A phase II study of pevonedistat in combination with carboplatin and paclitaxel in advanced intrahepatic cholangiocarcinoma: ECOG-ACRIN EA2187.

4115 Background: Cholangiocarcinoma is a rare and aggressive malignancy with limited therapeutic options, particularly in advanced stages. Resistance to first-line chemotherapy underscores the urgent need for novel therapeutic strategies. Pevonedistat, a first-in-class NEDD8-activating enzyme inhibitor, demonstrated promising activity in this disease in a phase I trial. This study evaluates pevonedistat alone and in combination with carboplatin and paclitaxel in patients with advanced intrahepatic cholangiocarcinoma (ICC). Methods: This was a randomized, non-comparative Phase II trial investigating two treatment arms: pevonedistat monotherapy (Arm A) and pevonedistat combined with carboplatin and paclitaxel (Arm B). Both arms utilized a two-stage minimax design, targeting an objective response rate (ORR) of 30% (null hypothesis: 10%). Eligible patients had unresectable or metastatic ICC with progression after gemcitabine-based therapy. The primary endpoint was ORR per RECIST v1.1. Secondary endpoints included clinical benefit rate (CBR), progression-free survival (PFS), overall survival (OS), and safety. Toxicities were graded using CTCAE v5.0. Results: A total of 40 patients were enrolled, with 34 eligible and treated (17 per arm). Median follow-up was 29.3 months. No objective responses were observed in either arm. Stable disease was the best response in 35.3% (n = 12) of patients (11.8% Arm A, 58.8% Arm B). One patient on Arm B achieved stable disease lasting ≥24 weeks, corresponding to a CBR of 5.9% (95% CI: 0.1%-28.7%). Median PFS was 1.54 months (Arm A) and 2.92 months (Arm B). Median OS was 4.80 months (Arm A) and 6.54 months (Arm B). Grade 3 or higher toxicities occurred in 44.1% of patients, with higher incidence in Arm B (70.6% vs. 17.6% in Arm A). Most common toxicities included fatigue, cytopenias, febrile neutropenia, nausea/vomiting, among others. Two treatment-related fatalities were reported on Arm B: sepsis and colonic perforation. Conclusions: Pevonedistat, alone or in combination with carboplatin and paclitaxel, did not demonstrate sufficient efficacy to warrant further evaluation in advanced ICC. These findings highlight the challenges in treating this aggressive malignancy. Despite the rarity of ICC, the rapid accrual of this study during a global pandemic indicates the potential for continued exploration of novel therapeutic approaches in this disease. Clinical trial information: NCT04175912 .