Promising Initial Trial of Immunotherapy Agent in Anal Cancer

Cathy Eng, MD

Cathy Eng, MD

A study of nivolumab (Opdivo) in patients with squamous cell carcinoma of the anal canal (SCCA), which recently presented findings at the 2016 World Congress on Gastrointestinal (GI) Cancer, is the first prospective trial to examine immunotherapy agents in the treatment of SCCA.

The trial met the primary endpoint of objective response rate (ORR). Patients with metastatic SCCA (N = 37) showed a 24.3% ORR following nivolumab that included 2 complete responses and 7 partial responses. Stable disease was achieved by 17 patients, and 8 patients experienced progressive disease. Three patients were unevaluable for response.

“Over 27,000 new cases of anal cancer are diagnosed annually worldwide, and the incidence has been increasing by about 3% per year,” noted lead author Cathy Eng, MD, professor of gastrointestinal medical oncology at the University of Texas MD Anderson Cancer Center and co-leader of MD Anderson's HPV-related Cancer Moon Shot.

The American Cancer Society estimates that more than 8000 people will be diagnosed with anal cancer in the United States in 2016 and more than 1000 people will die from the disease.

"About 20% of patients present with metastatic SCCA, and there is currently no established chemotherapy regimen for metastatic patients, where the 5-year overall survival is just 31%," Eng commented. “5-FU/cisplatin is recommended for metastatic disease, but no other regimens have been found to be effective. This is the first prospective trial to evaluate immunotherapy in this setting.”

Approximately 80% to 95% of cases are linked to human papillomavirus (HPV) infection, according to Eng who explained: "The role of HPV in the tumorigenesis of SCCA provides rationale for the use of immune checkpoint agents as a novel therapy for patients with a virally driven disease."

This was a Simon Optimal, two-stage phase II study enrolling patients that had received prior treatment but who were immunotherapy naïve. The study closed within 5 months of opening because of the rapid accrual rate, which, researchers note, underscores the unmet need in this population. Median age of participants in the trial was 56 years (range: 51-64). PD-L1 expression was not required for participation in the study.

Patients were treated with nivolumab at 3 mg/kg IV every 2 weeks. Optional pretreatment and on-treatment tissue biopsies were performed, plasma samples were collected for evaluation of immune biomarkers and HPV/p16 status, and diagnostic imaging was completed every 6 weeks. Patients had received a median of 2 prior treatments (range: 1-8) and 2 patients were HIV positive. Of the treated patients, 34 patients were evaluable for response.

Median progression-free survival, a secondary endpoint, was 3.9 months. “This result is not surprising, given that our data have shown a progression-free survival of about 5 months in treatment-naive patients receiving cytotoxic chemotherapy."

The investigators performed cell free DNA (cfDNA) analysis on 30 plasma samples taken prior to nivolumab treatment; 4 samples contained no DNA. Analysis of the remaining 26 samples showed that mutations p53 occurred at a frequency of 46%, PIK3CA at 19%, and PIK3CA amplification occurred at 12%.

However, “no predictive correlation for responders versus non-responders was noted with cfDNA, perhaps due to the sample size, but data suggest there is a difference in the tumor immune microenvironment at baseline in responders versus non-responders,” she said. Immunohistochemistry confirmed by flow cytometry showed a population of cells with increased expression at baseline of CD8, PD-1, and PD-L1 in responders versus non-responders.

Nivolumab was well tolerated. Grade 3 toxicities occurred in just 5 patients; 2 patients experienced anemia, and one patient each had grade 3 fatigue, rash, and hyperthyroidism. No unexpected serious adverse events were observed in patients with HIV. There was one incidence of grade 2 pneumonitis.

“These initial data support further investigation of immunotherapy in patients with squamous cell carcinoma of the anal canal,” Eng remarked.

Reference:

Morris V, Ciombor K, Salem M, et al. A multi-institutional phase II study of single agent nivolumab in previously treated metastatic squamous cell carcinoma of the anal canal (SCCA). Presented at: 2016 World Congress on GI Cancer; June 28 - July 2, 2016; Barcelona, Spain. Oral abstract 022.