Phase II trial of atezolizumab and bevacizumab for treatment of HPV-positive unresectable or metastatic squamous cell carcinoma of the anal canal.

Background: Anti-PD-(L)1 antibodies are associated with responses in <25% of patients with metastatic human papillomavirus (HPV)-associated malignancies. VEGF signaling causes intratumoral immune evasion and immune suppression. We evaluated the anti-PD-L1 antibody atezolizumab and anti-VEGF antibody bevacizumab for patients with unresectable, advanced anal cancer.

Patients And Methods: For this phase II study, participants with previously treated, immunotherapy-naïve anal cancer received atezolizumab (1200 mg) and bevacizumab (15 mg/kg) intravenously every 21 days. Responses were evaluated every 9 weeks (RECIST v1.1). The primary endpoint was best radiographic response. Median survival was estimated by Kaplan-Meier and compared for selected biomarkers (including paired pretreatment/on-treatment biopsies) using a log-rank test.

Results: Among 20 participants, the overall response rate was 11% (95% confidence interval (CI): 1.2-32). Median PFS and OS were 4.1 months (95% CI: 2.6-not assessable) and 11.6 months (95% CI, 9.5-20), respectively. One grade 5 bevacizumab-related bowel perforation occurred. Analyses of 16 paired biopsies linked increases in interferon gamma (P=.03) and inflammatory response (P =.02) gene expression signatures with prolonged PFS, as did rises in CD3+CD8+PD1+ (P=.02) cells and decreases in CD3+FoxP3+ cells (P=.04) from 10 paired biopsies with multiplex immunoflorescence. A subgroup of anal cancers characterized by the SBS31 "prior-platinum" signature demonstrated shorter OS (HR 6.3, 95% CI 1.2-32; P=.01).

Conclusions: Atezolizumab and bevacizumab demonstrate activity similar to anti-PD-1 monotherapy for unresectable anal cancer. Our translational data identify undescribed chromosomal and transcriptomic biomarkers associated with survival. These correlative findings warrant confirmation and further validation in larger, prospective immunotherapy trials for advanced anal cancer.