Prognostic biomarkers for pancreatic ductal adenocarcinoma: A contemporary systematic review and modelling study

Table 3 Characteristics and reported outcomes of interventional trials included for clinical context in pancreatic ductal adenocarcinoma

NCT	Study design	n	Intervention	Stage	Primary outcome	Result	Secondary outcomes	Key finding	Ref.
NCT01726582	Single-arm	130	Personalised perioperative treatment (chemo/CRT/surgery)	Resectable/borderline resectable	Completion of surgery (feasibility)	108/130 (83.1%)	OS: 45 months vs 11 months; PFS: 36/130 (27.7%); Biomarker: 93/130 (71.5%); CR: 0/107; Near CR: 17/107; PR: 44/107; Poor: 42/107	The study demonstrated a high rate of completion of surgery (83.1%)	Tsai et al[71]
NCT00536874	Single-arm	35	Gem + oxaliplatin (neoadjuvant)	Resectable	18-month OS rate	63% (95%CI: 45-76)	OS: 39.6 months; PR: 4/35; SD: 28/35; PD: 3/35; CEA Δ: -5.1%; CA19-9 Δ: -25.6%	The 18-month OS rate was 63% (95%CI: 45%-76%)	O’Reilly et al[72]
NCT01926197	Randomised	13/12	mFOLFIRINOX vs mFOLFIRINOX + SBRT	Locally advanced (unresectable)	PFS (median)	6.5 months vs 8.4 months	Local PFS: 6.5 vs 8.4; PFS 1 year: 5/13 vs 2/12; MFS: 12.9 vs 10.8; OS: 12.9 vs 13.4; GI toxicity events: 16 vs 19	Median PFS was numerically higher in the SBRT arm (8.4 months vs 6.5 months)	Vitzthum[73]
NCT00810719	Single-arm	30	Gem + erlotinib	Advanced/metastatic	PFS (median)	2.07 months (1.87-5.50)	ORR: 11%; OS: 5.67 months (2.83-11.87)	The observed median PFS of 2.07 months indicated limited disease control	Semrad et al[74]
NCT00769483	Phase I/II, non-randomised, multi-arm	Approximately 15/arm	MK-0646 + Gem ± erlotinib	Stage IV (metastatic)	MTD + PFS (time to progression/death)	MTD: 10 mg/kg (Gem), 5 mg/kg (Gem + erlotinib); PFS: Approximately 1.8-2.0 months	OS: 5.7-10.4 months; ORR: Approximately 13%-17%; Toxicity: High	The study achieved its dose-escalation objective (MTD), but showed limited efficacy with median PFS of approximately 2 months	Abdel-Wahab et al[75]
NCT00365144	Single-arm	36	Bevacizumab + erlotinib	Metastatic, Gem-refractory	OS rate (6 months) + safety	8/36 (22.2%)	ORR: 1/36 (2.8%); TTP: 40 days (35-41); CA19-9 decline ≥ 25%: 4/26 (15.4%)	Low 6-month OS rate (22.2%)	Ko et al[76]
NCT00550836	Randomised	46/46	Gem + erlotinib vs + panitumumab	Metastatic	OS (median; arm A vs arm B)	4.2 months vs 8.3 months; P = 0.36	ORR: 8.7% vs 6.5%; PFS: 2.0 months vs 3.6 months, P = 0.419; TTF: 2.0 months vs 3.8 months, P = 0.36; G3+ AE: 41/46 vs 41/46; G4+ AE: 15/46 vs 14/46	Primary endpoint was not met	Halfdanarson et al[77]
NCT03941093	Randomised, double-blind	143/141	Pamrevlumab + G/nab-P or FOLFIRINOX vs placebo + G/nab-P or FOLFIRINOX	Locally advanced, unresectable	OS	17.25 months vs 17.94 months; HR 1.08 (0.83-1.41); P = 0.5487	EFS: 5.72 months vs 5.78 months; PFS: 9.36 months vs 9.40 months; ORR: 43/143 (30.1%) vs 64/141 (45.4%)	Primary endpoint not met	Picozzi et al[78]
NCT00408564	Single-arm	38-39	Gem + oxaliplatin + cetuximab, reassessment, surgery or RT/capecitabine	Locally advanced, unresectable, nonmetastatic	6-month PFS rate	82% (70%-95%)	G3-4 AE: 9/39 (23.1%); OS rate: 49% (36%-68%); ORR: 5/38 (13.2%)	High 6-month PFS rate	Medical University of South Carolina[79]
NCT00521404	Single-arm	61	CS-1008 (anti-DR5) + Gem	Unresectable/metastatic (chemo-naive)	16-week PFS rate	52.5% (39.3%-64.1%)	PFS: 3 months 59%, 6 months 34.4%; OS: 6 months 55.7%, 12 months 24.6%; ORR: 5/61 (8.2%); SD: 28/61 (45.9%)	Modest activity	Sankyo[80]
NCT00417976	Single-arm	39-40	Bevacizumab + Gem + infusional 5-FU	Stage III-IV	6-month PFS rate	49%	ORR: 12/40 (30%); SD: 18/40 (45%); PD: 10/40 (25%)	Moderate activity	Bekaii-Saab[81]
NCT00499486	Single-arm	31	Sirolimus monotherapy	Advanced PDAC, post-Gem (refractory)	6-month OS rate	26%	CR + PR: 0%. SD: 4 patients (approximately 13%). ORR = 0%	mTOR inhibition alone is insufficient in PDAC	Garrido-Laguna et al[82]
NCT01560949	Single-arm	33	mFOLFIRINOX, Gem-based CRT, surgery	Borderline resectable/high-risk resectable	Resectability rate	15/33 (45.5%)	R0: 10/15 (66.7%); DFS: 11.1 months (5.8-NA); OS: 24.0 months (16.2-29.6); SMAD4+ pre: 4/15 (26.7%); SMAD4+ post: 4/15 (26.7%); Local recurrence: 0/15; Distant recurrence: 10/15 (66.7%)	Moderate conversion to surgery; distant failure predominates	M.D. Anderson Cancer Center[83]
NCT01146054	Single-arm	49	SBRT + Gem	Locally advanced, unresectable, nonmetastatic	Late GI toxicity ≥ grade 2 at 1 year	5/49 (10.2%)	Acute GI toxicity: 14/49 (28.6%); PFS: 7.8 months (5.8-10.2); OS: 13.9 months (10.2-16.7); FFLP: 0.78 (0.60-0.89)	Low late GI toxicity; local control > systemic control	Koong[84]

NA: Not available; NCT: National clinical trial; CRT: Chemoradiotherapy; Gem: Gemcitabine; SBRT: Stereotactic body radiotherapy; FOLFIRINOX: Fluorouracil, leucovorin, irinotecan, and oxaliplatin; 5-FU: 5-Fluorouracil; DR5: Death receptor 5; RT: Radiotherapy; PDAC: Pancreatic ductal adenocarcinoma; MTD: Maximum tolerated dose; GI: Gastrointestinal; OS: Overall survival; PFS: Progression-free survival; CI: Confidence interval; HR: Hazard ratio; CR: Complete response; CEA: Carcinoembryonic antigen; PR: Partial response; SD: Stable disease; PD: Progressive disease; MFS: Metastasis-free survival; CA19-9: Carbohydrate antigen 19-9; TTP: Time to progression; ORR: Objective response rate; EFS: Event-free survival; TTF: Time to treatment failure; AE: Adverse event; FFLP: Freedom from local progression; R0: Microscopically margin-negative resection; DFS: Disease-free survival; mTOR: Mammalian target of rapamycin.