Nivolumab/Ipilimumab Combo Data Encouraging in Advanced GISTs

Arun S. Singh, MD

Nivolumab (Opdivo) alone and in combination with ipilimumab (Yervoy) induced responses in patients with heavily pretreated gastrointestinal stromal tumor (GIST), according to findings presented at the 2018 Gastrointestinal Cancers Symposium.

Interim data from the first 14 patients enrolled in a randomized phase II study showed stable disease (SD) as best response in 3 of 7 patients treated with nivolumab monotherapy and 1 partial response and 2 SD in patients receiving both nivolumab and ipilimumab. The responses have been durable.

Planned enrollment in the unblinded parallel group study is 40 patients (20 in each arm), said lead author Arun S. Singh, MD, Assistant Professor, Division of Hematology/Oncology, University of California, Los Angeles.

Median progression-free survival was 8.6 weeks in the nivolumab arm and 9.86 weeks in the nivolumab plus ipilimumab arm. Fatigue, arthralgia, pruritus, and rash have been the main treatment-related adverse events.

Five of the 14 patients have been on therapy for more than 6 months, “so, it’s roughly one-third of the patients who receive definite clinical benefit. We’re really encouraged by this study,” he said.

The 3 agents approved for the treatment of GISTs are imatinib (Gleevec), sunitinib (Sutent), and regorafenib (Stivarga). All patients in the trial had disease progression after imatinib. Secondary mutations in KIT and PDGFRa are believed to confer resistance to tyrosine kinase inhibitors (TKIs).

“This group of patients has really advanced GISTs. The median number of therapies they had was 4. So, these are fifth line and beyond—very advanced patients who have no good therapeutic options. The benefit of second- and third-line therapy goes down from sunitinib to regorafenib, so certainly new therapies are needed,” said Singh.

“We need a different approach other than TKIs, which have induced amazing responses in GIST. It has been known for several years that there is a tremendous immune infiltrate in GISTs including T cells and macrophages, which can be immunostimulatory or immunosuppressive. There are several lines of data, including in mice, that immune checkpoint blockers can be beneficial in GIST.”

Ipilimumab is a CTLA4 blocker that has improved outcomes when added to single-agent nivolumab in other malignancies, particularly melanoma, “so, we thought it was a reasonable thing to consider here as well,” he added. When used on a compassionate use basis, immunotherapy has been associated with marked responses, including tumor shrinkage of 40% in at least 1 patient with advanced GIST who had no other treatment options, he said.

In the study, patients with advanced/metastatic GIST and an ECOG performance status of 0 or 1 who progressed on imatinib were randomized to either nivolumab (240 mg every 2 weeks) alone or nivolumab plus ipilimumab (1 mg/kg every 6 weeks), for up to 2 years. The primary endpoint was the objective response rate by RECIST 1.1 criteria.

The clinical benefit rate in each group has been 42.8%. The mean PFS was 15.3 weeks in the nivolumab arm and 18 weeks in the combination arm.

Adverse events related to nivolumab included fatigue (26.3%), pruritus (15.8%), arthralgia (10.5%), and rash (10.5%). The most common adverse events related to ipilimumab were rash (21.1%), arthralgia (10.5%), and pruritus (10.5%). One patient in the nivolumab-alone arm had grade 3 fatigue. Grade 3 adverse events related to ipilimumab included 1 case each of diarrhea and weakness.

Pretreatment biopsies have been obtained in all patients and blood has been collected for correlative analysis.

Singh AS, Chmielowski BC, Hecht JR, et al. A randomized phase 2 study of nivolumab monotherapy versus nivolumab combined with ipilimumab in patients with metastatic or unresectable gastrointestinal stromal tumor (GIST). Presented at: 2018 Gastrointestinal Cancers Symposium; January 18-20, 2018; San Francisco, CA. Abstract 55.

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