Clinical Summary:

• Nilofer Azad, MD, discusses results from a randomized phase 3 trial evaluating paclitaxel with or without tovecimig, a bispecific antibody targeting VEGF-A and DLL4, in patients with previously treated advanced biliary tract cancer.

• Tovecimig plus paclitaxel significantly improved objective response rates (18% vs 5%) and progression-free survival compared with paclitaxel alone, although overall survival was not significantly improved and treatment discontinuations were more frequent with the combination.

• These findings support further investigation of dual VEGF-A/DLL4 inhibition as a treatment strategy for previously treated advanced biliary tract cancer, highlighting improved antitumor activity while emphasizing the importance of balancing efficacy with treatment-related toxicity.

Nilofer Azad, MD, Johns Hopkins University, Baltimore, Maryland, discusses results from a randomized phase 3 trial evaluating paclitaxel with or without tovecimig in patients with previously treated advanced biliary tract cancer. 

Dr Azad reviews the significant improvements in objective response rate and progression-free survival observed with tovecimig plus paclitaxel, while addressing the absence of a statistically significant overall survival benefit and the potential influence of treatment crossover. She also discusses the safety profile of dual VEGF-A/DLL4 inhibition, including increased treatment discontinuations and antiangiogenic toxicities, and the potential role of this combination in expanding later-line treatment options.

Transcript: 

Hi, I'm Nilofer Azad and I am a professor of oncology at Johns Hopkins, and I had the pleasure of reporting the COMPANION-002 study at ESMO just last week.

The COMPANION-002 study is a randomized phase 3 trial of tovecimig and paclitaxel compared to paclitaxel alone. Tovecimig is a bispecific antibody that targets VEGF-A as well as DLL4.

By targeting both of these proteins together, this is really an anti-angiogenic strategy, and the trial was enrolled for patients with biliary tract cancer. The study moved forward because there was both pre-clinical and early clinical data showing that that combination would be effective in biliary tract cancer.

So the way the study was designed, it was a 2:1 randomization, tovecimig plus paclitaxel versus paclitaxel alone. Patients were stratified based on their performance status, whether they had metastatic or localized disease that recurred, and their anatomical subsite of biliary tract cancer. And the primary end point of the study was overall response rate.

Now, the trial allowed for crossover if patients were randomized to the single-agent paclitaxel arm. While progression-free survival was a key secondary end point, overall survival was measured, but we knew that there may be some challenges due to the crossover design.

When we look at the patient population that was enrolled, they were very balanced, with a little over half of the patients being intrahepatic cholangiocarcinoma patients and about 90% of the patients being metastatic at diagnosis.

The trial was overall positive with a statistically significant improvement in overall response rate. That response rate was 18% compared to 5% in the paclitaxel-alone arm. There was also a statistically significant improvement in progression-free survival.

There was not a statistically significant difference in overall survival, but over half of the patients in the paclitaxel arm did cross over. So approximately 88% of patients had exposure to tovecimig, which likely compromised that overall survival end point.

In terms of toxicity and tolerability, there was about a third of patients (30%) that discontinued tavegimab or paclitaxel compared to 15% with the paclitaxel-alone arm. But when we look at that kind of sweet spot of dose intensity of 90% to 110% of the intended dose, that was the highest in the tovecimig arm at 42%.

If you overall look at the toxicity of the regimen, the combination had a slightly increased number of patients that had grade 3 toxicities associated with anti-VEGF agents like hypertension, but there were no new safety signals with the combination than what had been reported previously.

In total, we have an active regimen of tovecimig plus paclitaxel in the second-line setting for patients with biliary tract cancer. There was a statistically significant difference in both response and progression-free survival. And this regimen is something really worth considering for further exploration for patients with biliary tract cancers.

Source: 

Azad NS, Hu ZI, Pathak PS, et al. A randomized trial of paclitaxel ± tovecimig in previously treated patients with advanced biliary tract cancer. Presented at ESMO Congress. October 23-27, 2026; Madrid, Spain. 459O.