Efficacy and safety of durvalumab in locally advanced or metastatic urothelial carcinoma

Updated results from a phase 1/2 open-label study

Thomas Powles, Peter H. O'Donnell, Christophe Massard, Hendrik Tobias Arkenau, Terence W. Friedlander, Christopher J. Hoimes, Jae Lyun Lee, Michael Ong, Srikala S. Sridhar, Nicholas J. Vogelzang, Mayer N. Fishman, Jingsong Zhang, Sandy Srinivas, Jigarkumar Rasiklal Parikh, Joyce Antal, Xiaoping Jin, Ashok K. Gupta, Yong Ben, Noah M. Hahn

Research output: Contribution to journalArticle

187 Citations (Scopus)

Abstract

IMPORTANCE: The data reported herein were accepted for assessment by the US Food and Drug Administration for Biologics License Application under priority review to establish the clinical benefit of durvalumab as second-line therapy for locally advanced or metastatic urothelial carcinoma (UC), resulting in its recent US approval. OBJECTIVE: To report a planned update of the safety and efficacy of durvalumab in patients with locally advanced/metastatic UC. DESIGN, SETTING, AND PARTICIPANTS: This is an ongoing phase 1/2 open-label study of 191 adult patients with histologically or cytologically confirmed locally advanced/metastatic UC whose disease had progressed on, were ineligible for, or refused prior chemotherapy from 60 sites in 9 countries as reported herein. INTERVENTION: Patients were administered durvalumab intravenous infusion, 10 mg/kg every 2 weeks, for up to 12 months or until progression, starting another anticancer therapy, or unacceptable toxic effects. MAIN OUTCOMES AND MEASURES: Primary end points were safety and confirmed objective response rate (ORR) per blinded independent central review (Response Evaluation Criteria In Solid Tumors [RECIST], version 1.1). RESULTS: A total of 191 patients with UC had received treatment. As of October 24, 2016 (90-day update), the median follow-up was 5.78 months (range, 0.4-25.9 months). The median age of patients was 67.0 years and most were male (136 [71.2%]) and white (123 [71.1%]). All patients had stage 4 disease, and 190 (99.5%) had prior anticancer therapy (182 [95.3%] postplatinum). The ORR was 17.8% (34 of 191; 95% CI, 12.7%-24.0%), including 7 complete responses. Responses were early (median time to response, 1.41 months), durable (median duration of response not reached), and observed regardless of programmed cell death ligand-1 (PD-L1) expression (ORR, 27.6% [n = 27; 95% CI, 19.0%-37.5%] and 5.1% [n = 4; 95% CI, 1.4%-12.5%] in patients with high and low or negative expression of PD-L1, respectively). Median progression-free survival and overall survival were 1.5 months (95% CI, 1.4-1.9 months) and 18.2 months (95% CI, 8.1 months to not estimable), respectively; the 1-year overall survival rate was 55% (95% CI, 44%-65%), as estimated by Kaplan-Meier method. Grade 3/4 treatment-related adverse events (AEs) occurred in 13 patients (6.8%); grade 3/4 immune-mediated AEs occurred in 4 patients (2.1%); and treatment-related AEs led to discontinuation of 3 patients (1.6%), 2 of whom had immune-mediated AEs that led to death (autoimmune hepatitis and pneumonitis). CONCLUSIONS AND RELEVANCE: Durvalumab, 10 mg/kg every 2 weeks, demonstrates favorable clinical activity and an encouraging and manageable safety profile in patients with locally advanced/metastatic UC. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01693562.

Original languageEnglish (US)
Article numbere172411
JournalJAMA Oncology
Volume3
Issue number9
DOIs
StatePublished - Sep 1 2017

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Carcinoma
Safety
Cell Death
Therapeutics
Ligands
Autoimmune Hepatitis
Poisons
United States Food and Drug Administration
Licensure
Biological Products
Intravenous Infusions
Disease-Free Survival
Pneumonia
Survival Rate
Drug Therapy
Survival

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Powles, T., O'Donnell, P. H., Massard, C., Arkenau, H. T., Friedlander, T. W., Hoimes, C. J., ... Hahn, N. M. (2017). Efficacy and safety of durvalumab in locally advanced or metastatic urothelial carcinoma: Updated results from a phase 1/2 open-label study. JAMA Oncology, 3(9), [e172411]. https://doi.org/10.1001/jamaoncol.2017.2411

Efficacy and safety of durvalumab in locally advanced or metastatic urothelial carcinoma : Updated results from a phase 1/2 open-label study. / Powles, Thomas; O'Donnell, Peter H.; Massard, Christophe; Arkenau, Hendrik Tobias; Friedlander, Terence W.; Hoimes, Christopher J.; Lee, Jae Lyun; Ong, Michael; Sridhar, Srikala S.; Vogelzang, Nicholas J.; Fishman, Mayer N.; Zhang, Jingsong; Srinivas, Sandy; Parikh, Jigarkumar Rasiklal; Antal, Joyce; Jin, Xiaoping; Gupta, Ashok K.; Ben, Yong; Hahn, Noah M.

In: JAMA Oncology, Vol. 3, No. 9, e172411, 01.09.2017.

Research output: Contribution to journalArticle

Powles, T, O'Donnell, PH, Massard, C, Arkenau, HT, Friedlander, TW, Hoimes, CJ, Lee, JL, Ong, M, Sridhar, SS, Vogelzang, NJ, Fishman, MN, Zhang, J, Srinivas, S, Parikh, JR, Antal, J, Jin, X, Gupta, AK, Ben, Y & Hahn, NM 2017, 'Efficacy and safety of durvalumab in locally advanced or metastatic urothelial carcinoma: Updated results from a phase 1/2 open-label study', JAMA Oncology, vol. 3, no. 9, e172411. https://doi.org/10.1001/jamaoncol.2017.2411
Powles, Thomas ; O'Donnell, Peter H. ; Massard, Christophe ; Arkenau, Hendrik Tobias ; Friedlander, Terence W. ; Hoimes, Christopher J. ; Lee, Jae Lyun ; Ong, Michael ; Sridhar, Srikala S. ; Vogelzang, Nicholas J. ; Fishman, Mayer N. ; Zhang, Jingsong ; Srinivas, Sandy ; Parikh, Jigarkumar Rasiklal ; Antal, Joyce ; Jin, Xiaoping ; Gupta, Ashok K. ; Ben, Yong ; Hahn, Noah M. / Efficacy and safety of durvalumab in locally advanced or metastatic urothelial carcinoma : Updated results from a phase 1/2 open-label study. In: JAMA Oncology. 2017 ; Vol. 3, No. 9.
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title = "Efficacy and safety of durvalumab in locally advanced or metastatic urothelial carcinoma: Updated results from a phase 1/2 open-label study",
abstract = "IMPORTANCE: The data reported herein were accepted for assessment by the US Food and Drug Administration for Biologics License Application under priority review to establish the clinical benefit of durvalumab as second-line therapy for locally advanced or metastatic urothelial carcinoma (UC), resulting in its recent US approval. OBJECTIVE: To report a planned update of the safety and efficacy of durvalumab in patients with locally advanced/metastatic UC. DESIGN, SETTING, AND PARTICIPANTS: This is an ongoing phase 1/2 open-label study of 191 adult patients with histologically or cytologically confirmed locally advanced/metastatic UC whose disease had progressed on, were ineligible for, or refused prior chemotherapy from 60 sites in 9 countries as reported herein. INTERVENTION: Patients were administered durvalumab intravenous infusion, 10 mg/kg every 2 weeks, for up to 12 months or until progression, starting another anticancer therapy, or unacceptable toxic effects. MAIN OUTCOMES AND MEASURES: Primary end points were safety and confirmed objective response rate (ORR) per blinded independent central review (Response Evaluation Criteria In Solid Tumors [RECIST], version 1.1). RESULTS: A total of 191 patients with UC had received treatment. As of October 24, 2016 (90-day update), the median follow-up was 5.78 months (range, 0.4-25.9 months). The median age of patients was 67.0 years and most were male (136 [71.2{\%}]) and white (123 [71.1{\%}]). All patients had stage 4 disease, and 190 (99.5{\%}) had prior anticancer therapy (182 [95.3{\%}] postplatinum). The ORR was 17.8{\%} (34 of 191; 95{\%} CI, 12.7{\%}-24.0{\%}), including 7 complete responses. Responses were early (median time to response, 1.41 months), durable (median duration of response not reached), and observed regardless of programmed cell death ligand-1 (PD-L1) expression (ORR, 27.6{\%} [n = 27; 95{\%} CI, 19.0{\%}-37.5{\%}] and 5.1{\%} [n = 4; 95{\%} CI, 1.4{\%}-12.5{\%}] in patients with high and low or negative expression of PD-L1, respectively). Median progression-free survival and overall survival were 1.5 months (95{\%} CI, 1.4-1.9 months) and 18.2 months (95{\%} CI, 8.1 months to not estimable), respectively; the 1-year overall survival rate was 55{\%} (95{\%} CI, 44{\%}-65{\%}), as estimated by Kaplan-Meier method. Grade 3/4 treatment-related adverse events (AEs) occurred in 13 patients (6.8{\%}); grade 3/4 immune-mediated AEs occurred in 4 patients (2.1{\%}); and treatment-related AEs led to discontinuation of 3 patients (1.6{\%}), 2 of whom had immune-mediated AEs that led to death (autoimmune hepatitis and pneumonitis). CONCLUSIONS AND RELEVANCE: Durvalumab, 10 mg/kg every 2 weeks, demonstrates favorable clinical activity and an encouraging and manageable safety profile in patients with locally advanced/metastatic UC. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01693562.",
author = "Thomas Powles and O'Donnell, {Peter H.} and Christophe Massard and Arkenau, {Hendrik Tobias} and Friedlander, {Terence W.} and Hoimes, {Christopher J.} and Lee, {Jae Lyun} and Michael Ong and Sridhar, {Srikala S.} and Vogelzang, {Nicholas J.} and Fishman, {Mayer N.} and Jingsong Zhang and Sandy Srinivas and Parikh, {Jigarkumar Rasiklal} and Joyce Antal and Xiaoping Jin and Gupta, {Ashok K.} and Yong Ben and Hahn, {Noah M.}",
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T1 - Efficacy and safety of durvalumab in locally advanced or metastatic urothelial carcinoma

T2 - Updated results from a phase 1/2 open-label study

AU - Powles, Thomas

AU - O'Donnell, Peter H.

AU - Massard, Christophe

AU - Arkenau, Hendrik Tobias

AU - Friedlander, Terence W.

AU - Hoimes, Christopher J.

AU - Lee, Jae Lyun

AU - Ong, Michael

AU - Sridhar, Srikala S.

AU - Vogelzang, Nicholas J.

AU - Fishman, Mayer N.

AU - Zhang, Jingsong

AU - Srinivas, Sandy

AU - Parikh, Jigarkumar Rasiklal

AU - Antal, Joyce

AU - Jin, Xiaoping

AU - Gupta, Ashok K.

AU - Ben, Yong

AU - Hahn, Noah M.

PY - 2017/9/1

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N2 - IMPORTANCE: The data reported herein were accepted for assessment by the US Food and Drug Administration for Biologics License Application under priority review to establish the clinical benefit of durvalumab as second-line therapy for locally advanced or metastatic urothelial carcinoma (UC), resulting in its recent US approval. OBJECTIVE: To report a planned update of the safety and efficacy of durvalumab in patients with locally advanced/metastatic UC. DESIGN, SETTING, AND PARTICIPANTS: This is an ongoing phase 1/2 open-label study of 191 adult patients with histologically or cytologically confirmed locally advanced/metastatic UC whose disease had progressed on, were ineligible for, or refused prior chemotherapy from 60 sites in 9 countries as reported herein. INTERVENTION: Patients were administered durvalumab intravenous infusion, 10 mg/kg every 2 weeks, for up to 12 months or until progression, starting another anticancer therapy, or unacceptable toxic effects. MAIN OUTCOMES AND MEASURES: Primary end points were safety and confirmed objective response rate (ORR) per blinded independent central review (Response Evaluation Criteria In Solid Tumors [RECIST], version 1.1). RESULTS: A total of 191 patients with UC had received treatment. As of October 24, 2016 (90-day update), the median follow-up was 5.78 months (range, 0.4-25.9 months). The median age of patients was 67.0 years and most were male (136 [71.2%]) and white (123 [71.1%]). All patients had stage 4 disease, and 190 (99.5%) had prior anticancer therapy (182 [95.3%] postplatinum). The ORR was 17.8% (34 of 191; 95% CI, 12.7%-24.0%), including 7 complete responses. Responses were early (median time to response, 1.41 months), durable (median duration of response not reached), and observed regardless of programmed cell death ligand-1 (PD-L1) expression (ORR, 27.6% [n = 27; 95% CI, 19.0%-37.5%] and 5.1% [n = 4; 95% CI, 1.4%-12.5%] in patients with high and low or negative expression of PD-L1, respectively). Median progression-free survival and overall survival were 1.5 months (95% CI, 1.4-1.9 months) and 18.2 months (95% CI, 8.1 months to not estimable), respectively; the 1-year overall survival rate was 55% (95% CI, 44%-65%), as estimated by Kaplan-Meier method. Grade 3/4 treatment-related adverse events (AEs) occurred in 13 patients (6.8%); grade 3/4 immune-mediated AEs occurred in 4 patients (2.1%); and treatment-related AEs led to discontinuation of 3 patients (1.6%), 2 of whom had immune-mediated AEs that led to death (autoimmune hepatitis and pneumonitis). CONCLUSIONS AND RELEVANCE: Durvalumab, 10 mg/kg every 2 weeks, demonstrates favorable clinical activity and an encouraging and manageable safety profile in patients with locally advanced/metastatic UC. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01693562.

AB - IMPORTANCE: The data reported herein were accepted for assessment by the US Food and Drug Administration for Biologics License Application under priority review to establish the clinical benefit of durvalumab as second-line therapy for locally advanced or metastatic urothelial carcinoma (UC), resulting in its recent US approval. OBJECTIVE: To report a planned update of the safety and efficacy of durvalumab in patients with locally advanced/metastatic UC. DESIGN, SETTING, AND PARTICIPANTS: This is an ongoing phase 1/2 open-label study of 191 adult patients with histologically or cytologically confirmed locally advanced/metastatic UC whose disease had progressed on, were ineligible for, or refused prior chemotherapy from 60 sites in 9 countries as reported herein. INTERVENTION: Patients were administered durvalumab intravenous infusion, 10 mg/kg every 2 weeks, for up to 12 months or until progression, starting another anticancer therapy, or unacceptable toxic effects. MAIN OUTCOMES AND MEASURES: Primary end points were safety and confirmed objective response rate (ORR) per blinded independent central review (Response Evaluation Criteria In Solid Tumors [RECIST], version 1.1). RESULTS: A total of 191 patients with UC had received treatment. As of October 24, 2016 (90-day update), the median follow-up was 5.78 months (range, 0.4-25.9 months). The median age of patients was 67.0 years and most were male (136 [71.2%]) and white (123 [71.1%]). All patients had stage 4 disease, and 190 (99.5%) had prior anticancer therapy (182 [95.3%] postplatinum). The ORR was 17.8% (34 of 191; 95% CI, 12.7%-24.0%), including 7 complete responses. Responses were early (median time to response, 1.41 months), durable (median duration of response not reached), and observed regardless of programmed cell death ligand-1 (PD-L1) expression (ORR, 27.6% [n = 27; 95% CI, 19.0%-37.5%] and 5.1% [n = 4; 95% CI, 1.4%-12.5%] in patients with high and low or negative expression of PD-L1, respectively). Median progression-free survival and overall survival were 1.5 months (95% CI, 1.4-1.9 months) and 18.2 months (95% CI, 8.1 months to not estimable), respectively; the 1-year overall survival rate was 55% (95% CI, 44%-65%), as estimated by Kaplan-Meier method. Grade 3/4 treatment-related adverse events (AEs) occurred in 13 patients (6.8%); grade 3/4 immune-mediated AEs occurred in 4 patients (2.1%); and treatment-related AEs led to discontinuation of 3 patients (1.6%), 2 of whom had immune-mediated AEs that led to death (autoimmune hepatitis and pneumonitis). CONCLUSIONS AND RELEVANCE: Durvalumab, 10 mg/kg every 2 weeks, demonstrates favorable clinical activity and an encouraging and manageable safety profile in patients with locally advanced/metastatic UC. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01693562.

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