Combined KIT and CTLA-4 blockade in patients with refractory GIST and other advanced sarcomas: A phase Ib study of dasatinib plus ipilimumab Journal Article

Authors: D'Angelo, S. P.; Shoushtari, A. N.; Keohan, M. L.; Dickson, M. A.; Gounder, M. M.; Chi, P.; Loo, J. K.; Gaffney, L.; Schneider, L.; Patel, Z.; Erinjeri, J. P.; Bluth, M. J.; Sjoberg, A.; Streicher, H.; Takebe, N.; Qin, L. X.; Antonescu, C.; DeMatteo, R. P.; Carvajal, R. D.; Tap, W. D.
Article Title: 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 immunerelated 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. ©2016 AACR.
Journal Title: Clinical Cancer Research
Volume: 23
Issue: 12
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2017-06-01
Start Page: 2972
End Page: 2980
Language: English
DOI: 10.1158/1078-0432.ccr-16-2349
PROVIDER: scopus
PMCID: PMC5486863
PUBMED: 28007774
Notes: Article -- Export Date: 3 July 2017 -- Source: Scopus
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MSK Authors
  1. Ronald P DeMatteo
    597 DeMatteo
  2. Cristina R Antonescu
    606 Antonescu
  3. Mark J Bluth
    11 Bluth
  4. Ping Chi
    44 Chi
  5. Li-Xuan Qin
    114 Qin
  6. Mary Louise Keohan
    64 Keohan
  7. Mrinal M Gounder
    68 Gounder
  8. Mark Andrew Dickson
    77 Dickson
  9. William Douglas Tap
    122 Tap
  10. Jennifer Loo
    9 Loo
  11. Zarine Shirine Patel
    2 Patel