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Background: Programmed death-ligand 1 (PD-L1) protein is expressed in various cancers, including small-cell lung cancer (SCLC). Atezolizumab inhibits PD-L1 signaling, thus restoring tumor-specific T-cell immunity. Here, we report results from the first-in-human phase 1 PCD4989g study (NCT01375842) of atezolizumab, in a cohort of patients with relapsed/refractory SCLC., Patients and Methods: Eligible patients with incurable or metastatic SCLC, which was advanced or recurrent since the last antitumor therapy, received atezolizumab 15 mg/kg or 1200 mg intravenously every 3 weeks for 16 cycles or until loss of clinical benefit. The primary endpoint was safety. Efficacy and biomarkers of antitumor activity were also assessed., Results: Seventeen patients were enrolled. Any-grade and grade ≥3 treatment-related adverse events (TRAEs) occurred in 11 (64.7%) and 5 (29.4%) patients, respectively. The most common any-grade TRAE was fatigue (4 patients [23.5%]). Partial response to atezolizumab was achieved in 1 patient (5.9%) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1), and 3 (17.6%) per immune-related response criteria (irRC). Durations of response were 2.8 to > 45.7 months. Median investigator-assessed progression-free survival (PFS) per RECIST v1.1 and irRC was 1.5 (95% confidence interval [CI], 1.2-2.7) and 2.9 (95% CI, 1.2-6.1) months, respectively. Median overall survival (OS) was 5.9 months (95% CI, 4.3-12.6). Patients with high (≥ median expression) T-effector gene signature and PD-L1 mRNA expression appeared to show a trend toward improved PFS (per irRC) and OS., Conclusion: Atezolizumab was generally well tolerated and exhibited antitumor activity in a small cohort of patients with relapsed/refractory SCLC., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Metastatic TNBC (mTNBC) has a poor prognosis and few treatment options. The anti-PD-L1 antibody atezolizumab demonstrated clinical activity in mTNBC patients with PD-L1-positive tumor-infiltrating immune cells. The current study describes the tumor immune microenvironment (TiME) and genomic evolution across sequential therapies in a patient with a 31-year history of TNBC and a complete response (CR) to atezolizumab monotherapy., Materials and Methods: In 1986, the patient had surgery and radiotherapy (XRT) for newly diagnosed TNBC, followed by surgery and adjuvant chemotherapy for two locoregional recurrences. She developed mTNBC in 2009 and was sequentially treated with capecitabine, gemcitabine-carboplatin-iniparib (GCI), XRT and an experimental vaccine. She experienced disease progression (PD) to all these therapies. In 2013, she had a PD-L1 positive tumor and enrolled in a phase 1 atezolizumab monotherapy study (PCD4989g; NCT01375842). She received atezolizumab for 1 year with initial pseudo-progression followed by a partial response. After 1 year without treatment she experienced PD, reinitiated atezolizumab and subsequently achieved CR. Tumor specimens were collected at numerous times between 2008 and 2015 and assessed by immunohistochemistry, RNA-seq and DNA-seq., Results: TiME biomarkers, including CD8, ICs and PD-L1 on IC, increased after capecitabine and remained high after GCI, XRT and through pseudo-progression on atezolizumab. At PD post-atezolizumab exposure, TiME biomarkers decreased but PD-L1 status remained positive. Immune-related RNA signatures confirmed these findings. TNBC subtyping revealed evolution from luminal androgen receptor (LAR) to basal-like immune activated (BLIA). Genomic profiling showed truncal alterations in RB1 and TP53, while the presence of other genomic alterations varied over time. Tumor mutational burden peaked after XRT and declined after atezolizumab exposure., Conclusions: This case report describes the evolution of TiME and TNBC molecular subtypes/genomics over time with sequential therapies in a TNBC patient with a CR to atezolizumab monotherapy. These data suggest the TiME is pliable and may be manipulated to maximize response to immunotherapy (NCT01375842, https://clinicaltrials.gov/ct2/show/NCT01375842?term=NCT01375842&rank=1 ).

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., (©2019 American Association for Cancer Research.)

Importance: Atezolizumab (anti-programmed cell death ligand 1 [PD-L1]) is well tolerated and clinically active in multiple cancer types. Its safety and clinical activity in metastatic triple-negative breast cancer (mTNBC) has not been reported., Objective: To evaluate the safety, clinical activity, and biomarkers associated with the use of single-agent atezolizumab in patients with mTNBC., Design, Setting, and Participants: Women with mTNBC (defined by investigator assessment) were enrolled between January 2013 and February 2016 in a multicohort open-label, phase 1 study at US and European academic medical centers. Median follow-up was 25.3 months (range, 0.4-45.6 months). Eligible patients regardless of line of therapy had measurable disease by Response Evaluation Criteria in Solid Tumors, version 1.1; Eastern Cooperative Oncology Group performance status of 0 to 1; and a representative tumor sample for assessment of immune cell (IC) PD-L1 expression., Interventions: Atezolizumab was given intravenously every 3 weeks until unacceptable toxic effects or loss of clinical benefit., Main Outcomes and Measures: Primary outcome was safety and tolerability. Activity and exploratory outcomes included objective response rate (ORR), duration of response, progression-free survival (PFS), and overall survival (OS). Outcomes were assessed in all patients and in key patient subgroups., Results: Among 116 evaluable patients (median age, 53 years [range, 29-82 years]), treatment-related adverse events occurred in 73 (63%); 58 (79%) were grade 1 to 2. Most adverse events occurred within the first treatment year. The ORRs were numerically higher in first-line (5 of 21 [24%]) than in second-line or greater patients (6 of 94 [6%]). Median duration of response was 21 months (range, 3 to ≥38 months). Median PFS was 1.4 (95% CI, 1.3-1.6) months by RECIST and 1.9 (95% CI, 1.4-2.5) months by irRC. In first-line patients, median OS was 17.6 months (95% CI, 10.2 months to not estimable). Patients with PD-L1 expression of at least 1% tumor-infiltrating ICs had higher ORRs and longer OS (12% [11 of 91]; 10.1 [95% CI, 7.0-13.8] months, respectively) than those with less than 1% ICs (0 of 21; 6.0 [95% CI, 2.6-12.6] months, respectively). High levels of ICs (>10%) were independently associated with higher ORRs and longer OS., Conclusions and Relevance: Single-agent atezolizumab was well tolerated and provided durable clinical benefit in patients with mTNBC with stable or responding disease and in earlier lines of treatment., Trial Registration: ClinicalTrials.gov identifier: NCT01375842.