; comparing TNT sequence (consolidation vs induction).

3-year DFS noninferiority confirmed: short-course RT + CAPOX 64.5% vs CRT 62.3% (HR 0.883, noninferiority P=0.006); pCR 22.9% vs 11.4% (P<0.001); 3-year OS 86.5% vs 75.1% (HR 0.649, P=0.028) favoring TNT approach. First Chinese RCT validating short-course RT TNT strategy.

Population: Locally advanced rectal cancer (cT3–4 or N+), China multicenter (N=599); China-led TNT trial.

5-year DFS: FOLFOX 80.8% vs CRT 78.6% (HR 0.92, 90.2% CI 0.74-1.14; noninferiority P=0.005); OS and local recurrence similar. Only 9.1% of FOLFOX arm received salvage preoperative CRT. First trial showing that radiation can be selectively omitted for favorable-risk LARC without compromising DFS.

Population: cT2N+ or cT3N0/N+ rectal cancer eligible for sphincter-sparing surgery (lower-risk locally advanced rectal cancer), N=1,194.