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Clinical Trial
. 2025 May 1;31(9):1657-1666.
doi: 10.1158/1078-0432.CCR-24-1512.

Phase II Trial of Atezolizumab and Bevacizumab for Treatment of HPV-Positive Unresectable or Metastatic Squamous Cell Carcinoma of the Anal Canal

Van K Morris  1 , Suyu Liu  2 , Kangyu Lin  1 , Haifeng Zhu  3 , Seema Prasad  1 , Armeen Mahvash  4 , Priya Bhosale  4 , Baohua Sun  5 , Edwin R Parra  5 , Ignacio Wistuba  5 , Arjun Peddireddy  6 , James Yao  1 , Julia Mendoza-Perez  5 , Mark Knafl  3 , Scott E Woodman  3 , Cathy Eng  7 , Daniel Halperin  1
Affiliations
Clinical Trial

Phase II Trial of Atezolizumab and Bevacizumab for Treatment of HPV-Positive Unresectable or Metastatic Squamous Cell Carcinoma of the Anal Canal

Van K Morris et al. Clin Cancer Res. .

Abstract

Purpose: Anti-PD-L1 antibodies are associated with responses in <25% of patients with metastatic human papillomavirus-associated malignancies. VEGF signaling causes immune evasion and immune suppression within the tumor. 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 (1,200 mg) and bevacizumab (15 mg/kg) intravenously every 21 days. Responses were evaluated every 9 weeks (RECIST version 1.1). The primary endpoint was the best radiographic response. Median survival was estimated by Kaplan-Meier and compared for selected biomarkers (including paired pre- and 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 progression-free survival and overall survival 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 IFN-γ (P = 0.03) and inflammatory response (P = 0.02) gene expression signatures with prolonged progression-free survival, as did increases in CD3+CD8+PD1+ (P = 0.02) cells and decreases in CD3+FoxP3+ cells (P = 0.04) from 10 paired biopsies with multiplex immunofluorescence. A subgroup of anal cancers characterized by the SBS31 "prior-platinum" signature demonstrated shorter median overall survival (HR, 6.3; 95% CI, 1.2-32; P = 0.01).

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

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Conflict of interest statement

V.K. Morris reports other support from Genentech during the conduct of the study as well as other support from Bristol Myers Squibb, Pfizer, Novartis, BioNTech, Sumitomo, Redx Pharma, Regeneron, and Scandion Oncology outside the submitted work. A. Mahvash reports grants and personal fees from Sirtex Medical and grants from Boston Scientific and Siemens outside the submitted work. I. Wistuba reports grants and personal fees from Genentech/Roche, Bayer, Bristol Myers Squibb, AstraZeneca, Pfizer, Merck, Novartis, Amgen, and Johnson and Johnson; personal fees from Guardant Health, Flame, Sanofi, Daiichi Sankyo, Jansen, Merus, G1 Therapeutics, AbbVie, Catalyst Therapeutics, Boehringer Ingelheim, Regeneron, Oncocyte, Medscape, and Platform Health; grants from Medimmune, Adaptimmune, EMD Serono, Takeda, Karus, Iovance, 4D, and Akoya outside the submitted work. J. Yao reports grants from Genentech during the conduct of the study as well as personal fees from HUTCHMED, Exelixis, TaiRx, and Sanofi outside the submitted work. S.E. Woodman reports other support from Genentech/Roche during the conduct of the study. D. Halperin reports grants from Genentech during the conduct of the study as well as grants and personal fees from Novartis, ITM, and Camurus; grants from Rayzebio; and personal fees from Exelixis, Chimeric Therapeutics, Crinetics, Lantheus, Harpoon Therapeutics, RadioMedix, and Amryt outside the submitted work. No disclosures were reported by the other authors.

Figures

Figure 1.
Figure 1.
Consort diagram (A), waterfall plot (B), spider plot (C), PFS (D), swimmer’s plot (E), and OS (F) for atezolizumab and bevacizumab.
Figure 2.
Figure 2.
Volcano plots for changes in gene expression according to PFS (A) and OS (B) and changes in normalized enrichment scores (NES) for Hallmark signatures and immune cell signatures for gene expression according to higher PFS (C and D) and OS (E and F) following treatment with atezolizumab and bevacizumab for metastatic anal cancer.
Figure 3.
Figure 3.
mIF visualization of CD3+CD8+ cells increases from pretreatment (A) to on-treatment (B) biopsies in a tumor responding to treatment, consistent with favorable PFS for tumors with higher CD3+CD8+PD1+ expression (C). Decreases from pretreatment (D) to on-treatment (E) tumor biopsies in a tumor responding to treatment, corresponding to improved PFS for lower expression of CD3+FoxP3+ cells (F).
Figure 4.
Figure 4.
Most commonly mutated genes (A) and chromosome alterations (B) for study participants; unsupervised clustering according to SBS signatures (C) reveals SBS31 as unique to cluster 2 (D) and OS (E) according to SBS31 signature.
See this image and copyright information in PMC

References

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