[Skip to Navigation]
Sign In
Figure 1.  CONSORT Diagram
CONSORT Diagram
Figure 2.  Percentage of Change in Target Lesion Size
Percentage of Change in Target Lesion Size

Percentage of change was assessed by the investigator at each study site. Dotted reference lines at −30% and 20% denote thresholds for partial response (PR) and progressive disease (PD), respectively. The censored case was of a patient treated with durvalumab plus tremelimumab therapy who maintained stable disease until week 43 (PD on day 302). This patient was re-treated with tremelimumab therapy after PD and survived without appearance of new lesions until data cutoff (day 467).

Figure 3.  Progression-Free Survival (PFS) and Overall Survival (OS) in Patients With Metastatic Pancreatic Ductal Adenocarcinoma Treated With Durvalumab Plus Tremelimumab (D + T) Therapy vs Durvalumab Monotherapy (D)
Progression-Free Survival (PFS) and Overall Survival (OS) in Patients With Metastatic Pancreatic Ductal Adenocarcinoma Treated With Durvalumab Plus Tremelimumab (D + T) Therapy vs Durvalumab Monotherapy (D)
Table.  Common Treatment-Related Adverse Eventsa
Common Treatment-Related Adverse Eventsa
1.
Amundadottir  LT.  Pancreatic cancer genetics.  Int J Biol Sci. 2016;12(3):314-325. doi:10.7150/ijbs.15001PubMedGoogle ScholarCrossref
2.
Chiaravalli  M, Reni  M, O’Reilly  EM.  Pancreatic ductal adenocarcinoma: state-of-the-art 2017 and new therapeutic strategies.  Cancer Treat Rev. 2017;60:32-43. doi:10.1016/j.ctrv.2017.08.007PubMedGoogle ScholarCrossref
3.
Hidalgo  M, Cascinu  S, Kleeff  J,  et al.  Addressing the challenges of pancreatic cancer: future directions for improving outcomes.  Pancreatology. 2015;15(1):8-18. doi:10.1016/j.pan.2014.10.001PubMedGoogle ScholarCrossref
4.
Uccello  M, Moschetta  M, Mak  G, Alam  T, Henriquez  CM, Arkenau  HT.  Towards an optimal treatment algorithm for metastatic pancreatic ductal adenocarcinoma (PDA).  Curr Oncol. 2018;25(1):e90-e94. doi:10.3747/co.25.3708PubMedGoogle ScholarCrossref
5.
Fokas  E, O’Neill  E, Gordon-Weeks  A, Mukherjee  S, McKenna  WG, Muschel  RJ.  Pancreatic ductal adenocarcinoma: from genetics to biology to radiobiology to oncoimmunology and all the way back to the clinic.  Biochim Biophys Acta. 2015;1855(1):61-82.PubMedGoogle Scholar
6.
Imai  D, Yoshizumi  T, Okano  S,  et al.  The prognostic impact of programmed cell death ligand 1 and human leukocyte antigen class I in pancreatic cancer.  Cancer Med. 2017;6(7):1614-1626. doi:10.1002/cam4.1087PubMedGoogle ScholarCrossref
7.
Tessier-Cloutier  B, Kalloger  SE, Al-Kandari  M,  et al.  Programmed cell death ligand 1 cut-point is associated with reduced disease specific survival in resected pancreatic ductal adenocarcinoma.  BMC Cancer. 2017;17(1):618. doi:10.1186/s12885-017-3634-5PubMedGoogle ScholarCrossref
8.
Yamaki  S, Yanagimoto  H, Tsuta  K, Ryota  H, Kon  M.  PD-L1 expression in pancreatic ductal adenocarcinoma is a poor prognostic factor in patients with high CD8+ tumor-infiltrating lymphocytes: highly sensitive detection using phosphor-integrated dot staining.  Int J Clin Oncol. 2017;22(4):726-733. doi:10.1007/s10147-017-1112-3PubMedGoogle ScholarCrossref
9.
Antonia  SJ, Villegas  A, Daniel  D,  et al; PACIFIC Investigators.  Durvalumab after chemoradiotherapy in stage III non–small-cell lung cancer.  N Engl J Med. 2017;377(20):1919-1929. doi:10.1056/NEJMoa1709937PubMedGoogle ScholarCrossref
10.
Azad  A, Yin Lim  S, D’Costa  Z,  et al.  PD-L1 blockade enhances response of pancreatic ductal adenocarcinoma to radiotherapy.  EMBO Mol Med. 2017;9(2):167-180. doi:10.15252/emmm.201606674PubMedGoogle ScholarCrossref
11.
Kyi  C, Postow  MA.  Immune checkpoint inhibitor combinations in solid tumors: opportunities and challenges.  Immunotherapy. 2016;8(7):821-837. doi:10.2217/imt-2016-0002PubMedGoogle ScholarCrossref
12.
Segal  NH, Hamid  O, Hwu  WJ,  et al.  A phase 1 multi-arm dose-expansion study of the anti-programmed cell death-ligand-1 (PD-L1) antibody MEDI4736: preliminary data  [abstract].  Ann Oncol. 2014; 25(suppl 4):iv365.Google Scholar
13.
Eroglu  Z, Kim  DW, Wang  X,  et al.  Long term survival with cytotoxic T lymphocyte–associated antigen 4 blockade using tremelimumab.  Eur J Cancer. 2015;51(17):2689-2697. doi:10.1016/j.ejca.2015.08.012PubMedGoogle ScholarCrossref
14.
Pardoll  DM.  The blockade of immune checkpoints in cancer immunotherapy.  Nat Rev Cancer. 2012;12(4):252-264. doi:10.1038/nrc3239PubMedGoogle ScholarCrossref
15.
Royal  RE, Levy  C, Turner  K,  et al.  Phase 2 trial of single agent ipilimumab (anti–CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma.  J Immunother. 2010;33(8):828-833. doi:10.1097/CJI.0b013e3181eec14cPubMedGoogle ScholarCrossref
16.
Hu  ZI, Shia  J, Stadler  ZK,  et al.  Evaluating mismatch repair deficiency in pancreatic adenocarcinoma: challenges and recommendations.  Clin Cancer Res. 2018;24(6):1326-1336. doi:10.1158/1078-0432.CCR-17-3099PubMedGoogle ScholarCrossref
17.
Antonia  S, Goldberg  SB, Balmanoukian  A,  et al.  Safety and antitumour activity of durvalumab plus tremelimumab in non–small cell lung cancer: a multicentre, phase 1b study.  Lancet Oncol. 2016;17(3):299-308. doi:10.1016/S1470-2045(15)00544-6PubMedGoogle ScholarCrossref
18.
Callahan  MK, Kluger  H, Postow  MA,  et al.  Nivolumab plus ipilimumab in patients with advanced melanoma: updated survival, response, and safety data in a phase I dose-escalation study.  J Clin Oncol. 2018;36(4):391-398. doi:10.1200/JCO.2017.72.2850PubMedGoogle ScholarCrossref
19.
Hao  C, Tian  J, Liu  H, Li  F, Niu  H, Zhu  B.  Efficacy and safety of anti–PD-1 and anti–PD-1 combined with anti–CTLA-4 immunotherapy to advanced melanoma: a systematic review and meta-analysis of randomized controlled trials.  Medicine. 2017;96(26):e7325. doi:10.1097/MD.0000000000007325PubMedGoogle ScholarCrossref
20.
Hellmann  MD, Rizvi  NA, Goldman  JW,  et al.  Nivolumab plus ipilimumab as first-line treatment for advanced non–small-cell lung cancer (CheckMate 012): results of an open-label, phase 1, multicohort study.  Lancet Oncol. 2017;18(1):31-41. doi:10.1016/S1470-2045(16)30624-6PubMedGoogle ScholarCrossref
21.
Hodi  FS, Chesney  J, Pavlick  AC,  et al.  Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial.  Lancet Oncol. 2016;17(11):1558-1568. doi:10.1016/S1470-2045(16)30366-7PubMedGoogle ScholarCrossref
22.
Le  DT, Lutz  E, Uram  JN,  et al.  Evaluation of ipilimumab in combination with allogeneic pancreatic tumor cells transfected with a GM-CSF gene in previously treated pancreatic cancer.  J Immunother. 2013;36(7):382-389. doi:10.1097/CJI.0b013e31829fb7a2PubMedGoogle ScholarCrossref
23.
Schwartz  LH, Litière  S, de Vries  E,  et al.  RECIST 1.1-Update and clarification: From the RECIST committee.  Eur J Cancer. 2016;62:132-137. doi:10.1016/j.ejca.2016.03.081PubMedGoogle ScholarCrossref
24.
National Institutes of Health. Common Terminology Criteria for Adverse Events (CTCAE). Version 4.03. https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf. Updated June 14, 2010. Accessed June 11, 2019.
25.
Jeanson  A, Barlesi  F.  MEDI 4736 (durvalumab) in non–small cell lung cancer.  Expert Opin Biol Ther. 2017;17(10):1317-1323. doi:10.1080/14712598.2017.1351939PubMedGoogle ScholarCrossref
26.
Ferris  RL, Blumenschein  G  Jr, Fayette  J,  et al.  Nivolumab for recurrent squamous-cell carcinoma of the head and neck.  N Engl J Med. 2016;375(19):1856-1867. doi:10.1056/NEJMoa1602252PubMedGoogle ScholarCrossref
27.
Bauml  J, Seiwert  TY, Pfister  DG,  et al.  Pembrolizumab for platinum- and cetuximab-refractory head and neck cancer: results from a single-arm, phase II study.  J Clin Oncol. 2017;35(14):1542-1549. doi:10.1200/JCO.2016.70.1524PubMedGoogle ScholarCrossref
28.
Dougan  SK.  The pancreatic cancer microenvironment.  Cancer J. 2017;23(6):321-325. doi:10.1097/PPO.0000000000000288PubMedGoogle ScholarCrossref
29.
Zhang  J, Wolfgang  CL, Zheng  L.  Precision immuno-oncology: prospects of individualized immunotherapy for pancreatic cancer.  Cancers. 2018;10(2):E39. doi:10.3390/cancers10020039PubMedGoogle Scholar
30.
Brahmer  JR, Tykodi  SS, Chow  LQ,  et al.  Safety and activity of anti–PD-L1 antibody in patients with advanced cancer.  N Engl J Med. 2012;366(26):2455-2465. doi:10.1056/NEJMoa1200694PubMedGoogle ScholarCrossref
31.
Sharma  P, Dirix  L, De Vos  FYFL,  et al.  Efficacy and tolerability of tremelimumab in patients with metastatic pancreatic ductal adenocarcinoma.  J Clin Oncol. 2018;36(4)(suppl):470. doi:10.1200/JCO.2018.36.4_suppl.470Google ScholarCrossref
32.
Ene-Obong  A, Clear  AJ, Watt  J,  et al.  Activated pancreatic stellate cells sequester CD8+ T cells to reduce their infiltration of the juxtatumoral compartment of pancreatic ductal adenocarcinoma.  Gastroenterology. 2013;145(5):1121-1132. doi:10.1053/j.gastro.2013.07.025PubMedGoogle ScholarCrossref
33.
Lunardi  S, Muschel  RJ, Brunner  TB.  The stromal compartments in pancreatic cancer: are there any therapeutic targets?  Cancer Lett. 2014;343(2):147-155. doi:10.1016/j.canlet.2013.09.039PubMedGoogle ScholarCrossref
34.
Bailey  P, Chang  DK, Forget  MA,  et al.  Exploiting the neoantigen landscape for immunotherapy of pancreatic ductal adenocarcinoma.  Sci Rep. 2016;6:35848. doi:10.1038/srep35848PubMedGoogle ScholarCrossref
35.
Porembka  MR, Mitchem  JB, Belt  BA,  et al.  Pancreatic adenocarcinoma induces bone marrow mobilization of myeloid-derived suppressor cells which promote primary tumor growth.  Cancer Immunol Immunother. 2012;61(9):1373-1385. doi:10.1007/s00262-011-1178-0PubMedGoogle ScholarCrossref
36.
Soares  KC, Rucki  AA, Wu  AA,  et al.  PD-1/PD-L1 blockade together with vaccine therapy facilitates effector T-cell infiltration into pancreatic tumors.  J Immunother. 2015;38(1):1-11. doi:10.1097/CJI.0000000000000062PubMedGoogle ScholarCrossref
37.
Zhu  Y, Knolhoff  BL, Meyer  MA,  et al.  CSF1/CSF1R blockade reprograms tumor-infiltrating macrophages and improves response to T-cell checkpoint immunotherapy in pancreatic cancer models.  Cancer Res. 2014;74(18):5057-5069. doi:10.1158/0008-5472.CAN-13-3723PubMedGoogle ScholarCrossref
38.
Decaup  E, Rochotte  J, Pyronnet  S, Bousquet  C, Jean  C.  Focal adhesion kinase: a promising therapeutic target in pancreatic adenocarcinoma.  Clin Res Hepatol Gastroenterol. 2017;41(3):246-248. doi:10.1016/j.clinre.2016.10.010PubMedGoogle ScholarCrossref
39.
Jiang  H, Hegde  S, Knolhoff  BL,  et al.  Targeting focal adhesion kinase renders pancreatic cancers responsive to checkpoint immunotherapy.  Nat Med. 2016;22(8):851-860. doi:10.1038/nm.4123PubMedGoogle ScholarCrossref
40.
Mehla  K, Tremayne  J, Grunkemeyer  JA,  et al.  Combination of mAb-AR20.5, anti–PD-L1 and polyICLC inhibits tumor progression and prolongs survival of MUC1.Tg mice challenged with pancreatic tumors.  Cancer Immunol Immunother. 2018;67(3):445-457. doi:10.1007/s00262-017-2095-7PubMedGoogle ScholarCrossref
41.
Skelton  RA, Javed  A, Zheng  L, He  J.  Overcoming the resistance of pancreatic cancer to immune checkpoint inhibitors.  J Surg Oncol. 2017;116(1):55-62. doi:10.1002/jso.24642PubMedGoogle ScholarCrossref
42.
Farren  MR, Mace  TA, Geyer  S,  et al.  Systemic immune activity predicts overall survival in treatment-naive patients with metastatic pancreatic cancer.  Clin Cancer Res. 2016;22(10):2565-2574. doi:10.1158/1078-0432.CCR-15-1732PubMedGoogle ScholarCrossref
43.
Le  DT, Uram  JN, Wang  H,  et al.  PD-1 blockade in tumors with mismatch-repair deficiency.  N Engl J Med. 2015;372(26):2509-2520. doi:10.1056/NEJMoa1500596PubMedGoogle ScholarCrossref
44.
Hellmann  MD, Ciuleanu  TE, Pluzanski  A,  et al.  Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden.  N Engl J Med. 2018;378(22):2093-2104. doi:10.1056/NEJMoa1801946PubMedGoogle ScholarCrossref
45.
Di Marco  M, Grassi  E, Durante  S,  et al.  State of the art biological therapies in pancreatic cancer.  World J Gastrointest Oncol. 2016;8(1):55-66. doi:10.4251/wjgo.v8.i1.55PubMedGoogle ScholarCrossref
Original Investigation
July 18, 2019

Durvalumab With or Without Tremelimumab for Patients With Metastatic Pancreatic Ductal Adenocarcinoma: A Phase 2 Randomized Clinical Trial

Author Affiliations
  • 1Gastrointestinal Medical Oncology, David M. Rubenstein Center for Pancreatic Cancer, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, New York
  • 2Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
  • 3Cancer Clinical Research Unit, Princess Margaret Cancer Centre, Toronto, Ontario, Canada
  • 4Medical Oncology, BC Cancer, Vancouver, British Columbia, Canada
  • 5Department of Oncology, Seoul St Mary’s Hospital, The Catholic University of Korea, Seoul, South Korea
  • 6Division of Medical Oncology, University of Kansas Medical Center, Kansas City
  • 7Department of Medicine–Medical Oncology, Stanford University, Stanford, California
  • 8Division of Hematology and Oncology, University of Rochester, Rochester, New York
  • 9AstraZeneca, Gaithersburg, Maryland
  • 10Independent Biostatistician, Durham, North Carolina
  • 11Department of Oncology, Barbara Ann Karmanos Cancer Institute, Detroit, Michigan
JAMA Oncol. 2019;5(10):1431-1438. doi:10.1001/jamaoncol.2019.1588
Key Points

Question  Does combination immuno-oncology therapy (anti–programmed death–ligand 1 and anticytotoxic T-lymphocyte–associated antigen 4) provide clinical benefit for patients with metastatic pancreatic ductal adenocarcinoma?

Findings  In part A of this phase 2 randomized clinical trial of 65 patients, durvalumab plus tremelimumab therapy was tolerated in patients with metastatic pancreatic ductal adenocarcinoma and had an objective response rate of 3.1%, and no patients responded to durvalumab monotherapy. The threshold for continuation to part B of the study was an objective response rate of 10% for either arm (durvalumab plus tremelimumab therapy or durvalumab monotherapy), so part B was not conducted based on the findings of part A.

Meaning  The efficacy of immunotherapy in part A of this trial was reflective of a population of patients with metastatic pancreatic ductal adenocarcinoma who had poor prognoses and rapidly progressing disease.

Abstract

Importance  New therapeutic options for patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) are needed. This study evaluated dual checkpoint combination therapy in patients with mPDAC.

Objective  To evaluate the safety and efficacy of the anti–PD-L1 (programmed death-ligand 1) antibody using either durvalumab monotherapy or in combination with the anticytotoxic T-lymphocyte antigen 4 antibody using durvalumab plus tremelimumab therapy in patients with mPDAC.

Design, Setting, and Participants  Part A of this multicenter, 2-part, phase 2 randomized clinical trial was a lead-in safety, open-label study with planned expansion to part B pending an efficacy signal from part A. Between November 26, 2015, and March 23, 2017, 65 patients with mPDAC who had previously received only 1 first-line fluorouracil–based or gemcitabine-based treatment were enrolled at 21 sites in 6 countries. Efficacy analysis included the intent-to-treat population; safety analysis included patients who received at least 1 dose of study treatment and for whom any postdose data were available.

Interventions  Patients received durvalumab (1500 mg every 4 weeks) plus tremelimumab (75 mg every 4 weeks) combination therapy for 4 cycles followed by durvalumab therapy (1500 mg every 4 weeks) or durvalumab monotherapy (1500 mg every 4 weeks) for up to 12 months or until the onset of progressive disease or unacceptable toxic effects.

Main Outcomes and Measures  Safety and efficacy were measured by objective response rate, which was used to determine study expansion to part B. The threshold for expansion was an objective response rate of 10% for either treatment arm.

Results  Among 65 randomized patients, 34 (52%) were men and median age was 61 (95% CI, 37-81) years. Grade 3 or higher treatment-related adverse events occurred in 7 of 32 patients (22%) receiving combination therapy and in 2 of 32 patients (6%) receiving monotherapy; 1 patient randomized to the monotherapy arm did not receive treatment owing to worsened disease. Fatigue, diarrhea, and pruritus were the most common adverse events in both arms. Overall, 4 of 64 patients (6%) discontinued treatment owing to treatment-related adverse events. Objective response rate was 3.1% (95% CI, 0.08-16.22) for patients receiving combination therapy and 0% (95% CI, 0.00-10.58) for patients receiving monotherapy. Low patient numbers limited observation of the associations between treatment response and PD-L1 expression or microsatellite instability status.

Conclusion and Relevance  Treatment was well tolerated, and the efficacy of durvalumab plus tremelimumab therapy and durvalumab monotherapy reflected a population of patients with mPDAC who had poor prognoses and rapidly progressing disease. Patients were not enrolled in part B because the threshold for efficacy was not met in part A.

Trial Registration  ClinicalTrials.gov identifier: NCT02558894

Introduction

In the United States, pancreatic cancer is predicted to become the second leading cause of cancer-related deaths by 2030.1 Pancreatic ductal adenocarcinoma (PDAC) accounts for more than 90% of pancreatic tumors, with a 5-year overall survival (OS) rate of 8%.2,3 Low survival rates are associated with rapid tumor progression and late presentation owing to the absence of early symptoms.3 Patients with advanced or metastatic PDAC (mPDAC) have few established therapeutic options beyond initial gemcitabine-based or fluorouracil-based chemotherapy.4

The therapeutic potential of immune checkpoint therapy has been of increasing interest.5-8 Durvalumab is a human anti–programmed death–ligand 1 (anti–PD-L1), IgG class 1 monoclonal antibody (mAb) approved for second-line urothelial carcinoma and unresectable stage III non–small cell lung cancer that has not progressed following concurrent platinum-based chemotherapy and radiotherapy.9 Increased PD-L1 expression in PDAC correlates with less favorable prognosis.6-8 Blockade of PD-L1 and its receptors by durvalumab may relieve PD-L1–dependent immunosuppressive effects, potentially enhancing the cytotoxic activity of antitumor T cells.10,11 Preliminary data from a multi-arm, phase 1 expansion study of durvalumab monotherapy had acceptable safety and showed partial responses in 2 of 29 patients with PDAC who had evaluable data.12

Tremelimumab, another immune checkpoint therapy, is a human anticytotoxic T-lymphocyte–associated antigen 4 (CTLA-4), IgG class 2 mAb.13 Blockade of CTLA-4–associated negative regulation of T-cell activation has been shown to increase immune activation and antitumor activity.13,14 Monotherapy with another anti–CTLA-4 mAb resulted in delayed response after initial progressive disease in 1 patient with PDAC and had acceptable tolerability.15

Immune checkpoint blockade in PDAC as a single-agent therapy was not currently indicated beyond the subgroup of patients with microsatellite instability or mismatch repair deficiency16; however, a precedent existed for evaluating a combination of 2 immune checkpoint antagonists in this setting. The mechanisms of action of anti–PD-L1 and anti–CTLA-4 mAbs are nonredundant; thus, the combination may have additive or synergistic activity.14 In fact, the combination of anti–programmed cell death 1 (anti–PD-1)/anti–PD-L1 and anti–CTLA-4 mAb, including durvalumab with tremelimumab, has shown enhanced activity in certain tumor types.17-21 Moreover, a clinical trial of patients with PDAC demonstrated that anti–CTLA-4 blockade as part of a combination approach had a positive antitumor effect22; therefore, a rationale existed for evaluating the potential of dual immune checkpoint combination therapy in patients with PDAC while also assessing single-agent immune checkpoint blockade.

This phase 2 randomized clinical trial evaluated the safety and efficacy of durvalumab with or without tremelimumab in patients with previously treated mPDAC. The study design consisted of 2 parts, with a planned interim analysis of part A after enrollment of 30 patients in either treatment arm (durvalumab plus tremelimumab therapy or durvalumab monotherapy). Part B of the study was not conducted based on the findings of part A, which are reported herein.

Methods
Study Design

Part A of the study was a multicenter, randomized, open-label, signal-seeking evaluation of durvalumab plus tremelimumab therapy (combination therapy) and durvalumab monotherapy (monotherapy) (eMethods in Supplement 1). Patients were randomized on a 1:1 ratio to receive either durvalumab therapy (1500 mg every 4 weeks) plus tremelimumab therapy (75 mg every 4 weeks) for 4 cycles followed by durvalumab therapy (1500 mg every 4 weeks) or durvalumab monotherapy (1500 mg every 4 weeks) for up to 12 months or until confirmed progressive disease or unacceptable toxic effects. Part B of the study was planned as either a nonrandomized or randomized clinical trial, which would be determined based on efficacy signals from part A. Review and approval of the study and diagnostic testing by an institutional review board or ethics committee were obtained for each site. The full trial protocol is provided in Supplement 2. Written informed consent from participants and additional locally required authorizations were obtained before performing any protocol-related procedures.

Patients

Patients 18 years or older were eligible to participate if they had histologically or cytologically confirmed mPDAC and tumor progression and had previously received only 1 first-line fluorouracil-based or gemcitabine-based chemotherapy regimen for recurrent PDAC or mPDAC (eMethods in Supplement 1).

Assessments

The primary end point was investigator-assessed objective response rate (ORR) based on the Response Evaluation Criteria in Solid Tumors, version 1.1.23 Secondary end points included duration of response, disease control rate (DCR) at 3 months (defined after the protocol amendment as complete response or partial response in the first 3 months or stable disease for at least 13 weeks following the start of treatment), progression-free survival (PFS), and OS.

Tumor samples, either acquired from recent biopsies performed during screening (preferred) or from existing samples taken less than 3 years before screening, were required for PD-L1 and other biomarker assessments. Testing for PD-L1 was performed by immunohistochemistry using formalin-fixed, paraffin-embedded tumor tissue and the VENTANA PD-L1 (SP263) Assay (Roche Diagnostics). The baseline PD-L1 expression level was summarized for the safety analysis population (eMethods in Supplement 1). A cutoff of 25% or more tumor cells with membrane staining for PD-L1 was chosen to designate PD-L1–high expression.

Adverse events, including treatment-related adverse events (trAEs), were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03.24 Adverse events of special interest included events with a potential inflammatory or immune-mediated mechanism that may have required frequent monitoring and/or intervention with immunosuppressant drugs or hormone therapy.

Statistical Methods

Continuation to part B of the study was determined based on efficacy signals from part A. The prespecified expansion criteria were: (1) part B would be initiated as a nonrandomized clinical trial, and an additional 70 patients per arm enrolled, if an ORR of more than 25% (≥8 responses) was recorded in part A; (2) part B would be initiated as a randomized clinical trial if an ORR of more than 15% (≥5 responses) in at least 1 study arm was recorded in part A; and (3) recruitment for part B would be halted if the predictive probability of either arm achieving minimum criteria for initiating part B was less than 10% for both ORR and DCR at 12 weeks. The primary end point (ORR) for part A was estimated with 95% exact Clopper-Pearson CIs. Kaplan-Meier estimates were used for analyses of PFS and OS.

The efficacy analysis represented the intent-to-treat population and included all randomized patients by assigned treatment regardless of treatment actually received. Patients who received at least 1 dose of study treatment and for whom any postdose data were available comprised the safety analysis population according to treatment actually received.

Results
Patient Disposition and Baseline Characteristics in Part A

The first patient received treatment on November 26, 2015, and the last patient received final treatment on March 23, 2017. Data cutoff was May 26, 2017. Sixty-five patients at 21 sites in 6 countries (Canada, Germany, the Netherlands, South Korea, Spain, and the United States) were randomized to treatment. Thirty-two patients were randomized to the combination therapy arm and 33 were randomized to the monotherapy arm; 1 patient randomized to the monotherapy arm experienced worsened disease and was withdrawn from the study before receiving treatment (Figure 1). Median follow-up was 3.2 months (range, 0.4-18.1 months). Among the 65 patients, 34 (52%) were men and 31 (48%) were women, and they had a median age of 61 years (95% CI, 37-81 years). Patient characteristics and demographics were generally distributed evenly for each arm and representative of patients with treatment-refractory mPDAC (eTable in Supplement 1).

Safety

Approximately one-third of patients receiving treatment had at least 1 trAE (11 of 32 patients [34%] in the combination therapy arm and 10 of 32 [31%] in the monotherapy arm); 7 of 32 patients (22%) in the combination therapy arm and 2 of 32 (6%) in the monotherapy arm had trAEs of grade 3 or higher (eResults in Supplement 1). Common trAEs (ie, occurring in ≥5% of patients) in the combination therapy arm and the monotherapy arm were fatigue (4 of 32 patients [13%] and 3 of 32 [9%], respectively); diarrhea (4 of 32 [13%] and 2 of 32 [6%], respectively); pruritus (1 of 32 [3%] and 2 of 32 [6%], respectively); and hypothyroidism (3 of 32 [9%] in the combination therapy arm only). Grade 3 or higher fatigue (2 of 32 patients [6%]) and diarrhea (3 of 32 [9%]) occurred in the combination therapy arm only (Table). Overall, 4 of 64 patients (6%) discontinued treatment because of trAEs. There were no treatment-related deaths.

Efficacy

The ORR was 3.1% (95% CI, 0.08-16.22) for patients treated with combination therapy and 0% (95% CI, 0.00-10.58) for patients treated with monotherapy (eResults in Supplement 1). The DCR at 3 months was 9.4% for patients treated with combination therapy and 6.1% for patients treated with monotherapy; the percentage of change in target lesion size is summarized in Figure 2.

Median PFS was 1.5 months in both arms (95% CI, 1.2-1.5 months in the combination therapy arm and 1.3-1.5 months in the monotherapy arm) (Figure 3). The 6-month PFS rate was 9.4% (95% CI, 2.4-22.3) in the combination therapy arm and 3.6% (95% CI, 0.3%-15.4%) in the monotherapy arm. Median OS was 3.1 months (95% CI, 2.2-6.1 months) in the combination therapy arm vs 3.6 months (95% CI, 2.7-6.1 months) in the monotherapy arm. The 6-month OS rate was 36.2% (95% CI, 20.0%-52.7%) in the combination therapy arm and 34.9% (95% CI, 19.2%-51.1%) in the monotherapy arm, and the 12-month OS rate was 8.8% (95% CI, 1.8%-22.8%) and 6.3% (95% CI, 1.1%-18.4%), respectively. Three patients experienced long-term survival (ie, patients were alive at data cutoffs during weeks 61-65).

PD-L1 Expression

A cutoff of 25% or more tumor cells was chosen to evaluate PD-L1 expression in PDAC tumor samples, although this cutoff criterion has not been validated in PDAC. The number of respondents was insufficient to establish any association between clinical outcomes and PD-L1 expression. Of 65 samples available for testing, 8 (12%) were from patients with PD-L1–high (≥25% tumor cells) expression and 48 (74%) were from patients with PD-L1–low (<25% tumor cells) expression. The single patient with a confirmed partial response had PD-L1–low/negative expression, with no PD-L1–expressing tumor cells. Of 12 patients with stable disease, 9 had tumors evaluable for PD-L1 expression, and all had PD-L1–low/negative expression, including 6 patients with no tumor cells, 2 patients with 1% or more tumor cells, and 1 patient with 10% or more tumor cells.

Discussion

To our knowledge, this study is the first phase 2 randomized clinical trial to evaluate dual immune checkpoint combination therapy in patients with mPDAC. It is important to undertake studies such as this, even though previous research has reported only modest antitumor activity with immune checkpoint blockade.12,15 Although combination therapy and monotherapy had modest efficacy (a 3-month DCR of 9.4% and 6.1%, respectively), this result must be interpreted in light of the study’s short follow-up time and the ongoing, unmet need for efficacious therapies for patients with mPDAC. The duration of the confirmed partial response in the combination therapy arm was 55 weeks (until data cutoff) and, overall, 15% of patients in this arm had confirmed stable disease lasting more than 6 weeks. The study also provided important toxic effects data related to dual immune checkpoint blockade in the mPDAC setting. Patients in both arms showed acceptable tolerability, and all adverse events were manageable. The observed safety profiles of combination therapy and monotherapy were consistent with profiles in early-phase trials of non–small cell lung cancer.17,25 The safety profile of durvalumab monotherapy was consistent with the class of anti–PD-1/PD-L1 mAbs.26,27 Because part A results did not meet the prespecified end point criteria (10% ORR in either arm) to proceed to the part B evaluation, the study was closed.

The tumor microenvironment in PDAC is an immunosuppressive, hypoxic, and fibrotic setting, which may contribute to the failure of conventional and targeted therapies owing to the unusual combination of physical barriers and strong inhibitory immune signaling.28,29 Early signals may indicate activity, but blockade of immune checkpoints with single-agent therapy has not shown significant and durable responses in patients with mPDAC.12,15,30,31 The absence of significant activity of durvalumab with or without tremelimumab in patients with mPDAC indicates that combining modes of action in this small study did not sufficiently overcome the immune inhibitory environment known to be a key contributor to poor response in patients with mPDAC.

Accumulating evidence suggests that stromal responses in PDAC contribute to tumor progression through a range of mechanisms involving activated pancreatic stellate cells, myeloid-derived suppressor cells, and regulatory T cells.32,33 Preclinical data show that dysregulated signaling by pancreatic stellate cells activated within the tumor microenvironment can reduce migration of CD8-positive T cells, preventing their access to tumor cells.32 In addition, the tumor microenvironment is associated with overexpression of nitric oxide synthase, which can cause active T-cell suppression despite the presence of tumor-specific antigens.34 Myeloid-derived suppressor cells further contribute to immune suppression and tumor progression following their accumulation in bone marrow and subsequent recruitment to the tumor site; they can produce high amounts of nitric oxide in the tumor microenvironment when activated, further inhibiting antitumor responses.35 Collectively, these data suggest that immune checkpoint blockade must be part of a comprehensive strategy aimed at reprogramming local immunity toward an effective antitumor response. Preclinical studies continue to support PD-L1/CTLA-4 blockade in conjunction with immunomodulation at the level of antigen-presenting cells to produce tumor regression, even in established tumors.36,37 One of those studies showed that treatment with a granulocyte-macrophage colony-stimulating factor–secreting PDAC vaccine upregulated PD-L1 membrane expression and, in combination with PD-1 blockade, led to improved survival in tumor-bearing mice.36 Other novel strategies are also aimed at potentiating immune checkpoint blockade in PDAC.38-41

With the exception of data regarding increased CTLA-4 expression on CD8-positive T cells, which is associated with shorter OS in treatment-naive patients,42 data to derive an association between the expression of immune checkpoint markers and survival in patients with mPDAC are lacking to date. Meaningful evaluation of response and PD-L1 expression in this study was constrained by the low DCR and ORR, which also limited additional biomarker analyses (eg, microsatellite instability status, tumor mutation burden, and breast cancer gene mutations); thus, no conclusions about biomarkers, including tumor mutation burden or microsatellite instability, could be drawn. Nevertheless, microsatellite instability status, tumor mutation burden, and other biomarkers may prove to be important for patients with PDAC. Programmed cell death 1 blockade has shown efficacy in previously treated patients who had unresectable or metastatic solid tumors with microsatellite instability–high status or mismatch repair deficiency.16,43 In patients with non–small cell lung cancer and high tumor mutation burden, PFS was longer with dual anti–PD-1/anti–CTLA-4 blockade than with chemotherapy as first-line treatment.44

Limitations

This study’s limitations included the lack of a control arm, which prevented direct comparison of either treatment with another therapeutic option, such as combination chemotherapy. However, patients with mPDAC that is progressing after chemotherapy have few therapeutic options other than enrollment in a clinical trial with no standard of care beyond the second-line setting. Another study limitation was the small number of patients who responded to treatment, which precluded meaningful appraisal of PD-L1 expression or other biomarkers in relation to clinical benefit. The general difficulty in achieving objective responses in the second-line setting points to an inherent challenge for phase 2 studies of patients with mPDAC. In recent years, several targeted therapies and cancer vaccines have been evaluated in PDAC studies, and almost all have failed to demonstrate efficacy in late-stage clinical trials.45

Conclusions

The observed efficacy of durvalumab plus tremelimumab therapy and durvalumab monotherapy was reflective of a population of patients with mPDAC who had poor prognoses and rapidly progressing disease; however, treatment was well tolerated. Future studies are needed to evaluate how to best combine immune checkpoint blockade with other agents, including cytotoxic and targeted therapies, with the intention of overcoming the unique immunosuppressive, hypoxic, and fibrotic tumor microenvironment of PDAC. Such studies should evaluate biomarker expression to identify patients most likely to benefit from immune checkpoint blockade.

Back to top
Article Information

Accepted for Publication: March 14, 2019.

Corresponding Author: Eileen M. O’Reilly, MD, Gastrointestinal Medical Oncology, David M. Rubenstein Center for Pancreatic Cancer, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, 300 E 66th St, Office 1021, New York, NY 10065 (oreillye@mskcc.org).

Published Online: July 18, 2019. doi:10.1001/jamaoncol.2019.1588

Author Contributions: Dr O’Reilly had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: O’Reilly, Sun, Hezel, Takahashi.

Acquisition, analysis, or interpretation of data: O’Reilly, Oh, Dhani, Renouf, Lee, Sun, Fisher, Chang, Vlahovic, Takahashi, Yang, Fitts, Philip.

Drafting of the manuscript: O’Reilly, Oh, Fisher, Takahashi, Yang.

Critical revision of the manuscript for important intellectual content: O’Reilly, Oh, Dhani, Renouf, Lee, Sun, Fisher, Hezel, Chang, Vlahovic, Takahashi, Fitts, Philip.

Statistical analysis: Oh, Yang, Fitts.

Administrative, technical, or material support: O’Reilly, Lee, Chang, Takahashi, Philip.

Supervision: Lee, Chang, Vlahovic, Philip.

Conflict of Interest Disclosures: Dr O’Reilly reported holding a consulting or advisory role with Aduro Biotech, Agios, ASLAN Pharmaceuticals, Astellas Pharma, AstraZeneca, Bayer, Blueprint Medicines, Boston Scientific, Bristol-Myers Squibb, CASI Pharmaceuticals, Celgene, Celsion, Delcath Systems, Eisai, Gilead Sciences, Halozyme, IntegraGen, Ipsen, Janssen, MedImmune, Merck, Merrimack, New B Innovation, Newlink Genetics, Onxeo, Sanofi, Servier, Silenseed, Sillajen, Sirtex Medical, VAXIMM, Vicus Therapeutics, and Westhaven; receiving grants from AstraZeneca during the conduct of the study; receiving grants from MabVax Therapeutics, Genentech, Celgene, Bristol-Myers Squibb, Silenseed, Momenta Pharmaceuticals, OncoMed Pharmaceuticals, Halozyme, and Pfizer outside the submitted work; and receiving personal fees from Celgene, BioLine, Bayer, and Sobi outside the submitted work. Dr Oh reported holding a consulting or advisory role with Debiopharm Group, Lilly, MSD, and Roche; receiving research funding from AstraZeneca and from AstraZeneca and Array outside the submitted work; holding a consulting or advisory role with Halozyme, Merck, and Debio outside this work. Dr Dhani reported receiving honoraria from Celgene; receiving research funding from AstraZeneca, Celgene, and Halozyme; receiving funds for travel, accommodations, and expenses from Celgene; and receiving compensation for participation in the advisory boards of AstraZeneca, Celgene, and Shire Baxalta outside the submitted work. Dr Renouf reported holding a consulting or advisory role with Celgene and Shire receiving personal fees from Amgen, Celgene, Shire, Servier, Taiho Pharma, Bayer, and Ipsen outside the submitted work. Dr Sun reported receiving honoraria from Genentech/Roche and Taiho Pharmaceutical, holding a consulting or advisory role with Bayer, and receiving research funding from Bayer and Merck. Dr Fisher reported having stock and other ownership interests in Seattle Genetics; receiving honoraria from Merck, Genentech, and Ipsen; hold a consulting or advisory role with Celgene and Ipsen; receiving research funding from Aduro Biotech, Bristol-Myers Squibb, EpicentRx, Forty seven, Genentech/Roche, Ipsen, Merck, Newlink Genetics, Pharmaceutical Research Associates, Polaris, Sun Pharma, and XBiotech; and receiving funding for travel, accommodations, and expenses from Genentech/Roche and Merck. Dr Hezel reported receiving personal fees from Novartis, Merck, BioTelemetry, Eisai, and Bayer outside the submitted work. Dr Chang reported having stock and other ownership interests in AstraZeneca and receiving funding for travel, accommodations, and expenses from MedImmune. Dr Vlahovic reported having stock and other ownership interests in AstraZeneca. Dr Takahashi reported receiving stock grants as long-term incentives from AstraZeneca in 2017 and 2018, with vesting complete in March 2020. Dr Yang reported having stock and other ownership interests in AstraZeneca. Dr Philip reported receiving honoraria from Amgen, Bayer, Bristol-Myers Squibbm, Celgene, Halozyme, Ipsen, Merrimack, Novartis, Roche, and Sanofi; holding a consulting or advisory role with Celgene, Gilead Sciences, Halozyme, Ipsen, Merrimack, and Novartis; being a member of the speakers bureau for Amgen, Bayer, Celgene, Roche, and Sanofi; and receiving research funding from Bayer, Genentech, Immunomedics, Incyte, Karyopharm Therapeutics, Merck, Momenta Pharmaceuticals, Novartis, Plexxikon, Regeneron, and Taiho Pharmaceutical; receiving grants from AstraZeneca during the conduct of the study; and having a relationship with Celgene, EMD Serono, Halozyme, Roche, and Sanofi. No other disclosures were reported.

Funding/Support: This research was funded by AstraZeneca.

Role of the Funder/Sponsor: The protocol for this study was developed by AstraZeneca and its advisors. Data were collected collaboratively by AstraZeneca and the clinical investigators, with the support of a clinical research organization funded by AstraZeneca. Statisticians employed by AstraZeneca analyzed the data. AstraZeneca participated in the preparation, review, and approval of the manuscript and the decision to submit the manuscript for publication.

Disclaimer: All information and materials in this article are original.

Meeting Presentation: These data were presented in part in poster format at the 2018 American Society of Clinical Oncology Gastrointestinal Cancers Symposium; January 18-20, 2018; San Francisco, California.

Data Sharing Statement: See Supplement 3.

Additional Contributions: Contributors to the biomarker analysis included Mark Gustavson, PhD, and Mark Fidock, PhD, of AstraZeneca, and Philip Browhan, MBA, of MedImmune/AstraZeneca (currently employed by Immunocore), who received no compensation for this work outside of their regular salaries. The authors thank the patients, their families and caregivers, and all investigators involved in this study. Medical writing support in accordance with Good Publication Practice guidelines was provided by Jubilee Stewart, PhD, and Edwin Thrower, PhD, of Parexel, and was funded by AstraZeneca.

References
1.
Amundadottir  LT.  Pancreatic cancer genetics.  Int J Biol Sci. 2016;12(3):314-325. doi:10.7150/ijbs.15001PubMedGoogle ScholarCrossref
2.
Chiaravalli  M, Reni  M, O’Reilly  EM.  Pancreatic ductal adenocarcinoma: state-of-the-art 2017 and new therapeutic strategies.  Cancer Treat Rev. 2017;60:32-43. doi:10.1016/j.ctrv.2017.08.007PubMedGoogle ScholarCrossref
3.
Hidalgo  M, Cascinu  S, Kleeff  J,  et al.  Addressing the challenges of pancreatic cancer: future directions for improving outcomes.  Pancreatology. 2015;15(1):8-18. doi:10.1016/j.pan.2014.10.001PubMedGoogle ScholarCrossref
4.
Uccello  M, Moschetta  M, Mak  G, Alam  T, Henriquez  CM, Arkenau  HT.  Towards an optimal treatment algorithm for metastatic pancreatic ductal adenocarcinoma (PDA).  Curr Oncol. 2018;25(1):e90-e94. doi:10.3747/co.25.3708PubMedGoogle ScholarCrossref
5.
Fokas  E, O’Neill  E, Gordon-Weeks  A, Mukherjee  S, McKenna  WG, Muschel  RJ.  Pancreatic ductal adenocarcinoma: from genetics to biology to radiobiology to oncoimmunology and all the way back to the clinic.  Biochim Biophys Acta. 2015;1855(1):61-82.PubMedGoogle Scholar
6.
Imai  D, Yoshizumi  T, Okano  S,  et al.  The prognostic impact of programmed cell death ligand 1 and human leukocyte antigen class I in pancreatic cancer.  Cancer Med. 2017;6(7):1614-1626. doi:10.1002/cam4.1087PubMedGoogle ScholarCrossref
7.
Tessier-Cloutier  B, Kalloger  SE, Al-Kandari  M,  et al.  Programmed cell death ligand 1 cut-point is associated with reduced disease specific survival in resected pancreatic ductal adenocarcinoma.  BMC Cancer. 2017;17(1):618. doi:10.1186/s12885-017-3634-5PubMedGoogle ScholarCrossref
8.
Yamaki  S, Yanagimoto  H, Tsuta  K, Ryota  H, Kon  M.  PD-L1 expression in pancreatic ductal adenocarcinoma is a poor prognostic factor in patients with high CD8+ tumor-infiltrating lymphocytes: highly sensitive detection using phosphor-integrated dot staining.  Int J Clin Oncol. 2017;22(4):726-733. doi:10.1007/s10147-017-1112-3PubMedGoogle ScholarCrossref
9.
Antonia  SJ, Villegas  A, Daniel  D,  et al; PACIFIC Investigators.  Durvalumab after chemoradiotherapy in stage III non–small-cell lung cancer.  N Engl J Med. 2017;377(20):1919-1929. doi:10.1056/NEJMoa1709937PubMedGoogle ScholarCrossref
10.
Azad  A, Yin Lim  S, D’Costa  Z,  et al.  PD-L1 blockade enhances response of pancreatic ductal adenocarcinoma to radiotherapy.  EMBO Mol Med. 2017;9(2):167-180. doi:10.15252/emmm.201606674PubMedGoogle ScholarCrossref
11.
Kyi  C, Postow  MA.  Immune checkpoint inhibitor combinations in solid tumors: opportunities and challenges.  Immunotherapy. 2016;8(7):821-837. doi:10.2217/imt-2016-0002PubMedGoogle ScholarCrossref
12.
Segal  NH, Hamid  O, Hwu  WJ,  et al.  A phase 1 multi-arm dose-expansion study of the anti-programmed cell death-ligand-1 (PD-L1) antibody MEDI4736: preliminary data  [abstract].  Ann Oncol. 2014; 25(suppl 4):iv365.Google Scholar
13.
Eroglu  Z, Kim  DW, Wang  X,  et al.  Long term survival with cytotoxic T lymphocyte–associated antigen 4 blockade using tremelimumab.  Eur J Cancer. 2015;51(17):2689-2697. doi:10.1016/j.ejca.2015.08.012PubMedGoogle ScholarCrossref
14.
Pardoll  DM.  The blockade of immune checkpoints in cancer immunotherapy.  Nat Rev Cancer. 2012;12(4):252-264. doi:10.1038/nrc3239PubMedGoogle ScholarCrossref
15.
Royal  RE, Levy  C, Turner  K,  et al.  Phase 2 trial of single agent ipilimumab (anti–CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma.  J Immunother. 2010;33(8):828-833. doi:10.1097/CJI.0b013e3181eec14cPubMedGoogle ScholarCrossref
16.
Hu  ZI, Shia  J, Stadler  ZK,  et al.  Evaluating mismatch repair deficiency in pancreatic adenocarcinoma: challenges and recommendations.  Clin Cancer Res. 2018;24(6):1326-1336. doi:10.1158/1078-0432.CCR-17-3099PubMedGoogle ScholarCrossref
17.
Antonia  S, Goldberg  SB, Balmanoukian  A,  et al.  Safety and antitumour activity of durvalumab plus tremelimumab in non–small cell lung cancer: a multicentre, phase 1b study.  Lancet Oncol. 2016;17(3):299-308. doi:10.1016/S1470-2045(15)00544-6PubMedGoogle ScholarCrossref
18.
Callahan  MK, Kluger  H, Postow  MA,  et al.  Nivolumab plus ipilimumab in patients with advanced melanoma: updated survival, response, and safety data in a phase I dose-escalation study.  J Clin Oncol. 2018;36(4):391-398. doi:10.1200/JCO.2017.72.2850PubMedGoogle ScholarCrossref
19.
Hao  C, Tian  J, Liu  H, Li  F, Niu  H, Zhu  B.  Efficacy and safety of anti–PD-1 and anti–PD-1 combined with anti–CTLA-4 immunotherapy to advanced melanoma: a systematic review and meta-analysis of randomized controlled trials.  Medicine. 2017;96(26):e7325. doi:10.1097/MD.0000000000007325PubMedGoogle ScholarCrossref
20.
Hellmann  MD, Rizvi  NA, Goldman  JW,  et al.  Nivolumab plus ipilimumab as first-line treatment for advanced non–small-cell lung cancer (CheckMate 012): results of an open-label, phase 1, multicohort study.  Lancet Oncol. 2017;18(1):31-41. doi:10.1016/S1470-2045(16)30624-6PubMedGoogle ScholarCrossref
21.
Hodi  FS, Chesney  J, Pavlick  AC,  et al.  Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial.  Lancet Oncol. 2016;17(11):1558-1568. doi:10.1016/S1470-2045(16)30366-7PubMedGoogle ScholarCrossref
22.
Le  DT, Lutz  E, Uram  JN,  et al.  Evaluation of ipilimumab in combination with allogeneic pancreatic tumor cells transfected with a GM-CSF gene in previously treated pancreatic cancer.  J Immunother. 2013;36(7):382-389. doi:10.1097/CJI.0b013e31829fb7a2PubMedGoogle ScholarCrossref
23.
Schwartz  LH, Litière  S, de Vries  E,  et al.  RECIST 1.1-Update and clarification: From the RECIST committee.  Eur J Cancer. 2016;62:132-137. doi:10.1016/j.ejca.2016.03.081PubMedGoogle ScholarCrossref
24.
National Institutes of Health. Common Terminology Criteria for Adverse Events (CTCAE). Version 4.03. https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf. Updated June 14, 2010. Accessed June 11, 2019.
25.
Jeanson  A, Barlesi  F.  MEDI 4736 (durvalumab) in non–small cell lung cancer.  Expert Opin Biol Ther. 2017;17(10):1317-1323. doi:10.1080/14712598.2017.1351939PubMedGoogle ScholarCrossref
26.
Ferris  RL, Blumenschein  G  Jr, Fayette  J,  et al.  Nivolumab for recurrent squamous-cell carcinoma of the head and neck.  N Engl J Med. 2016;375(19):1856-1867. doi:10.1056/NEJMoa1602252PubMedGoogle ScholarCrossref
27.
Bauml  J, Seiwert  TY, Pfister  DG,  et al.  Pembrolizumab for platinum- and cetuximab-refractory head and neck cancer: results from a single-arm, phase II study.  J Clin Oncol. 2017;35(14):1542-1549. doi:10.1200/JCO.2016.70.1524PubMedGoogle ScholarCrossref
28.
Dougan  SK.  The pancreatic cancer microenvironment.  Cancer J. 2017;23(6):321-325. doi:10.1097/PPO.0000000000000288PubMedGoogle ScholarCrossref
29.
Zhang  J, Wolfgang  CL, Zheng  L.  Precision immuno-oncology: prospects of individualized immunotherapy for pancreatic cancer.  Cancers. 2018;10(2):E39. doi:10.3390/cancers10020039PubMedGoogle Scholar
30.
Brahmer  JR, Tykodi  SS, Chow  LQ,  et al.  Safety and activity of anti–PD-L1 antibody in patients with advanced cancer.  N Engl J Med. 2012;366(26):2455-2465. doi:10.1056/NEJMoa1200694PubMedGoogle ScholarCrossref
31.
Sharma  P, Dirix  L, De Vos  FYFL,  et al.  Efficacy and tolerability of tremelimumab in patients with metastatic pancreatic ductal adenocarcinoma.  J Clin Oncol. 2018;36(4)(suppl):470. doi:10.1200/JCO.2018.36.4_suppl.470Google ScholarCrossref
32.
Ene-Obong  A, Clear  AJ, Watt  J,  et al.  Activated pancreatic stellate cells sequester CD8+ T cells to reduce their infiltration of the juxtatumoral compartment of pancreatic ductal adenocarcinoma.  Gastroenterology. 2013;145(5):1121-1132. doi:10.1053/j.gastro.2013.07.025PubMedGoogle ScholarCrossref
33.
Lunardi  S, Muschel  RJ, Brunner  TB.  The stromal compartments in pancreatic cancer: are there any therapeutic targets?  Cancer Lett. 2014;343(2):147-155. doi:10.1016/j.canlet.2013.09.039PubMedGoogle ScholarCrossref
34.
Bailey  P, Chang  DK, Forget  MA,  et al.  Exploiting the neoantigen landscape for immunotherapy of pancreatic ductal adenocarcinoma.  Sci Rep. 2016;6:35848. doi:10.1038/srep35848PubMedGoogle ScholarCrossref
35.
Porembka  MR, Mitchem  JB, Belt  BA,  et al.  Pancreatic adenocarcinoma induces bone marrow mobilization of myeloid-derived suppressor cells which promote primary tumor growth.  Cancer Immunol Immunother. 2012;61(9):1373-1385. doi:10.1007/s00262-011-1178-0PubMedGoogle ScholarCrossref
36.
Soares  KC, Rucki  AA, Wu  AA,  et al.  PD-1/PD-L1 blockade together with vaccine therapy facilitates effector T-cell infiltration into pancreatic tumors.  J Immunother. 2015;38(1):1-11. doi:10.1097/CJI.0000000000000062PubMedGoogle ScholarCrossref
37.
Zhu  Y, Knolhoff  BL, Meyer  MA,  et al.  CSF1/CSF1R blockade reprograms tumor-infiltrating macrophages and improves response to T-cell checkpoint immunotherapy in pancreatic cancer models.  Cancer Res. 2014;74(18):5057-5069. doi:10.1158/0008-5472.CAN-13-3723PubMedGoogle ScholarCrossref
38.
Decaup  E, Rochotte  J, Pyronnet  S, Bousquet  C, Jean  C.  Focal adhesion kinase: a promising therapeutic target in pancreatic adenocarcinoma.  Clin Res Hepatol Gastroenterol. 2017;41(3):246-248. doi:10.1016/j.clinre.2016.10.010PubMedGoogle ScholarCrossref
39.
Jiang  H, Hegde  S, Knolhoff  BL,  et al.  Targeting focal adhesion kinase renders pancreatic cancers responsive to checkpoint immunotherapy.  Nat Med. 2016;22(8):851-860. doi:10.1038/nm.4123PubMedGoogle ScholarCrossref
40.
Mehla  K, Tremayne  J, Grunkemeyer  JA,  et al.  Combination of mAb-AR20.5, anti–PD-L1 and polyICLC inhibits tumor progression and prolongs survival of MUC1.Tg mice challenged with pancreatic tumors.  Cancer Immunol Immunother. 2018;67(3):445-457. doi:10.1007/s00262-017-2095-7PubMedGoogle ScholarCrossref
41.
Skelton  RA, Javed  A, Zheng  L, He  J.  Overcoming the resistance of pancreatic cancer to immune checkpoint inhibitors.  J Surg Oncol. 2017;116(1):55-62. doi:10.1002/jso.24642PubMedGoogle ScholarCrossref
42.
Farren  MR, Mace  TA, Geyer  S,  et al.  Systemic immune activity predicts overall survival in treatment-naive patients with metastatic pancreatic cancer.  Clin Cancer Res. 2016;22(10):2565-2574. doi:10.1158/1078-0432.CCR-15-1732PubMedGoogle ScholarCrossref
43.
Le  DT, Uram  JN, Wang  H,  et al.  PD-1 blockade in tumors with mismatch-repair deficiency.  N Engl J Med. 2015;372(26):2509-2520. doi:10.1056/NEJMoa1500596PubMedGoogle ScholarCrossref
44.
Hellmann  MD, Ciuleanu  TE, Pluzanski  A,  et al.  Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden.  N Engl J Med. 2018;378(22):2093-2104. doi:10.1056/NEJMoa1801946PubMedGoogle ScholarCrossref
45.
Di Marco  M, Grassi  E, Durante  S,  et al.  State of the art biological therapies in pancreatic cancer.  World J Gastrointest Oncol. 2016;8(1):55-66. doi:10.4251/wjgo.v8.i1.55PubMedGoogle ScholarCrossref
×