Nivolumab shows promise in first-ever trial for
patients with refractory, metastatic anal cancer
June 5, 2016
In the first-ever clinical trial for metastatic patients previously treated for the disease, research led by The University of Texas MD Anderson Cancer Center found that the immune checkpoint blockade nivolumab shows promise for the majority of patients with squamous cell carcinoma of the anal canal (SCCA). The study also is the first to investigate the use of immunotherapy in this patient population. The prospective Phase II findings will be presented at the American Society of Clinical Oncology's annual meeting by Cathy Eng, M.D., professor of Gastrointestinal Medical Oncology at MD Anderson and the study's national principal investigator.
According to the American Cancer Society, 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 an additional 20 percent who had early-stage disease will later develop metastatic anal cancer, explained Eng.
"Although a rare malignancy, the incidence is on the rise and has a strong association with the HPV virus," said Eng, the study's senior author and co-leader of MD Anderson's HPV-related Cancer Moon Shot. "There are no standardized treatment options for metastatic anal cancer patients, so there's truly an unmet need in those whose disease has not responded to initial therapy."
Nivolumab unleashes an immune system attack on cancer by blocking activation of a protein called PD-1 on T cells, white blood cells that find and attack cells, viruses or bacteria that have specific targets. PD-1 acts as a brake, or checkpoint, to shut down activated T cells. PD-1 is turned on by a ligand called PD-L1, which often is found on cancer cells and other types of cells.
Conducted through the National Cancer Institute's (NCI) Experimental Therapeutic Clinical Trial Network and Cancer Therapy Evaluation Program, 39 patients enrolled in the trial, NCI9673, with 37 patients receiving treatment. MD Anderson enrolled 18 patients. All were previously treated; however, prior immunotherapy treatment was not allowed. PD-L1 expression was not required for participation. The study's primary endpoint was response rate, with overall and progression-free survival rates (OS and PFS, respectively) and toxicity as secondary endpoints.
The study closed within five months of opening because of the rapid accrual rate - underscoring the unmet need in this patient population.
Also of note, this is the first completed anti-PD1 study to include HIV-positive patients as well as patients with Hepatitis B or C. Two HIV-positive patients were enrolled in the trial.
"Immunosuppression is a known risk factor for this disease. Since HIV predisposes patients to compromised immune systems, it is a well-defined risk factor for anal cancer," said Van Morris, M.D., assistant professor of Gastrointestinal Medical Oncology at MD Anderson. "It was important to include a patient population that was representative of this disease."
All patients received nivolumab every two weeks. Of the 37 patients evaluable for response based on intent to treat, two patients (5 percent) had a complete response, seven (19 percent) had a partial response, and 17 (46 percent) had stable disease - a control rate of 70 percent. The median PFS was 3.9 months. Six patients remain on study. Common adverse events include: fatigue, anemia and rash; there was one incident of pneumonitis.
"Our findings represent an exciting step forward for patients with no standard of care. We now plan to expand the study further looking at combined immunotherapy agents," said Eng.
The researchers will also report on additional biomarkers samples later in June at the ESMO World Congress on Gastrointestinal Cancers. Preliminary correlative research was presented by MD Anderson researchers in April at AACR.
Objective Responses in Anal Carcinoma With PD-1 Inhibitor
25 August 2016
AASLD: Nivolumab in Patients With Advanced Hepatocellular Carcinoma: the CheckMate 040 Study- (11/16/16)
HIV STUDY STARTING - Nivolumab and Ipilimumab in Treating Patients With HIV Associated Solid Tumors That Are Metastatic or Cannot Be Removed by Surgery
Can immunotherapy cure HIV? - meeting at Fred Hutchinson Cancer Research Center last week - (08/10/16)
Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy - (08/10/16)
In the first-ever clinical trial for metastatic patients previously treated for the disease, research led by The University of Texas MD Anderson Cancer Center found that the immune checkpoint blockade nivolumab shows promise for the majority of patients with squamous cell carcinoma of the anal canal (SCCA)......Also of note, this is the first completed anti-PD1 study to include HIV-positive patients as well as patients with Hepatitis B or C. Two HIV-positive patients were enrolled in the trial........http://www.natap.org/2016/newsUpdates/060816_01.htm
Objective Responses in Anal Carcinoma With PD-1 Inhibitor......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.......http://journals.lww.com/oncology-times/pages/articleviewer.aspx?year=2016&issue=08250&article=00014&type=Fulltext
Carlson, Robert H.
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.
"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 naïve 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."