Irinotecan Monotherapy Shows Similar Activity, Improved Safety as Chemo Combo in Advanced Gallbladder Cancer

Irinotecan monotherapy demonstrated similar clinical activity and improved safety compared with capecitabine plus irinotecan in patients with advanced gallbladder cancer, representing a potential second-line treatment for frail patients.

Irinotecan monotherapy demonstrated similar clinical activity and improved safety compared with capecitabine plus irinotecan (CAPIRI) in patients with advanced gallbladder cancer, representing a potential second-line treatment for frail patients, according to findings from the phase 2 GB-SELECT trial that were presented at the 2020 ESMO World Congress on Gastrointestinal Cancer.

The 6-month overall survival (OS) rate was 38.4% in the CAPIRI arm versus 54.2% in the irinotecan-alone arm (P = .93). The median OS was 5.16 months (95% CI, 4.26-6.06) versus 6.28 months (95% CI, 4.25-8.3), respectively.

“Monotherapy with irinotecan is a reasonable second-line option and should be the comparator regimen for future trials,” lead study author, Anant Ramaswamy, MD, DM, ECMO, of Tata Memorial Hospital, in Mumbai, India, said in a virtual presentation during the Congress.

Gallbladder cancers are significantly more common in certain parts of India compared with other parts of the world. Limited data are available on the use of chemotherapy or targeted therapy as second-line therapy in gallbladder cancer. In 2014, a metanalysis suggested that there was inadequate evidence to support the use of chemotherapy as second-line treatment in all patients, but that a subset may benefit.

Over the past 2 years, a number of investigational regimens have emerged as potential second-line treatments, including modified FOLFOX, modified XELIRI, pemigatinib (Pemazyre), and nivolumab (Opdivo).

Without a definitive standard of care, investigators launched the GB-SELECT trial in India to evaluate the efficacy and safety of CAPIRI versus irinotecan alone.

To be eligible for enrollment, patients had to be between the ages of 18 and 70, have a diagnosis of gallbladder cancer, and have received gemcitabine-based therapy in the frontline setting.

In the open-label trial, patients were randomized 1:1 to 1700 mg/m2 of capecitabine on days to 1 to 14 plus 200 mg/m2 of irinotecan every 3 weeks (n = 49) versus 240 mg/m2 of irinotecan every 3 weeks (n = 49). Patients received follow-up every 3 weeks while on chemotherapy, and post progression per physician discretion.

The percentage of patients who were alive at 6 months served as the primary end point of the trial. Key secondary end points included the 6-month progression-free survival (PFS) rate, response rate, adverse event (AE) rate according to Common Terminology Criteria for AEs version 4.03, and quality of life (QoL).

With an alpha of 10%, power of 80%, 2-year accrual, and study duration of 1 year, the study required a total of 89 patients. Factoring in the 10% attrition rate of randomized patients, investigators enrolled a total of 98 patients.

Baseline characteristics were generally well balanced between arms. Numerically more males were randomized to CAPIRI (47% vs 31%), and more females were randomized to irinotecan alone (69% vs 53%). However, this was not found to be statistically significant. In both arms, patients had a median age of 51 and a majority had an ECOG performance status of 1 (92%). A total of 37% of patients in the CAPIRI arm and 41% of patients in the irinotecan-alone arm had prior cholecystectomy, and 61% and 65% of patients had raised CA 19.9 above the upper limit of normal, respectively.

Regarding disease characteristics, approximately 36% of patients had poorly differentiated major sites of metastases or recurrence in locoregional, hepatic, pulmonary, or peritoneal areas. Approximately half of patients had at least 1 site of metastatic disease and 45% were platinum sensitive.

Patients received a median of 3 cycles of CAPIRI versus 4 cycles of irinotecan and 12 continued on treatment in both arms. The clinical benefit rate was 41% and 47%, respectively. More patients achieved stable disease on irinotecan versus CAPIRI (47% vs 35%). However, a higher percentage of patients on CAPIRI achieved a complete response and partial response, at 4% and 2%, respectively, versus 0% on irinotecan.

Dose modifications were made for 27% of patients who received CAPIRI versus 9% of patients who received irinotecan alone (P = .016).

The 6-month PFS rate was 20.4% in the CAPIRI arm versus 16.5% in the irinotecan arm (P = .56). The median PFS was 2.27 months (95% CI, 1.37-3.17) and 3.12 months (95% CI, 1.04-5.2), respectively.

In terms of safety, grade 3/4 hematologic AEs in the CAPIRI and irinotecan-alone arms, respectively, included neutropenia (2% vs 8%), thrombocytopenia (4% vs 4%), febrile neutropenia 4% vs 0%), and anemia (4% vs 4%). Grade 3/4 GI AEs consisted of diarrhea (16% vs 10%), constipation (8% vs 4%), nausea and vomiting (4% vs 8%), fatigue (20% vs 14%), and hyponatremia (4% vs 6%), respectively.

The QoL analysis showed no difference in the Functional Assessment of Cancer Therapy-Hepatobiliary Cancer (FACT-HEP) scores at 2 months (P = .38). The estimated mean value of the change in FACT-HEP scores at 2 months was 19.441 (standard error [SE] = 5.717) in the CAPIRI arm versus 12.649 (SE = 4.810) in the irinotecan-alone arm.

Prognostic factors of significance included prior cholecystectomy (HR, 0.47; 95% CI, 0.28-0.81), raised CA 19.9 (HR, 1.6; 95% CI, 0.93-2.73) and platinum sensitivity (HR, 0.71; 95% CI, 0.43-1.15).

“Patients with gallbladder cancer are already a fragile group of patients because of the degree of liver metastases, pretreatment, and prior history of obstructive jaundice. Treatments should be safe and easily useable. In this study, we showed [that irinotecan] monotherapy is very safe and [leads to] moderately efficacious survival,” concluded Ramaswamy.


  1. Ramaswamy A, et al. 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: 2020 ESMO World Congress on Gastrointestinal Cancer 2020; July 1-4, 2020; Virtual. Abstract LBA-2.