Encouraging Phase 2 Trial Data Seen With Immunotherapy in Metastatic Anal Cancer

Opdivo (nivolumab) showed promising results in the first prospective study investigating investigate the use of immunotherapy in patients with squamous cell carcinoma of the anal canal (SCCA). The findings were presented at the European Society for Medical Oncology 18th World Congress on Gastrointestinal Cancer, a gathering of oncologists and oncology professionals in Barcelona, Spain, from June 29 to July 2, 2016.

The trial met the primary endpoint of objective response rate (ORR). Patients with metastatic SCCA (37 patients) showed a 24.3 percent ORR following Opdivo that included two complete responses and seven partial responses. Stable disease was achieved by 17 patients, and eight 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 percent per year,” noted lead author Cathy Eng, 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 8,000 people will be diagnosed with anal cancer in the United States in 2016 and more than 1,000 people will die from the disease.

"About 20 percent of patients present with metastatic SCCA, and there is currently no established chemotherapy regimen for metastatic patients, where the five-year overall survival is just 31 percent," 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 percent to 95 percent 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 2 study enrolling patients that had received prior treatment but who were immunotherapy naïve. The study closed within five 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 Opdivo at 3 mg/kg IV every two 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 six weeks. Patients had received a median of two prior treatments (range: one to eight) and two 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 five months in treatment-naive patients receiving cytotoxic chemotherapy."

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

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.

Opdivo was well tolerated. Grade 3 toxicities occurred in just five patients; two 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 two pneumonitis.

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