Futibatinib

Compass Therapeutics (Nasdaq: CMPX) reported that tovecimig, its DLL4/VEGF-A bispecific antibody, met the key secondary endpoint of progression-free survival in the randomized COMPANION-002 trial, cutting the risk of disease progression by 56% compared with paclitaxel alone in previously treated biliary tract cancer — a disease where no FDA-approved second-line therapy exists for the majority of patients. COMPANION-002 is a Phase II/III randomized, controlled study (NCT05506943) evaluating tovecimig plus paclitaxel versus paclitaxel alone in 168 adults with unresectable advanced, metastatic, or recurrent biliary tract cancer who had received one prior systemic chemotherapy regimen, randomized 2:1. Median progression-free survival was 4.7 months in the tovecimig arm versus 2.6 months with paclitaxel alone (HR=0.44, p<0.0001). The overall response rate primary endpoint, previously disclosed in April 2025, was 17.1% versus 5.3% (p=0.031), with all responses confirmed by blinded independent central review. The overall survival analysis did not meet statistical significance, substantially confounded by a 54% crossover rate from the control arm; in a post-hoc subset analysis, crossover patients who subsequently received tovecimig had a median OS of 12.8 months compared with 6.1 months in those who did not cross over (HR=0.54, p=0.04). Biliary tract cancers — encompassing intrahepatic and extrahepatic cholangiocarcinoma, gallbladder cancer, and ampullary carcinoma — affect an estimated 26,500 patients annually in the United States. For the roughly 80–85% of patients whose tumors lack an actionable mutation, second-line treatment options are limited to off-label chemotherapy regimens, principally FOLFOX, which produces response rates of approximately 5% or less and a median overall survival of around six months. The ABC-06 Phase III trial, published in The Lancet Oncology in 2021, established FOLFOX as the closest thing to a standard of care in this setting, though it carries no discrete FDA approval for BTC. Tovecimig is engineered to simultaneously block two distinct pro-tumorigenic signaling axes: VEGF-A, which drives classical tumor angiogenesis, and DLL4, a Notch pathway ligand implicated in vascular remodeling and cancer stem cell maintenance. The rationale for dual blockade is that each pathway can partially compensate for inhibition of the other when targeted individually — a limitation observed with single-agent anti-VEGF therapies in several solid tumor types. Whether that mechanistic logic translates into durable clinical benefit in biliary tract cancer remains to be fully established, but the PFS data from COMPANION-002 are consistent with the hypothesis. Cross-trial comparisons are limited by differences in patient populations, prior treatment histories, and study designs, but the 4.7-month median PFS compares with the approximately 4-month PFS reported with FOLFOX in the ABC-06 dataset, and the response rate of 17.1% is substantially higher than the roughly 5% seen with chemotherapy in unselected second-line BTC. The OS picture is harder to interpret. The 54% crossover rate — which Compass permitted on ethical grounds, allowing control-arm patients who progressed to receive tovecimig — materially diluted any OS signal in the intent-to-treat analysis. The ITT OS was 8.9 months in the tovecimig arm versus 9.4 months in the control arm (HR=1.05, p=0.78), a result the company acknowledges is uninterpretable as a measure of tovecimig’s survival effect. The rank-preserving structural failure time analysis, intended to adjust for crossover, also failed to meet its underlying assumptions and produced similarly uninterpretable results. The post-hoc crossover analysis offers a more suggestive, if exploratory, survival signal. Crossover patients — who initially progressed faster on paclitaxel monotherapy (median PFS 1.9 months) than non-crossover patients (3.6 months) — ultimately achieved a median OS of 12.8 months after receiving tovecimig, comparable to outcomes seen in some first-line BTC studies. That finding is hypothesis-generating rather than confirmatory, given its post-hoc nature and the inherent selection effects in crossover populations. The competitive landscape in second-line BTC has grown modestly more complex in recent years, though predominantly for biomarker-selected subgroups. Pemigatinib (Pemazyre) and futibatinib (Lytgobi) carry FDA accelerated approval for FGFR2 fusion-positive cholangiocarcinoma; ivosidenib (Tibsovo) holds regular approval for IDH1-mutated cholangiocarcinoma; and zanidatamab (Ziihera) received accelerated approval in November 2024 for HER2 IHC 3-positive BTC. Each of these agents addresses a molecularly defined minority — collectively covering perhaps 20–30% of the BTC population. Tovecimig, if approved, would be the first mechanism-based therapy available to the unselected majority. The safety profile from COMPANION-002 was consistent with prior tovecimig data. The most common treatment-emergent adverse events in the combination arm were hypertension (69%) and fatigue (67%); grade 3 or higher events included hypertension (44%) and neutropenia (36%). The hypertension rate warrants attention given that VEGF pathway inhibition is a known driver of blood pressure elevation, and the 44% rate of high-grade hypertension is higher than typically observed with standard chemotherapy regimens. Compass intends to meet with the FDA in the coming months to discuss the COMPANION-002 dataset ahead of a planned Biologics License Application submission. The complete dataset, including duration of response, is expected to be presented at a medical conference later in 2026. Your email address will not be published. Required fields are marked * Comment * Name * Email * Website

Partner Therapeutics submitted a supplemental Biologics License Application (sBLA) to the US FDA on April 14, 2026 for Bizengri (zenocutuzumab-zbco), seeking approval for adults with advanced unresectable or metastatic cholangiocarcinoma harboring an NRG1 gene fusion. The filing marks the first regulatory submission for Bizengri in this bile duct malignancy with the aim of adding a third indication to the molecule’s existing accelerated approvals in NRG1 fusion-positive non-small cell lung cancer and pancreatic adenocarcinoma. The sBLA seeks approval without restriction to a specific line of therapy, the company said. The filing is supported by data from the eNRGy study, a basket trial evaluating zenocutuzumab-zbco across NRG1 fusion-positive solid tumors. No priority review or accelerated pathway designation was disclosed in the announcement, and the company did not provide a projected PDUFA date. Bizengri’s cholangiocarcinoma data The cholangiocarcinoma cohort of the eNRGy study generated an overall response rate of 36.8% (95% CI: 16.3, 61.6%) and a median duration of response of 12.9 months, as assessed by blinded independent central review. No patients in that cohort discontinued therapy due to adverse events, the company said. The mechanism underlying the filing differs from all currently approved CCA therapies: zenocutuzumab-zbco is a bispecific antibody that simultaneously blocks HER2/HER3 heterodimerization and NRG1 fusion interactions with HER3, disrupting downstream signaling driven by NRG1 chimeric ligands rather than the chimeric receptors targeted by FGFR inhibitors such as pemigatinib and futibatinib. NRG1 fusions are estimated to occur in fewer than 2% of cholangiocarcinoma cases, and the source material states that no approved therapies currently target this molecular subgroup in the disease. The rarity of the alteration creates a diagnostic challenge: unlike NTRK, RET, or FGFR fusions, NRG1 fusions produce chimeric ligands that are frequently missed by DNA-only next-generation sequencing panels and require tissue-based RNA testing for reliable detection. Partner Therapeutics noted this in its announcement, with Chief Development Officer Pritesh Gandhi stating that RNA testing is essential to ensure patients with NRG1-driven tumors are identified. NCCN guidelines The filing arrives alongside a notable guideline development. The National Comprehensive Cancer Network added zenocutuzumab-zbco to its oncology clinical practice guidelines for biliary tract cancers as a Category 2A subsequent-line therapy and as a Category 2B recommendation for front-line treatment of NRG1 fusion-positive cholangiocarcinoma — the latter positioning preceding any formal regulatory approval for the indication. Dr. James Cleary of Dana-Farber Cancer Institute, commenting in the release, described NRG1 gene fusions as an actionable biomarker in this disease and said the eNRGy data suggest targeted inhibition with zenocutuzumab may represent a meaningful treatment approach. The cholangiocarcinoma treatment landscape has undergone substantial change since 2020, when pemigatinib became the first targeted therapy approved in the disease. Ivosidenib followed in 2021 for IDH1-mutant CCA, futibatinib in 2022 for FGFR2 fusion-positive intrahepatic disease, and durvalumab in combination with gemcitabine and cisplatin was approved the same year for first-line biliary tract cancer regardless of biomarker status. Pembrolizumab combined with gemcitabine and cisplatin received approval in 2023 for the same unselected population. Despite this expansion, the molecular subgroup defined by NRG1 fusions has remained without a specifically labeled therapy, and the eNRGy data represent the primary clinical evidence base for this population in CCA. The sBLA adds to a field where accelerated approval pathways have played a central role, and where the durability of those approvals has varied. Infigratinib, an FGFR1–3 inhibitor that received accelerated approval in 2021 for FGFR2 fusion-positive CCA, was voluntarily withdrawn in 2024 after a confirmatory trial failed to verify clinical benefit — a precedent that underscores the regulatory risk associated with response-rate-based submissions in this disease. The eNRGy cholangiocarcinoma cohort was small, as is typical for trials enrolling rare fusion-defined populations, and the 95% confidence interval for the reported ORR is correspondingly wide. Bizengri’s existing accelerated approvals in NSCLC and pancreatic adenocarcinoma were also granted based on overall response rate and duration of response, with continued approval in those indications contingent on confirmatory trial data. The cholangiocarcinoma sBLA follows the same evidentiary model. Partner Therapeutics holds exclusive US rights to develop and commercialize zenocutuzumab-zbco under an agreement with Merus B.V., a wholly owned subsidiary of Genmab. Leave a Reply Cancel reply Your email address will not be published. Required fields are marked * Comment * Name * Email * Website