Pembrolizumab explored in the treatment of advanced biliary tract cancer

21st April 2023

Pembrolizumab plus gemcitabine and cisplatin improved overall survival compared to chemotherapy alone in advanced biliary tract cancer

Patients with biliary tract cancers often present at a late stage when curative surgery is not possible. Current treatment for advanced biliary cancer involves chemotherapy with cisplatin plus gemcitabine and which improves survival. Other work suggests that cisplatin treatment together with PD-1/PD-L1 blockade could increase the clinical response, particularly in lung cancer. In addition, treating advanced biliary cancer with pembrolizumab alone provides a small, but durable anti-tumour activity. However, one study with the PD-L1 inhibitor, durvalumab in advanced biliary tract cancer with cisplatin chemotherapy, showed good efficacy and an acceptable safety profile.

Researchers in the current study, sought to assess whether pembrolizumab plus cisplatin and gemcitabine chemotherapy might improve overall survival in advanced biliary tract cancer. Their randomised, placebo-controlled trial involved adult patients with previously untreated, unresectable, locally advanced or metastatic biliary tract cancer. Adults were randomised 1:1 to pembrolizumab plus chemotherapy or placebo and chemotherapy. The primary outcome was overall survival whereas the secondary outcome explored safety.

Pembrolizumab plus chemotherapy and overall survival

There were 1069 participants of whom, 533 had pembrolizumab followed for 25.6 months. Median overall survival was 12·7 months with pembrolizumab plus chemotherapy and 10·9 months in the placebo group (hazard ratio, HR = 0·83, 95% CI 0·72 – 0·95, p = 0.0034).

A similar proportion of pembrolizumab and placebo patients had treatment-related adverse events with a maximum grade of 3 to 4 (70% vs 69%). However, death due to adverse events was slightly less with pembrolizumab (6% vs 9%).

Citation
Kelly KR et al. Pembrolizumab in combination with gemcitabine and cisplatin compared with gemcitabine and cisplatin alone for patients with advanced biliary tract cancer (KEYNOTE-966): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2023

CTX-009 shows promise in biliary tract cancer

27th January 2023

CTX-009 and paclitaxel improved the overall response rate in advanced biliary tract cancer when used as a second and third-line treatment

CTX-009 in combination with paclitaxel improved the overall response rate in patients with unresectable, advanced, metastatic or recurrent biliary tract cancer, according to findings presented at the 2023 ASCO Gastrointestinal Cancer Symposium in San Francisco.

CTX-009 is a novel, bispecific antibody which causes blockade of delta-like ligand 4 Notch-1 signalling, inhibiting tumour growth as well as an blocking vascular endothelial growth factors (VEGF), that are recognised as important factors in tumour biology with role in angiogenesis. Since the overall response rate to the use of a single VEGF inhibitor is often low, there is a need for additional angiogenesis-based therapies. In a previously reported release from the manufacturer, Compass Therapeutics, data from a phase 2 trial showed that when added to paclitaxel, CTX-009 demonstrated a 42% overall response rate based on data from 10 patients with partial responses.

The findings presented at ASCO 2023, relate to an open-label, multi-centre, single arm, phase 2 trial, in patients with unresectable, advanced biliary tract cancer. Individuals were given CTX-009 as either a second or third-line treatment at a dose of 10 mg/kg biweekly in combination with paclitaxel. The primary aim of the study was to assess the objective response rate (ORR) based on RECIST v1.1.

CTX-009 and overall response rate

A total of 24 patients (median age = 61.5 years, 58.3% male) were included and of whom, 11 were receiving CTX-009 as a second-line treatment and the remainder as a third-line agent. The median duration of follow-up was 12.1 months.

The ORR was 37.5% (95% CI 18.8 – 59.4%) and this was higher for patients receiving the drug as a second-line treatment (ORR = 63.6%) though lower when used third-line (ORR = 15.4%). In addition, the median progression-free survival was 9.4 months and the median overall survival 12.5 months.

In terms of safety, treatment-emergent adverse events > grade 3 occurred in 95.8% of patients and 6 patients discontinued treatment due to adverse events.

The authors concluded that CTX-009 showed promise in biliary tract cancer patients and called for further studies to examine the efficacy and safety of the regime.

Citation
Oh DY et al. CTX-009(ABL001), a bispecific antibody targeting DLL4 and VEGF A, in combination with paclitaxel in patients with advanced biliary tract cancer (BTC): A Phase 2 study. ACSO GI Cancer Symposium 2023