Immunity as biophysics at the surface of a T cell.

Different antibodies can bind to the same targets on the surface of immune cells with opposite biologic effects. These effects-agonism, antagonism, or partial agonism-are so poorly understood that drug developers must screen antibodies for relevant desired characteristics. In this issue of Immunity, Lippert et al. define molecular mechanisms that dictate antibody behavior, ushering in an era of directed antibody design.

The cancer-immunity cycle: Indication, genotype, and immunotype.

The cancer-immunity cycle provides a framework to understand the series of events that generate anti-cancer immune responses. It emphasizes the iterative nature of the response where the killing of tumor cells by T cells initiates subsequent rounds of antigen presentation and T cell stimulation, maintaining active immunity and adapting it to tumor evolution. Any step of the cycle can become rate-limiting, rendering the immune system unable to control tumor growth. Here, we update the cancer-immunity cycle based on the remarkable progress of the past decade. Understanding the mechanism of checkpoint inhibition has evolved, as has our view of dendritic cells in sustaining anti-tumor immunity. We additionally account for the role of the tumor microenvironment in facilitating, not just suppressing, the anti-cancer response, and discuss the importance of considering a tumor's immunological phenotype, the "immunotype". While these new insights add some complexity to the cycle, they also provide new targets for research and therapeutic intervention.

Maximizing the value of phase III trials in immuno-oncology: A checklist from the Society for Immunotherapy of Cancer (SITC).

The broad activity of agents blocking the programmed cell death protein 1 and its ligand (the PD-(L)1 axis) revolutionized oncology, offering long-term benefit to patients and even curative responses for tumors that were once associated with dismal prognosis. However, only a minority of patients experience durable clinical benefit with immune checkpoint inhibitor monotherapy in most disease settings. Spurred by preclinical and correlative studies to understand mechanisms of non-response to the PD-(L)1 antagonists and by combination studies in animal tumor models, many drug development programs were designed to combine anti-PD-(L)1 with a variety of approved and investigational chemotherapies, tumor-targeted therapies, antiangiogenic therapies, and other immunotherapies. Several immunotherapy combinations improved survival outcomes in a variety of indications including melanoma, lung, kidney, and liver cancer, among others. This immunotherapy renaissance, however, has led to many combinations being advanced to late-stage development without definitive predictive biomarkers, limited phase I and phase II data, or clinical trial designs that are not optimized for demonstrating the unique attributes of immune-related antitumor activity-for example, landmark progression-free survival and overall survival. The decision to activate a study at an individual site is investigator-driven, and generalized frameworks to evaluate the potential for phase III trials in immuno-oncology to yield positive data, particularly to increase the number of curative responses or otherwise advance the field have thus far been lacking. To assist in evaluating the potential value to patients and the immunotherapy field of phase III trials, the Society for Immunotherapy of Cancer (SITC) has developed a checklist for investigators, described in this manuscript. Although the checklist focuses on anti-PD-(L)1-based combinations, it may be applied to any regimen in which immune modulation is an important component of the antitumor effect.

Dendritic cells dictate responses to PD-L1 blockade cancer immunotherapy.

PD-L1/PD-1 blocking antibodies have demonstrated therapeutic efficacy across a range of human cancers. Extending this benefit to a greater number of patients, however, will require a better understanding of how these therapies instigate anticancer immunity. Although the PD-L1/PD-1 axis is typically associated with T cell function, we demonstrate here that dendritic cells (DCs) are an important target of PD-L1 blocking antibody. PD-L1 binds two receptors, PD-1 and B7.1 (CD80). PD-L1 is expressed much more abundantly than B7.1 on peripheral and tumor-associated DCs in patients with cancer. Blocking PD-L1 on DCs relieves B7.1 sequestration in cis by PD-L1, which allows the B7.1/CD28 interaction to enhance T cell priming. In line with this, in patients with renal cell carcinoma or non-small cell lung cancer treated with atezolizumab (PD-L1 blockade), a DC gene signature is strongly associated with improved overall survival. These data suggest that PD-L1 blockade reinvigorates DC function to generate potent anticancer T cell immunity.

Top 10 Challenges in Cancer Immunotherapy.

Cancer immunotherapy is a validated and critically important approach for treating patients with cancer. Given the vast research and clinical investigation efforts dedicated to advancing both endogenous and synthetic immunotherapy approaches, there is a need to focus on crucial questions and define roadblocks to the basic understanding and clinical progress. Here, we define ten key challenges facing cancer immunotherapy, which range from lack of confidence in translating pre-clinical findings to identifying optimal combinations of immune-based therapies for any given patient. Addressing these challenges will require the combined efforts of basic researchers and clinicians, and the focusing of resources to accelerate understanding of the complex interactions between cancer and the immune system and the development of improved treatment options for patients with cancer.

Safety, Clinical Activity, and Biological Correlates of Response in Patients with Metastatic Melanoma: Results from a Phase I Trial of Atezolizumab.

PURPOSE: Atezolizumab [anti-programmed death-ligand 1 (PD-L1)] selectively targets PD-L1 to block its interaction with receptors programmed death 1 and B7.1, thereby reinvigorating antitumor T-cell activity. We evaluated the long-term safety and activity of atezolizumab, along with biological correlates of clinical activity endpoints, in a cohort of patients with melanoma in an ongoing phase Ia study (NCT01375842). PATIENTS AND METHODS: Patients with unresectable or metastatic melanoma were enrolled to receive atezolizumab 0.1 to 20 mg/kg or ≥10 mg/kg every 3 weeks. Primary study objectives were safety and tolerability. Secondary objectives included investigator-assessed efficacy measures; pharmacodynamic and predictive biomarkers of antitumor activity were explored. RESULTS: Forty-five patients were enrolled and were evaluable for safety. Most treatment-related adverse events (AE) were grade 1/2 (60%). Fatigue (44%), pruritus (20%), pyrexia (18%), and rash (18%) were the most common treatment-related AEs of any grade. No treatment-related deaths occurred. Overall response rate was 30% among 43 efficacy- evaluable patients, with a median duration of response of 62 months [95% CI, 35-not estimable (NE)]. Clinically meaningful long-term survival was observed, with a median overall survival of 23 months (95% CI, 9-66). Baseline biomarkers of tumor immunity [PD-L1 expression on immune cells, T effector (Teff), and antigen presentation gene signatures) and tumor mutational burden (TMB) were associated with improved response, progression-free survival, and overall survival. CONCLUSIONS: Atezolizumab was well tolerated, with durable responses and survival in patients with melanoma. PD-L1 expression, TMB, and Teff signatures may indicate improved benefit with atezolizumab in these patients.

VEGF in Signaling and Disease: Beyond Discovery and Development.

The discovery of vascular endothelial-derived growth factor (VEGF) has revolutionized our understanding of vasculogenesis and angiogenesis during development and physiological homeostasis. Over a short span of two decades, our understanding of the molecular mechanisms by which VEGF coordinates neurovascular homeostasis has become more sophisticated. The central role of VEGF in the pathogenesis of diverse cancers and blinding eye diseases has also become evident. Elucidation of the molecular regulation of VEGF and the transformative development of multiple therapeutic pathways targeting VEGF directly or indirectly is a powerful case study of how fundamental research can guide innovation and translation. It is also an elegant example of how agnostic discovery and can transform our understanding of human disease. This review will highlight critical nodal points in VEGF biology, including recent developments in immunotherapy for cancer and multitarget approaches in neovascular eye disease.

Differential regulation of PD-L1 expression by immune and tumor cells in NSCLC and the response to treatment with atezolizumab (anti-PD-L1).

Programmed death-ligand 1 (PD-L1) expression on tumor cells (TCs) by immunohistochemistry is rapidly gaining importance as a diagnostic for the selection or stratification of patients with non-small cell lung cancer (NSCLC) most likely to respond to single-agent checkpoint inhibitors. However, at least two distinct patterns of PD-L1 expression have been observed with potential biological and clinical relevance in NSCLC: expression on TC or on tumor-infiltrating immune cells (ICs). We investigated the molecular and cellular characteristics associated with PD-L1 expression in these distinct cell compartments in 4,549 cases of NSCLC. PD-L1 expression on IC was more prevalent and likely reflected IFN-γ-induced adaptive regulation accompanied by increased tumor-infiltrating lymphocytes and effector T cells. High PD-L1 expression on TC, however, reflected an epigenetic dysregulation of the PD-L1 gene and was associated with a distinct histology described by poor immune infiltration, sclerotic/desmoplastic stroma, and mesenchymal molecular features. Importantly, durable clinical responses to atezolizumab (anti-PD-L1) were observed in patients with tumors expressing high PD-L1 levels on either TC alone [40% objective response rate (ORR)] or IC alone (22% ORR). Thus, PD-L1 expression on TC or IC can independently attenuate anticancer immunity and emphasizes the functional importance of IC in regulating the antitumor T cell response.

Publisher Correction: Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma.

In the version of this article originally published, there was an error in Fig. 2n. The top line of the HR comparison chart originally was Atezo + bev vs sun. It should have been Atezo + bev vs atezo. The error has been corrected in the HTML and PDF versions of this article.

Combinations of Bevacizumab With Cancer Immunotherapy.

Cancer immunotherapy (CIT) has transformed cancer treatment. In particular, immunotherapies targeting the programmed death ligand 1 (PD-L1)/programmed death 1 pathway have demonstrated durable clinical benefit in some patients. However, CIT combinations may create a more favorable environment in which to maximize the potential of the immune system to eliminate cancer. Here we describe 3 key mechanisms related to vascular endothelial growth factor (VEGF)-mediated immunosuppression: inhibition of dendritic cell maturation, reduction of T-cell tumor infiltration, and promotion of inhibitory cells in the tumor microenvironment; supporting data are also described. In addition, we discuss immunomodulatory properties observed within tumors following bevacizumab treatment. Combining anti-PD-L1 and anti-VEGF therapies has shown synergy and positive outcomes in phases I to III studies, particularly in settings where high VEGF levels are known to play an important role in tumor growth. We also review data from key studies supporting combination of bevacizumab and CIT, with a focus on PD-L1/programmed death 1 inhibitors.

Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma.

We describe results from IMmotion150, a randomized phase 2 study of atezolizumab (anti-PD-L1) alone or combined with bevacizumab (anti-VEGF) versus sunitinib in 305 patients with treatment-naive metastatic renal cell carcinoma. Co-primary endpoints were progression-free survival (PFS) in intent-to-treat and PD-L1+ populations. Intent-to-treat PFS hazard ratios for atezolizumab + bevacizumab or atezolizumab monotherapy versus sunitinib were 1.0 (95% confidence interval (CI), 0.69-1.45) and 1.19 (95% CI, 0.82-1.71), respectively; PD-L1+ PFS hazard ratios were 0.64 (95% CI, 0.38-1.08) and 1.03 (95% CI, 0.63-1.67), respectively. Exploratory biomarker analyses indicated that tumor mutation and neoantigen burden were not associated with PFS. Angiogenesis, T-effector/IFN-γ response, and myeloid inflammatory gene expression signatures were strongly and differentially associated with PFS within and across the treatments. These molecular profiles suggest that prediction of outcomes with anti-VEGF and immunotherapy may be possible and offer mechanistic insights into how blocking VEGF may overcome resistance to immune checkpoint blockade.

TGFß attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells.

Therapeutic antibodies that block the programmed death-1 (PD-1)-programmed death-ligand 1 (PD-L1) pathway can induce robust and durable responses in patients with various cancers, including metastatic urothelial cancer. However, these responses only occur in a subset of patients. Elucidating the determinants of response and resistance is key to improving outcomes and developing new treatment strategies. Here we examined tumours from a large cohort of patients with metastatic urothelial cancer who were treated with an anti-PD-L1 agent (atezolizumab) and identified major determinants of clinical outcome. Response to treatment was associated with CD8+ T-effector cell phenotype and, to an even greater extent, high neoantigen or tumour mutation burden. Lack of response was associated with a signature of transforming growth factor ß (TGFß) signalling in fibroblasts. This occurred particularly in patients with tumours, which showed exclusion of CD8+ T cells from the tumour parenchyma that were instead found in the fibroblast- and collagen-rich peritumoural stroma; a common phenotype among patients with metastatic urothelial cancer. Using a mouse model that recapitulates this immune-excluded phenotype, we found that therapeutic co-administration of TGFß-blocking and anti-PD-L1 antibodies reduced TGFß signalling in stromal cells, facilitated T-cell penetration into the centre of tumours, and provoked vigorous anti-tumour immunity and tumour regression. Integration of these three independent biological features provides the best basis for understanding patient outcome in this setting and suggests that TGFß shapes the tumour microenvironment to restrain anti-tumour immunity by restricting T-cell infiltration.

Immune-Modified Response Evaluation Criteria In Solid Tumors (imRECIST): Refining Guidelines to Assess the Clinical Benefit of Cancer Immunotherapy.

Purpose Treating solid tumors with cancer immunotherapy (CIT) can result in unconventional responses and overall survival (OS) benefits that are not adequately captured by Response Evaluation Criteria In Solid Tumors (RECIST) v1.1. We describe immune-modified RECIST (imRECIST) criteria, designed to better capture CIT responses. Patients and Methods Atezolizumab data from clinical trials in non-small-cell lung cancer, metastatic urothelial carcinoma, renal cell carcinoma, and melanoma were evaluated. Modifications to imRECIST versus RECIST v1.1 included allowance for best overall response after progressive disease (PD) and changes in PD definitions per new lesions (NLs) and nontarget lesions. imRECIST progression-free survival (PFS) did not count initial PD as an event if the subsequent scan showed disease control. OS was evaluated using conditional landmarks in patients whose PFS differed by imRECIST versus RECIST v1.1. Results The best overall response was 1% to 2% greater, the disease control rate was 8% to 13% greater, and the median PFS was 0.5 to 1.5 months longer per imRECIST versus RECIST v1.1. Extension of imRECIST PFS versus RECIST v1.1 PFS was associated with longer or similar OS. Patterns of progression analysis revealed that patients who developed NLs without target lesion (TL) progression had a similar or shorter OS compared with patients with RECIST v1.1 TL progression. Patients infrequently experienced a spike pattern (TLs increase, then decrease) but had longer OS than patients without TL reversion. Conclusion Evaluation of PFS and patterns of response and progression revealed that allowance for TL reversion from PD per imRECIST may better identify patients with OS benefit. Progression defined by the isolated appearance of NLs, however, is not associated with longer OS. These results may inform additional modifications to radiographic criteria (including imRECIST) to better reflect efficacy with CIT agents.

New Cancer Immunotherapy Agents in Development: a report from an associated program of the 31stAnnual Meeting of the Society for Immunotherapy of Cancer, 2016.

This report is a summary of 'New Cancer Immunotherapy Agents in Development' program, which took place in association with the 31st Annual Meeting of the Society for Immunotherapy of Cancer (SITC), on November 9, 2016 in National Harbor, Maryland. Presenters gave brief overviews of emerging clinical and pre-clinical immune-based agents and combinations, before participating in an extended panel discussion with multidisciplinary leaders, including members of the FDA, leading academic institutions and industrial drug developers, to consider topics relevant to the future of cancer immunotherapy.

Elements of cancer immunity and the cancer-immune set point.

Immunotherapy is proving to be an effective therapeutic approach in a variety of cancers. But despite the clinical success of antibodies against the immune regulators CTLA4 and PD-L1/PD-1, only a subset of people exhibit durable responses, suggesting that a broader view of cancer immunity is required. Immunity is influenced by a complex set of tumour, host and environmental factors that govern the strength and timing of the anticancer response. Clinical studies are beginning to define these factors as immune profiles that can predict responses to immunotherapy. In the context of the cancer-immunity cycle, such factors combine to represent the inherent immunological status - or 'cancer-immune set point' - of an individual.

Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial.

BACKGROUND: Atezolizumab is a humanised antiprogrammed death-ligand 1 (PD-L1) monoclonal antibody that inhibits PD-L1 and programmed death-1 (PD-1) and PD-L1 and B7-1 interactions, reinvigorating anticancer immunity. We assessed its efficacy and safety versus docetaxel in previously treated patients with non-small-cell lung cancer. METHODS: We did a randomised, open-label, phase 3 trial (OAK) in 194 academic or community oncology centres in 31 countries. We enrolled patients who had squamous or non-squamous non-small-cell lung cancer, were 18 years or older, had measurable disease per Response Evaluation Criteria in Solid Tumors, and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients had received one to two previous cytotoxic chemotherapy regimens (one or more platinum based combination therapies) for stage IIIB or IV non-small-cell lung cancer. Patients with a history of autoimmune disease and those who had received previous treatments with docetaxel, CD137 agonists, anti-CTLA4, or therapies targeting the PD-L1 and PD-1 pathway were excluded. Patients were randomly assigned (1:1) to intravenously receive either atezolizumab 1200 mg or docetaxel 75 mg/m2 every 3 weeks by permuted block randomisation (block size of eight) via an interactive voice or web response system. Coprimary endpoints were overall survival in the intention-to-treat (ITT) and PD-L1-expression population TC1/2/3 or IC1/2/3 (≥1% PD-L1 on tumour cells or tumour-infiltrating immune cells). The primary efficacy analysis was done in the first 850 of 1225 enrolled patients. This study is registered with ClinicalTrials.gov, number NCT02008227. FINDINGS: Between March 11, 2014, and April 29, 2015, 1225 patients were recruited. In the primary population, 425 patients were randomly assigned to receive atezolizumab and 425 patients were assigned to receive docetaxel. Overall survival was significantly longer with atezolizumab in the ITT and PD-L1-expression populations. In the ITT population, overall survival was improved with atezolizumab compared with docetaxel (median overall survival was 13·8 months [95% CI 11·8-15·7] vs 9·6 months [8·6-11·2]; hazard ratio [HR] 0·73 [95% CI 0·62-0·87], p=0·0003). Overall survival in the TC1/2/3 or IC1/2/3 population was improved with atezolizumab (n=241) compared with docetaxel (n=222; median overall survival was 15·7 months [95% CI 12·6-18·0] with atezolizumab vs 10·3 months [8·8-12·0] with docetaxel; HR 0·74 [95% CI 0·58-0·93]; p=0·0102). Patients in the PD-L1 low or undetectable subgroup (TC0 and IC0) also had improved survival with atezolizumab (median overall survival 12·6 months vs 8·9 months; HR 0·75 [95% CI 0·59-0·96]). Overall survival improvement was similar in patients with squamous (HR 0·73 [95% CI 0·54-0·98]; n=112 in the atezolizumab group and n=110 in the docetaxel group) or non-squamous (0·73 [0·60-0·89]; n=313 and n=315) histology. Fewer patients had treatment-related grade 3 or 4 adverse events with atezolizumab (90 [15%] of 609 patients) versus docetaxel (247 [43%] of 578 patients). One treatment-related death from a respiratory tract infection was reported in the docetaxel group. INTERPRETATION: To our knowledge, OAK is the first randomised phase 3 study to report results of a PD-L1-targeted therapy, with atezolizumab treatment resulting in a clinically relevant improvement of overall survival versus docetaxel in previously treated non-small-cell lung cancer, regardless of PD-L1 expression or histology, with a favourable safety profile. FUNDING: F. Hoffmann-La Roche Ltd, Genentech, Inc.

Atezolizumab in combination with bevacizumab enhances antigen-specific T-cell migration in metastatic renal cell carcinoma.

Anti-tumour immune activation by checkpoint inhibitors leads to durable responses in a variety of cancers, but combination approaches are required to extend this benefit beyond a subset of patients. In preclinical models tumour-derived VEGF limits immune cell activity while anti-VEGF augments intra-tumoral T-cell infiltration, potentially through vascular normalization and endothelial cell activation. This study investigates how VEGF blockade with bevacizumab could potentiate PD-L1 checkpoint inhibition with atezolizumab in mRCC. Tissue collections are before treatment, after bevacizumab and after the addition of atezolizumab. We discover that intra-tumoral CD8(+) T cells increase following combination treatment. A related increase is found in intra-tumoral MHC-I, Th1 and T-effector markers, and chemokines, most notably CX3CL1 (fractalkine). We also discover that the fractalkine receptor increases on peripheral CD8(+) T cells with treatment. Furthermore, trafficking lymphocyte increases are observed in tumors following bevacizumab and combination treatment. These data suggest that the anti-VEGF and anti-PD-L1 combination improves antigen-specific T-cell migration.

De-Risking Immunotherapy: Report of a Consensus Workshop of the Cancer Immunotherapy Consortium of the Cancer Research Institute.

With the recent FDA approvals of pembrolizumab and nivolumab, and a host of additional immunomodulatory agents entering clinical development each year, the field of cancer immunotherapy is changing rapidly. Strategies that can assist researchers in choosing the most promising drugs and drug combinations to move forward through clinical development are badly needed in order to reduce the likelihood of late-stage clinical trial failures. On October 5, 2014, the Cancer Immunotherapy Consortium of the Cancer Research Institute, a collaborative think tank composed of stakeholders from academia, industry, regulatory agencies, and patient interest groups, met to discuss strategies for de-risking immunotherapy development, with a focus on integrating preclinical and clinical studies, and conducting smarter early-phase trials, particularly for combination therapies. Several recommendations were made, including making better use of clinical data to inform preclinical research, obtaining adequate tissues for biomarker studies, and choosing appropriate clinical trial endpoints to identify promising drug candidates and combinations in nonrandomized early-phase trials.

Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial.

BACKGROUND: Outcomes are poor for patients with previously treated, advanced or metastatic non-small-cell lung cancer (NSCLC). The anti-programmed death ligand 1 (PD-L1) antibody atezolizumab is clinically active against cancer, including NSCLC, especially cancers expressing PD-L1 on tumour cells, tumour-infiltrating immune cells, or both. We assessed efficacy and safety of atezolizumab versus docetaxel in previously treated NSCLC, analysed by PD-L1 expression levels on tumour cells and tumour-infiltrating immune cells and in the intention-to-treat population. METHODS: In this open-label, phase 2 randomised controlled trial, patients with NSCLC who progressed on post-platinum chemotherapy were recruited in 61 academic medical centres and community oncology practices across 13 countries in Europe and North America. Key inclusion criteria were Eastern Cooperative Oncology Group performance status 0 or 1, measurable disease by Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1), and adequate haematological and end-organ function. Patients were stratified by PD-L1 tumour-infiltrating immune cell status, histology, and previous lines of therapy, and randomly assigned (1:1) by permuted block randomisation (with a block size of four) using an interactive voice or web system to receive intravenous atezolizumab 1200 mg or docetaxel 75 mg/m(2) once every 3 weeks. Baseline PD-L1 expression was scored by immunohistochemistry in tumour cells (as percentage of PD-L1-expressing tumour cells TC3≥50%, TC2≥5% and <50%, TC1≥1% and <5%, and TC0<1%) and tumour-infiltrating immune cells (as percentage of tumour area: IC3≥10%, IC2≥5% and <10%, IC1≥1% and <5%, and IC0<1%). The primary endpoint was overall survival in the intention-to-treat population and PD-L1 subgroups at 173 deaths. Biomarkers were assessed in an exploratory analysis. We assessed safety in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01903993. FINDINGS: Patients were enrolled between Aug 5, 2013, and March 31, 2014. 144 patients were randomly allocated to the atezolizumab group, and 143 to the docetaxel group. 142 patients received at least one dose of atezolizumab and 135 received docetaxel. Overall survival in the intention-to-treat population was 12·6 months (95% CI 9·7-16·4) for atezolizumab versus 9·7 months (8·6-12·0) for docetaxel (hazard ratio [HR] 0·73 [95% CI 0·53-0·99]; p=0·04). Increasing improvement in overall survival was associated with increasing PD-L1 expression (TC3 or IC3 HR 0·49 [0·22-1·07; p=0·068], TC2/3 or IC2/3 HR 0·54 [0·33-0·89; p=0·014], TC1/2/3 or IC1/2/3 HR 0·59 [0·40-0·85; p=0·005], TC0 and IC0 HR 1·04 [0·62-1·75; p=0·871]). In our exploratory analysis, patients with pre-existing immunity, defined by high T-effector-interferon-γ-associated gene expression, had improved overall survival with atezolizumab. 11 (8%) patients in the atezolizumab group discontinued because of adverse events versus 30 (22%) patients in the docetaxel group. 16 (11%) patients in the atezolizumab group versus 52 (39%) patients in the docetaxel group had treatment-related grade 3-4 adverse events, and one (<1%) patient in the atezolizumab group versus three (2%) patients in the docetaxel group died from a treatment-related adverse event. INTERPRETATION: Atezolizumab significantly improved survival compared with docetaxel in patients with previously treated NSCLC. Improvement correlated with PD-L1 immunohistochemistry expression on tumour cells and tumour-infiltrating immune cells, suggesting that PD-L1 expression is predictive for atezolizumab benefit. Atezolizumab was well tolerated, with a safety profile distinct from chemotherapy. FUNDING: F Hoffmann-La Roche/Genentech Inc.