The safety and efficacy of PEN-221 somatostatin analog (SSA)-DM1 conjugate in patients (PTS) with advanced GI mid-gut neuroendocrine tumor (NET): Phase 2 results.
Authors: Daniel M. Halperin, Melissa Lynne Johnson, Jennifer A. Chan, Lowell L. Hart, Natalie Cook, Vipul M. Patel, Benjamin L. Schlechter, Judith Cave, Afshin Dowlati, Lawrence Scott Blaszkowsky, Tim Meyer, Jennifer Rachel Eads, Daniel Culp, Kristina Kriksciukaite, Laura Mei, Mark Bilodeau, Jeffrey Bloss, Matthew H. Kulke
Journal: Journal of Clinical Oncology (2021)

4110 Background: PEN-221 is a small molecule drug conjugate composed of a SSTR2 binding somatostatin analog linked to the toxin DM1. PEN-221-001 was a study which assessed the safety, tolerability, pharmacokinetics (PK), and preliminary efficacy of PEN-221 in well differentiated neuroendocrine tumors (NETs) and small cell lung cancer. Here we present the efficacy outcomes for patients enrolled in the GI mid-gut cohort and the safety data for the entire study. Methods: Pts with advanced, SSTR2+ (by imaging) GI mid-gut NETs were enrolled in this cohort of the study. The primary objective was to determine the safety and efficacy of PEN-221 given intravenously, every (q) 3 weeks in patients with documented radiographic progression within the 6 months prior to enrollment. Patients previously treatment with cytotoxic chemotherapy were excluded. Preliminary efficacy was assessed using RECIST 1.1. A clinically meaningful efficacy result was defined as a Clinical Benefit Rate (CBR) &gt; 75% and a median progression-free survival (mPFS) &gt; 8 months. Results: 32 patients (17M/15F) were enrolled between January 2018 to June 2020 and the data cut-off for this report is July 31, 2020. The first nine patients were treated at the phase 1 determined Maximum Tolerated Dose of 18 mg. After review of the safety, tolerability, and PK data from these pts, the regimen was amended to 8.8 mg/m 2 for all subsequent pts to achieve more uniform exposures (AUC) across all pts and reduce toxicity in pts with lower body-surface areas (BSA). The mean number of cycles received by pts in this cohort was 7 (range 1-18), with 5 pts still on treatment at time of data lock. PEN-221 was well tolerated in all pts at the dose of 8.8 mg/m 2 . The most frequent (≥20% pts) PEN-221 related adverse events of any grade were fatigue (39%), nausea (38%), diarrhea (35%), decreased appetite (30%), infusion reaction (24%), AST/ALT/Alk Phos increase (24%), and peripheral neuropathy (21%). Only 14 (10%) of these events were grade 3 or greater. Grade 3 PEN-221 related adverse events which were reported in 2 or more pts included fatigue (7.6%), ALT/AST/Alk Phos increase (7.6%), and peripheral neuropathy (3%). PEN-221 plasma median t 1/2 was ̃4.5 h, with exposures uniform using BSA based dosing. Of the 26 pts who were evaluable for response, 23 (88.5%) had stable disease (SD) reported as their best response with a CBR of 88.5%. Target lesion shrinkage was observed in 10 (38%) patients. The median PFS for this cohort was 9 months (CI 5 – 16.5 months). Tumor marker data (Neuron Specific Enolase, Chromogranin A, 5-Hydroxyindoleacetic Acid, and Circulating Tumor Cells) will also be presented. Conclusions: PEN-221 appears well tolerated at 8.8 mg/m 2 q 3 weeks and has demonstrated efficacy exceeding its clinical efficacy goals with a CBR of 88.5% and a mPFS of 9 months. A randomized trial of PEN-221 in GI mid-gut NET patients is now in development. Clinical trial information: NCT02936323.