BARCELONA – The immune checkpoint inhibitor nivolumab (Opdivo) shows activity against biliary tract cancers (BTC) that have progressed on prior systemic therapies, investigators report.
Among 27 patients with intra- and extrahepatic cholangiocarcinoma and cancers of the gallbladder for whom at least one prior line of therapy had failed, the overall response rate with nivolumab monotherapy was 18.5%, reportedof Moffitt Cancer Center, in Tampa.
“Nivolumab demonstrated clinical efficacy in BTC patients. It was very well tolerated, with few grade 3 or 4 adverse events,” he said at the European Society of Medical Oncology World Congress on Gastrointestinal Cancer.
The worldwide incidence of biliary tract cancers has grown over the last 4 decades.
“It is a very aggressive disease, with 5-year overall survival rate of advance disease of less than 2%,” he said.
The standard of care for first-line treatment of advanced disease is gemcitabine and cisplatin, but there is no standard treatment available for patients for whom first-line therapy fails.
Median survival of patients with biliary tract cancers who are receiving second- or third-line therapies is approximately 6-7 months, Dr. Kim said.
The rationale for using nivolumab in this setting comes from evidence suggesting that cholangiocarcinoma is related to dysregulated immunity, with carcinogenesis linked to autoimmune conditions such as primary sclerosing cholangitis, and to chronic parasitic infections.
“Immune regulatory protein PD-1 is upregulated more in intrahepatic cholangiocarcinoma tissues than in adjacent normal tissue, and patients with memory CD8 T cells had longer relapse-free survival and overall survival in extrahepatic cholangiocarcinoma after resection,” he explained.
To see whether the use of an immune checkpoint inhibitor could provide clinically meaningful benefit in patients with advance biliary tract cancers, the investigators conducted a phase 2, two-stage study. They first accrued 18 patients with histologically confirmed, treatment-refractory biliary tract malignancies and treated them with nivolumab 240 mg IV every 2 weeks for 16 weeks, followed by 480 mg IV every 4 weeks.
According to the study protocol, if one or more patients had a complete or partial response, additional patients would be enrolled. As of May 2018, 34 patients had been treated.
The median patient age was 64.5 years. Two-thirds of the patients (64.7%) had intrahepatic cholangiocarcinoma, 2.9% had extrahepatic cholangiocarcinoma, and 32.4% had tumors of the gallbladder.
Twenty patients were failed by their first-line therapies, and 14 were failed by two or more lines of therapy. All 34 received at least one dose of nivolumab.
Of this group, 10 patients remained on study at the time of Dr. Kim’s presentation. Fifteen were withdrawn for progressive disease according to Response Evaluation Criteria in Solid Tumors (RECIST) revision 1.1, and 9 due to clinical progression.
Of 27 patients evaluable for investigator-assessed overall responses – the primary endpoint – 5 patients (18.5%) had a partial response, and 11 (40.7%) had stable disease, for a disease-control rate of 59.3%. The remaining 11 evaluable patients had progressive disease.
“Of interest, of our five patients who had a partial response, three had a diagnosis of intrahepatic cholangiocarcinoma, and two had a diagnosis of a gallbladder tumor,” Dr. Kim said.
All five patients remained on treatment at the time of the presentation, with response duration ranging from 24 to 64 weeks. The median duration of response in these patients has not been reached.
Median progression-free survival for all 34 patients treated with at least one dose was 3.5 months. Overall survival with a median follow-up of 9.9 months has not been reached. The 6-months overall survival rate was 73.5%.
Approximately 20% of patients experienced grade 3 or 4 treatment-related adverse events. There were no grade 4 events and no treatment-related deaths.
The most common grade 3 events were hyponatremia in three patients (8.8%), and lymphopenia, colitis, and hyperbilirubinemia in one patient each (2.9%).
The investigators have collected tissues from all patients and plan to present data from biomarker studies at future meetings. Based on the results of this study, they plan to add 20 more patients to the phase 2 trial to confirm efficacy of nivolumab in this setting.