Combined KIT and CTLA-4 Blockade in Patients with Refractory GIST and Other Advanced Sarcomas: A Phase Ib Study of Dasatinib plus Ipilimumab

Abstract

Purpose A phase Ib study of dasatinib plus ipilimumab in patients with gastrointestinal stromal tumor (GIST) and other sarcomas was performed on the basis of preclinical data demonstrating that combined KIT and CTLA-4 blockade is synergistic. Experimental Design A standard 3 + 3 design was used to evaluate the safety, efficacy, and immune correlates of treatment. Dose escalation cohorts received ipilimumab 10 or 3 mg/kg every 3 weeks, followed by maintenance every 12 weeks with escalating doses of dasatinib (70 mg daily, 100 mg daily, or 70 mg twice daily). Response was assessed by RECIST 1.1, Choi, and immune-related RECIST criteria (irRC). Results A total of 28 patients (17 male) were enrolled. Histologic subtypes included GISTs (n = 20) and other sarcomas (n = 8.) Dasatinib 70 mg/day with ipilimumab 10 mg/kg or dasatinib 140 mg/day with ipilimumab 3 mg/kg can be safely administered. Dose-limiting toxicities included grade 3 gastric hemorrhage and anemia. No partial or complete responses were noted by RECIST or irRC. There were 7 of 13 partial responses in the GIST patients by Choi criteria, and 3 of 13 patients each had stable and progressive disease, respectively. Conclusions Dasatinib and ipilimumab can be safely administered to GIST and sarcoma patients. However, dasatinib was not synergistic with ipilimumab, as there was limited clinical efficacy with the combination. This limited cohort provides prospective data that indoleamine-2,3-dioxygenase (IDO) suppression may potentially correlate with antitumor efficacy in GIST. Given the small cohort, it is only hypothesis generating and additional data would be required. In the era of more modern and effective checkpoint inhibitors, next steps could be consideration of tyrosine kinase inhibitors or IDO inhibitors in combination with anti-PD-1 therapy.

Role of immune microenvironment in gastrointestinal stromal tumours

“…However, complete response rates are low and KIT mutations are not uniformly responsive to imatinib, and resistance to TKI therapy may develop over the course of treatment . Therefore, for GIST, as for other malignancies, alternative therapeutic targets to monotherapy or combination therapy present the possibility of increased tumour responsiveness to improve outcomes …”

Targeting the complexity of Src signalling in the tumour microenvironment of pancreatic cancer: from mechanism to therapy

“…Moreover, in CML and head and neck cancers, dasatinib has been shown to reduce the number of myeloid-derived suppressor cells (MDSCs), and induce anti-inflammatory macrophages (defined by increased production of IL-10, decreased production of IL6, IL-12p40 and TNF-alpha, and high expression of LIGHT, SPHK1 and arginase 1), via the inhibition of salt-inducible kinases [160,162,163]. However in a clinical study of gastrointestinal stromal tumours (GIST), dasatinib and anti-CTLA4 antibody ipilimumab were well tolerated yet the combination was not synergistic, potentially due to the lack of a biomarker-driven approach [165]. Preclinical data in head and neck squamous cell carcinoma (HNSCC) showed inhibition of tumour growth, suggesting that combining dasatinib with anti-CTLA4 immunotherapy may be a viable treatment approach [164].…”

Phase I clinical trial of combination imatinib and ipilimumab in patients with advanced malignancies.

“…A recently published study examining combination of ipilimumab with dasatinib reported limited efficacy with this combination. However, their correlative data suggests that IDO suppression may correlate with antitumor efficacy in GIST [37]. Future investigation should focus on changes to the tumor microenvironment (such as IDO expression) and systemically with therapy and evaluate combination of KIT inhibition with other checkpoint blockade agents.…”