Dual-Immunotherapy Approach Shows Efficacy in High-Grade Neuroendocrine Tumors

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COMBINING TWO established immunotherapy agents achieved tumor shrinkage in rare, aggressive, extrapancreatic high-grade neuroendocrine tumors, according to the results of SWOG S1609, a phase II clinical basket trial also known as DART (Dual Anti– CLTA-4 and Anti–PD-1 Blockade in Rare Tumors). The combination of the anti–cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) agent ipilimumab plus the anti–programmed cell death protein 1 (PD-1) agent nivolumab achieved tumor shrinkage (either a complete or partial response) in 44% of high-grade tumors but no tumor shrinkage in low-grade tumors.1

Sandip P. Patel, MD

Sandip P. Patel, MD

“We saw a benefit in patients with high-grade carcinoma, which is the population that really needs an effective treatment option. Treatment options are limited for these patients,” said Sandip P. Patel, MD, DART Clinical Study Chair; Associate Professor of Medicine at the University of California, San Diego, School of Medicine; and medical oncologist at Moores Cancer Center, who presented the results at the 2019 American Association for Cancer Research (AACR) Annual Meeting.

“These early results are encouraging and intriguing. 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,” Dr. Patel told listeners.

Study Details

DART IS the first National Cancer Institute (NCI)-sponsored basket study for rare tumors. The design allows testing a single drug or drug combination in a variety of tumor types. The ipilimumab/ nivolumab combination is being tested in patients with 37 types of rare cancer. At the AACR meeting, Dr. Patel presented data on a cohort of 33 patients with neuroendocrine tumors.

“These early results are encouraging and intriguing. We found a clear difference in response to treatment between the high-grade and low-grade forms of [neuroendocrine tumors], so tumor biology makes a difference.”
— Sandip P. Patel, MD

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“In the aggregate, rare cancers are not that rare because they represent almost 25% of all cancers,” Dr. Patel noted. “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 told listeners.

“We wanted to show that this type of study is not only feasible, but can benefit patients. About two-thirds of patients are treated in the community setting,” Dr. Patel said.

Neuroendocrine tumors are a heterogeneous group of cancers that can occur throughout the body. Many are well-differentiated/ low-grade tumors with more indolent biology. Poorly differentiated tumors are often high grade and most commonly develop in the lung or gastrointestinal tract, or they are designated as “cancer of unknown primary.” High-grade tumors are more aggressive, and previous studies of immune checkpoint inhibitor monotherapy show low response rates of around 5%.

Methods and Findings

THE COMBINATION regimen used in the trial was ipilimumab at 1 mg/kg given intravenously every 6 weeks plus nivolumab at 240 mg IV every 2 weeks. “This is slightly different from the regimen used to treat melanoma,” Dr. Patel said. Patients were treated until disease progression, unacceptable toxicity, or withdrawal of consent.

The study enrolled 32 eligible patients, excluding those with pancreatic neuroendocrine tumors. Of these patients, 18 (56%) had high-grade carcinoma, 10 (31%) had intermediate-grade tumors, and 4 (12%) had low-grade tumors. At baseline, the median age was 60.5 years, 41% were female and 59%, male, and 75% had a performance status of 1. The most common sites of the primary tumor were the lungs (6 patients) and small intestine (6 patients); 2 were in the stomach, 4 were in the rectum, 1 was in the cecum, and 8 were at various other sites. Five patients had tumors of unknown primary. The median number of prior lines of therapy was two.


  • In a cohort of patients with extrapancreatic neuroendocrine tumors, the combination of ipilimumab plus nivolumab achieved tumor shrinkage in 44% of patients with high-grade tumors, and responses were durable.
  • No responses were observed in low-grade tumors.
  • An arm including only high-grade tumors will be added to this basket trial and studied further.

For the whole cohort of neuroendocrine tumors, the overall response rate was 25%, which included 1 complete response and 7 partial responses. These responses were observed only in patients with high-grade disease. When only those with high-grade disease were evaluated, the overall response rate was 44% (independent of the site of the tumor), whereas the response rate was 0% for patients with low- or intermediate-grade tumors (P = .004).

“Several patients have durable responses, including those previously treated with chemotherapy,” Dr. Patel said.

The clinical benefit rate (response or stable disease for more than 6 months) was 42% in patients with high-grade tumors. The 6-month progression-free survival rate was 31%, and the median overall survival was more than 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 the median overall survival is around 3 months,” Dr. Patel said.

The combination regimen was well tolerated. The most common overall toxicities were fatigue (30%) and nausea (27%). The most frequent immune-related toxicities of any grade were hypothyroidism (31.3%) and aspartate transaminase elevation (25%). The most common grade 3 and immune-related toxicities were liver function abnormalities (9%) and colitis (6%). There were no cases of immune-related pneumonitis and no fatal toxicities.

Study Limitations

LIMITATIONS OF the study include a lack of central pathology review, and the high-grade vs low-grade tumor analysis was not prespecified. Additionally, this was a single-arm, nonrandomized group of patients.

“One of the main take-home messages of this study is that clinical trials in rare tumors are feasible.”
— Sandip P. Patel, MD

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“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 biologic reasons why combinatorial immune blockade achieves different responses according to tumor grade,” he said.

“The response rate is promising in patients with high-grade neuroendocrine tumors independent of the primary site. Additional analyses of these data are underway. Upcoming studies will include the high-grade neuroendocrine disease arm in DART as well as translational analysis,” Dr. Patel told the audience.

DISCLOSURE: Dr. Patel has received research grants from Bristol-Myers Squibb, Eli Lilly, Incyte, AstraZeneca/MedImmune, Merck, Pfizer, Roche/Genentech, Xcovery, Fate Therapeutics, Genocea, and Iovance and consultant fees from Bristol-Myers Squibb, AstraZeneca, Illumina, Tempus, and Novartis.


1. Patel SP, Othus M, Chae YK, et al: A phase II basket trial of dual anti–CTLA-4 and anti–PD-1 blockade in rare tumors (DART) S1609: The neuroendocrine cohort. 2019 AACR Annual Meeting. Abstract CT039. Presented March 31, 2019.

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