Up-to-Date Tailored Systemic Treatment in Pancreatic Ductal Adenocarcinoma

Table 3

Selected immunotherapy combination studies in metastatic pancreatic ductal adenocarcinoma.

Combination	Reference	Intervention	Phase	Status		Endpoints	Results
Chemotherapy + ICPi	Renouf et al. [114]; NCT02879318	Durvalumab+tremelimumab+gemcitabine/nab-paclitaxel vs. gemcitabine/nab-paclitaxel	II	Ongoing	11	OS, PFS, ORR, safety	(i) Data from safety run-in: (a) AEs: fatigue, myelosuppression, hyponatraemia, hypoalbuminaemia, deranged lipase, colitis; (b) PR in 8/11 patients (73%); (c) Median DOR 7.4 months; (d) Median PFS 7.9 months (95% CI 3.5-9.2 months)
	O’Reilly et al. [71]; NCT02558894	Durvalumab (D) vs. durvalumab+tremelimumab (D+T)	II	Completed	65	ORR, PFS, OS, BOR, DCR, PK (durvalumab+tremelimumab), presence of ADAs	(i) ORR 3.1% (D+T) vs. 0% (D); (ii) Median PFS 1.5 months (both arms); (iii) Median OS 3.1 (D+T) vs. 3.6 months (D); (iv) trAEs in D+T arm: diarrhoea, fatigue. Treatment discontinued in 3 patients
	Wainberg et al. [115]; NCT02309177	Nivolumab+gemcitabine/nab-paclitaxel	I	Completed	50	DLT, safety, PFS, OS, DCR, ORR, DOR	(i) Hepatitis as DLT, related to gemcitabine/nab-paclitaxel; (ii) teAEs in 48/50 patients (96%) including anaemia, neutropenia, gastrointestinal events, hepatotoxicity, peripheral neuropathy, thrombocytopenia, and colitis; (iii) 1 grade 5 teAE (respiratory failure); (iv) Median PFS 5.5 months; (v) Median OS 9.9 months
PARPi+ICPi	NCT03851614	Olaparib+durvalumab	II	Ongoing	N/A	Genomic and immune biomarker changes, ORR, CBR, PFS, OS, safety	N/A
Desmoplastic stromal agent+ICPi	NCT02758587	Defactinib+pembrolizumab	I/II	Ongoing	N/A	Safety, ORR, DOR, PFS, change in FAK Y397 phosphorylation and immune cell infiltrate	N/A
	Wang-Gillam et al. [116]; NCT02546531	Defactinib+pembrolizumab+gemcitabine	I/II	Ongoing	17	RP2D, safety, ORR, PFS, OS	(i) Results from dose escalation cohort: (a) No DLTs; (b) Level 5 dose as RP2D (defactinib 400 mg, pembrolizumab 200 mg, gemcitabine 1,000 mg/m^2); (c) Common trAEs: fatigue, nausea, myalgia, vomiting, anorexia, pruritus, fever; (d) SD in 7/13 evaluable patients (54%)
	Desai et al. [117]; NCT03193190	Atezolizumab+PEGPH20	Ib/II	Ongoing	N/A	ORR, safety, PFS, OS, DOR, PKs	N/A
	NCT03481920	Avelumab+PEGPH20	I	Ongoing	N/A	ORR, safety, OS, PFS, change in CA19-9	N/A
	Hidalgo et al. [79]; NCT02826486	Pembrolizumab+BL-8040	II	Ongoing	37	ORR, OS, PFS, DOR	(i) 29 evaluable patients; (ii) PR in 1 patient (3.5%); SD in 10 patients (34.5%); (iii) Overall median OS 3.4 months; 7.5 months in second-line subgroup
Bruton’s tyrosine kinase+ICPi	Overman et al. [118]; NCT02362048	Pembrolizumab+acalabrutinib vs. acalabrutinib	II	Ongoing	58	Safety	(i) No DLTs; (ii) AEs in combination arm: dehydration, anaemia, hypotension; (iii) AEs in monotherapy arm: anaemia, abdominal pain; (iv) SD in 4/21 evaluable patients in monotherapy arm; (v) PR in 3/23 and SD in 5/23 evaluable patients in combination arm
Myeloid inhibitor+ICPi	Wainberg et al. [119]; NCT02526017	Cabiralizumab+nivolumab	I	Ongoing	205	Safety, ORR, RD, PK, immunogenicity, biomarker analysis	(i) trAEs due to cabiralizumab in 43% of patients; (ii) Treatment discontinuation due to AEs in 13%; (iii) Most common AEs: elevated CPK and AST. Reversible without sequalae; (iv) 31 evaluable pretreated patients; (a) 3 PR; 1 SD; (b) ORR 10%
	NCT02777710	Pexidartinib+durvalumab	I	Ongoing	N/A	DLT, ORR, DOR, PFS, safety, PK	N/A
CXCR2 inhibitor+ICPi	NCT02583477	AZD5069+durvalumab	Ib/II	Completed	N/A	DLT, ORR, DOR, DCR, PFS, presence of ADAs, PK, safety	No results available
Oncolytic virus+ICPi	Mahalingam et al. [99]; NCT02620423	Pelareorep+pembrolizumab+chemotherapy (5-FU/leucovorin, gemcitabine, or irinotecan)	I	Completed	11	Safety, DLTs, ORR, PFS, immune markers	(i) teAEs in 8 patients; (ii) PR in 1/5 and SD in 2/5 evaluable patients; (iii) On-treatment biopsy showed reovirus infection and immune infiltrates
Vaccines+ICPi	Le et al. [120]; NCT02243371	GVAX/Cy+CRS-207±nivolumab	II	Ongoing	N/A	OS, safety, PFS, TTP, ORR, tumour marker kinetics	N/A
	NCT03190265	CRS-207 (±GVAX/Cy)+nivolumab+ipilimumab	II	Ongoing	N/A	ORR, safety, OS, PFS, DOR, TTP, tumour marker kinetics	N/A

References marked with denote results derived from published abstracts. Abbreviations: ADA: antidrug antibodies; AE: adverse event; AST: aspartate transaminase; BOR: best objective response; CBR: clinical benefit rate; CI: confidence interval; CPK: creatinine phosphokinase; DLT: dose-limiting toxicities; DCR: disease control rate; DOR: duration of response; ICPi: immune checkpoint inhibitor; ORR: overall response rate; OS: overall survival; PARPi: polyADP-ribose polymerase inhibitor; PK: pharmacokinetics; PR: partial response; PFS: progression-free survival; RP2D: recommended phase 2 dose; SD: stable disease; teAEs: treatment-emergent adverse events; trAEs: treatment-related adverse events; TTP: time to tumour progression.