Currently, there are no standard therapy options for patients with treatment-refractory metastatic squamous cell carcinoma of the anal canal (SCCA), but early results of a multiinstitutional clinical trial (No. NCI9673) led by researchers at The University of Texas MD Anderson Cancer Center show that the immunotherapy drug nivolumab may be effective against the disease.
“Although a rare malignancy, SCCA is on the rise and has a strong association with the human papillomavirus (HPV) and impaired immune function,” said Cathy Eng, M.D., a professor in the Department of Gastrointestinal Medical Oncology and the national trial’s principal investigator. She added that anal cancer rates increase 2%–3% each year.
About 20% of the more than 8,000 patients diagnosed with SCCA each year in the United States present with metastatic disease. Additionally, 20% of patients who have early-stage SCCA will later develop metastatic disease. Metastatic SCCA is typically treated with platinum-based chemotherapy; however, such regimens have not been fully evaluated in clinical trials for patients with metastatic SCCA, and there is no established standard of care for refractory metastatic disease.
Nivolumab is a monoclonal antibody that blocks the programmed cell death protein 1 (PD-1) by binding to the PD-1 ligand (PD-L1). PD-1 is an immune checkpoint that shuts down T lymphocyte attacks when activated by PD-L1. HPV-related anal cancer tumors have proteins produced by the virus, so nivolumab could help the immune system recognize and attack anal tumor cells infected with HPV.
The ongoing phase II clinical trial is the first study to evaluate the efficacy of nivolumab in the treatment of refractory metastatic SCCA. Dr. Eng said that the trial, which completed enrollment after only 5 months, addresses an unmet need for treatment.
Patients in the trial, all of whom have previously undergone at least one treatment for metastatic SCCA, receive nivolumab intravenously every 2 weeks until they experience disease progression or unacceptable toxic effects.
It was important to researchers that the patient population be representative of those whom SCCA typically affects, so HIV-positive patients were eligible provided that their CD4-positive T lymphocyte count was at least 300/μL. “Since HIV predisposes patients to compromised immune systems, it is a well-defined risk factor for anal cancer,” said Van Morris, M.D., an assistant professor in the Department of Gastrointestinal Medical Oncology. Two HIV-positive patients were enrolled in the trial, making it the first completed trial of a PD-1 or PD-L1 inhibitor to include HIV-positive patients.
In an exploratory correlative study of tumor biopsy samples taken from nine patients before and during nivolumab treatment, pretreatment tumor samples from the five patients whose disease responded to nivolumab showed significantly higher percentages of CD3-positive and CD8- positive T lymphocytes compared with pretreatment samples from patients whose disease did not respond. Pretreatment tumor samples from the patients whose disease responded to nivolumab also had higher frequencies of CD8-positive T lymphocytes expressing PD-1 and CD45-positive immune cells expressing PD-L1 compared with pretreatment samples from patients whose disease did not respond. These exploratory findings, presented at the American Association for Cancer Research’s annual meeting in April, pointed to correlations between immunological biomarkers and responses to nivolumab treatment.
Clinical results for the trial were reported at the American Society of Clinical Oncology’s annual meeting in June. Of 37 patients evaluable for response, two had a complete response, seven had a partial response, and 17 had stable disease. These numbers add up to a 70% control rate and a 24% overall response rate. The median progression-free survival duration was 3.9 months.
No grade 4 toxic effects were observed among the patients treated with nivolumab; however, five occurrences of grade 3 fatigue, anemia, rash, and hypothyroidism were reported. Grade 1 or 2 fatigue, anemia, and rash also occurred. The HIV positive patients did not experience any additional toxic effects.
Six patients currently remain in the trial, three at MD Anderson and three at other participating institutions. The trial is being amended to enroll additional patients later this year. “Our findings represent an exciting step forward for patients with no standard of care,” Dr. Eng said. “We now plan to extend our research further by looking at combined immunotherapy agents.”
For more information, contact Dr. Cathy Eng at 713-792-2828 or Dr. Van Morris at 713-745-8466. Laura Sussman contributed to this article.
OncoLog, September 2016, Volume 61, Number 9