In the phase II/III COMPANION-002 trial, investigational tovecimig combined with paclitaxel significantly improved response rate and progression-free survival (PFS) in patients with previously treated advanced or metastatic biliary tract cancer.
The randomized study showed that the first-in-class bispecific antibody, tovecimig, plus paclitaxel produced a response in 18.0% of patients versus 5.3% with paclitaxel alone (P=0.0228), meeting the trial’s primary endpoint, reported Nilofer S. Azad, MD, of Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore.
The doublet also significantly improved PFS, with a median of 4.7 months versus 2.6 months for paclitaxel alone (HR 0.44, 95% CI 0.30-0.66, P<0.0001).
There was no overall survival (OS) benefit with tovecimig plus paclitaxel, at 8.9 months versus 9.4 months with paclitaxel alone (HR 1.05, 95% CI 0.7-1.5, P=0.77). Azad suggested that the crossover allowed in the trial may have confounded the OS results.
“Altogether, this combination represents a promising new strategy for patients with biliary tract cancer,” Azad said at the European Society for Medical Oncology (ESMO) annual congress in Madrid. Trial data were published simultaneously in the Journal of Clinical Oncology.
The results were described as encouraging given the combination’s mechanism of action and the high unmet need in this setting, said Sebastián Mondaca, MD, MBA, an ESMO invited discussant from the Pontificia Universidad Católica de Chile in Santiago. He noted, however, that it was unclear whether the findings would change clinical practice.
“Ideally, we would want a phase III trial comparing the doublet with FOLFOX [fluorouracil, leucovorin, and oxaliplatin] to demonstrate a clear overall survival benefit,” he added. “On the other hand, tovecimig has shown clinical activity, and given the high unmet need of these patients, a formal review by guideline committees is warranted to address this question.”
Biliary tract cancers are aggressive malignancies with increasing incidence and mortality, and the median OS is about 12 months in patients with advanced cancer.
Tovecimig is a recombinant bispecific antibody targeting VEGF-A and DLL4. Azad said that in early clinical testing, the agent, as a monotherapy, showed activity in colorectal cancer and gastric cancer. In preclinical and clinical data in biliary tract cancer, a combination with paclitaxel also showed compelling activity and formed the basis for the COMPANION-002 study, which enrolled 168 patients who had previously received one line of gemcitabine and cisplatin chemotherapy and were treated as second-line patients.
Patients with either metastatic or locally advanced disease were allowed, but they had to have good performance status defined as ECOG 0/1. Known targetable mutations were an exclusion factor.
They were randomized 2:1 to the doublet of tovecimig and paclitaxel versus paclitaxel alone. Patients randomized to paclitaxel alone were allowed to cross over to receive tovecimig and paclitaxel once progression was documented by blinded independent central review.
Of the 57 patients on paclitaxel alone, 54% crossed over, and among those patients, median PFS was 3.5 months post-crossover versus 1.9 months pre-crossover (HR 0.40, 95% CI 0.2-0.7, P=0.0035).
In addition, a subset analysis of the 57 patients in the paclitaxel arm showed median OS was 12.8 months among the 31 patients who crossed over to the tovecimig arm compared with 6.1 months among the 26 patients who did not (HR 0.54, 95% CI 0.3-0.98, P=0.04).
The doublet’s safety profile was manageable and consistent with what has been seen with similar agents, Azad observed.
The most common treatment-emergent adverse events (TEAEs) with tovecimig plus paclitaxel were hypertension (69.4%) and fatigue (66.7%). Grade ≥3 TEAEs occurred in 93.5% and 64.2%, respectively.
TEAEs leading to treatment modification or interruption, as well as treatment discontinuation, were higher in the tovecimig and paclitaxel arm.
There were six fatal TEAEs in the combination arm, including two treatment-related deaths due to septic shock and renal failure/sepsis, and one fatal TEAE in the paclitaxel arm.