Opdivo-Yervoy Combo Shrinks Aggressive Neuroendocrine Tumors, Phase 2 Trial Shows

A combination treatment with Opdivo (nivolumab) and Yervoy (ipilimumab) reduces tumor size in four of 10 patients with aggressive neuroendocrine carcinoma, according to early results of a Phase 2 trial.

The research was described in the presentation, “A Phase II basket trial of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART) S1609: The neuroendocrine cohort,” at the American Association for Cancer Research Annual Meeting 2019, held March 29–April 3 in Atlanta.

Therapies known as immune checkpoint inhibitors target specific proteins to block strategies that are used by tumors to evade immune attack. These treatments, which target either CTLA-4 or PD-1 on immune T-cells or PD-L1 on cancer cells, have shown efficacy in various tumor types. However, little is known about their benefits in aggressive and rare solid tumors.

The DART trial (NCT02834013), conducted by the SWOG Cancer Research Network — part of the National Cancer Institute’s National Clinical Trials Network (NCTN) — was thus designed to assess a combination of Bristol-Myers Squibb‘s anti-PD-1 therapy Opdivo plus the anti-CTLA-4 medication Yervoy across 37 subtypes of rare tumors.

Researchers examined DART’s results in a population of patients with neuroendocrine carcinoma. This cancer, whose prevalence has been increasing in the last decades, often develops in the lungs and digestive tract.

The open-label, multi-center study — which is still enrolling participants (more information is available here) — has so far included 33 patients with neuroendocrine tumors, 19 of whom had high-grade disease. The most frequent tumor sites were gastrointestinal (non-pancreatic) in 15 patients and lung in six cases. The patients had received a median of two lines of therapy before the study.

The trial’s primary goal was overall response rate, which included complete responses — the disappearance of all cancer signs — and partial responses. Secondary objectives included the time patients lived without cancer progression, overall survival, and the treatment’s toxicity.

The results revealed that 24% of patients responded to the combination, including 3% with complete responses. These responses, however, were all seen in patients with high-grade neuroendocrine cancer — 42% overall response rate and 5% complete responses — as no patients with low or intermediate grade tumors responded to treatment.

Also, 30% of patients were alive with no cancer progression at six months. The median overall survival was 11 months, with some patients living more than one year after treatment.

The most frequent side effects were fatigue (30% of patients) and nausea (27%). Among serious or life-threatening adverse events, increased alanine aminotransferase, a liver enzyme, was the most common (9%).

“Ipilimumab plus nivolumab was well tolerated with a 42% (overall response rate) in patients with high-grade neuroendocrine cancer, regardless of primary site,” the researchers wrote.

“We saw a benefit in patients with high-grade carcinoma, which is the population that really needs an effective treatment option,” Sandip Patel, MD, the DART study’s chair, said in a press release.

Patel, a professor of medicine at the University of California (UC) at San Diego and a medical oncologist at Moores Cancer Center at UC San Diego Health, considered the difference between high-grade and low-grade tumors “really encouraging — and intriguing.”

“So tumor biology makes a difference,” he added. “We’ve opened another treatment arm of the trial to patients with just high-grade neuroendocrine carcinoma to see if we see the same response to the immunotherapy combination.”

Patel also addressed the large number of patients (550) enrolled in DART since it opened in 2017.

“There’s a myth that you can’t successfully complete clinical trials in rare cancers,” he said. “DART shows us that we can run rare cancer trials, and enroll patients quickly and learn if therapies are effective in rare diseases.”

Through the NCTN, patients can receive investigational therapies right in their communities, he added: “They don’t necessarily need to travel to a cancer center to get enrolled in a clinical trial.”

Of note, five of the study’s authors have received funding or fees from Bristol-Myers Squibb.