Phase 1 combination therapy with pexidartinib (PEX) and sirolimus (S) to target tumor-associated macrophages in pigmented villonodular synovitis, malignant peripheral nerve sheath tumors, and other soft tissue sarcomas.

Abstract

11055 Background: No effective therapy exists for unresectable malignant peripheral nerve sheath tumors (MPNSTs). We previously reported that the combination of PEX and the mTOR inhibitor S synergistically inhibited MPNST growth (CCR 20: 3146, 2014) by depleting M2 TAMs and by inhibiting receptor tyrosine kinases (RTKs), including c-KIT, PDGFR, CSF1R. We characterized the safety, tolerability, recommended phase 2 dose (RP2D) of PEX plus S in all sarcoma sub-types. Methods: Patients (pts) received PEX plus S orally in 28 days cycle as per Table. The RP2D was determined using the time-to-event continual reassessment method (TITE-CRM) in advanced sarcoma who have progressed on standard therapy. DLT was defined as any need for a dose reduction. Results: 24 pts were accrued (Acr) of which 18 were evaluable (MPNST – 6, pigmented villonodular synovitis (PVNS) – 3, leiomyosarcoma – 5, and other – 9). The mean age was 46y, 56% were male, and 67% had greater than 2 prior therapies. Most common ( > 20%) grade 2 or higher TEAEs were anemia (33%), WBC count decrease (28%), fatigue, neutropenia, and lymphopenia (22% each). There were 5 dose limiting toxicities (DLT): 2 for elevated LFTs both of which resolved with dose reduction, 2 for supra-therapeutic S trough levels, and 1 for grade 5 dehydration at dose level (DL) 3. Four subjects experienced a partial response (PR; -44% to -77% by RECIST, 18 – 61 wks on therapy). Seven subjects experienced stable disease (SD; +19.7% to -20.7% by RECIST; 9.4 – 30 wks on therapy). Five subjects progressed on therapy and two subjects experienced early DLTs and did not undergo tumor assessment. The RP2D is DL 3 (S 2mg/PEX 1000mg) with an estimated probability of DLT of 26.7% as determined by TITE-CRM. This recommendation is based on a target DLT rate of 25%. TAMs and immune subtypes from available tissue specimens and historical controls will be presented. Conclusions: 1000mg of PEX in combination with 2mg of S daily has an acceptable safety profile. Objective responses and durable SD was observed in PNVS and MPNST patients justifying proceeding with a multi-center single arm phase 2 study in advanced MPNST. Clinical trial information: NCT02584647. [Table: see text]

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].…”

Cutaneous Findings in Neurofibromatosis Type 1

“…Biological therapies combining MEK/mTOR inhibition are still under investigation in preclinical and clinical trials. Pexidartinib (tyrosine kinase inhibitor) and sirolimus (mTOR inhibitor) combination contributed to stabilize the disease in a phase I study [ 52 ]. Additionally, immunotherapy has also opened up a method for the treatment of MPNST [ 53 ].…”

SHP2 Inhibition as a Promising Anti-cancer Therapy: Function in Tumor Cell Signaling and Immune Modulation

“…A previous study reported a marked depletion of TAM and a shift from M2 to M1 TAM upon CSF1R inhibition, and demonstrated the combination benefit of co-targeting CSF1R and mTOR using PLX3397 and rapamycin in an MPNST xenograft model [87], which provided a translational basis for the MPNSTspecific prospective phase 2 clinical trial (NCT02584647). Preliminary data from this trial reported objective responses and durable stable disease in MPNST patients treated with PLX3397 and sirolimus [88]. Furthermore, combined SHP2i and CSF1Ri demonstrated additive anti-tumor activity in CT26 colon syngeneic mice, a model known to express high levels of TIL [50].…”