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Clinical Trial
. 2017 Jun 15;23(12):2972-2980.
doi: 10.1158/1078-0432.CCR-16-2349. Epub 2016 Dec 22.

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

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Clinical Trial

Combined KIT and CTLA-4 Blockade in Patients with Refractory GIST and Other Advanced Sarcomas: A Phase Ib Study of Dasatinib plus Ipilimumab (V体育平台登录)

Sandra P D'Angelo et al. Clin Cancer Res. .

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) VSports手机版. 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. Clin Cancer Res; 23(12); 2972-80. ©2016 AACR. .

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Conflict of interest statement

Disclosure of Potential Conflicts of Interest: A. N V体育ios版. Shoushtari is a consultant/advisory board member for Immunocore and Vaccinex and reports receiving commercial research support from Bristol-Myers Squibb and Immunocore. R. D. Carvajal is a consultant/advisory board member for AstraZeneca, Aura Biosciences, Iconic Therapeutics, Janssen, Merck, and Novartis. No potential conflicts of interest were disclosed by the other authors.

"V体育官网入口" Figures

Figure 1
Figure 1
A, Kaplan–Meier curve of PFS. The median follow-up on these 18 patients was 17.1 months. The median PFS was 2.8 months (95% CI, 2.7–3.0). B, Kaplan–Meier curve of OS. The median follow-up on these 18 patients was 17.1 months. The median OS was 13.5 months (95% CI, 11.4–NR).
Figure 2
Figure 2
A, For GIST patients (n = 8), VEGF is detectable in plasma, and there are nonsignificant trends toward decrease with therapy. B, IL8 is widely variable at baseline without any changes seen with therapy. C, For patients (n =13), median ALC at baseline =1,100; after 1 week of dasatinib = 1,300 (P = NS); dasatinib and two doses of ipilimumab = 1,550 (P = 0.04, paired t test). No relationship with clinical benefit was observed. D, Western blot analysis: Pre represents prior to treatment, post #1 is after dasatinib alone, and post #2 is after dasatinib + two doses of ipilimumab. There were 4 of 6 patients with adequate tissue for analysis. All patients had baseline expression of KIT, p-KIT, and IDO. Patients 1 and 2 had no changes after treatment (Tx) and evidence of progression. Patient 5 (duodenal GIST, exon 13 mutation) had loss of IDO expression at the second posttreatment biopsy with stable disease per RECIST, irRC, and Choi lasting 19 weeks. Patient 6 had SDH-deficient GIST with evidence of stable disease for 48 weeks without loss of IDO expression.

References (V体育官网入口)

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