Investigational tovecimig combined with paclitaxel significantly improved the response rate and progression-free survival (PFS) in patients with previously treated advanced or metastatic biliary tract cancer, according to the COMPANION-002 trial.
The phase II/III randomized study showed treatment with tovecimig, a first-in-class bispecific antibody, and paclitaxel elicited a response in 18.0% of patients versus 5.3% with paclitaxel alone (P=0.0228), thus meeting the trial’s primary endpoint, reported Nilofer S. Azad, MD, of Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore.
Treatment with the doublet also significantly improved PFS at 4.7 months versus 2.6 months, respectively (HR 0.44, 95% CI 0.30-0.66, P<0.0001),
While there was no overall survival (OS) benefit with tovecimig and paclitaxel, at 8.9 months versus 9.4 months with paclitaxel alone (HR 1.05, 95% CI 0.7-1.5, P=0.77), the crossover allowed in the trial may have confounded those OS results, Azad suggested.
“Altogether, this combination presents a promising new strategy for patients with biliary tract cancer,” she said at the European Society for Medical Oncology (ESMO) annual congress in Madrid. Trial data were simultaneously published in the Journal of Clinical Oncology.
The results of the study are encouraging “given the promising mechanism of action and the low bar that we have in this setting,” said ESMO invited discussant Sebastián Mondaca, MD, MBA, of the Pontificia Universidad Católica de Chile in Santiago. However, he noted that it was not clear if the findings will change clinical practice.
“Ideally, we would like to have a phase III trial with FOLFOX [fluorouracil, leucovorin, and oxaliplatin] as the comparison arm, demonstrating a clear benefit in overall survival,” 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 committee is warranted to address this question.”
Biliary tract cancers are aggressive malignancies with increasing incidence and mortality, with a median OS of about 12 months in patients with advanced cancer.
Tovecimig is a recombinant bispecific antibody targeting VEGF-A and DLL4. “In early clinical testing, this molecule, as a monotherapy, showed activity in colorectal cancer and gastric cancer,” Azad said. “In preclinical data as well as 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, previously treated with one prior line of gemcitabine and cisplatin chemotherapy, 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 was an exclusion factor.
They were randomized 2:1 to the doublet of tovecimig and paclitaxel versus paclitaxel alone. Those randomized to paclitaxel alone were allowed to cross over to receive tovecimig and paclitaxel once progression was documented by blinded independent central view.
Of the 57 patients on paclitaxel alone, 54% crossed over, and among those 31 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 before with these kinds of 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.
