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

Abstract

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.

Results: 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.

Conflict of interest statement

Declaration of interests

PSi has received fees from Bayer Pharmaceuticals and personal fees from Merrimack Pharma. EC has received grants from National Cancer Institute to her institution, and personal fees for advisory boards from Advaxis, Lilly, Merrimack, Bayer, Taiho, and Amgen. MP has received grants from the National Cancer Institute/Cancer Therapy Evaluation Program. KB has received personal fees from Guardant Health. RL has received personal fees from Guardant Health. JA owns stock in, and has acted as a consultant or on advisory boards for, Jounce, Kite Pharma, Evelo, Constellation, Bristol-Myers Squibb, GlaxoSmithKline, AstraZeneca, Amgen, and Neon. PSh owns stock in, and has acted as a consultant for, Jounce, Kite Pharma, Neon, Bristol-Myers Squibb, GlaskoSmithKline, AstraZeneca, Amgen, Constellation, Evelo. CE has received grants from Daiichi and Keryx, and personal fees from Bayer, Sirtex, Genentech, Roche/Genentech, and Bayer. VKM, MES, HN, SI, KC, BP, DD, JLW, LX, TB-S, LV, JB, AM, WCF, CO, GB, AO, JR, AM, RAW, and HS declare no completing interests.

Copyright © 2017 Elsevier Ltd. All rights reserved.

Figures

Figure 1. Tumour response in 34 assessable patients

(A) Waterfall plot. (B) Duration of response. The dotted line represents RECIST 1.1 markers of disease progression. Three patients who received only one dose of nivolumab were not assessed.

Figure 2

Progression-free survival (A) and overall survival (B)

Figure 3. Immune profiling comparing expression of various biomarkers in pretreatment biopsies between responders and non-responders

Assessed by immunohistochemistry (A–D) and flow cytometry (E–H). The bars are means (SDs).