Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial.

Arjun V. Balar, Matthew D. Galsky, Jonathan E. Rosenberg, Thomas Powles, Daniel P. Petrylak, Joaquim Bellmunt, Yohann Loriot, Andrea Necchi, Jean Hoffman-Censits, Jose Luis Perez-Gracia, Nancy A. Dawson, Michiel S. Van Der Heijden, Robert Dreicer, Sandy Srinivas, Margitta M. Retz, Richard W. Joseph, Alexandra Drakaki, Ulka N. Vaishampayan, Srikala S. Sridhar, David I. Quinn & 15 others Ignacio Duran, David R. Shaffer, Bernhard J. Eigl, Petros D. Grivas, Evan Y. Yu, Lei Shi Li, Edward E. 3rd Kadel, Zachary Boyd, Richard Bourgon, Priti S. Hegde, Sanjeev Mariathasan, AnnChristine Thastrom, Oyewale Abidoye, Gregg D. Fine, Dean F. Bajorin

Research output: Contribution to journalArticle

486 Citations (Scopus)

Abstract

BACKGROUND: First-line chemotherapy for patients with cisplatin-ineligible locally advanced or metastatic urothelial carcinoma is associated with short response duration, poor survival, and high toxicity. This study assessed atezolizumab (anti-programmed death-ligand 1 [PD-L1]) as treatment for metastatic urothelial cancer in cisplatin-ineligible patients. METHODS: For this single-arm, multicentre, phase 2 study, in 47 academic medical centres and community oncology practices in seven countries in North America and Europe, we recruited previously untreated patients with locally advanced or metastatic urothelial cancer who were cisplatin ineligible. Patients were given 1200 mg intravenous atezolizumab every 21 days until progression. The primary endpoint was independently confirmed objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1 (central review), assessed in prespecified subgroups based on PD-L1 expression and in all patients. All participants who received one or more doses of atezolizumab were included in the primary and safety analyses. This study was registered with ClinicalTrials.gov, number NCT02108652. FINDINGS: Between June 9, 2014, and March 30, 2015, we enrolled 123 patients, of whom 119 received one or more doses of atezolizumab. At 17.2 months' median follow-up, the objective response rate was 23% (95% CI 16 to 31), the complete response rate was 9% (n=11), and 19 of 27 responses were ongoing. Median response duration was not reached. Responses occurred across all PD-L1 and poor prognostic factor subgroups. Median progression-free survival was 2.7 months (2.1 to 4.2). Median overall survival was 15.9 months (10.4 to not estimable). Tumour mutation load was associated with response. Treatment-related adverse events that occurred in 10% or more of patients were fatigue (36 [30 patients), diarrhoea (14 [12 patients), and pruritus (13 [11 patients). One treatment-related death (sepsis) occurred. Nine (8 patients had an adverse event leading to treatment discontinuation. Immune-mediated events occurred in 14 (12 patients. INTERPRETATION: Atezolizumab showed encouraging durable response rates, survival, and tolerability, supporting its therapeutic use in untreated metastatic urothelial cancer. FUNDING: F Hoffmann-La Roche, Genentech.
Original languageUndefined/Unknown
Pages (from-to)67-76
Number of pages10
JournalThe Lancet
Volume389
Issue number10064
DOIs
Publication statusPublished - Jan 1 2017

Keywords

  • Aged, Aged, 80 and over, Antibodies, Monoclonal/administration dosage/adverse effects/*therapeutic use, Antigens, CD274/blood, Antineoplastic Agents/administration dosage/adverse effects/*therapeutic use, Biomarkers, Tumor/blood, Carcinoma, Transitional Cell/blood/*drug therapy/*secondary, Cisplatin/contraindications, Female, Humans, Infusions, Intravenous, Kaplan-Meier Estimate, Lymphatic Metastasis, Male, Middle Aged, Response Evaluation Criteria in Solid Tumors, Urologic Neoplasms/blood/*drug therapy

Cite this

Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. / Balar, Arjun V.; Galsky, Matthew D.; Rosenberg, Jonathan E.; Powles, Thomas; Petrylak, Daniel P.; Bellmunt, Joaquim; Loriot, Yohann; Necchi, Andrea; Hoffman-Censits, Jean; Perez-Gracia, Jose Luis; Dawson, Nancy A.; Van Der Heijden, Michiel S.; Dreicer, Robert; Srinivas, Sandy; Retz, Margitta M.; Joseph, Richard W.; Drakaki, Alexandra; Vaishampayan, Ulka N.; Sridhar, Srikala S.; Quinn, David I.; Duran, Ignacio; Shaffer, David R.; Eigl, Bernhard J.; Grivas, Petros D.; Yu, Evan Y.; Li, Lei Shi; Kadel, Edward E. 3rd; Boyd, Zachary; Bourgon, Richard; Hegde, Priti S.; Mariathasan, Sanjeev; Thastrom, AnnChristine; Abidoye, Oyewale; Fine, Gregg D.; Bajorin, Dean F.

In: The Lancet, Vol. 389, No. 10064, 01.01.2017, p. 67-76.

Research output: Contribution to journalArticle

Balar, AV, Galsky, MD, Rosenberg, JE, Powles, T, Petrylak, DP, Bellmunt, J, Loriot, Y, Necchi, A, Hoffman-Censits, J, Perez-Gracia, JL, Dawson, NA, Van Der Heijden, MS, Dreicer, R, Srinivas, S, Retz, MM, Joseph, RW, Drakaki, A, Vaishampayan, UN, Sridhar, SS, Quinn, DI, Duran, I, Shaffer, DR, Eigl, BJ, Grivas, PD, Yu, EY, Li, LS, Kadel, EE, Boyd, Z, Bourgon, R, Hegde, PS, Mariathasan, S, Thastrom, A, Abidoye, O, Fine, GD & Bajorin, DF 2017, 'Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial.', The Lancet, vol. 389, no. 10064, pp. 67-76. https://doi.org/10.1016/S0140-6736(16)32455-2
Balar, Arjun V. ; Galsky, Matthew D. ; Rosenberg, Jonathan E. ; Powles, Thomas ; Petrylak, Daniel P. ; Bellmunt, Joaquim ; Loriot, Yohann ; Necchi, Andrea ; Hoffman-Censits, Jean ; Perez-Gracia, Jose Luis ; Dawson, Nancy A. ; Van Der Heijden, Michiel S. ; Dreicer, Robert ; Srinivas, Sandy ; Retz, Margitta M. ; Joseph, Richard W. ; Drakaki, Alexandra ; Vaishampayan, Ulka N. ; Sridhar, Srikala S. ; Quinn, David I. ; Duran, Ignacio ; Shaffer, David R. ; Eigl, Bernhard J. ; Grivas, Petros D. ; Yu, Evan Y. ; Li, Lei Shi ; Kadel, Edward E. 3rd ; Boyd, Zachary ; Bourgon, Richard ; Hegde, Priti S. ; Mariathasan, Sanjeev ; Thastrom, AnnChristine ; Abidoye, Oyewale ; Fine, Gregg D. ; Bajorin, Dean F. / Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. In: The Lancet. 2017 ; Vol. 389, No. 10064. pp. 67-76.
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title = "Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial.",
abstract = "BACKGROUND: First-line chemotherapy for patients with cisplatin-ineligible locally advanced or metastatic urothelial carcinoma is associated with short response duration, poor survival, and high toxicity. This study assessed atezolizumab (anti-programmed death-ligand 1 [PD-L1]) as treatment for metastatic urothelial cancer in cisplatin-ineligible patients. METHODS: For this single-arm, multicentre, phase 2 study, in 47 academic medical centres and community oncology practices in seven countries in North America and Europe, we recruited previously untreated patients with locally advanced or metastatic urothelial cancer who were cisplatin ineligible. Patients were given 1200 mg intravenous atezolizumab every 21 days until progression. The primary endpoint was independently confirmed objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1 (central review), assessed in prespecified subgroups based on PD-L1 expression and in all patients. All participants who received one or more doses of atezolizumab were included in the primary and safety analyses. This study was registered with ClinicalTrials.gov, number NCT02108652. FINDINGS: Between June 9, 2014, and March 30, 2015, we enrolled 123 patients, of whom 119 received one or more doses of atezolizumab. At 17.2 months' median follow-up, the objective response rate was 23{\%} (95{\%} CI 16 to 31), the complete response rate was 9{\%} (n=11), and 19 of 27 responses were ongoing. Median response duration was not reached. Responses occurred across all PD-L1 and poor prognostic factor subgroups. Median progression-free survival was 2.7 months (2.1 to 4.2). Median overall survival was 15.9 months (10.4 to not estimable). Tumour mutation load was associated with response. Treatment-related adverse events that occurred in 10{\%} or more of patients were fatigue (36 [30 patients), diarrhoea (14 [12 patients), and pruritus (13 [11 patients). One treatment-related death (sepsis) occurred. Nine (8 patients had an adverse event leading to treatment discontinuation. Immune-mediated events occurred in 14 (12 patients. INTERPRETATION: Atezolizumab showed encouraging durable response rates, survival, and tolerability, supporting its therapeutic use in untreated metastatic urothelial cancer. FUNDING: F Hoffmann-La Roche, Genentech.",
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TY - JOUR

T1 - Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial.

AU - Balar, Arjun V.

AU - Galsky, Matthew D.

AU - Rosenberg, Jonathan E.

AU - Powles, Thomas

AU - Petrylak, Daniel P.

AU - Bellmunt, Joaquim

AU - Loriot, Yohann

AU - Necchi, Andrea

AU - Hoffman-Censits, Jean

AU - Perez-Gracia, Jose Luis

AU - Dawson, Nancy A.

AU - Van Der Heijden, Michiel S.

AU - Dreicer, Robert

AU - Srinivas, Sandy

AU - Retz, Margitta M.

AU - Joseph, Richard W.

AU - Drakaki, Alexandra

AU - Vaishampayan, Ulka N.

AU - Sridhar, Srikala S.

AU - Quinn, David I.

AU - Duran, Ignacio

AU - Shaffer, David R.

AU - Eigl, Bernhard J.

AU - Grivas, Petros D.

AU - Yu, Evan Y.

AU - Li, Lei Shi

AU - Kadel, Edward E. 3rd

AU - Boyd, Zachary

AU - Bourgon, Richard

AU - Hegde, Priti S.

AU - Mariathasan, Sanjeev

AU - Thastrom, AnnChristine

AU - Abidoye, Oyewale

AU - Fine, Gregg D.

AU - Bajorin, Dean F.

PY - 2017/1/1

Y1 - 2017/1/1

N2 - BACKGROUND: First-line chemotherapy for patients with cisplatin-ineligible locally advanced or metastatic urothelial carcinoma is associated with short response duration, poor survival, and high toxicity. This study assessed atezolizumab (anti-programmed death-ligand 1 [PD-L1]) as treatment for metastatic urothelial cancer in cisplatin-ineligible patients. METHODS: For this single-arm, multicentre, phase 2 study, in 47 academic medical centres and community oncology practices in seven countries in North America and Europe, we recruited previously untreated patients with locally advanced or metastatic urothelial cancer who were cisplatin ineligible. Patients were given 1200 mg intravenous atezolizumab every 21 days until progression. The primary endpoint was independently confirmed objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1 (central review), assessed in prespecified subgroups based on PD-L1 expression and in all patients. All participants who received one or more doses of atezolizumab were included in the primary and safety analyses. This study was registered with ClinicalTrials.gov, number NCT02108652. FINDINGS: Between June 9, 2014, and March 30, 2015, we enrolled 123 patients, of whom 119 received one or more doses of atezolizumab. At 17.2 months' median follow-up, the objective response rate was 23% (95% CI 16 to 31), the complete response rate was 9% (n=11), and 19 of 27 responses were ongoing. Median response duration was not reached. Responses occurred across all PD-L1 and poor prognostic factor subgroups. Median progression-free survival was 2.7 months (2.1 to 4.2). Median overall survival was 15.9 months (10.4 to not estimable). Tumour mutation load was associated with response. Treatment-related adverse events that occurred in 10% or more of patients were fatigue (36 [30 patients), diarrhoea (14 [12 patients), and pruritus (13 [11 patients). One treatment-related death (sepsis) occurred. Nine (8 patients had an adverse event leading to treatment discontinuation. Immune-mediated events occurred in 14 (12 patients. INTERPRETATION: Atezolizumab showed encouraging durable response rates, survival, and tolerability, supporting its therapeutic use in untreated metastatic urothelial cancer. FUNDING: F Hoffmann-La Roche, Genentech.

AB - BACKGROUND: First-line chemotherapy for patients with cisplatin-ineligible locally advanced or metastatic urothelial carcinoma is associated with short response duration, poor survival, and high toxicity. This study assessed atezolizumab (anti-programmed death-ligand 1 [PD-L1]) as treatment for metastatic urothelial cancer in cisplatin-ineligible patients. METHODS: For this single-arm, multicentre, phase 2 study, in 47 academic medical centres and community oncology practices in seven countries in North America and Europe, we recruited previously untreated patients with locally advanced or metastatic urothelial cancer who were cisplatin ineligible. Patients were given 1200 mg intravenous atezolizumab every 21 days until progression. The primary endpoint was independently confirmed objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1 (central review), assessed in prespecified subgroups based on PD-L1 expression and in all patients. All participants who received one or more doses of atezolizumab were included in the primary and safety analyses. This study was registered with ClinicalTrials.gov, number NCT02108652. FINDINGS: Between June 9, 2014, and March 30, 2015, we enrolled 123 patients, of whom 119 received one or more doses of atezolizumab. At 17.2 months' median follow-up, the objective response rate was 23% (95% CI 16 to 31), the complete response rate was 9% (n=11), and 19 of 27 responses were ongoing. Median response duration was not reached. Responses occurred across all PD-L1 and poor prognostic factor subgroups. Median progression-free survival was 2.7 months (2.1 to 4.2). Median overall survival was 15.9 months (10.4 to not estimable). Tumour mutation load was associated with response. Treatment-related adverse events that occurred in 10% or more of patients were fatigue (36 [30 patients), diarrhoea (14 [12 patients), and pruritus (13 [11 patients). One treatment-related death (sepsis) occurred. Nine (8 patients had an adverse event leading to treatment discontinuation. Immune-mediated events occurred in 14 (12 patients. INTERPRETATION: Atezolizumab showed encouraging durable response rates, survival, and tolerability, supporting its therapeutic use in untreated metastatic urothelial cancer. FUNDING: F Hoffmann-La Roche, Genentech.

KW - Aged, Aged, 80 and over, Antibodies, Monoclonal/administration dosage/adverse effects/therapeutic use, Antigens, CD274/blood, Antineoplastic Agents/administration dosage/adverse effects/therapeutic use, Biomarkers, Tumor/blood, Carcinoma, Transitional C

U2 - 10.1016/S0140-6736(16)32455-2

DO - 10.1016/S0140-6736(16)32455-2

M3 - Articolo

VL - 389

SP - 67

EP - 76

JO - The Lancet

JF - The Lancet

SN - 0140-6736

IS - 10064

ER -