BARCELONA, Spain-There is no standard of care for patients with refractory metastatic squamous cell carcinoma of the anus (SCCA), but the anti PD-1 antibody nivolumab may have a role.
A phase II multi-institutional trial of single-agent nivolumab in SCCA (NCI9673) showed an objective response rate of 26.5 percent (9/34 evaluable patients), and a median progression free survival of 3.9 months.
The trial's results were presented here at the recent European Society of Medical Oncology World Congress on Gastrointestinal Cancer by principal investigator Cathy Eng, MD, Professor in the Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston (Abstract O-022).
SCCA will develop in approximately 7,200 patients in the U.S. and 27,000 worldwide, 20 percent of whom will develop metastatic disease, according to Eng. The 2016 National Comprehensive Cancer Network guidelines list only a recommendation for 5-FU/cisplatin with or without radiotherapy for metastatic anal cancer, but no other regimens have been found to be effective.
Immunotherapy may be relevant in this disease because more than 90 percent of metastatic SCCA is associated with human papillomavirus (HPV) carcinogenesis, and others have reported 80-95 percent of cases are linked to HPV.
"The role of HPV in tumorigenesis of SCCA provides a rationale for the use of immune a checkpoint blockade agent as a novel therapy for treatment of patients with a virally driven disease, and nivolumab promotes immune-mediated anti-tumor activity of T cells against HPV-positive cells in vitro," Eng said.
Circulating Cell-Free DNA Not Correlative
The trial was somewhat disappointing in that assays of circulating cell-free DNA (cfDNA) using the Guardant360 70-gene panel showed had no predictive correlation for responders versus non-responders, and no prognostic correlation, as researchers had hypothesized.
There is a strong rationale for testing cfDNA, Eng said, as a non-invasive approach to mutation analysis and real time capture of underlying tumor biology. Also, optimal evaluation of available blood correlates from outside sites can be done with a minimum of 2.5-3.0cc of plasma.
In this trial, among 30 plasma samples analyzed pretreatment, the incidence of p53 was 46 percent (12 patients), PIK3A with E545K mutation was in 19 percent (5 patients), and PIK3CA amplified was seen in 12 percent (3 patients)
"There was no predictive correlation for responders versus non responders, and no prognostic correlation with cfDNA," Eng reported.
PD-1 expression was not required for patients in this trial of a PD-1 inhibitor. Patients had ECOG Performance Scores of 0 or 1; median age was 56 years; three-quarters female.
"These were heavily pretreated patients with at least one prior therapy for metastatic disease, but no prior immunotherapies, and no chromic steroid use," Eng said.
Two patients were HIV-positive patients, and the trial also enrolled patient with Hepatitis B and C, but none with active autoimmune disease.
Response, Adverse Events
Among 39 patients enrolled, 37 were evaluable for toxicity and intent to treat and 34 were evaluable for response. Patients were treated with nivolumab 3 mg/kg IV every 2 weeks until progression or discontinuation.
There were two complete responses (CR) and seven partial responses (PR) among 34 patients evaluable for response, for an objective response rate of 26.5 percent. That rate included two patients achieving CR (5.4%), seven with PR (18.9%), stable disease in 17 (45.9%), progressive disease in eight (21.6%), and three patients were not unevaluable (8.1%).
Eng said nivolumab was well tolerated. The most common grade-3 toxicities were fatigue, rash, and hypothyroidism (1 patient each), and anemia (2 patients). There were no grade-4 toxicities reported.
"And there was no additional unexpected adverse event seen I the HIV-positive patients," she said.
Future Directions
"Continued clinical trial enrollment is crucial in the hope of obtaining an FDA indication for this 'rare' cancer," Eng said, listing ongoing clinical trials:
* Treatment naive patients: InterAACT/ECOG EA#2133, a randomized phase II study of cytotoxic chemotherapy (NCT02051868), from the International Rare Cancers Initiative (IRCI);
* Refractory disease: ADXS11-011, using live listeria vaccine with the fusion protein of HPV16/E7; and also "Amendment of NCI19673 in development (estimated for fall 2016);
* HIV-positive patients: HIV Consortium phase I study (NCT02408861).
Eng noted the trial accrued the required number of patients in less than 6 months. "Rapid enrollment in the trial Eng reported here was feasible via the ETCTN (NCI Experimental Therapeutics Clinical Trials Network)," she explained.
Eng acknowledged that the sample size of this trial was small," but it suggests there is a difference in the tumor immune microenvironment at baseline between responders versus non-responders."
Robert H. Carlson is a contributing writer.