Combined immune checkpoint inhibition with durvalumab and tremelimumab with and without radiofrequency ablation in patients with advanced biliary tract carcinoma

Abstract

Background: Current standard of care for advanced biliary tract cancer (BTC) is gemcitabine, cisplatin plus anti-PD1/PD-L1, but response rates are modest. The purpose of this study was to explore the efficacy and safety of durvalumab (anti-PD-L1) and tremelimumab (anti-CTLA-4), with and without an interventional radiology (IR) procedure in advanced BTC.

Methods: Eligible patients with advanced BTC who had received or refused at least one prior line of systemic therapy were treated with tremelimumab and durvalumab for four combined doses followed by monthly durvalumab alone with and without an IR procedure until the progression of disease or unacceptable toxicity. Objective response was assessed through CT or MRI by Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1) every 8 weeks. Adverse events (AEs) were recorded and managed. The primary endpoint was 6-month progression-free survival (PFS).

Results: Twenty-three patients with advanced BTC were enrolled; 17 patients were assigned to treatment with durvalumab and tremelimumab (Durva/Treme); and 6 patients were treated with the combination of durvalumab, tremelimumab plus IR procedure (Durva/Treme + IR). The best clinical responses in the Durva/Treme arm were partial response (n = 1), stable disease (n = 5), progressive disease (n = 5), and in the Durva/Treme + IR arm: partial response (n = 0), stable disease (n = 3), progressive disease (n = 3). The median PFS was 2.2 months (95% CI: 1.3-3.1 months) in the Durva/Treme arm and 2.9 months (95% CI: 1.9-4.7 months) in the Durva/Treme + IR arm (p = 0.27). The median OS was 5.1 months (95% CI: 2.5-6.9 months) in the Durva/Treme arm and 5.8 months (95% CI: 2.9-40.1 months) in the Durva/Treme + IR arm (p = 0.31). The majority of AEs were grades 1-2.

Conclusion: Durva/Treme and Durva/Treme + IR showed similar efficacy. With a manageable safety profile. Larger studies are needed to fully characterize the efficacy of Durva/Treme ± IR in advanced BTC.

Trial registration: ClinicalTrials.gov NCT02821754.

Keywords: biliary tract cancer; cholangiocarcinoma; cryoablation; durvalumab; immune checkpoint inhibitor; interventional radiology; radiofrequency ablation; tremelimumab.

FIGURE 1

Study enrollment profile.

FIGURE 2

Treatment paradigm. Patients were treated with durvalumab 1500 mg intravenously (IV) and tremelimumab 75 mg (IV) every 4 weeks for 4 cycles followed by monthly durvalumab 1500 mg IV alone until progression of disease or unacceptable toxicity. Patients in Cohort 1 received drug only. Patients in Cohort 2 received drug and additionally underwent an interventional radiology (IR) procedure on day 36. All patients received a baseline biopsy and on‐treatment biopsy at the time of the interventional radiation procedure. An optional third biopsy was requested on day 85. MRI or CT scan performed every 8 weeks.

FIGURE 3

Efficacy results. (A) Number of months between the on‐study date and the date of death for participants in Cohort 1 and Cohort 2. Colors in (A) represent the reason for treatment termination. (B) Maximal change in tumor size in participants in Cohort 1 and Cohort 2. Colors in (B) represent a clinical response to treatment. AE, adverse event; clin, clinical; PD, progressive disease; PR, partial response; SD, stable disease.

FIGURE 4

Survival plots. (A) Progression‐free survival (PFS) and (B) overall survival (OS) for participants in Cohort 1 and Cohort 2. No significant difference between the two cohorts for PFS (0.27) or OS (p = 0.31).

FIGURE 5

Gene expression and somatic variant analysis of tumor biopsies. (A) Oncoplot of known driver genes in baseline tumor samples; gene expression (RNASeq) for CIBERSORTx. The top bar plot presents the tumor mutation burden (TMB) from WES per sample, defined as the number of nonsynonymous mutations per Mb of coding region. The right bar plot presents the number and percent of samples in which the gene is mutated. Samples were analyzed for immune cell subsets according to Job et al. (B) Relative abundance of different immune cell types in baseline tumors, as estimated by CIBERSORTx.

FIGURE 6

Immune cell profiles of tumor biopsies. RNAseq results from tumor biopsies from 15 patients. Immune cell subtypes are shown on the right of matrix plot. All five previously described immune subtypes were present. The “immune classical” subtype was the most common subtype.