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Immunotherapy combination of nivolumab, ipilimumab confers benefit in rare neuroendocrine carcinoma
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ATLANTA — Patients with rare, high-grade neuroendocrine tumors derived clinical benefit from a combination of the immune checkpoint inhibitors ipilimumab, which targets CTLA-4, and nivolumab, which targets PD-1, according to results from the phase 2 DART trial presented at American Association for Cancer Research Annual Meeting.
Sandip Patel, MD, associate professor of medicine at UC San Diego School of Medicine and medical oncologist with Moores Cancer Center at US San Diego Health, told HemOnc Today. “That’s a reasonable, utilitarian calculus. However, one thing that’s not appreciated is that while each cancer type is exceedingly rare, if you add all these rare cancer types together, it represents about 22% of all cancers. The overall burden of rare cancers is quite high.”
Neuroendocrine carcinoma, which frequently forms tumors in the lungs and along the digestive tract, is rare, with only about 12,000 patients diagnosed in the U.S. annually. However, prevalence increased sixfold between 1973 and 2012, and patients with the high-grade form of the disease have limited treatment options.
The DART trial, managed by Southwest Oncology Group, utilizes a “basket” design that allows for testing of a single drug or drug combination in various tumor types. DART is currently testing the immunotherapy combination of ipilimumab (Yervoy, Bristol-Myers Squibb) and nivolumab (Opdivo, Bristol-Myers Squibb) in patients with 37 types of rare cancers, which account for nearly a quarter of all cancers diagnosed worldwide.
In the prospective, open-label, multicenter phase 2 trial, Patel and colleagues evaluated the combination in 33 patients with neuroendocrine tumors, including 19 patients (58%) with high-grade disease, who had a median two lines of prior therapy. Most of the tumors were in the gastrointestinal tract (n= 15) or the lungs (n = 6).
Patients received 1 mg/kg ipilimumab every 6 weeks and 240 mg IV nivolumab every 2 weeks.
Overall response rate served as the study’s primary endpoint, with PFS, OS, stable disease for more than 6 months and toxicity as secondary endpoints.
Results showed an ORR of 24%, including one complete response and seven partial responses, all of which were among patients with high-grade neuroendocrine tumors.
One-third of all patients (n = 11) had stable disease, including two patients with stable disease for more than 6 months. Both of those patients had low/intermediate-grade disease.
Researchers observed 6-month PFS of 30% and median OS of 11 months.
The most prevalent toxicities were fatigue (30%) and nausea (27%) The most prevalent immune-related adverse event was grade 3 to grade 4 alanine aminotransferase elevation (9%). No grade 5 toxicities occurred.
Since its inception in 2017, DART has enrolled more than 550 patients. The trial is open at more than 800 cancer centers and community clinics across the U.S.
“I think if we confirm these very initially promising results that these two drugs are effective in high-grade neuroendocrine tumors, regardless of what organ this cancer originates in, that will represent a new and very promising treatment option for patients who historically have had cytotoxic chemotherapy as their traditional therapeutic option,” Patel told HemOnc Today. “The idea that these patients may have the potential for long-term benefit from immunotherapy is something we’re very excited about.” – by Jennifer Byrne
Reference:
Patel S, et al. Abstract CT039. Presented at: AACR Annual Meeting; March 29- April 3, 2019; Atlanta.
Disclosures: Patel reports research funding to his institution from AstraZeneca/MedImmune, Bristol-Myers Squibb, Eli Lilly, Incyte, Fate Therapeutics, Genocea, Iovance, Merck Pfizer, Roche/Genentech and Xcovery. Please see the abstract for all other authors’ relevant financial disclosures.
Perspective
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Namrata Vijayvergia, MD
High-grade neuroendocrine neoplasms are an area of unmet therapeutic need. Single-agent PD-1/PD-L1 inhibitors have not shown significant activity in extra-pulmonary high-grade neuroendocrine neoplasms per recent data.
These promising results from DART provide rationale for combination immunotherapy for these rare cancers. What remains an open question is what the activity will be in the gastrointestinal cohorts as their role in high-grade neuroendocrine tumors of lung origin has already been established if we extrapolate from available lung cancer data.
References:
Hooker C, et al. J Clin Oncol. 2018;doi:10.1200/JCO.2018.36.15_suppl.TPS4147.
Vijayvergia N, et al. J Clin Oncol. 2018;doi:10.1200/JCO.2018.36.15_suppl.4104.
Yao JC, et al. Ann Oncol. 2018;doi.org/10.1093/annonc/mdy293.001.
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