Musculoskeletal adverse events with PEGPH20 treatment and management in patients with previously untreated metastatic pancreatic ductal adenocarcinoma (PDA)

Abstract

Introduction: Hyaluronan (HA) accumulation in the tumor microenvironment is associated with aggressive malignancy and poor outcomes in solid tumors. PEGylated recombinant human hyaluronidase PH20 (PEGPH20) is an investigational agent that degrades HA, thus remodeling the tumor stroma to facilitate access of cancer therapies. Specific musculoskeletal events (MSEs), such as muscle spasms, arthralgia, and myalgia, are well documented during PEGPH20 treatment. In Phase 1 studies of PEGPH20 monotherapy, MSEs were dose‐limiting. Here we further characterize MSEs observed in the phase 2 study of PEGPH20 in combination with gemcitabine and nab‐paclitaxel (AG) in patients with previously untreated metastatic PDA. Methods: In Stage 1 of the study, patients were randomized 1:1 to AG with or without PEGPH20 (PAG) (P; 3 mg/kg IV 2x/wk x 3 wks in Cycle 1, then once weekly x 3 wks in Cycles 2+) every 28 days. A clinical hold related to an imbalance in thromboembolic events in the PAG arm resulted in ≥40% of patients discontinuing PEGPH20 at the time of the clinical hold. Following the clinical hold (Stage 2), additional patients were randomized 2:1 to PAG vs AG. Dexamethasone 8 mg was administered orally within 2 hours before and 8‐12 hours after each dose of PEGPH20 to lessen the incidence and severity of MSEs (based on Phase 1 single‐agent data in patients with solid tumors). We analyzed data relating to adverse event frequency, severity, timing, and management in patients who received at least one dose of study medication. Results: 279 patients were enrolled; 260 patients comprise the safety population for this analysis. Patients in the PAG and AG arms each received a median of 3.3 months of study treatment. Overall, the proportion of patients with treatment‐emergent MSEs was higher in the PAG armcompared with the AG arm(86% vs 46%); the corresponding rates for Grade 3 MSEs were 19%and 6%. Grade 4 or 5 MSEs were not observed. Most common MSEs (all grade/grade 3) were muscle spasms in the lower and upper extremities (58%/13% PAG vs. 6%/1% AG), and less frequently arthralgia (28%/2% PAG vs.14%/1% AG) and myalgia (27%/5% PAG vs.12%/0 AG). Median (range) time to (any Grade) MSE onset was 2 (0‐287) days in the PAG armand 8 (0‐196) days in the AG arm. Median duration of Grade 3 MSEs was 9 (5‐14) days for PAG vs 8.5 (2‐22) days for AG. Five (4%) patients experienced MSEs that led to PAG discontinuation: muscle spasms (n=4) and myalgia (n=1). Medications were administered in 57(PAG) vs. 20(AG) of the MSE episodes to manage musculoskeletal events, predominantly in patients with Grade 3 MSEs. Conclusion: MSEs are commonly observed with PAG and AG treatment when administered at the specified doses, but with a higher incidence in patients treated with PAG. MSEs are primarily Grade 1 or 2 in severity and infrequently lead to treatment discontinuation. Additional data describing the time course, associated dose modifications, and management of MSEs will be presented.