Tovecimig-Based Doublet Boosts Response And PFS In Advanced Biliary Tract Cancer

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In the COMPANION-002 trial, tovecimig plus paclitaxel improved response rate and progression-free survival compared with paclitaxel alone for previously treated advanced biliary tract cancer. The study did not show an overall-survival benefit, and serious adverse events, including treatment-related deaths, were reported with the combination.

The investigational drug tovecimig plus paclitaxel improved response rate and progression-free survival compared with paclitaxel alone in previously treated advanced or metastatic biliary tract cancer, according to the randomized COMPANION-002 trial. The study did not find an overall-survival benefit, leaving the combination’s effect on how long patients live—and its place in treatment—unsettled.

In the phase II/III trial, 18.0% of patients receiving the combination had a response, compared with 5.3% receiving paclitaxel alone (P=0.0228). The result met the trial’s primary endpoint. Median progression-free survival, the time patients lived without their cancer worsening, was 4.7 months versus 2.6 months (hazard ratio 0.44, 95% CI 0.30-0.66; P<0.0001).

Overall survival was 8.9 months with the doublet and 9.4 months with paclitaxel (hazard ratio 1.05, 95% CI 0.7-1.5; P=0.77). The trial allowed patients assigned to paclitaxel to switch to the combination after their cancer progressed. Among 57 patients in the paclitaxel group, 31 crossed over. Presenter Nilofer S. Azad, MD, said that crossover may have confounded the overall-survival comparison; it does not, however, establish that the combination improves survival.

The study enrolled 168 patients whose disease had progressed after one prior line of gemcitabine and cisplatin. Participants had locally advanced or metastatic cancer and an ECOG performance status of 0 or 1; patients with known targetable mutations were excluded. They were assigned in a 2:1 ratio to the combination or paclitaxel alone.

Response Gains Without Longer Survival

The findings offer a potential treatment signal for patients whose advanced biliary tract cancer has progressed after first-line chemotherapy, a group with limited treatment options. The response and progression-free survival results were statistically significant, but they do not answer whether patients live longer or whether the added time without progression outweighs the treatment burden.

Safety is part of that assessment. The most common treatment-emergent adverse events with the doublet were hypertension (69.4%) and fatigue (66.7%). Grade 3 or higher events occurred in 93.5% of combination recipients and 64.2% of those given paclitaxel alone. Six fatal adverse events were reported in the combination arm, including two deaths considered treatment-related—one from septic shock and one involving renal failure and sepsis. One fatal adverse event occurred in the paclitaxel arm. These results warrant attention in any discussion of the regimen’s potential role.

How COMPANION-002 Tested the Drug

Tovecimig is a bispecific antibody targeting VEGF-A and DLL4. Azad said earlier testing and preclinical work supported studying it with paclitaxel in biliary tract cancer. The COMPANION-002 data were presented at the European Society for Medical Oncology annual congress in Madrid and published at the same time in the Journal of Clinical Oncology.

Invited discussant Sebastián Mondaca, MD, MBA, described the results as encouraging in a setting with substantial unmet need, while questioning whether they are enough to change practice. He said a phase III comparison against FOLFOX—fluorouracil, leucovorin and oxaliplatin—with a clear overall-survival benefit would be preferable. The trial’s paclitaxel control arm and permitted crossover are relevant when interpreting its survival findings.

“Altogether, this combination presents a promising new strategy for patients with biliary tract cancer.”

— Nilofer S. Azad, MD, presenting investigator

Survival Benefit and Practice Role

The trial showed no overall-survival advantage in its main comparison, and the reported crossover is a possible complication in interpreting that result. The source report does not establish what the survival comparison would have been without crossover. A subgroup comparison among patients who crossed over and those who did not is also not the same as a randomized comparison: the 31 crossover patients had median overall survival of 12.8 months, versus 6.1 months among 26 who did not cross over, but patients were not randomly assigned to those two post-progression groups.

It remains unclear whether the response and PFS gains will lead to a change in treatment guidelines or routine care. The supplied report does not provide detailed results for every patient subgroup, duration of response, or a further confirmatory trial plan. The frequency of serious adverse events and the two treatment-related deaths also matter when weighing the potential benefit.

Guideline Review and Further Testing

Mondaca called for a formal guideline committee review, but the source report does not give a decision date or say whether a committee has begun that review. The results may inform that discussion; they do not, by themselves, establish a new standard of care.

A phase III study comparing the regimen with FOLFOX and showing an overall-survival benefit was identified by Mondaca as a desired next step, not as a confirmed trial plan. Further evidence would need to clarify the survival effect, account for crossover, and characterize the balance between disease control and toxicity. Until such developments are reported, the treatment’s regulatory status and clinical availability are not established by the information provided.

Key Questions

What did COMPANION-002 find?

The trial found a higher response rate with tovecimig plus paclitaxel than with paclitaxel alone (18.0% versus 5.3%) and longer median progression-free survival (4.7 versus 2.6 months). It did not find an overall-survival benefit.

Did the combination help patients live longer?

The reported overall-survival comparison did not show a benefit: median survival was 8.9 months with the combination and 9.4 months with paclitaxel. Investigators said crossover from paclitaxel to the combination may have affected the analysis, but the reported results do not prove a survival benefit.

Who was included in the trial?

The 168 participants had advanced or metastatic biliary tract cancer that had progressed after one prior line of gemcitabine and cisplatin. They had an ECOG performance status of 0 or 1, and people with known targetable mutations were excluded.

What side effects and safety concerns were reported?

Common treatment-emergent events with the doublet included hypertension and fatigue. Grade 3 or higher adverse events occurred in 93.5% of combination recipients. Six fatal adverse events were reported in that group, including two considered treatment-related; one fatal adverse event occurred with paclitaxel alone.

Does the result mean the combination is now standard treatment?

The report does not establish that. The trial showed response and PFS gains but no overall-survival improvement, and the invited discussant said a phase III comparison with FOLFOX and a clear survival benefit would be desirable. Guideline and regulatory decisions were not reported.

Source: rss