Clinical advances in later-line therapy for metastatic or refractory colorectal cancer

Table 1 Later-line treatment studies of trifluridine/tipiracil hydrochloride mixture

Trial name/Ref.	Regimen	Sample size	Dosage and administration (experimental group)	mPFS (months, 95%CI)	Hazard ratio (95%CI), P value	mOS (months, 95%CI)	Hazard ratio (95%CI), P value	ORR (%), P value
Mayer et al[9], 2015	TAS-102 vs placebo	800	TAS-102: 35 mg/m2 bid, days 1–5 and 8–12, q28d	2.0 (1.9–2.1) vs 1.7 (1.7–1.8)	0.48 (0.41–0.57); P < 0.001	7.1 (6.5–7.8) vs 5.3 (4.6–6.0)	0.68 (0.58-0.81); P < 0.001	1.6 vs 0.4; P = 0.29
Martínez-Lago et al[11], 2022	TAS-102 + bevacizumab	35	TAS-102: 30–35 mg/m2 bid, days 1–5 and 8–12, q28d; bevacizumab: 5 mg/kg, q14d	4.3 (3.4–5.1)		9.3 (6.6–12.1)		3.20%
TAS-CC4 study[12], 2022	TAS-102 + bevacizumab	44	TAS-102: 35 mg/m2 bid, days 1–5 and 15–19, q28d; bevacizumab: 5 mg/kg, q14d	4.6 (3.6–5.3)		10.5 (9.6–11.4)		4.50%
E-BiTS study[13], 2025	TAS-102 + bevacizumab	33	TAS-102: 35 mg/m2 bid, days 1–5, q14d1; bevacizumab: 5 mg/kg q14d	5.6 (2.7–6.5)		17.6 (10.1–not available)		9.10%
Kuboki et al[14], 2023	TAS-102 + bevacizumab vs FOLFIRI + bevacizumab	397	TAS-102: 35 mg/m2 bid, days 1–5 and 8–12, q28d; bevacizumab: 5 mg/kg, q14d	4.5 (3.8–5.8) vs 6.0 (5.6–6.7)	1.45 (1.14–1.84)	14.8 (12.6–19.1) vs 18.1 (16.0–23.2)	1.38 (0.99-1.93); P = 0.5920	3.8% vs 7.1%; P = 0.2498
Li et al[15], 2024	TAS-102 + bevacizumab + irinotecan	35	TAS-102: 30 mg/m2 bid, days 1–5, q14d; bevacizumab: 5 mg/kg, q14d; irinotecan: 150 mg/m2, q14d	9.2 (6.285–12.115)				25.80%
Yang et al[16], 2026	TAS-102 + bevacizumab + irinotecan	60	TAS-102: 30 mg/m2 bid, days 1–5, q14d; bevacizumab: 5 mg/kg, q14d; irinotecan: 150 mg/m2 q14d	6.6 (4.39–8.81)		17.3 (13.55–21.05)		18.30%
Bordonaro et al[18], 2021	TAS-102 + oxaliplatin + bevacizumab vs TAS-102 + oxaliplatin + nivolumab	54	TAS-102: 35 mg/m2 bid, days 1–5, q14d; oxaliplatin: 85 mg/m2, q14d; bevacizumab: 5 mg/kg; nivolumab: 3 mg/kg, q14d	6.3 (5.5–15.6) vs 6.0 (2.0–8.0)		15.1 (10.7–NR) vs NR (6.5–NR)		17.1% vs 7.1%
Napolitano et al[20], 2023	TAS-102 + panitumumab vs TAS-102	62	TAS-102: 35 mg/m2 bid, days 1–5 and 8–12, q28d; panitumumab: 6 mg/kg days 1 and 15, q28d	4.0 (2.8–5.3)	0.48 (0.28–0.82); P = 0.007

¹Escalated by 10 mg/day per cycle, up to a maximum of 30 mg/day, during cycles 2–4.

CI: Confidence interval; mOS: Median overall survival; mPFS: Median progression-free survival; NR: Not reached; ORR: Objective response rate; TAS-102: Trifluridine/tipiracil hydrochloride mixture.

Table 2 Targeted therapy involving gene mutations or gene amplifications

Trial name/Ref.	Type	Sample size	Regimen	Dosage and administration (combination therapy group)	mPFS (months, 95%CI)	Hazard ratio (95%CI); P value	mOS (months, 95%CI)	Hazard ratio (95%CI); P value	ORR (%); P value
Fakih et al[37], 2023	KRAS G12C	160	Sotorasib + panitumumab	Sotorasib: 960 mg/240 mg qd; panitumumab: 6 mg/kg q2w	5.6 (4.2–6.3)1 vs 3.9 (3.7–5.8)2 vs 2.2 (1.9–3.9)3	0.49 (0.30–0.80)4; P = 0.006			26.4%1 vs 0.0%3
Pietrantonio et al[38], 2025	KRAS G12C	160	Sotorasib + panitumumab	Sotorasib: 960 mg/240 mg qd; panitumumab: 6 mg/kg q2w	5.7 (4.2–7.5)1 vs 4.01 (3.7–5.9)2 vs 2.04 (1.9–3.9)3	0.45 (0.29– 0.72)4	NE (8.61–NE)1 vs 11.9 (7.52–NE)2 vs 10.3 (7.00–NE)3	0.70 (0.41–1.18)4; P = 0.20	30.2%1 vs 7.5%2 vs 1.9%3
Kuboki et al[39], 2024	KRAS G12C	40	Sotorasib + panitumumab	Sotorasib: 960 mg qd; panitumumab: 6 mg/kg q2w	5.7 (4.2–7.7)		15.2 (12.5–NE)		30%
KRYSTAL-1 trial[40], 2024	KRAS G12C	94	Adagrasib + cetuximab	Adagrasib: 600 mg bid; cetuximab: 400 mg/m2 d1, then 250 mg/m2 qw or 500 mg/m2 q2w	6.9 (5.7–7.4)		15.9 (11.8–18.8)		34%
Li et al[41], 2026 (involves 2 trials)	KRAS G12C	JAB-21822-1007: 47; JAB-21822-1002: 44	Glecirasib + cetuximab; glecirasib	Glecirasib: 800 mg qd; cetuximab: 400 mg/m2 d1, then 250 mg/m2 qw or 500 mg/m2 q2w	6.9 (5.4–6.9); 5.6 (4.1–7.0)		19.3 (13.1–NE); 16.0 (8.8–26.3)		50%; 23%
BEACON CRC[69], 2019	BRAF V600E	665	Encorafenib + binimetinib + cetuximab	Encorafenib: 300 mg qd q4w; binimetinib: 45 mg bid q4w; cetuximab: 400 mg/m2 d1, then 250 mg/m2 qw	4.3 (4.1–5.2)5 vs 4.2 (3.7–5.4)6 vs 1.5 (1.5–1.7)7	0.38 (0.29–0.49)8; P < 0.001	9.0 (8.0–11.4)5 vs 8.4 (7.5–11.0)6 vs 5.4 (4.8–6.6)7	0.52 (0.39–0.70)8; P < 0.001	26%5 vs 20%6 vs 2%7
Morris et al[99], 2025	BRAF V600E, MSS	26	Encorafenib + cetuximab + nivolumab	Encorafenib: 300 mg qd; cetuximab: 500 mg/m2 q2w; nivolumab: 480 mg q4w	7.4 (5.6–9.6)		22.0 (11.2–25.8)		42%
Wei et al[100], 2025	BRAF V600E, MSS	12	Vemurafenib + cetuximab + camrelizumab	Cetuximab: 500 mg/m2 q2w; vemurafenib: 960 mg qd/bid; camrelizumab: 200 mg q2w	3.47 (1.76–5.18)		7.19 (4.97–NA)		33.30%
Fu et al[32], 2023	HER2	20	Pyrotinib + trastuzumab	Pyrotinib: 400 mg qd; trastuzumab: 8 mg/kg d1, then 6 mg/kg q3w	3.4 (1.8–4.3)				22.20%
Yang et al[33], 2025	HER2	20	Pyrotinib + trastuzumab	Pyrotinib: 400 mg qd; trastuzumab: 8 mg/kg d1, then 6 mg/kg q3w	6.2 (0.42–11.98)		21.1 (15.84–26.36)		23.50%
MOUNTAINEER[34,35], 2023	HER2	117	Tucatinib + trastuzumab	Tucatinib: 300 mg bid; trastuzumab: 8 mg/kg d1, then 6 mg/kg q3w	8.1 (4.2–10.2)		23.9 (18.7–28.3)		39.30%
Raghav et al[36], 2025	HER2	54	Trastuzumab + pertuzumab vs cetuximab + irinotecan	Trastuzumab: 8 mg/kg d1, then 6 mg/kg q3w; pertuzumab: 840 mg d1, then 420 mg q3w	4.7 (1.9–7.6) vs 3.7 (1.6–6.7)	0.79 (0.43–1.45); P = 0.44	NR (19.4–NR) vs 24.7 (15.2–33.8)	0.56 (0.25–1.29); P = 0.17	34.6% vs 28.0%
Xu et al[72], 2023	HER2	21	Trastuzumab + irinotecan	Trastuzumab: 8 mg/kg d1, then 6 mg/kg q3w; irinotecan: 120 mg/m2 d1, 8 q3w	4.3 (2.7–5.9)		17.9 (11.8–24.1)		33.30%
DESTINY-CRC01[108], 2021	HER2	78	Trastuzumab deruxtecan	Trastuzumab deruxtecan: 6.4 mg/kg q3w	6.9 (4.1–not evaluable)9		5.4 (IQR 4.1–8.3)		45.3%9

¹Sotorasib-panitumumab group (960 mg).

²Sotorasib-panitumumab group (240 mg).

³The standard-care group.

⁴Sotorasib-panitumumab group (960 mg) compared with the standard-care group.

⁵Encorafenib + binimetinib + cetuximab.

⁶Encorafenib + cetuximab.

⁷Cetuximab + irinotecan/FOLFIRI.

⁸Encorafenib + binimetinib + cetuximab group compared with the cetuximab + irinotecan/FOLFIRI group.

⁹IHC 3+ or IHC 2+ and ISH-positive.

CI: Confidence interval; IQR: Interquartile range; mOS: Median overall survival; mPFS: Median progression-free survival; NA: Not applicable; NE: Not estimable; NR: Not reached; ORR: Objective response rate.

Table 3 Aflibercept-based treatment strategies

Trial name/Ref.	Regimen	Sample size	Dosage and administration (experimental group)	mPFS (months, 95%CI)	Hazard ratio (95%CI); P value	mOS (months, 95%CI)	Hazard ratio (95%CI); P value	ORR (%); P value
Beom et al[61], 2023	Aflibercept + FOLFIRI	185	Aflibercept: 4 mg/kg q2w; FOLFIRI1	7.3		9.4		14.60%
HGCSG1801[62], 2024	Aflibercept + FOLFIRI	43	Aflibercept: 4 mg/kg q2w; irinotecan: 180 mg/m2 q2w; leucovorin: 200 mg/m2 q2w; 5-FU: 400 mg/m2 and 2400 mg/m2 (46 hours) q2w	7.3 (5.5–11.0)		18.8 (12.9–26.6)		20.90%
Martínez-Lago et al[63], 2022	Aflibercept + FOLFIRI	75	Aflibercept: 4 mg/kg q2w; irinotecan: 180 mg/m2 q2w; leucovorin: 400 mg/m2 q2w; 5-FU: 400 mg/m2 and 2400 mg/m2 (46 hours) q2w	6.6 (5.3–7.9)		15.1 (12.5–17.8)		33.80%
Claramunt García et al[66], 2022	Bevacizumab + FOLFIRI vs aflibercept + FOLFIRI	84		9.9 (7.5–12.2) vs 4.7 (3.6–5.7)	0.67 (0.39–1.12); P = 0.159	16.2 (13.3–19.1) vs 9.3 (5.3–13.4)	0.57 (0.34–0.94); P = 0.026

¹Not reported.

5-FU: 5-Fluorouracil; CI: Confidence interval; mOS: Median overall survival; mPFS: Median progression-free survival; ORR: Objective response rate.