Clinical and Biomarker Analysis of a Phase I/II Study of PDR001 Plus Imatinib for Advanced Treatment-Refractory Gastrointestinal Stromal Tumors

Clin Cancer Res. 2024 Jul 1;30(13):2743-2750. doi: 10.1158/1078-0432.CCR-23-4065.

Abstract

Purpose: In this phase Ib/II study, we aimed to evaluate the safety and efficacy of PDR001, an anti-PD1 antibody, in combination with imatinib in patients with treatment-refractory gastrointestinal stromal tumor (GIST).

Patients and methods: Patients with advanced GIST whose disease had progressed on imatinib, sunitinib, and regorafenib were enrolled. In phase Ib, the standard 3 + 3 dose escalation scheme was applied. Intravenous administration of PDR001 at 400 mg for every 4 weeks plus imatinib (300 and 400 mg daily for dose levels I and II, respectively) was given. The primary outcome for phase II was the disease control rate at 12 weeks. Exploratory biomarker analysis was performed based on PDL1 IHC, next-generation sequencing, and multiplexed IHC.

Results: No dose-limiting toxicity was observed in the phase Ib part (n = 10), and dose level II was selected as the recommended phase II dose. In the phase II part (n = 29), there was no objective response, and the disease control rate at 12 weeks was 37.9%, not meeting the primary efficacy endpoint. For patients in phase Ib-dose level II and phase II (n = 36), the median progression-free survival (PFS) and overall survival were 2.3 and 9.5 months, respectively. The most common grade 3 to 4 adverse event was anemia. Exploratory biomarker analysis indicated that a higher CD8+ T-cell density was associated with a favorable PFS but to a limited degree. Tumor mutational burden and PDL1 were not associated with better PFS.

Conclusions: In patients with treatment-refractory GIST, PDR001 in combination with imatinib was generally tolerable, but it was not effective.

Publication types

  • Clinical Trial, Phase II
  • Clinical Trial, Phase I

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Combined Chemotherapy Protocols* / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols* / therapeutic use
  • Biomarkers, Tumor*
  • Drug Resistance, Neoplasm
  • Female
  • Gastrointestinal Neoplasms / drug therapy
  • Gastrointestinal Neoplasms / pathology
  • Gastrointestinal Stromal Tumors* / drug therapy
  • Gastrointestinal Stromal Tumors* / genetics
  • Gastrointestinal Stromal Tumors* / pathology
  • Humans
  • Imatinib Mesylate* / administration & dosage
  • Imatinib Mesylate* / adverse effects
  • Imatinib Mesylate* / therapeutic use
  • Male
  • Middle Aged

Substances

  • Imatinib Mesylate
  • Biomarkers, Tumor