Chamberlain, Marc C.

Background Novel treatment options are required in patients with platinum-resistant ovarian cancer (PROC). Myeloid-derived suppressor cells promote a hostile tumor microenvironment and are associated with worse clinical outcomes in PROC. We evaluated the safety and preliminary efficacy of PY159, an agonist antibody to Triggering receptor expressed on myeloid cells-1 (TREM1) that reprograms immunosuppressive intratumoral myeloid cells, and PY314, an antagonist antibody to Triggering receptor expressed on myeloid cells-2 (TREM2) that depletes tumor-associated macrophages, as single agents and in combination with pembrolizumab in subjects with PROC. Methods PY159 and PY314 were individually evaluated in patients with PROC. Patients were treated with monotherapy (PY159 3 mg/kg or PY314 10 mg/kg), based on the recommended dose for expansion derived from the phase 1a studies. At the time of first progression, patients could continue study drug and crossover to combination therapy with pembrolizumab (200 mg) every 3 weeks at the discretion of the investigator. Disease assessment by Response Evaluation Criteria in Solid Tumor version 1.1 was performed every 6 weeks. Results 17 patients were enrolled in the PY159 study (median age 67, range 22–77; median prior therapies 6, range 2–18) and 16 patients in PY314 (median age 65.5, range 49–81; median prior therapies 4, range 2–10). 7 patients in PY159 and 8 patients in PY314 crossed over to combination therapy. Safety events included the following: treatment-related adverse events occurred in 15 patients (88.2%) in PY159 and 9 patients (56.3%) in PY314. Infusion-related reactions occurred in 6 patients (35.3%) in PY159 and 3 patients (18.8%) in PY314. Immune-related adverse events occurred in 13 patients (76.5%) in PY159 (arthralgias) and 1 patient (6.3%) in PY314 (diarrhea). Serious adverse events occurred in 6 patients (36.3%) in PY159 (1 related) and 12 patients (75%) in PY314 (all unrelated). The best radiographic response in PY159 was stable disease in 8/16 patients (50%; median 16 weeks, range 9–33), and in PY314, it was stable disease in 8/16 patients (50%; median 12 weeks, range 6–36). Median PFS was 2.76 months and 2.69 months in PY159 and PY314, respectively. There were no responses in the crossover arm. Conclusions Both PY159 and PY314 were well tolerated, with an acceptable safety profile, as both single agents and in combination with pembrolizumab. Both agents warrant further investigation in heavily pretreated PROC.

Abstract Background Glioblastoma (GBM) has a median survival of <2 years. Pexidartinib (PLX3397) is a small-molecule inhibitor of CSF1R, KIT, and oncogenic FTL3, which are implicated in GBM treatment resistance. Results from glioma models indicate that combining radiation therapy (RT) and pexidartinib reduces radiation resistance. We added pexidartinib to standard-of-care RT/temozolomide (TMZ) in patients with newly diagnosed GBM to assess the therapeutic benefit of altering the tumor microenvironment with pexidartinib. Methods In this open-label, dose-escalation, multicenter, Phase 1b/2 trial, pexidartinib was administered in combination with RT/TMZ followed by adjuvant pexidartinib + TMZ. During Phase 1b, pexidartinib was given 5 or 7 days/week at multiple dosing levels. The primary Phase 1b endpoint was the recommended Phase 2 dose (RP2D). Phase 2 patients received the RP2D with the primary endpoint of median progression-free survival (mPFS). Secondary objectives were median overall survival (mOS), pharmacokinetics, and safety. Results The RP2D of pexidartinib was 800 mg/day for 5 days/week during RT/TMZ, followed by 800 mg/day for 7 days/week with adjuvant TMZ. mPFS was 6.7 months (90% CI: 4.5, 11.5) for the modified intention-to-treat population. The actual mOS was 13.1 months (90% CI: 11.5, 24.5), and the mOS corrected for comparison with matched historical controls was 18.8 months (95% CI: 12.6, 28.0). Conclusions This trial established the RP2D of pexidartinib in combination with RT/TMZ and adjuvant TMZ. Pexidartinib was generally safe and well tolerated. Although the study regimen with pexidartinib was not efficacious, pharmacodynamic studies showed modulation of systemic markers that could lead to alteration of the tumor microenvironment.

2648 Background: To characterize the safety and tolerability of PY314, an immunosuppressive macrophage depleting antibody, as a single agent and in combination with pembrolizumab in subjects with advanced refractory solid tumors including subject’s refractory to checkpoint inhibitors if approved for that indication. Methods: Two were evaluated in subjects with advanced solid tumors, single agent PY314 and PY314 in combination with 200 mg of pembrolizumab using a 3+3 dose escalation study design. Dosing was intravenous and administered once every 3-weeks, a defined cycle. Disease assessment by RECIST 1.1 was performed every 6 weeks. Each stratum included 4 dose levels of PY314 (1, 3, 10, and 20 mg/kg). Pharmacokinetics were evaluated at specified time points. Archival tumor tissue was analyzed for TREM2 expression by immunohistochemistry. Based on preclinical evaluation of TREM2 expression, HR+ HER2- and triple negative breast cancer, colorectal cancer, renal cell cancer, non-small cell lung cancer and gynecologic cancers were studied. Results: 28 subjects (median age 60 years [range 26-76], 22 females and 6 ) with an ECOG PS <2 were enrolled and all, but one was (1 subject withdrew consent after dosing). 15 subjects were treated with single agent PY314 and 13 were treated with the combination. No infusion-related reactions, dose limiting toxicities, suspected unexpected serious adverse reactions or high-grade treatment related adverse events (TRAEs) that resulted in treatment discontinuance was seen. 12 subjects experienced at least one TRAE, and in all but one subject, these were low grade. One subject experienced a treatment-related immune system disorder. serious adverse events, all unrelated to treatment. TREM2 expression in archival tumor ranged from 0.0-20%. PY314 pharmacokinetics were linear, dose proportional, unaffected by concomitant pembrolizumab and with a half-life of 8-9 days. Best radiographic response was stable disease seen in 11 subjects (39.3%) ranging in duration from 9-42 weeks. 6 subjects with stable disease have progressed and 5 remain on treatment. Conclusions: PY314 was well tolerated and has an excellent safety profile both as a single agent and in combination with pembrolizumab. A recommended dose for expansion was derived and enrollment in five prespecified cancers is ongoing. Clinical trial information: 04691375.