Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial - PubMed (original) (raw)

Clinical Trial

. 2016 May 7;387(10031):1909-20.

doi: 10.1016/S0140-6736(16)00561-4. Epub 2016 Mar 4.

Jean Hoffman-Censits 2, Tom Powles 3, Michiel S van der Heijden 4, Arjun V Balar 5, Andrea Necchi 6, Nancy Dawson 7, Peter H O'Donnell 8, Ani Balmanoukian 9, Yohann Loriot 10, Sandy Srinivas 11, Margitta M Retz 12, Petros Grivas 13, Richard W Joseph 14, Matthew D Galsky 15, Mark T Fleming 16, Daniel P Petrylak 17, Jose Luis Perez-Gracia 18, Howard A Burris 19, Daniel Castellano 20, Christina Canil 21, Joaquim Bellmunt 22, Dean Bajorin 23, Dorothee Nickles 24, Richard Bourgon 24, Garrett M Frampton 25, Na Cui 24, Sanjeev Mariathasan 24, Oyewale Abidoye 24, Gregg D Fine 24, Robert Dreicer 26

Affiliations

Clinical Trial

Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial

Jonathan E Rosenberg et al. Lancet. 2016.

Abstract

Background: Patients with metastatic urothelial carcinoma have few treatment options after failure of platinum-based chemotherapy. In this trial, we assessed treatment with atezolizumab, an engineered humanised immunoglobulin G1 monoclonal antibody that binds selectively to programmed death ligand 1 (PD-L1), in this patient population.

Methods: For this multicentre, single-arm, two-cohort, phase 2 trial, patients (aged ≥18 years) with inoperable locally advanced or metastatic urothelial carcinoma whose disease had progressed after previous platinum-based chemotherapy were enrolled from 70 major academic medical centres and community oncology practices in Europe and North America. Key inclusion criteria for enrolment were Eastern Cooperative Oncology Group performance status of 0 or 1, measurable disease defined by Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1), adequate haematological and end-organ function, and no autoimmune disease or active infections. Formalin-fixed paraffin-embedded tumour specimens with sufficient viable tumour content were needed from all patients before enrolment. Patients received treatment with intravenous atezolizumab (1200 mg, given every 3 weeks). PD-L1 expression on tumour-infiltrating immune cells (ICs) was assessed prospectively by immunohistochemistry. The co-primary endpoints were the independent review facility-assessed objective response rate according to RECIST v1.1 and the investigator-assessed objective response rate according to immune-modified RECIST, analysed by intention to treat. A hierarchical testing procedure was used to assess whether the objective response rate was significantly higher than the historical control rate of 10% at an α level of 0·05. This study is registered with ClinicalTrials.gov, number NCT02108652.

Findings: Between May 13, 2014, and Nov 19, 2014, 486 patients were screened and 315 patients were enrolled into the study. Of these patients, 310 received atezolizumab treatment (five enrolled patients later did not meet eligibility criteria and were not dosed with study drug). The PD-L1 expression status on infiltrating immune cells (ICs) in the tumour microenvironment was defined by the percentage of PD-L1-positive immune cells: IC0 (<1%), IC1 (≥1% but <5%), and IC2/3 (≥5%). The primary analysis (data cutoff May 5, 2015) showed that compared with a historical control overall response rate of 10%, treatment with atezolizumab resulted in a significantly improved RECIST v1.1 objective response rate for each prespecified immune cell group (IC2/3: 27% [95% CI 19-37], p<0·0001; IC1/2/3: 18% [13-24], p=0·0004) and in all patients (15% [11-20], p=0·0058). With longer follow-up (data cutoff Sept 14, 2015), by independent review, objective response rates were 26% (95% CI 18-36) in the IC2/3 group, 18% (13-24) in the IC1/2/3 group, and 15% (11-19) overall in all 310 patients. With a median follow-up of 11·7 months (95% CI 11·4-12·2), ongoing responses were recorded in 38 (84%) of 45 responders. Exploratory analyses showed The Cancer Genome Atlas (TCGA) subtypes and mutation load to be independently predictive for response to atezolizumab. Grade 3-4 treatment-related adverse events, of which fatigue was the most common (five patients [2%]), occurred in 50 (16%) of 310 treated patients. Grade 3-4 immune-mediated adverse events occurred in 15 (5%) of 310 treated patients, with pneumonitis, increased aspartate aminotransferase, increased alanine aminotransferase, rash, and dyspnoea being the most common. No treatment-related deaths occurred during the study.

Interpretation: Atezolizumab showed durable activity and good tolerability in this patient population. Increased levels of PD-L1 expression on immune cells were associated with increased response. This report is the first to show the association of TCGA subtypes with response to immune checkpoint inhibition and to show the importance of mutation load as a biomarker of response to this class of agents in advanced urothelial carcinoma.

Funding: F Hoffmann-La Roche Ltd.

Copyright © 2016 Elsevier Ltd. All rights reserved.

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Figures

Figure 1

Figure 1. Trial profile for Cohort 2

*Based on May 5, 2015 data cut. Two Cohort 2 patients and one Cohort 1 patient were re-assigned to the alternate cohort based on eligibility reassessments between the May 5 and September 14, 2015 data cuts (enrolled and treated n’s based on September data cut are 315 and 310, respectively). ‡Excludes 1 patient with unknown site. † Includes rescreened patients. ECOG PS, Eastern Cooperative Oncology Group performance status; ICF, informed consent form; UC, urothelial carcinoma.

Figure 2

Figure 2. Change in sum of longest diameters over time by best response in the PD-L1 IC2/3 group and comparison of overall survival among PD-L1 IC groups

Percent change in the sum of longest diameters (SLD) by independent review assessed RECIST v1.1 in the IC2/3 group by (A) responders; (B) stable disease; (C) progressive disease. Patients without a measurable baseline tumor assessment or without post-baseline tumor measurements were not included. (D) Kaplan-Meier overall survival curves for the IC0, IC1, and IC2/3 groups. IC, immune cell; CI, confidence interval.

Figure 3

Figure 3. Association of response and PD-L1 IHC status with gene expression profiling and mutation load

(A) Association of PD-L1 IHC IC with gene expression for CXCL9 and CXCL10, two representatives of a CD8 T effector gene set. For each gene, expression increased linearly with IC score (p<0·0001 and p<0·0001, respectively). The other genes in an eight-gene CD8 T effector gene set behaved similarly (figure 6A, appendix). (B) CXCL9 and CXCL10 were significantly associated with response (p=0·0057 and p=0·0079, respectively). The other genes in the set did not achieve statistical significance individually, likely due to lower RNA-seq read counts, but they exhibited behavior qualitatively similar to that of CXCL9 and CXCL10 (figure 6B, appendix). (C) Tumor CD8+ T cell infiltration in the tumor center was significantly associated with PD-L1 IC (p<0·0001). (D) Response was significantly associated with increased CD8+ IHC staining in the tumor center (p=0.0265). (E) IC score distribution by TCGA subtype. IC2/3 was significantly more common in the basal subtypes (III and IV, p<0·0001), though IC2 was present in all subtypes. (F) TC score distributions by TCGA subtype. TC2/3 was almost exclusively seen in basal subtypes (p<0·0001). (G) Objective response rate by TCGA subtype. Response was significantly associated with TCGA subtype: 10% for subtype I, 34% for II, 16% for III, and 20% for IV (p=0·0102). (H) Estimated mutation load per megabase (Mb) vs patient response, overall (n=150) and also disaggregated by TCGA subtype. Mutation load was strongly associated with response (p<0·0001), but to a similar degree in all TCGA subtypes. IC, immune cell; TC, tumor cell; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease.

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