Long-term Clinical Outcomes and Biomarker Analyses of Atezolizumab Therapy for Patients With Metastatic Triple-Negative Breast Cancer: A Phase 1 Study

Abstract

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.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Emens has received research support from Roche/Genentech, Corvus, AstraZeneca, and EMD Serono; research grants from Aduro Biotech, Merck, Maxcyte, and the Breast Cancer Research Foundation; advisory board honoraria from Medimmune, AstraZeneca, Celgene, Vaccinex, Peregrine, Bayer, Gritstone, Abbvie, Replimune, Roche-Genentech, Bristol-Myers Squibb, Syndax, and Amgen; other financial support for advisory boards from eTHeRNA and Molecuvax; royalties from Aduro Biotech; and stock options from Molecuvax. Dr Emens was also a member of the US Food and Drug Administration Advisory Committee on Tissue, Cell, and Gene Therapies; and is currently on the Board of Directors for the Society of Immunotherapy of Cancer, and chair of a Data and Safety Monitoring Board for Syndax. Dr Braiteh has received speaking and consulting fees from Amgen, AstraZeneca/Medimmune, Biotheranostics, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Clovis, Eli Lilly, Incyte, Ipsen, Insys, Merck, Merrimack, Pfizer, and Roche/Genentech; advisory board honoraria from Amgen, AstraZeneca/Medimmune, Bayer, Biotheranostics, Boehringer Ingelheim, Clovis, Eli Lilly, Heron Therapeutics, Incyte, Ipsen, Insys, Lexicon, Merck, Merrimack, Pfizer, and Roche/Genentech; and travel support from Amgen, AstraZeneca/Medimmune, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Halozyme Therapeutics, Heron Therapeutics, Incyte, Ipsen, Insys, Merck, Merrimack, Pfizer, and Roche/Genentech. Dr Tolaney has received research funding from Roche/Genentech; research funding/consulting fees from Eli Lilly, Novartis, AstraZeneca, Merck, Pfizer, Nektar, Nanostring, and Eisai; and grant support from Exelixis. Dr Nanda has received research funding from Celgene, Corcept, and Merck; and advisory board honoraria from AstraZeneca, Celgene, Roche/Genentech, Merck, Novartis, Pfizer, Syndax, and Puma. She also reports DSMB participation for G1 Therapeutics. Dr Cassier has received grants from Novartis, AstraZeneca, Bristol-Myers Squib, and MSD; personal fees from Novartis, Amgen, and AstraZeneca; and nonfinancial support from Plexxikon, AstraZeneca, and MSD. Dr Gordon has received research funding from AbbVie, Amgen, Array BioPharma, Calithera Biosciences, Celldex, Deciphera, Endocyte, ESSA Pharma, Gilead Sciences, GlaxoSmithKline, Incyte, Lilly, Lilly/ImClone, MedImmune, Merck Serono, Millennium, OncoMed, Pfizer, Plexxikon, Roche/Genentech, Seattle Genetics, Tokai Pharmaceuticals, and TRACON Pharma; and consulting or advisory honoraria from Castle Biosciences, Deciphera, and RedHill Biopharma. Dr ElGabry is a Roche employee. Dr Chang, Ms Sarkar, and Drs Grossman, O’Hear, Fassò, and Molinero are Genentech employees. Drs O’Hear and Molinero are holders of Roche stock. Dr Schmid’s spouse is an employee of Roche/Genentech. Dr Schmid has received honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Celgene, Eisai, Novartis, Pfizer, Puma, and Roche/Genentech. His institution has received research funding or grants from Astellas, AstraZeneca, Medivation, Novartis, Oncogenex, and Roche/Genentech. No other disclosures are reported.

Figures

Figure 1.. Study Flowchart

Flowchart shows enrolled and treated patients from the triple-negative breast cancer cohort of the PCD4989g study. Patients in this cohort were enrolled in the United States, United Kingdom, France, and Spain. Population definitions are depicted, including reasons for discontinuation, and noninclusion into efficacy analysis. Baseline programmed cell death ligand 1 (PD-L1) expression on tumor-infiltrating immune cells was evaluated with 4 scoring bins: IC3 (≥10%), IC2 (≥5% and

Figure 2.. Disease Burden Over Time and Overall Survival by Response

Change in tumor burden over time in all response-evaluable patients with triple-negative breast cancer receiving atezolizumab. Tumor burden was measured as the sum of the longest diameters. Confirmed investigator-assessed Response Evaluation Criteria in Solid Tumors responses are included for patients with postbaseline tumor measurements.

Figure 3.. Duration of Treatment and Response in Patients With Triple-Negative Breast Cancer Treated With Atezolizumab

Time on treatment is plotted for patients with confirmed investigator-assessed Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST), and immune-related response criteria (irRC) responses. Baseline programmed cell death ligand 1 expression on tumor-infiltrating immune cells was evaluated with 4 scoring bins: IC3 (≥10%), IC2 (≥5% and aNo death or PD status. bPatient is deceased. cAtezolizumab had been withdrawn from this patient owing to grade 3 dementia unrelated to the study treatment; the patient had died by follow-up.

Figure 4.. Measures of Clinical Efficacy

A, Kaplan-Meier curves depict the overall survival (OS) by line of treatment. B, Kaplan-Meier curves depict the OS by programmed cell death ligand 1 (PD-L1) expression on tumor-infiltrating immune cells (ICs). C, Kaplan-Meier curves depict the OS by level of ICs greater than 10%. Log-rank (Mantel-Cox) P value is exploratory. Baseline PD-L1 expression on ICs was assessed as less than 1% (IC0) or at least 1% (IC1/2/3). Two- and 3-year landmark OS rates for patients in the IC0 subgroup were not evaluable (NE). 1L indicates first line; 2L+, second line and beyond; HR, hazard ratio.