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

• Published in: Clinical cancer research Vol. 25; no. 20; pp. 6061 - 6072
• Main Authors: Hamid, Omid, Molinero, Luciana, Bolen, Christopher R, Sosman, Jeffrey A, Muñoz-Couselo, Eva, Kluger, Harriet M, McDermott, David F, Powderly, John D, Sarkar, Indrani, Ballinger, Marcus, Fassò, Marcella, O'Hear, Carol, Chen, Daniel S, Hegde, Priti S, Hodi, F Stephen
• Format: Journal Article
• Language: English
• Published: United States 15.10.2019
• Subjects: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized - administration & dosage; Antibodies, Monoclonal, Humanized - adverse effects; Antineoplastic Agents, Immunological - administration & dosage; Antineoplastic Agents, Immunological - adverse effects; B7-H1 Antigen - analysis; B7-H1 Antigen - antagonists & inhibitors; B7-H1 Antigen - immunology; Biomarkers, Tumor - analysis; Biomarkers, Tumor - immunology; Fatigue - chemically induced; Fatigue - diagnosis; Female; Fever - chemically induced; Fever - diagnosis; Follow-Up Studies; Humans; Male; Melanoma - drug therapy; Melanoma - immunology; Melanoma - mortality; Melanoma - secondary; Middle Aged; Prognosis; Progression-Free Survival; Pruritus - chemically induced; Pruritus - diagnosis; Retrospective Studies; Severity of Illness Index; Skin - immunology; Skin - pathology; Skin Neoplasms - drug therapy; Skin Neoplasms - immunology; Skin Neoplasms - mortality; Skin Neoplasms - pathology; T-Lymphocytes, Cytotoxic - immunology; Transcriptome; Young Adult
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-18-3488

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 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. 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. 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.