Capecitabine-irinotecan (CAPIRI) not superior to irinotecan monotherapy as second-line treatment for patients with advanced gall bladder cancers
The phase II, randomised, open-label GB SELECT study compared the efficacy of a capecitabine-irinotecan doublet (CAPIRI regimen) to that of irinotecan monotherapy in adult patients with advanced gall bladder cancers with disease progression after first-line chemotherapy. Both regimens were found to yield comparable clinical benefit rates, without a statistical improvement in overall or progression-free survival (PFS) with CAPIRI. In contrast, CAPIRI did induce a higher rate of grade 3-4 adverse events. As such, monotherapy with irinotecan was as efficacious as CAPIRI with less toxicity and should be considered as a more reasonable second-line treatment option.
In certain parts of India, the incidence of gallbladder cancers is much higher than in other parts of the world. Thus far, there has been limited data on the use of chemotherapy or targeted therapy as a second-line treatment option in biliary tract cancers. In 2014, a meta-analysis suggested insufficient evidence to recommend chemotherapy or targeted therapy in the second-line treatment of biliary tract cancer, although a cohort of patients may benefit. In order to identify new therapy options for biliary tract cancer, the randomised (1:1) open-label phase II GB SELECT study assessed whether capecitabine (1700 mg/m2/day on days 1-14) plus irinotecan (200 mg/m2 once every three weeks) was superior to irinotecan monotherapy (240 mg/m2 once every three weeks). All patients (N=98) in the study were aged between 18 and 70 years old and suffered from an adenocarcinoma of the gallbladder. In order to be eligible for the study patients had to be previously treated with a gemcitabine-based first-line regimen. In addition, patients needed to have an adequate organ function and stage IV, or recurrent gallbladder cancer. The primary endpoint of the study was 6-month overall survival (OS) rate with 6-month PFS rate, overall response rate (ORR), adverse event rate and quality of life as secondary objectives.
In total, 98 patients were randomised in the study with a median age of 51 years. The vast majority (92%) of patients had an ECOG performance status of 1 and about 40% previously underwent a cholecystectomy. Two thirds of patients presented with elevated CA19.9 levels (> upper level of normal). A third of patients in the study had a poorly differentiated tumour histology and half of the patients had more than one metastatic site.
In the CAPIRI arm, a response rate of 6% was reported (4% complete [CR] and 2% partial response [PR]), while none of the irinotecan treated patients obtained a PR or CR. Clinical benefit rates were comparable between both treatment arms at 41% for CAPIRI and 47% for irinotecan. However, dose modifications due to toxicity were necessary in 27% of the patients treated with CAPIRI as compared to 9% among irinotecan treated patients (p= 0.03). At the six-month landmark, the OS rate was reported at 38.4% with CAPIRI arm and 54.2% in the irinotecan arm (p= 0.93). The median OS was 5.16 months in the CAPIRI arm, versus 6.28 months in the irinotecan arm. Also with respect to PFS, CAPIRI was not superior to irinotecan monotherapy, with six-months PFS rates of 20.4% and 16.5%, respectively (median PFS 2.27 vs. 3.12, respectively p= 0.56).
Quality of life, as assessed by Delta FACT-HEP scores, at two months did not significantly differ between treatment arms (p= 0.38). Looking at prognostic factors, a previous history of cholecystectomy predicted for superior survival rates (p= 0.006). In the CAPIRI arm, there was a numerically (although not statistically) higher incidence of grade 3-4 diarrhoea (16% vs. 10%) and fatigue (20% vs. 14%) as compared to the irinotecan arm.
Monotherapy with irinotecan is as efficacious as combination chemotherapy with CAPIRI as a second-line treatment option for patients with advanced gall bladder cancer. The clinical benefit rates were similar with CAPIRI and irinotecan monotherapy, but CAPIRI came with an increased rate of grade 3-4 adverse events. In addition, combination chemotherapy entails significant dose modifications, hampering the administration of treatment in these fragile patients and thereby contributing to the lack of efficacy. Monotherapy with irinotecan therefore is a reasonable second-line option and can be used as a comparator regimen for future trials.
Ramaswamy A. A randomized phase II multicentric study of capecitabine-irinotecan (doublet) versus irinotecan (monotherapy) in advanced gall bladder cancers progressing on first line chemotherapy (GB-SELECT). Presented at ESMO World GI 2020; Abstract LBA2.