Secondary Logo

Journal Logo

Dual Immunotherapy in High-Grade Neuroendocrine Carcinoma

Fuerst, Mark L.

doi: 10.1097/01.COT.0000559653.91486.9f
News
Free

ATLANTA—Immunotherapy with a combination of two checkpoint inhibitors showed clinical benefit among patients with a rare, high-grade neuroendocrine carcinoma, according to results from a non-randomized, phase II basket trial.

The Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors (DART) trial showed a high overall response rate (ORR) for those with high-grade tumors.

“Rare tumor types, as an aggregate, represent nearly a quarter of all cancers,” said Sandip Patel, MD, Associate Professor of Medicine at the University of California San Diego School of Medicine. “Our study highlights the feasibility of performing clinical trials among patients with rare cancers, and hopefully will help dispel the belief that clinical trials are not feasible for this patient population.”

Patel presented the results of the trial at the American Association for Cancer Research annual meeting (Abstract CT039).

“We were pleased to see that patients with high-grade neuroendocrine carcinoma derived benefit from a combination of the two immune checkpoint inhibitors in the DART trial,” said Patel, who is also a medical oncologist with Moores Cancer Center at UC San Diego Health. “Given that current treatment options for patients with high-grade neuroendocrine carcinoma are generally limited to aggressive chemotherapy regimens, this is an exciting finding for this patient population.”

Immune checkpoint blockade, in particular anti-cytotoxic T-lymphocyte–associated protein-4 blocker (CTLA-4) and anti-PD-1-directed approaches, have improved outcomes in various tumor types. However, little is known about the efficacy of these agents in combination in metastatic rare solid tumors, noted Patel. Prior studies using single anti-PD-1 checkpoint inhibitors in high-grade neuroendocrine disease yielded response rates of about 5 percent.

Back to Top | Article Outline

DART Trial Specifics

The aim of the DART trial is to evaluate the combination of the anti-CTLA-4 agent ipilimumab 1 mg/kg every 6 weeks and the anti-PD-1 agent nivolumab 240 mg every 2 weeks in patients with rare tumor types.

Patel summarized the findings from 33 patients with neuroendocrine tumors, with patients who have pancreatic neuroendocrine cancers currently being studied in a separate ongoing cohort of DART. The primary endpoint was ORR; secondary endpoints included progression-free survival (PFS) and overall survival (OS).

The most common tumor sites were gastrointestinal (15 patients) and lung (six patients); 58 percent (19 patients) of patients had high-grade disease. Patients had received a median of two lines of therapy prior to enrollment in the trial.

This was a heavily pretreated group of high-grade neuroendocrine tumors, which make up about one-third of these tumors, said Patel. Typically, these tumors have an aggressive biology and patients have few treatment options outside of cytotoxic chemotherapy.

In the neuroendocrine cohort, the ORR was 24 percent, which included one complete response (CR) and seven partial responses (PR). All patients who had a CR or PR had high-grade disease. The 6-month PFS was 30 percent, and the median OS was 11 months. These survival rates compare favorably with historical controls, who achieve about 10 percent PFS and OS of 3 months, he said.

A post-hoc analysis by tumor grade found that none of the 14 patients with low-grade or intermediate-grade neuroendocrine tumors responded to the combination immunotherapy. However, 44 percent (8 of 18 patients) of those with high-grade disease did respond, including patients with lung, gastrointestinal tract, and gynecologic primary tumors.

“We only observed complete and partial responses among patients with high-grade carcinoma, and one preliminary hypothesis for this finding is that high-grade neuroendocrine carcinomas may have a higher tumor mutational burden, which is an indicator of better response to immunotherapy,” said Patel. “We are planning to verify these results, specifically in patients with high-grade neuroendocrine carcinoma, later this year, as a separate cohort in the DART trial.”

Checkpoint blockade has the potential to lead to durable responses. “This is what we have seen in our study,” said Patel, who noted that some responses have lasted for more than 1 year.

Back to Top | Article Outline

Safety, Ongoing Study

The most common toxicities included fatigue (30% of patients) and nausea (27% of patients). The most common high-grade immune toxicities were liver function abnormalities in 9 percent of patients and colitis in 6 percent. No cases of pneumonitis were reported and there were no deaths due to adverse events. No grade 5 immune-related adverse events were observed.

DART is an ongoing phase II basket trial from the SWOG Cancer Research Network testing ipilimumab plus nivolumab. It has enrolled 560 patients at more than 800 sites across the country since opening in 2017. Overall, the basket trial includes 37 cohorts of rare cancers.

It took 3 months to accrue the neuroendocrine tumor cohort in the current trial. Patel noted that an advantage of the DART trial was that patients could be treated at local centers, which was convenient for participants and facilitated their accrual. However, due to this design, there was no central pathology review, which represents a key limitation of the study, he said.

Mark L. Fuerst is a contributing writer.

Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
Home  Clinical Resource Center
Current Issue       Search OT
Archives Get OT Enews
Blogs Email us!