MEDIPLEX: A phase 1 study of durvalumab (D) combined with pexidartinib (P) in patients (pts) with advanced pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC).

Abstract

2579 Background: Targeting tumor associated macrophages is an emerging strategy to increase the responsiveness of PDAC and CRC to anti-PD(L)1. Pexidartinib (P) is an orally active, small-molecule kinase inhibitor that targets the colony-stimulating factor-1 receptor (CSF1R) on macrophages. Methods: Adult pts with advanced/ metastatic PDAC or CRC were treated with a fixed dose of D (1500mg q4w, IV) and ascending doses of P (400, 600, 800 and 1000mg/d, orally). Dose escalation was conducted according to a Likelihood Continual Reassessment Method with a 28-day window to evaluate dose-limiting toxicity (DLT), a stopping rule advised dose escalation termination in case of a high probability ( > 90%) for the next 6 pts to be assigned to the same dose. Following the determination of RP2D, 14 pts with PDAC and 14 pts with CRC who consented to serial tumor biopsies were enrolled in expansion cohorts to assess preliminary anti-tumor activity and biomarkers. Results: 19 pts (12M, 7F, median age, 56 y [range, 43-76y]) were enrolled in 4 dose escalation cohorts (P 400, 600 and 800mg/d: 3 pts each and P 1000mg/d: 10 pts). Pharmacokinetic analysis showed dose-dependent increase in the exposure of P from 400 to 1000 mg. Two DLTs (AST/ALT elevations including one with bilirubin increase) were seen at dose level P 1000mg/d. The most frequent ( > 2pts) related (to either D, P or both) AEs were: fatigue, maculopapular rash/pruritus/dry skin, hair color changes, anorexia, edema (periorbital, limbs or face), AST/ALT increases, bilirubin increases, nausea, vomiting and diarrhea. The most frequent (≥2pts) Grade ≥ 3 AEs related to P were: AST/ALT increase, ALP increase, neutrophil or white blood cell count decrease, and fatigue. Clinical benefit rate at 2 months was 21% (4 SD /19pts), 2 pts with MSI-H CRC had SD for more than 6 months including 1 pt still receiving single agent D after > 18 months. The RP2D for the combination was P 800mg/d + D 1500mg q4w. Enrolment in the expansion cohorts was completed in January 2019. Conclusions: Toxicity was consistent with the expected profiles of the individual drugs and no unexpected events were seen with the combination. Updated data will be presented at the meeting. Clinical trial information: NCT02777710.

Pexidartinib: First Approval

“…In phase I studies, pexidartinib monotherapy (NCT01004861) [3], pexidartinib plus sirolimus (NCT02584647) [22], pexidartinib plus binimetinib (NCT03158103) [23], pexidartinib plus PLX9486 (NCT02401815) [24] and pexidartinib plus durvalumab (NCT02777710) [25] showed some antitumor activity in adult patients with solid tumors such as TGCT, unresectable malignant peripheral nerve sheath tumor (MPNST) and advanced gastrointestinal stromal tumor (GIST). Pexidartinib monotherapy was active against tumors in pediatric patients with neurofibromatosis type I related plexiform neurofibromas (NCT02390752; the recommended phase II dose was 800 mg/m 2 per day) [26] and produced an objective tumor response in one patient with TGCT in a trial in Asian patients with advanced solid tumors (NCT02734433; n = 8 evaluable) [27].…”

Safety and efficacy of AMG 820, an anti-colony-stimulating factor 1 receptor antibody, in combination with pembrolizumab in adults with advanced solid tumors

“…19 In a phase I study of durvalumab in combination with pexidartinib in 19 patients with CRC or pancreatic cancer, preliminary results showed a clinical benefit rate of 21% (unconfirmed stable disease in four patients), although this included two PD-1 inhibitor-naïve patients with high-level microsatellite instability CRC. 20 Because we were interested in overcoming checkpoint inhibition, we intentionally selected patient populations with tumor types that are known to be resistant to checkpoint inhibition. This study did not investigate whether on October 31, 2020 by guest.…”

“…19 In a phase I study of durvalumab in combination with pexidartinib in 19 patients with CRC or pancreatic cancer, preliminary results showed a clinical benefit rate of 21% (unconfirmed stable disease in four patients), although this included two PD-1 inhibitor-naïve patients with high-level microsatellite instability CRC. 20 …”

Next generation of immune checkpoint inhibitors and beyond

“…Another phase I clinical trial evaluated the use of pexidartinib with durvalumab in patients with advanced or metastatic pancreatic adenocarcinoma or CRC ( NCT02777710 ) [ 104 ]. Nineteen patients were included: 12 males and 7 females with a median age of 56 years.…”