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 language | English |
|---|---|
| Pages (from-to) | 1431-1438 |
| Number of pages | 8 |
| Journal | JAMA Oncology |
| Volume | 5 |
| Issue number | 10 |
| DOIs | |
| State | Published - Oct 2019 |
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© 2019 American Medical Association. All rights reserved.
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O'Reilly, E. M., Oh, D. Y., Dhani, N., Renouf, D. J., Lee, M. A., Sun, W., Fisher, G., Hezel, A., Chang, S. C., Vlahovic, G., Takahashi, O., Yang, Y., Fitts, D., & Philip, P. A. (2019). Durvalumab with or Without Tremelimumab for Patients with Metastatic Pancreatic Ductal Adenocarcinoma: A Phase 2 Randomized Clinical Trial. JAMA Oncology, 5(10), 1431-1438. https://doi.org/10.1001/jamaoncol.2019.1588
O'Reilly, Eileen M. ; Oh, Do Youn ; Dhani, Neesha et al. / 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.
@article{2a0e431e0c434d6584bea3cb4cf0b525,
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}",
note = "Publisher Copyright: {\textcopyright} 2019 American Medical Association. All rights reserved.",
year = "2019",
month = oct,
doi = "10.1001/jamaoncol.2019.1588",
language = "English",
volume = "5",
pages = "1431--1438",
journal = "JAMA Oncology",
issn = "2374-2437",
publisher = "American Medical Association",
number = "10",
}
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 et al.
In: JAMA Oncology, Vol. 5, No. 10, 10.2019, p. 1431-1438.
Research output: Contribution to journal › Article › peer-review
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
N1 - Publisher Copyright:© 2019 American Medical Association. All rights reserved.
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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U2 - 10.1001/jamaoncol.2019.1588
DO - 10.1001/jamaoncol.2019.1588
M3 - Article
C2 - 31318392
AN - SCOPUS:85069535178
SN - 2374-2437
VL - 5
SP - 1431
EP - 1438
JO - JAMA Oncology
JF - JAMA Oncology
IS - 10
ER -
O'Reilly EM, Oh DY, Dhani N, Renouf DJ, Lee MA, Sun W et al. Durvalumab with or Without Tremelimumab for Patients with Metastatic Pancreatic Ductal Adenocarcinoma: A Phase 2 Randomized Clinical Trial. JAMA Oncology. 2019 Oct;5(10):1431-1438. doi: 10.1001/jamaoncol.2019.1588
