Table 1.

Studies of FTD/TPI-containing combination regimens in metastatic colorectal cancer.

Study	Study type/phase	Population specifics	Intervention 1, n	Intervention 2, n	Treatment setting	Reported study endpointsa	Study location	Median follow-up, mo
FTD/TPI + BEV
Van Cutsem et al48,50,55	Phase II RCT	mCRC	FTD/TPI + BEV n = 77	CAP + BEV n = 76	1L	PE: PFS SE: OS, QoL, safety	12 countriesb	NA
Oki et al49	Phase II non-RCT	mCRC ≥70 years	FTD/TPI + BEV n = 39	—	1L	PE: PFS SE: OS, ORR, safety	Japan	18.9
Pfeiffer et al8	Phase II RCT	mCRC	FTD/TPI + BEV n = 46	FTD/TPI mono n = 47	2L+	PE: PFS SE: OS, ORR, DCR, safety	Denmark	10·0
Kuboki et al7	Phase I/II non-RCT	mCRC	FTD/TPI + BEV n = 25	—	2L+	PE: PFS at 16 wks SE: PFS, ORR, DCR, TTF, OS, PK, AEs	Japan	11·4
Takahashi et al46	Phase II non-RCT	mCRC	FTD/TPI + BEV n = 97 (safety data set, n = 102)	—	2L+	PE: DCR by RAS status SE: DCR overall, PFS, OS, ORR overall and by RAS status	Japan	15.8
Nose et al36	Retro Obs	mCRC	FTD/TPI + BEV n = 32	FTD/TPI mono n = 24	2L+	PE: PFS SE: OS, safety	Japan	11.6; 6.3
Fujii et al33	Retro Obs	mCRC	FTD/TPI + BEV n = 21	FTD/TPI mono n = 36	2L+	PE: OS SE: ORR, TTF	Japan	14.8
Hisamatsu et al27	Retro Obs	mCRC	FTD/TPI + BEV n = 24	—	2L+	PE: PFS SE: ORR, DCR, OS, safety	Japan	NA
Ishikawa et al22	Retro Obs	mCRC	FTD/TPI + BEV n = 22	FTD/TPI mono n = 23	2L+	DCR, PFS, OS, AEs	NA	NA
Makiyama et al23	Retro Obs	mCRC	FTD/TPI + BEV n = 11	FTD/TPI mono n = 33	2L+	PFS, OS, safety	Japan	NA
Yasuda et al24	Retro Obs	mCRC	FTD/TPI + BEV n = 33	—	2L+	Safety	Japan	NA
Ota et al20	Retro Obs	mCRC	FTD/TPI ± BEV n = 14	—	2L+	PFS, OS, safety	Japan	10.3
Miano et al34	Non-RCT	mCRC	FTD/TPI + BEV n = 15	—	3L+	PE: PFS SE: RR, OS, grade 3 neutropenia	Italy	100
Satake et al37	Phase Ib/II non-RCT	mCRC	FTD/TPI + BEV n = 44	—	3L+	PE: PFS at 16 wks SE: OS, PFS, TTF, ORR, DCR, safety	Japan	15.36
Yoshida et al31	Phase II non-RCT	mCRC	FTD/TPI + BEV n = 45	—	3L+	PE: PFS SE: RR, DCR, OS, safety	Japan	NA
Ishizaki et al43	Phase II non-RCT	mCRC	FTD/TPI + BEV n = 19	—	3L+	PE: PFS SE: OS, ORR, DCR, AEs, time to ECOG PS ≥ 2	Japan	11.5
Yoshida et al47	Phase II non-RCT	mCRC	FTD/TPI + BEV n = 32	—	3L+	PE: PFS SE: TTF, RR, OS, AEs	Japan	NA
Shibutani et al38	Retro Obs	mCRC	FTD/TPI + BEV n = 36	FTD/TPI mono n = 26	3L+	ORR, PFS, OS, safety	Japan	NA
Matsuhashi et al29	Retro Obs	mCRC	FTD/TPI + BEV n = 17	—	3L+	ORR, DCR, PFS, OS, safety	Japan	NA
Kotani et al28	Retro Obs	mCRC	FTD/TPI + BEV n = 60	FTD/TPI mono n = 66	3L+	PFS, ORR, DCR, OS, AEs	Japan	7.1; 7.2
Yoshida et al25	Retro Obs	mCRC	FTD/TPI + BEV n = 25	FTD/TPI mono n = 16	3L+	ORR, PFS, OS, AEs	Japan	NA
FTD/TPI + BEV + Chemo
Varghese et al40	Phase I non-RCT	mCRC	FTD/TPI + BEV + IRI n = 24	FTD/TPI + IRI n = 26	2L+	PE: Safety, MTD SE: Safety	NR	NA
Yamazaki et al41	Phase II non-RCT	mCRC	FTD/TPI + BEV + IRI n = 18	—	2L+	PE: ORR SE: Safety	Japan	NA
Bordonaro et al32	Phase I non-RCT	mCRC	FTD/TPI + BEV + OXA n = 37	FTD/TPI + OXA + NIVO n = 17	3L+	ORR, DCR, PFS, OS, safety	France, Spain, Italy, Germany, Austria, Hungary, UK	NA
FTD/TPI + Chemo
Doi et al19	Phase I non-RCT	mCRC	FTD/TPI + IRI n = 10	—	2L+	PE: RD, safety SE: Efficacy, PK	Japan	33.7
Argilés et al26	Phase I non-RCT	mCRC	FTD/TPI + OXA n = 24	—	2L+	PE: MTD, RD, safety SE: PK, anti-tumor activity	France, Spain	NA
Suenaga et al39	Phase I non-RCT	mCRC	FTD/TPI + OXA n = 12	—	3L+	Response, PFS, OS, safety	Japan	13.8
Cecchini et al42	Phase Ib/II non-RCT	mCRC	FTD/TPI + OXA n = 41	—	3L+	PE: ORR SE: PFS, OS, DCR, DOR, safety	NR	6.8
FTD/TPI + targeted therapy
Kato et al44	Phase I/II non-RCT	mCRC	FTD/TPI + PAN n = 54 (safety population: n = 55)	—	2L+	PE: PFS at 6 mo SE: PFS, OS, ORR, DCR, TTF, safety	Japan	16.5
Van Cutsem et al30	Phase II non-RCT	mCRC	FTD/TPI + MUR n = 15	MUR n = 14	2L+	Response, PFS, OS, PD, safety	Belgium, Czech Rep.	NA
Yamazaki et al21	Phase I/II non-RCT	mCRC	FTD/TPI + NIN n = 52	—	2L+	PE: PFS at 16 wks SE: OS, DCR, ORR, safety	Japan	NA
Moehler et al35	Phase I non-RCT	mCRC	FTD/TPI + REG n = 12	—	3L+	PE: MTD SE: DCR, PFS, OS, safety	Germany	NA
Patel et al45	Phase II non-RCT	mCRC	FTD/TPI + NIVO n = 18	—	3L+	PE: irORR SE: ORR, PFS, DCR, OS, safety	USA	NA
Kasper et al51	Phase IIb RCT	mCRC	FTD/TPI + RAM n = 40	FTD/TPI n = 40	NR	PE: OS SE: ORR, DCR, PFS, safety	Germany	NA

^aWhere PE and SE are not specified in the column, study endpoints were not classified as primary or secondary.

^bAustralia, Belgium, Brazil, Denmark, France, Germany, Italy, The Netherlands, Poland, Russia, Spain, and UK.

Abbreviations: 1L, first line; 2L, second line; 3L, third line; AE, adverse event; BEV, bevacizumab; CAP, capecitabine; DCR, disease control rate; DOR, duration of response; ECOG PS, Eastern Cooperative Oncology Group performance status; FTD/TPI, trifluridine/tipiracil; IRI, irinotecan; irORR, immune-related objective response rate; mCRC, metastatic colorectal cancer; mo, months; Mono, monotherapy; MTD, maximum tolerated dose; MUR, murlentamab; NA, not available; NIN, nintedanib; NIVO, nivolumab; Non-RCT, nonrandomized controlled trial; NR, not reported; ORR, overall response rate; OS, overall survival; OXA, oxaliplatin; PAN, panitumumab; PD, pharmacodynamics; PE, primary endpoint; PFS, progression-free survival; PK, pharmacokinetics; QoL, quality of life; RCT, randomized controlled trial; RD, recommended dose; REG, regorafenib; Retro Obs, retrospective observational, RR, response rate; SE, secondary endpoint(s); TTF, time to treatment failure; wks, weeks.