Defactinib, Pembrolizumab, and Gemcitabine in Patients with Advanced Treatment Refractory Pancreatic Cancer: A Phase I Dose Escalation and Expansion Study

Abstract

Purpose: Targeting focal adhesion kinase (FAK) renders checkpoint immunotherapy effective in pancreatic ductal adenocarcinoma (PDAC) mouse model. Defactinib is a highly potent oral FAK inhibitor that has a tolerable safety profile.

Patients and methods: We conducted a multicenter, open-label, phase I study with dose escalation and expansion phases. In dose escalation, patients with refractory solid tumors were treated at five escalating dose levels of defactinib and gemcitabine to identify a recommended phase II dose (RP2D). In expansion phase, patients with metastatic PDAC who progressed on frontline treatment (refractory cohort) or had stable disease (SD) after at least 4 months of standard gemcitabine/nab-paclitaxel (maintenance cohort) were treated at RP2D. Pre- and posttreatment tumor biopsies were performed to evaluate tumor immunity.

Results: The triple drug combination was well-tolerated, with no dose-limiting toxicities. Among 20 treated patients with refractory PDAC, the disease control rate (DCR) was 80%, with one partial response (PR) and 15 SDs, and the median progression-free survival (PFS) and overall survival (OS) were 3.6 and 7.8 months, respectively. Among 10 evaluable patients in the maintenance cohort, DCR was 70% with one PR and six SDs. Three patients with SD came off study due to treatment- or disease-related complications. The median PFS and OS on study treatment were 5.0 and 8.3 months, respectively.

Conclusions: The combination of defactinib, pembrolizumab, and gemcitabine was well-tolerated and safe, had promising preliminary efficacy, and showed biomarker activity in infiltrative T lymphocytes. Efficacy of this strategy may require incorporation of more potent chemotherapy in future studies.

Figure 1.

CONSORT flow diagram of patients enrolled in this study.

Figure 2.

A) Swimmer plot depicting prior treatment history and time on study for all PDAC patients enrolled in this study. Depicted on the plot are symbols for treatment response during study treatment and subsequent treatment (for maintenance cohort) after coming off study. Patient 1: off study per physician discretion due to severe fatigue and opted for hospice. Patient 2: developed congestive heart failure possibly related to gemcitabine, defactinib and pembrolizumab; Patient 3: Whipple procedure attempted and aborted due to intraoperative finding of liver metastases and later died from postoperative wound infection. Patient 4: poor oral intake despite stable CT scans and pursued hospice. B) Waterfall plot depicting best radiographic response for patients treated in each cohorts. Patients who had imaging studies and came off study prior to planned (post 3 cycle) evaluation per RECIST were included. C) Kaplan-Meier curves depicting the PFS and OS for refractory PDAC patients from dose escalation (n=10) and refractory expansion (n=10). D) Kaplan-Meier curves depicting the PFS and OS for PDAC patients treated in the dose expansion phase as maintenance cohort (n=10).

Figure 3.. Characteristics of two patients with partial response.

A-B) Prior treatment history, molecular features of tumors, serum CA19–9 and serial radiographic images of two patients who had radiographic partial response on study.

Figure 4.. Correlative studies on pre- and post-biopsy tissues.

A) Example image of standard immunohistochemistry (IHC) analysis for phosphorylated FAK1 (tyrosine 395) from paired patient samples taken pre- and post-treatment. B) Example image of multiplex IHC (left) and quantitation of pFAK high CK19+ cells in partied biopsies C) Patient biopsies were assessed by using flow cytometry (left) or IHC analysis (right) for the presence of different leukocyte subsets. These leukocytes for flow cytometry included the following T cell subsets: total CD8+ cytotoxic lymphocytes (CTLs), Ki67⁺CD8⁺ CTLs, CD4⁺ T effector cells, FOXP3⁺ regulatory T cells, and CD3/CD19⁻CD11b⁺CD14⁺CD68⁺ tumor-associated macrophages. For IHC analysis, total CD8⁺ T cells in the biopsy and CD8⁺ T cells present within 100 μm of CK19+ cells were analyzed by HALO software. All data are displayed as log₂fold changes between pre- and post-biopsies. D) Example IHC analyses for CD8 (brown) and CK19 (red) images for a pair of pre- and post-biopsies from a single patient. *denotes p<0.05 by paired parametric test (B) or Wilcoxon signed-rank test or one-sample test (C) as appropriate.