Safety and activity of the TGFβ receptor I kinase inhibitor galunisertib plus the anti-PD-L1 antibody durvalumab in metastatic pancreatic cancer

Abstract

BackgroundWe assessed the safety, efficacy, and pharmacokinetics of the transforming growth factor beta (TGFβ) receptor inhibitor galunisertib co-administered with the anti-programmed death-ligand 1 (PD-L1) antibody durvalumab in recurrent/refractory metastatic pancreatic cancer previously treated with ≤2 systemic regimens.MethodsThis was a two-part, single-arm, multinational, phase Ib study. In a dose-finding phase, escalating oral doses of galunisertib were co-administered on days 1–14 with fixed-dose intravenous durvalumab 1500 mg on day 1 every 4 weeks (Q4W), followed by an expansion cohort phase.ResultsThe galunisertib recommended phase II dose (RP2D) when co-administered with durvalumab 1500 mg Q4W was 150 mg two times per day. No dose-limiting toxicities were recorded. Among 32 patients treated with galunisertib RP2D, 1 patient had partial response, 7 had stable disease, 15 had objective progressive disease, and 9 were not evaluable. Disease control rate was 25.0%. Median overall survival and progression-free survival were 5.72 months (95% CI: 4.01 to 8.38) and 1.87 months (95% CI: 1.58 to 3.09), respectively. Pharmacokinetic profiles for combination therapy were comparable to those published for each drug. There was no association between potential biomarkers and treatment outcomes.ConclusionGalunisertib 150 mg two times per day co-administered with durvalumab 1500 mg Q4W was tolerable. Clinical activity was limited. Studying this combination in patients in an earlier line of treatment or selected for predictive biomarkers of TGFβ inhibition might be a more suitable approach.Trial registration numberClinicalTrials.gov identifier: NCT02734160.

TGFβ Signaling in the Pancreatic Tumor Microenvironment

“…Five patients experienced a grade 3/4 treatmentrelated adverse event in the form of elevated AST/ALT, neutropenia, anemia, and/or lymphopenia. Though encouraging given the highly advanced disease in this cohort, the authors recommended the continued investigation of this combination as an earlier line of treatment or in combination with predictive biomarkers for TGFβ inhibition [178].…”

The Multifaceted Role of TGF-β in Gastrointestinal Tumors

“…Its efficacy has been demonstrated in a phase 1b/2 study in patients with unresectable pancreatic cancer when in combination with gemcitabine, with minimal added toxicity [223,224]. Safety, efficacy, and pharmacokinetics of Galunisertib in combination with the anti-PD-1 antibody Nivolumab (NCT02423343) or with anti-PD-L1 antibody Durvalumab (NCT02734160) [225] have also been demonstrated recently in phase I/II trials. In HCC patients that were ineligible for Sorafenib, treatment with Galunisertib has been reported to increase the overall survival (7.91 months in patients with a reduction of TGF-β less than 20% vs. 21.8 months in patients with a reduction of TGF-β more than 20%) [226].…”

The Heterogeneity of the Tumor Microenvironment as Essential Determinant of Development, Progression and Therapy Response of Pancreatic Cancer

“…However, an early phase clinical trial testing the therapeutic efficacy of pharmacological TGF-blockade with the small molecule inhibitor Galunisertib in combination with chemotherapy for the treatment of unresectable PDAC did not reveal convincing results [ 129 ]. Additionally, data from a phase Ib clinical trial investigating Galunisertib in combination with the anti-PD-L1 antibody Durvalumab did not yield clinical improvements for patients with metastatic PDAC [ 130 ]. Of note, Özdemir et al showed in a PDAC mouse model that complete depletion of α-SMA+ myofibroblasts led to enhanced tumor growth, decreased immune cell infiltration and increased number of Treg in the TME.…”