Atlanta, GA—In a phase 2 “basket” clinical trial, the combination of ipilimumab (Yervoy), a CTLA-4 inhibitor, and nivolumab (Opdivo), a PD-1 inhibitor, led to tumor shrinkage in 44% of patients with rare, aggressive, extrapancreatic high-grade neuroendocrine tumors (NETs), and the responses were durable. No responses were seen in low-grade tumors. These results come from the Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors (DART) study, which was presented at the 2019 American Association for Cancer Research annual meeting, by Sandip P. Patel, MD, DART Clinical Study Chair, and Deputy Director, San Diego Center for Precision Immunotherapy, Moores Cancer Center, UC San Diego Health, La Jolla, CA.
“These early results are really encouraging and intriguing,” Dr Patel said. “We found a clear difference in response to treatment between the high-grade and low-grade forms of this cancer type, so tumor biology makes a difference. We don’t yet know why, but we have opened another treatment arm of the trial to enroll only patients with high-grade neuroendocrine tumors to see if we get the same response to this immunotherapy combination,” he emphasized.
NETs are heterogeneous tumors and can occur anywhere in the body. Many are well-differentiated or low-grade tumors with indolent biology. Poorly differentiated NETs are high-grade, and most often are in the lung, gastrointestinal tract, or of unknown origin. High-grade tumors are more aggressive, and the treatment options are limited.
The DART Basket Study
DART is the first National Cancer Institute–sponsored “basket” clinical trial for rare tumors and is designed to test a single drug or a drug combination in a variety of tumor types. The ipilimumab-nivolumab combination is being tested in patients with 37 types of rare cancers. Dr Patel presented the results of a cohort of 32 patients with NETs.
The 32 eligible patients received treatment with intravenous (IV) ipilimumab 1 mg/kg every 3 weeks plus IV nivolumab 240 mg every 2 weeks until disease progression, unacceptable toxicity, or withdrawal of consent. Patients with pancreatic NETs were excluded from the study.
Of the 32 patients, 18 (52%) patients had high-grade carcinoma, 10 (31%) had intermediate-grade, and 4 (12%) had low-grade carcinoma. The most common sites of primary tumor were lung (N = 6), small intestine (N = 6), rectum (N = 4), stomach (N = 2), and cecum (N = 1). Five patients had tumors of unknown primary origin, and 8 had tumors at other sites. The median number of previous lines of therapy was 2.
The overall response rate was 24% (N = 8), including 1 complete response and 7 partial responses. In addition, 2 patients had stable disease for >6 months. The responses were confined to patients with high-grade disease. Among high-grade tumors, the overall response rate was 44% (independent of the tumor site) versus 0% for patients with low- or intermediate-grade tumors (P = .004).
The clinical benefit rate was 42% in patients with high-grade tumors (combined response data plus stable disease for more than 6 months). The 6-month progression-free survival rate was 31%, and the median overall survival was 11 months.
“These outcomes compare favorably with historical patients, where the clinical benefit rate at 6 months is about 20% for patients with refractory tumors, the 6-month progression-free survival is around 10%, and median overall survival is around 3 months,” Dr Patel said.
The combination regimen was well-tolerated. The most common overall adverse events were fatigue (30%) and nausea (27%). The most frequent immune-related events of any grade were hypothyroidism (31.3%) and aspartate aminotransferase elevation (25%). No cases of immune-related pneumonitis and no fatal events were reported.
“Going into the study, we did not know we would see a differential response according to tumor grade. Now that we have efficacy in a subset of a rare histology, we want to proceed in that subset, and tease out the biological reasons why combinatorial [immune] blockade achieves different responses according to tumor grade,” Dr Patel said.
“One of the main take-home messages of this study is that clinical trials in rare tumors are feasible. In the past, the designation of ‘rare’ has put a damper on clinical trials. DART is open at 800 sites, and we were able to accrue this cohort within 3 months,” he added.