Pancreatic adenocarcinoma: Beyond first line, where are we?

Table 1 Studies of second-line treatment in metastatic pancreatic ductal adenocarcinoma

Ref.	Type of study	Patients (n)	1st-line regimen	2nd-line regimen	Median 2nd-line OS (mo)	Median 2nd-line PFS (mo)	2nd-line ORR (%)	2nd-line DCR (%)
Pelzer et al[35], 2011	Phase III	461	GEM monotherapy	OFF; BSC	4.8; 2.3	-	-	-
Oettle et al[36], 2014, CONKO-003	Phase III	160	GEM monotherapy	OFF; FF	5.9; 3.3	2.9; 2.0	-	-
Gill et al[37], 2016, PANCREOX	Phase III	108	GEM-based (approximately 75% monotherapy)	mFOLFOX6; FU/LV	6.1; 9.9	3.1; 2.9	13.2; 8.5	60; 63.8
Wang-Gillam et al[37], 2016, NAPOLI-1	Phase III	417	GEM-based2	Nal-IRI; FU/LV; Nal-IRI + FU/LV	4.9; 4.2; 6.1	2.7; 1.5; 3.1	6; 1; 16	44; 24; 52
Chung et al[29], 2018	Phase II	48	GEM-based	mFOLFIRINOX	9.0	5.8	18.8	62.5
Tsavaris et al[33], 2005	Phase II	30	GEM	OX 50 mg/mq + FU/LV (1-h iv infusion), weekly	6.25	-	23.3	53.3
Pelzer et al[32], 2009	Phase II	37	GEM	OFF	5.5	3.0	6	49
Yoo et al[34], 2009	Phase II	61	GEM-based	mFOLFIRI.3; mFOLFOX	3.9; 3.5	1.9; 1.4	0; 7	23; 17
Zaniboni et al[49], 2012	Phase II	50	GEM ± platinoid	FOLFIRI	5	3.2	8	36
Chung et al[29], 2018, SWOG S1115	Phase II	137	GEM-based	Selumetinib+ MK-2206; mFOLFOX	3.9; 6.7	1.9; 2.0	1.7; 8	22.4; 30.6
Portal et al[22], 2015	Prospective cohort	57	FOLFIRINOX	NabGem	8.8	5.1	17.5	58
Zaanan et al[47], 2014	Prospective cohort	46	GEM/FOLFIRI.3 in FIRGEM trial	FOLFOX	4.3	1.7	0	36
Wainberg et al[45], 2020	Meta-analysis	454	GEM-based	FOLFOX; Nal-IRI	6.3; 6.1	-	-	-
Sonbol et al[51], 2017	Meta-analysis	895	GEM-based	FPOX; FPIRIFP	FPIRI vs FP: HR OS 0.7, PFS 0.64; FPOX vs FP: HR OS 1.0, PFS 0.81
Citterio et al[52], 2018	Meta-analysis	1587	GEM-based	FP, OX or IRI-based	Most effective IRI-based regimens (results cannot be translated into the table)
Rahma et al[43], 2013	Systematic analysis	1503	GEM-based	GEM + platinum; FPOXBSC	6.0; 5.7; 2.8	4; 2.9; -	-	-
Petrelli et al[53], 2017	Systematic analysis	-	GEM-based	OX-based; IRI-based	5.3; 5.5	2.9; 2.7	11.9; 8.7	41.1; 29.4
Berk et al[48], 2012	Comparative	85	GEM-based	FOLFOX4; XELOX	5.8; 4.9	3.7; 3.7	17; 18	43; 59
Zhang et al[19], 2018	Retrospective	146	FOLFIRINOX	NabGem; Gem alone	5.69; 3.82	3.61; 2.51	-	-
Chae et al[21], 2020	Retrospective	102	FOLFIRINOX	NabGem	9.8	4.6	8.5	73.6
Viaud et al[17], 2017	Retrospective	96	FOLFIRINOX	GEM monotherapy	3.7	2.1	-	40
Gilabert et al[18], 2017	Retrospective	72	FOLFIRINOX	GEM monotherapy	-	2.5	11	-
Pointet et al[38], 2020	Retrospective	137	NabGem	FOLFOX; FOLFIRI; FOLFIRINOX	3.5; 9.7; 6.1	2; 6.6; 3.4	0; 9.5; 6.3	29.2; 61.9; 50
Lee et al[41], 2020	Retrospective	120	GEM-based	FPOX; FP	7.04; 7.43	2.89; 3.81	6.4; 5.4	52.6; 59.5
Neuzillet et al[50], 2012	Retrospective	63	GEM ± platinoid	FOLFIRI	6.6	3.0	7.9	39.7
Kieler et al[24], 2019	Retrospective	52	GEM-based	Nal-IRI + FU/LV	6.79	3.84	19.2	46.2

¹The trial was prematurely stopped due to insufficient accrual.

²Approximately 45% of gemcitabine alone and 55% in combination. About 30% of patients had received ≥ 2 previous lines for metastatic disease, with 45% of patients pretreated with fluorouracil/leucovorin-based regimens. GEM: Gemcitabine; DCR: Disease control rate; BSC: Best supportive care; OFF: Oxaliplatin, folinic acid and 5-fluorouracil; 5FU: 5-Fluorouracil; OX: Oxaliplatin; LV: Leucovorin; FF: Folinic acid and 5-fluorouracil; Nal-IRI: Liposomal irinotecan; FOLFIRINOX: 5-Fluorouracil, folinic acid, irinotecan and oxaliplatin; FOLFOX: 5-fluorouracil + leucovorin + oxaliplatin; FPOX: Fluoropyrimidine and oxaliplatin-based regimens; HR: Hazard ratio; OS: Overall survival; NabGem: Nb-paclitaxel and gemcitabine; FP: Fluoropyrimidine; IRI: Irinotecan.

Table 2 Main ongoing targeted therapy studies (clinicaltrial.gov) for advanced pancreatic adenocarcinoma

Treatment	Target	Phase of study	Setting
Ribociclib plus trametinib; NCT02703571	CDK4/6	Phase I/II trial, open label single arm	Advanced or metastatic pancreatic cancer and KRAS-mutant colorectal cancer
Palbociclib + the PI3K/mTOR inhibitor, gedatolisib; NCT03065062	CDK4/6	Phase I, open label single arm	Advanced squamous cell lung, pancreatic, head and neck and other solid tumours
Abemaciclib in combination with the TGF-β inhibitor galunisertib or other agents; NCT02981342	CDK4/6	Phase II, open label, randomized	Previously treated metastatic pancreatic ductal adenocarcinoma
BKM120 + mFOLFOX6; NCT01571024	PI3K	Phase I, open label, single arm	Advanced solid tumours including metastatic pancreatic cancer
Metformin + Gemcitabine + Erlotinib; NCT01210911	PI3K	Phase II, randomized, placebo controlled	Locally advanced or metastatic pancreatic cancer
Capecitabine + Cetuximab + Everolimus; NCT01077986	mTOR	Phase I/II, open label, single arm	Metastatic pancreatic cancer
Temsirolimus; NCT00075647	mTOR	Phase II, open label, single arm	Locally advanced or metastatic pancreatic cancer
MK2206 + Fluorouracil + Oxaliplatin + Selumetinib; NCT01658943	Akt	Phase II, open label, randomized	Metastatic pancreatic cancer
RX-0201 + Gemcitabine; NCT01028495	Akt	Phase II, open label, single arm	Metastatic pancreatic cancer
Gemcitabine ± nimotuzumab; NCT02395016	EGFR	Phase III, prospective, randomized, controlled, double-blind	Locally advanced or metastatic pancreatic cancer
MRTX849 (inhibitor of KRAS G12C) + TNO155 (inhibitor of SHP2); NCT04330664	KRASG12C	Phase I/II, open label, non-randomized	Advanced or metastatic cancer with a KRASG12C mutation
AMG 510 Monotherapy; NCT03600883	KRASG12C	Phase I/II, open label, non-randomized	KRAS p.G12C mutant advanced solid tumours
Gemcitabine + M7824 (TGF-β ligand trap); NCT03451773	TGF-β	Phase I/II, open label, single arm	Locally advanced or metastatic pancreatic cancer
FFX vs CPI-613 + mFFX; NCT03504423	CPI-613	Pase III, open-label randomized	Mtastatic adenocarcinoma of the pancreas

TGF-β: Transforming growth factor β.