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

Eileen M. O'Reilly, Do Youn Oh, Neesha Dhani, Daniel J. Renouf, Myung Ah Lee, Weijing Sun, George Fisher, Aram Hezel, Shao Chun Chang, Gordana Vlahovic, Osamu Takahashi, Yin Yang, David Fitts, Philip Agop Philip

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1431-1438
Number of pages8
JournalJAMA Oncology
Volume5
Issue number10
DOIs
StatePublished - Oct 2019

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Adenocarcinoma
Randomized Controlled Trials
Therapeutics
Safety
tremelimumab
gemcitabine
Microsatellite Instability
Antibodies
Poisons
Viral Tumor Antigens
Pruritus
Fluorouracil
Population
Fatigue
Diarrhea
Observation
Outcome Assessment (Health Care)

Cite this

O'Reilly, Eileen M. ; Oh, Do Youn ; Dhani, Neesha ; Renouf, Daniel J. ; Lee, Myung Ah ; Sun, Weijing ; Fisher, George ; Hezel, Aram ; Chang, Shao Chun ; Vlahovic, Gordana ; Takahashi, Osamu ; Yang, Yin ; Fitts, David ; Philip, Philip Agop. / Durvalumab with or Without Tremelimumab for Patients with Metastatic Pancreatic Ductal Adenocarcinoma : A Phase 2 Randomized Clinical Trial. In: JAMA Oncology. 2019 ; Vol. 5, No. 10. pp. 1431-1438.
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title = "Durvalumab with or Without Tremelimumab for Patients with Metastatic Pancreatic Ductal Adenocarcinoma: A Phase 2 Randomized Clinical Trial",
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.",
author = "O'Reilly, {Eileen M.} and Oh, {Do Youn} and Neesha Dhani and Renouf, {Daniel J.} and Lee, {Myung Ah} and Weijing Sun and George Fisher and Aram Hezel and Chang, {Shao Chun} and Gordana Vlahovic and Osamu Takahashi and Yin Yang and David Fitts and Philip, {Philip Agop}",
year = "2019",
month = "10",
doi = "10.1001/jamaoncol.2019.1588",
language = "English",
volume = "5",
pages = "1431--1438",
journal = "JAMA Oncology",
issn = "2374-2437",
publisher = "American Medical Association",
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}

O'Reilly, EM, Oh, DY, Dhani, N, Renouf, DJ, Lee, MA, Sun, W, Fisher, G, Hezel, A, Chang, SC, Vlahovic, G, Takahashi, O, Yang, Y, Fitts, D & Philip, PA 2019, 'Durvalumab with or Without Tremelimumab for Patients with Metastatic Pancreatic Ductal Adenocarcinoma: A Phase 2 Randomized Clinical Trial', JAMA Oncology, vol. 5, no. 10, pp. 1431-1438. https://doi.org/10.1001/jamaoncol.2019.1588

Durvalumab with or Without Tremelimumab for Patients with Metastatic Pancreatic Ductal Adenocarcinoma : A Phase 2 Randomized Clinical Trial. / O'Reilly, Eileen M.; Oh, Do Youn; Dhani, Neesha; Renouf, Daniel J.; Lee, Myung Ah; Sun, Weijing; Fisher, George; Hezel, Aram; Chang, Shao Chun; Vlahovic, Gordana; Takahashi, Osamu; Yang, Yin; Fitts, David; Philip, Philip Agop.

In: JAMA Oncology, Vol. 5, No. 10, 10.2019, p. 1431-1438.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Durvalumab with or Without Tremelimumab for Patients with Metastatic Pancreatic Ductal Adenocarcinoma

T2 - A Phase 2 Randomized Clinical Trial

AU - O'Reilly, Eileen M.

AU - Oh, Do Youn

AU - Dhani, Neesha

AU - Renouf, Daniel J.

AU - Lee, Myung Ah

AU - Sun, Weijing

AU - Fisher, George

AU - Hezel, Aram

AU - Chang, Shao Chun

AU - Vlahovic, Gordana

AU - Takahashi, Osamu

AU - Yang, Yin

AU - Fitts, David

AU - Philip, Philip Agop

PY - 2019/10

Y1 - 2019/10

N2 - 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.

AB - 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.

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DO - 10.1001/jamaoncol.2019.1588

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