PD-9 Three-arm phase II/III randomized controlled trial in patients with unresectable/metastatic gall bladder cancer with poor performance status: Erlotinib or capecitabine v/s best supportive care

Abstract

Currently there is no standard of care for Eastern Cooperative Oncology Group (ECOG) poor performance status (PS) patients (PS-III) with unresectable/metastatic Gall Bladder Cancer (GBC). Being unfit for chemotherapy, these patients receive only best supportive care (BSC) resulting in a very dismal outcome. A report published from M.D. Anderson Cancer Centre stated median overall survival (OS) of only one month in patients with poor PS with GBC. This single centre, prospective randomized controlled phase II/III, open label trial was done at a tertiary health care centre in India. Patients (above 18 years) with histologically confirmed unresectable/ metastatic GBC with adequate organ function and ECOG PS-III were included. Patients with prior adjuvant chemotherapy/erlotinib/capecitabine in last 6 months, active malignancy other than GBC, lactating and pregnant women, and HIV-positive status were excluded. Random allocation (1:1:1) was done to one of the three arms - Erlotinib (150 mg OD) + BSC, Capecitabine + BSC or BSC alone using computer-generated sequence. The primary end point was median OS, defined as time from randomisation to death, in the intention-to-treat population. A sample size of 105 was estimated, assuming median OS in BSC, Erlotinib+BSC and Capecitabine+BSC as 2, 4 and 5 months respectively (taking two-sided alpha error as 0.05 and power as 80%). Between Dec 27, 2017 and January 18, 2021, 201 patients were screened, of which 105 were randomized to Erlotinib +BSC (n = 36), Capecitabine +BSC (n = 36) or BSC alone arm (n = 33). After a median follow up of 10 months (IQR 3.9- 11.5), there were 82 deaths in the whole cohort. The median OS in Erlotinib arm was significantly higher at 3.84 months (2.33- 4.67) compared to 1.77 months (1.18- 2.73) in BSC only arm, with hazard ratio (HR) of 0.50 (95% CI - 0.26 -0.95), p = 0.02. However, there was no statistically significant difference observed in survival between Capecitabine +BSC over BSC alone - median OS 2.46 months (1.67-3.58), HR - 0.70 (95% CI - 0.38- 1.2), p = 0.30. Compared to only 15.1% (5/33) in BSC arm, the disease control rate (complete response + partial response + stable disease) at 6-8 weeks was 58.3% (21/36) in Erlotinib arm (p = 0.004) and 47.2% (17/36) in Capecitabine arm (p = 0.04). Grade III/IV toxicities were reported in 12 patients (33.3%) in Erlotinib arm (skin rash and diarrhea being most common at 8% each) and in 5 patients (13.8%) in Capecitabine arm (anemia and fatigue most common at 6 % each). No treatment related deaths were reported in either group. Addition of Erlotinib to BSC significantly improves OS in patients with unresectable/metastatic GBC, otherwise unfit to receive chemotherapy, with acceptable toxicity profile.