A phase II trial of pemetrexed plus oxaliplatin as ≥2nd-line therapy in patients with advanced biliary tract cancer after failure of gemcitabine plus cisplatin based chemotherapy

초록

Background: Gemcitabine/cisplatin (GP)-based chemotherapy (CTx) has been the 1st-line CTx for patients (pts) with advanced biliary tract cancer (aBTC). After progression on 1st line GP-based CTx, FOLFOX has been established as global standard for pts without actionable genetic alterations. But its efficacy is modest and further investigation is required. Pemetrexed is a folate antimetabolite, which has demonstrated its efficacy mainly in lung cancer, and pemetrexed/oxaliplatin (PemOx) has activity in advanced gastric or colorectal cancer. It has convenience of 3-week IV administration rather than continuous infusion, requiring fewer visits and shorter administration time than FOLFOX. This study aimed to evaluate the efficacy and safety of pemetrexed/oxaliplatin (PemOx) as ≥2nd-line therapy in pts with aBTC after the failure of GP-based CTx. Methods: This is an investigator-initiated multicenter trial conducted in four tertiary referral centers in Korea. PemOx was administered as ≥2nd-line therapy (Pem 500mg/m2 IV and Ox 120mg/m2 IV on day 1 every 3 weeks). The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and adverse events (AEs). Based on the Simon’s two stage design, a total of 30 pts were planned to enroll for improvement of ORR to 20% from 5% with 2nd line FOLFOX, with α = 0.05 (two-sided), β = 0.2, and a 10% dropout rate. Results: From Nov 2023 to Nov 2024, all 30 pts were enrolled. The median age of the pts was 68 years (range, 44 to 80 years), and 70% were male. Half of the pts had intrahepatic BTC (n = 16, 53%), followed by extrahepatic BTC (n = 7, 23%), gallbladder cancer (n = 6, 20%), and Ampulla of Vater cancer (n = 1, 3%). All pts received GP-containing CTx and 6 of them received GP plus immunotherapy. PemOx was administered as 2nd-line (n = 24, 80%) and ≥3rd-line therapy (n = 6, 20%). Five pts achieved partial response, resulting in an ORR of 17%. The primary endpoint was not met in this study. There was no difference in ORR according to primary tumor locations, and the disease control rate was 77%. With a median follow-up duration of 8.2 months (range 2.3-14.1), the median PFS and OS were 2.5 months (95% confidence interval [CI], 1.1-3.9) and 9.2 months (95% CI, 5.4-13.0), respectively. Common grade 1-2 AEs included fatigue (n = 8, 27%), pruritus (n = 6, 20%), sensory neuropathy (n = 6, 20%), and anorexia (n = 5, 17%). Grade 3 AEs were reported in 9 patients (30%); infection (n = 6, 20%), AST or ALT elevation (n = 2, 7%), hyperbilirubinemia (n = 2, 7%), and skin rash (n = 1, 3%). There were no grade≥4 AEs, including treatment-related death. Dose delays or reductions were required in 13 (43%) and 4 pts (13%), respectively. Conclusions: PemOx as ≥2nd-line therapy showed modest efficacy and manageable AE profile in pts with aBTC, although the primary endpoint was not met. Clinical trial information: KCT0008608.