Nivolumab for previously treated unresectable metastatic anal cancer (NCI9673): a multicentre, single-arm, phase 2 study

Abstract

Summary Background Squamous cell carcinoma of the anal canal (SCCA) is a rare malignancy associated with infection by human papillomavirus (HPV). No consensus treatment approach exists for the treatment of metastatic disease. Because intratumoral HPV oncoproteins upregulate immune checkpoint proteins such as PD-1 to evade immune-mediated cytotoxicity, we did a trial of the anti-PD-1 antibody nivolumab for patients with metastatic SCCA. Methods We did this single-arm, multicentre, phase 2 trial at ten academic centres in the USA. We enrolled patients with treatment-refractory metastatic SCCA, who were given nivolumab every 2 weeks (3 mg/kg). The primary endpoint was response according to Response Evaluation Criteria in Solid Tumors, version 1.1, in the intention-to-treat population. At the time of data cutoff, the study was ongoing, with patients continuing to receive treatment. The study is registered with ClinicalTrials.gov, number NCT02314169. Findings We screened 39 patients, of whom 37 were enrolled and received at least one dose of nivolumab. Among the 37 patients, nine (24% [95% CI 15–33]) had responses. There were two complete responses and seven partial responses. Grade 3 adverse events were anaemia (n=2), fatigue (n=1), rash (n=1), and hypothyroidism (n=1). No serious adverse events were reported. Interpretation To our knowledge, this is the first completed phase 2 trial of immunotherapy for SCCA. Nivolumab is well tolerated and effective as a monotherapy for patients with metastatic SCCA. Immune checkpoint blockade appears to be a promising approach for patients with this orphan disease. Funding National Cancer Institute/Cancer Therapy Evaluation Program, the HPV and Anal Cancer Foundation, the E B Anal Cancer Fund, The University of Texas MD Anderson Moon Shots Program, and an anonymous philanthropic donor.

High IDO1 Expression Is Associated with Poor Outcome in Patients with Anal Cancer Treated with Definitive Chemoradiotherapy

“…Ultimately, in describing the tumor microenvironment, we hoped to gain insight into potential avenues for therapeutic intervention that may improve outcomes for the subset of patients who are not cured by upfront chemoradiation. A phase II study of nivolumab in metastatic ASCC showed a 24% response rate to anti‐PD‐1‐directed therapy, which serves as proof of principle that immunotherapy can have an important role in this disease . Responders were found to have higher CD8, PD‐1, and PD‐L1 levels.…”

Immunologic Biomarkers and Biomarkers for Immunotherapies in Gastrointestinal Cancer

“…One phase II study investigated nivolumab in metastasized anal cancer and showed a response in 24% of patients. The response was dependent on PD-L1 expression [58]. Disappointing results came from investigations which aimed to introduce immuno-oncological approaches to the treatment of pancreatic cancer [59].…”

Immunotherapy of Colorectal and Anal Carcinoma

“…V jednoramenné klinické studii fáze II byl testován nivolumab u pa cientů s metastatickým análním karcinomem, kteří byli refrakterní na běžnou systémovou chemoterapii. Do studie bylo zařazeno 37 pa cientů a byly zaznamenány 2 CR a 7 PR -ORR 24 % (95% CI 15-33) [12]. Podobně příz-nivé výsledky byly zaznamenány ve studii KEYNOTE-028 s pembrolizumabem, kdy u obdobné skupiny pa cientů se spinocelulárním karcinomem anu byl ORR 17 % (95% CI 5-37), kontroly onemocnění bylo dosaženo u 58 % [13].…”