Formulary monograph

Tovecimig

Every statement is a verbatim quote from the source cited beneath it. · 49 sources

Monograph section

Field	Value
Drug	Tovecimig (CTX-009 and ABL001)
Indication reviewed	Second-line advanced biliary tract cancer
Therapeutic category	Bispecific antibodies targeting DLL4 and VEGF-A
Manufacturer	Compass Therapeutics
Regulatory status	Not approved in any country. FDA Fast Track designation granted April 2024 and orphan drug designation granted April 2026; biologics license application planned for the fourth quarter of 2026
Data as of	September 21, 2026
Prepared by	To be completed by the reviewing plan
Review status	Draft for pharmacy and therapeutics committee review

Introduction

Disease background

Definition: biliary tract cancer and the anatomical subtypes of cholangiocarcinoma

“Biliary tract cancer is a term that includes cholangiocarcinoma (either intrahepatic or extrahepatic in origin) and cancers of the gallbladder and ampulla of Vater. These uncommon cancers arising from the biliary tract account for less than 1% of all cancers worldwide.” (opens the source at this quote in a new tab)

“Biliary tract cancer (BTC), including cholangiocarcinoma, gallbladder cancer, and (to a lesser degree) ampullary tumours, are aggressive malignancies.” (opens the source at this quote in a new tab)

“Cholangiocarcinoma (CCA) constitutes a diverse group of malignancies emerging in the biliary tree. CCAs are divided into three subtypes depending on their anatomical site of origin: intrahepatic (iCCA), perihilar (pCCA) and distal (dCCA) CCA” (opens the source at this quote in a new tab)
“iCCAs arise above the second-order bile ducts, whereas the point of anatomical distinction between pCCA and dCCA is the insertion of the cystic duct.” (opens the source at this quote in a new tab)
“In the USA, pCCA is the single largest group, accounting for approximately 50–60% of all CCAs, followed by dCCA (20–30%) and iCCA (10–20%)” (opens the source at this quote in a new tab)

Incidence in the United States

Cancer site	Estimated new cases, both sexes	Estimated deaths, both sexes
Liver and intrahepatic bile duct	“42,340”	“30,980”
Gallbladder and other biliary	“12,640”	“4590”
All sites	“2,114,850”	“626,140”

“We estimate that there are approximately 26,500 patients newly diagnosed with BTC in the United States each year and over 200,000 patients worldwide.” (opens the source at this quote in a new tab)

“From 2001-2017, CCA, iCCA, and eCCA incidence (per 100 000 person-years) increased 43.8% (3.08 to 4.43), 148.8% (0.80 to 1.99), and 7.5% (2.28 to 2.45), respectively.” (opens the source at this quote in a new tab)
“The overall age-adjusted incidence of CCA from 2001 to 2017 was 3.65 per 100 000 p-y (iCCA, 1.19; eCCA, 2.46).” (opens the source at this quote in a new tab)

Prevalence and the proportion of participants who reach second-line therapy

“In 2023, there were an estimated 116,514 people living with liver and intrahepatic bile duct cancer in the United States.” (opens the source at this quote in a new tab)
“Approximately 1.1 percent of men and women will be diagnosed with liver and intrahepatic bile duct cancer at some point during their lifetime, based on 2021–2023 data.” (opens the source at this quote in a new tab)

“Patients with advanced biliary tract cancer often experience a rapid decline in performance status following progression on first-line chemotherapy, and only 15–25% receive second-line therapy.” (opens the source at this quote in a new tab)

“Of 413 patients, 84.5% received gemcitabine-based first-line (1L) treatment, 46% received second-line treatment, and 16.5% received third-line (3L) treatment.” (opens the source at this quote in a new tab)
“In total, 46% (n = 190) of patients initiated second line of therapy (2LOT), which predominantly involved 5-fluorouracil (5FU)-based mono- or combination chemotherapy” (opens the source at this quote in a new tab)

“Patients with BTC have a poor prognosis despite first-line treatment with chemotherapy and immunotherapy, and there is no generally accepted standard of care in later lines of treatment, except for therapies addressing targeted mutations, which is estimated to be approximately 15% to 20% of the patient population.” (opens the source at this quote in a new tab)

The second-line population: progression after first-line chemotherapy and immunotherapy

“Patients were eligible if they were aged 18 years or older and had histologically or cytologically verified locally advanced or metastatic biliary tract cancer (including cholangiocarcinoma, gallbladder carcinoma, and ampullary carcinoma) with documented radiological disease progression to previous first-line cisplatin and gemcitabine chemotherapy.” (opens the source at this quote in a new tab)
“In all enrolled patients, the primary tumour sites were intrahepatic cholangiocarcinoma (in 72 [44%] of 162 patients), extrahepatic cholangiocarcinoma (45 [28%]), gallbladder (34 [21%]), and ampullary cancer (11 [7%]).” (opens the source at this quote in a new tab)

“More recently, the addition of immune checkpoint inhibitors [specifically durvalumab (TOPAZ-1 trial3) and pembrolizumab (KEYNOTE-966 trial4)] to cisplatin–gemcitabine has demonstrated significant improvements in overall survival (OS).” (opens the source at this quote in a new tab)
“However, for ∼60% of patients diagnosed with ABC, there is currently no targetable alteration identified; thus second-line therapy options will be limited to further cytotoxic chemotherapy.” (opens the source at this quote in a new tab)

Signs and symptoms

“CCAs are usually asymptomatic during early stages. The most frequent symptom of pCCA and dCCA is jaundice due to biliary tract obstruction88. In iCCA, jaundice is less frequent and mostly associated with advanced disease.” (opens the source at this quote in a new tab)

“Patients with pCCA and dCCA typically present with painless jaundice owing to underlying biliary obstruction.” (opens the source at this quote in a new tab)

“Other symptoms of advanced disease include asthenia, abdominal pain, malaise, nausea, anorexia and weight loss.” (opens the source at this quote in a new tab)

“Patients with iCCA are often asymptomatic during early disease stages and develop symptoms or signs, such as abdominal pain or less commonly jaundice, during disease progression to an advanced stage.” (opens the source at this quote in a new tab)

Natural history: late presentation, stage at diagnosis, and survival from diagnosis

“CCAs are usually asymptomatic in early stages and, therefore, often diagnosed when the disease is already in advanced stages, which highly compromises therapeutic options, resulting in a dismal prognosis” (opens the source at this quote in a new tab)
“Despite advances in CCA awareness, knowledge, diagnosis and therapies, patient prognosis has not improved substantially in the past decade, with 5-year survival (7–20%) and tumour recurrence rates after resection still disappointing” (opens the source at this quote in a new tab)

“The prognosis is poor, with an all-stage 5-year overall survival of less than 20%.” (opens the source at this quote in a new tab)
“Patients are rarely diagnosed with early-stage disease and therefore curative surgery and adjuvant therapy is only feasible for a small proportion of patients.” (opens the source at this quote in a new tab)

Stage at diagnosis	Percent of cases	5-year relative survival
Localized	“45%”	“37.4%”
Regional	“23%”	“13.4%”
Distant	“21%”	“3.6%”
Unknown	“10%”	“11.6%”

“Median overall survival from diagnosis was 8, 6, 9, and 2 months for CCA, iCCA, eCCA, and CUP.” (opens the source at this quote in a new tab)
“The annual mortality rate declined from 45.2% in 2001 to 38.7% in 2016 for CCA, and from 57.1% in 2001 to 41.2% in 2016 for iCCA, but the rates for iCCA remained consistently higher than for eCCA, which generally remained stable (40.9% in 2001 vs 37.0% in 2016; Fig. 2F).” (opens the source at this quote in a new tab)

Survival after progression on first-line therapy

“Median overall survival was 6·2 months (95% CI 5·4–7·6) in the ASC plus FOLFOX group versus 5·3 months (4·1–5·8) in the ASC alone group (adjusted HR 0·69 [95% CI 0·50–0·97], p=0·031; figure 2).” (opens the source at this quote in a new tab)
“The overall survival rate in the ASC alone group was 35·5% (95% CI 25·2–46·0) at 6 months and 11·4% (5·6–19·5) at 12 months, compared with 50·6% (39·3–60·9) at 6 months and 25·9% (17·0–35·8) at 12 months in the ASC plus FOLFOX group.” (opens the source at this quote in a new tab)
“Median progression-free survival was 4·0 months (95% CI 3·2–5·0; appendix p 4).” (opens the source at this quote in a new tab)

“All-cause mortality was 53% with a median survival of 11.5 months.” (opens the source at this quote in a new tab)
“The median OS time from first presumed BTC diagnosis was 13.3 months.” (opens the source at this quote in a new tab)
“The median time on 2LOT was 3.6 months and was longer for patients with stage III disease (4.6 months) than for patients with stage IV and stage I/II disease (3.6 months).” (opens the source at this quote in a new tab)

Burden: quality of life, healthcare costs, and work loss

“Exposure to FOLFOX did not have a significant impact on the time to Global Health Scale deterioration (n = 76 participants; 36 patients ASC-alone arm; 40 patients in the FOLFOX arm), with similar TTD in both arms” (opens the source at this quote in a new tab)
“aHR 0.97, 95% CI 0.48-1.97, P = 0.937” (opens the source at this quote in a new tab)
“Addition of FOLFOX to ASC did not appear to induce worsening of the QoL parameters assessed (Table 3) at 4 months of study entry. In contrast, patients in the ASC-alone arm appeared to experience worsening of the EQ-5D utility values and most of the QLQ-C30 scales (including global, physical, social, and role scales), whereas these were stable in the FOLFOX arm.” (opens the source at this quote in a new tab)

“The mean PPPM costs for the overall population were $18,274 for all-cause costs, of which approximately 84% ($15,296) comprised BTC-related costs.” (opens the source at this quote in a new tab)
“The total mean (SD) PPPM all-cause costs by LOT were $19,589 ($22,603) for 1LOT, $22,617 ($19,302) for 2LOT and $33,534 ($40,588) for 3LOT.” (opens the source at this quote in a new tab)
“The primary driver of costs across all three LOTs was outpatient (including antineoplastic therapy visits) and inpatient utilization followed by outpatient pharmaceutical costs.” (opens the source at this quote in a new tab)

“One thousand and sixty-five patients with CCA were included (iCCA: n = 624 [58.6%]; eCCA: n = 380 [35.7%]). The mean age was 51.9-53.9 years across cohorts. In patients with iCCA and eCCA, respectively, the number of mean all-cause days absent PPPM for illness was 6.0 and 4.3, and 12.9 and 6.6% had ≥1 CCA-related short-term disability claim. Median indirect costs PPPM owing to absenteeism, short-term disability, and long-term disability, respectively, in patients with iCCA were $622, $635, and $690, and $304, $589, and $465 in patients with eCCA.” (opens the source at this quote in a new tab)
“In the absenteeism, short-term disability, and long-term disability cohorts, respectively, mean indirect costs associated with productivity loss contributed to 8.6, 7.2, and 6.7% of the total costs ($11,287, $11,887, and $11,977).” (opens the source at this quote in a new tab)
“This suggests that patients in our analysis are more economically advantaged than the overall population of the United States, many of whom do not have access to paid sick leave or are not provided with insurance by their employers. Thus, our analysis may underestimate the productivity losses within the overall population of the United States.” (opens the source at this quote in a new tab)

Development and regulatory status

Investigational status: tovecimig is a product candidate with no marketing approval

“Tovecimig (formerly known as CTX-009) is an investigational bispecific antibody that is designed to simultaneously block the DLL4 and VEGF-A signaling pathways, which are critical to angiogenesis and tumor vascularization.” (opens the source at this quote in a new tab)

“If we receive regulatory approval for tovecimig, CTX-471, CTX-8371, CTX-10726 or other product candidates, we expect to incur significant commercialization expenses related to product manufacturing, sales, marketing and distribution, depending on where we choose to commercialize these product candidates ourselves.” (opens the source at this quote in a new tab)

Current development phase: randomized phase 2/3 COMPANION-002 trial

“Tovecimig (CTX-009), our bispecific antibody targeting DLL4 and VEGF-A, is currently being evaluated in a randomized Phase 2/3 trial in the United States in combination with paclitaxel in patients with biliary tract cancer (“BTC”) who received one prior treatment regimen.” (opens the source at this quote in a new tab)

Field	Quoted record
Official title	“A Phase 2/3 Randomized, Controlled Study of CTX-009 in Combination With Paclitaxel Versus Paclitaxel Alone in Adult Patients With Unresectable Advanced, Metastatic or Recurrent Biliary Tract Cancers Who Have Received One Prior Systemic Chemotherapy Regimen”
Brief title	“A Study of CTX-009 in Combination With Paclitaxel in Adult Patients With Unresectable Advanced, Metastatic or Recurrent Biliary Tract Cancers (COMPANION-002)”
Lead sponsor	“Compass Therapeutics”
Brief summary	“This is a multi-center, open-label, randomized, phase 2/3 trial of the bispecific antibody CTX-009 plus paclitaxel versus paclitaxel in patients with previously treated, unresectable advanced or metastatic biliary tract cancers.”
Estimated primary completion	“2027-08-31”

Trial sites and enrollment

“168 patients across 34 sites in the U.S.” (opens the source at this quote in a new tab)

Prior clinical development completed in South Korea

“Previously, tovecimig underwent a Phase 1 dose escalation and dose expansion monotherapy trial in patients with solid tumors, a Phase 1b trial in combination with chemotherapy, and a Phase 2 trial in combination with chemotherapy in patients with advanced biliary tract cancer, all of which were completed in South Korea.” (opens the source at this quote in a new tab)
“Based on the efficacy data and following discussions with the FDA, while the trial had met the criteria to advance to Part 2, FDA recommended and we agreed to forego the second stage of the study and advance tovecimig directly to a randomized Phase 2/3 study in patients with BTC treated in the second-line setting.” (opens the source at this quote in a new tab)

Investigator-sponsored trials in progress

“The investigator sponsored trial (IST) of tovecimig in combination with the current first-line, standard-of-care regimen of gemcitabine, cisplatin, and durvalumab in patients with BTC (NCT06548412) is ongoing with expansion to additional sites expected.” (opens the source at this quote in a new tab)
“Additional ISTs of tovecimig have been initiated, including a study of tovecimig plus FOLFIRI in patients with colorectal cancer in the second line setting (NCT07662031); and a novel-novel combination study of tovecimig plus CTX-471 in patients with glioblastoma in the second line setting (NCT07392957).” (opens the source at this quote in a new tab)

United States: Fast Track designation

“today announced that the U.S. Food and Drug Administration (FDA) has granted Fast Track Designation (FTD) to CTX-009, the Company’s bispecific DLL4/VEGF-A antibody, in combination with paclitaxel for the treatment of patients with metastatic or locally advanced BTC that have been previously treated.” (opens the source at this quote in a new tab)

“This orphan drug designation follows a prior regulatory decision by the FDA to grant fast track designation to tovecimig in April 2024 for the treatment of metastatic or locally advanced biliary tract cancers in the second-line setting.” (opens the source at this quote in a new tab)

United States: orphan drug designation

“ABL Bio announced Wednesday that Tovecimig (CTX-009/ABL001), an innovative bispecific antibody cancer treatment, has been granted Orphan Drug Designation (ODD) by the U.S. Food and Drug Administration (FDA). The drug, currently in development by global partner Compass Therapeutics, targets bile duct cancer.” (opens the source at this quote in a new tab)
“Upon designation as an orphan drug, the company receives a period of market exclusivity, typically seven years, under U.S. regulations. It is also eligible for benefits such as tax credits, partial waivers of FDA review fees, clinical trial grants, and regulatory support for development.” (opens the source at this quote in a new tab)

“Tovecimig received Orphan Drug Designation in April and the Company intends to meet with the FDA in advance of its planned BLA submission later this year.” (opens the source at this quote in a new tab)

Regulatory submission: BLA planned for the fourth quarter of 2026

“The Company expects feedback from the FDA this quarter regarding the COMPANION-002 Phase 2/3 data for tovecimig (DLL4 x VEGF-A bispecific antibody) in patients with biliary tract cancer (BTC), prior to a potential BLA filing later this year.” (opens the source at this quote in a new tab)
“In April 2026, the Company announced positive data from its Phase 2/3 study of tovecimig, which it plans to include in a BLA submission later this year. The company expects to receive feedback from the FDA on these data in Q3 2026.” (opens the source at this quote in a new tab)

“Q3 26: Meet with FDA Q4 26: Submit BLA” (opens the source at this quote in a new tab)
“Expected FDA meeting in Q3 2026” (opens the source at this quote in a new tab)
“BLA filing initiating in late 2026” (opens the source at this quote in a new tab)

Presentation of the complete dataset

“Tovecimig data from this study has also been selected for an oral presentation at the 2026 European Society for Medical Oncology (ESMO) Congress in October.” (opens the source at this quote in a new tab)

Launch: anticipated in 2027

“2027 potential approval and launch” (opens the source at this quote in a new tab)
“Planning to file BLA based on data with potential approval in 2H 2027” (opens the source at this quote in a new tab)
“Highly focused US BTC market; targeted launch prep underway” (opens the source at this quote in a new tab)

Pharmacology and usage

Mechanism of action

Dual target: DLL4 and VEGF-A

“Our lead product candidate, tovecimig (formerly known as CTX-009), is a bispecific antibody targeting Delta-like ligand 4 (“DLL4”), a ligand of Notch-1, and vascular endothelial growth factor A (“VEGF-A”). Simultaneous blockade of the VEGF-A and the Notch pathways is known to turn productive angiogenesis into non-productive angiogenesis, which leads to tumor shrinkage and apoptosis.” (opens the source at this quote in a new tab)
“Tovecimig (formerly known as CTX-009) is an investigational bispecific antibody that is designed to simultaneously block the DLL4 and VEGF-A signaling pathways, which are critical to angiogenesis and tumor vascularization.” (opens the source at this quote in a new tab)

Molecular format: anti-VEGF antibody backbone linked to DLL4-binding single-chain variable fragments

“ABL001 is a bispecific antibody that simultaneously targets both DLL4 and VEGF, by linking each C-terminal of an anti-VEGF antibody (bevacizumab-similar) with a DLL4-binding single-chain Fv (scFv)” (opens the source at this quote in a new tab)

“CTX-009 is a recombinant bispecific antibody that contains two single chain variable fragments (scFv) binding to human DLL4 linked to the C-terminus of heavy chains that bind to human VEGF-A” (opens the source at this quote in a new tab)

Rationale for adding DLL4 blockade to VEGF blockade

“VEGF/VEGFR blockade can inhibit VEGF-driven tumor angiogenesis, and the regression of tumor vessels is dependent on the VEGF signaling pathway. However, VEGF inhibitors alone are not capable of destroying all tumor blood vessels.” (opens the source at this quote in a new tab)
“Several preclinical xenograft studies have demonstrated that DLL4/Notch blockade inhibited tumor progression by promoting hyperproliferation of endothelial cells, which resulted in an increase in vascular density and a decrease in functional tumor vasculature” (opens the source at this quote in a new tab)

“Hence, given that the VEGF/VEGFR signal transduction pathway and the DLL4/Notch signal transduction pathway affect angiogenesis via different mechanisms of action, CTX-009 was designed to block both pathways in a novel therapeutic format” (opens the source at this quote in a new tab)

Target biology in biliary tract cancer

“VEGF-A overexpression has been reported in BTC, correlating with stage, the presence of metastases and prognosis of the disease” (opens the source at this quote in a new tab)
“DLL4 is highly expressed in BTC and up-regulation of DLL4 expression is associated with poor survival in patients with BTC” (opens the source at this quote in a new tab)
“Importantly, DLL4-Notch 1 signaling can be a part of the development of resistance to anti-VEGF therapeutics” (opens the source at this quote in a new tab)

Pharmacodynamics

Preclinical antitumor activity in gastric and colon cancer xenograft models

“Both bispecific antibodies, mABL001 and ABL001, inhibited tumor progression in the tested xenograft models at doses ranging from 1 to 6.5 mg/kg” (opens the source at this quote in a new tab)
“The anti-cancer effects of mABL001 or ABL001 monotherapy were calculated as %TGI ranging from 27.4% to 57.2%, depending on the doses of mABL001 or ABL001 and cancer cell lines in xenograft models” (opens the source at this quote in a new tab)

Effect on tumor vasculature and on target expression in tumor endothelium

“Based on the results of immunohistochemical analysis of tumor blood vessels, the expression levels of VEGFR-2 and DLL4, dual targets of ABL001, were markedly reduced in tumor endothelial cells after ABL001 treatment compared to that of CD31, a conventional endothelial cell marker.” (opens the source at this quote in a new tab)
“The combination treatment synergistically inhibited tumor progression compared to each monotherapy. More tumor vessel regression and apoptotic tumor cell induction were observed in tumors treated with the combination therapy, which might be due to tumor vessel normalization.” (opens the source at this quote in a new tab)

Clinical pharmacodynamic or target-engagement biomarkers

No evidence found.

Pharmacokinetics

Population pharmacokinetic model in patients with solid tumors

“A total of 712 plasma concentrations from 30 patients with relapsed or refractory solid tumors were collected from a phase 1 study” (opens the source at this quote in a new tab)
“The PK of ABL001/CTX‐009 was well described by a two‐compartment model with a parallel first‐order and Michaelis–Menten elimination kinetics. Body weight was selected as a significant covariate on V1.” (opens the source at this quote in a new tab)

Model parameter estimates

Parameter	Estimate (relative standard error, %)
Clearance, L/h	“0.0184 (18)”
Central volume of distribution, L	“3.87 (5)”
Intercompartmental clearance, L/h	“0.0207 (16)”
Peripheral volume of distribution, L	“1.31 (28)”

Elimination half-life and time to steady state

“The model‐derived elimination half‐life was approximately 5.7 days, indicating that plasma ABL001/CTX‐009 concentrations would reach a steady‐state in patients with solid tumor in about 4–6 weeks.” (opens the source at this quote in a new tab)

Simulated exposure: fixed dosing compared with weight-based dosing and alternative intervals

“Simulations after administrations of fixed or weight‐based doses showed similar plasma concentrations. Additionally, 10 mg/kg for every other week and 15 mg/kg for every three‐week administration showed comparable plasma concentrations.” (opens the source at this quote in a new tab)
“When comparing the optimal dosing strategy, the ABL001/CTX‐009 plasma concentrations administered every 2 weeks of 10 mg/kg and every 3 weeks of 15 mg/kg showed similar average plasma concentrations” (opens the source at this quote in a new tab)

Simulated regimen	Maximal plasma concentration, mg/L	Average plasma concentration at steady state, mg/L
Fixed dose, 700 mg	“263.1 ± 68.5”	“123.9 ± 65.2”
Weight-based dose, 10 mg/kg	“232.3 ± 68.8”	“111.3 ± 66.0”
15 mg/kg every 3 weeks	“296.1 ± 77.4”	“107.6 ± 68.5”

Immunogenicity and pharmacokinetics in organ impairment

No evidence found.

Indications

Investigational product with no approved indication: population under study in COMPANION-002

“Following conversations with the FDA, we submitted a protocol for a randomized Phase 2/3 trial for tovecimig in combination with paclitaxel in adult patients with unresectable, advanced, metastatic or recurrent biliary tract cancers who have received one prior systemic chemotherapy regimen.” (opens the source at this quote in a new tab)

Criterion	Quoted record
Disease	“Histologically or cytologically confirmed unresectable advanced, metastatic, or recurrent biliary tract cancers (including intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, gallbladder cancer, and ampullary carcinoma)”
Prior therapy	“Patients must have radiologically documented progression after a prior gemcitabine and platinum containing chemotherapy regimen as first line therapy for locally advanced unresectable or metastatic disease.”
Measurable disease	“At least one lesion measurable as defined by RECIST v1.1”
Exclusion by alternative therapy	“Patients who are eligible to be treated with a molecularly targeted therapy on a labelled regimen after receiving first-line chemotherapy.”

Investigational use covered by the FDA Fast Track designation

“Compass Therapeutics Receives FDA Fast Track Designation for the Investigation of CTX-009 in Combination with Paclitaxel for the Treatment of Patients with Metastatic or Locally Advanced Biliary Tract Tumors That Have Been Previously Treated” (opens the source at this quote in a new tab)

“This orphan drug designation follows a prior regulatory decision by the FDA to grant fast track designation to tovecimig in April 2024 for the treatment of metastatic or locally advanced biliary tract cancers in the second-line setting.” (opens the source at this quote in a new tab)

Investigational use covered by the FDA orphan drug designation

“ABL Bio announced Wednesday that Tovecimig (CTX-009/ABL001), an innovative bispecific antibody cancer treatment, has been granted Orphan Drug Designation (ODD) by the U.S. Food and Drug Administration (FDA). The drug, currently in development by global partner Compass Therapeutics, targets bile duct cancer.” (opens the source at this quote in a new tab)

Investigational setting: size of the second-line population without an approved targeted option

“The only FDA approved therapies for second line treatment of BTC are targeted therapies that address specific tumor mutations or solid tumors that are microsatellite instability high.” (opens the source at this quote in a new tab)
“We believe that the combination of all targeted therapies are appropriately 10-15% of patients with BTC.” (opens the source at this quote in a new tab)

“Over 15K patients/yr potentially eligible for tovecimig” (opens the source at this quote in a new tab)

Investigational product currently under evaluation in a randomized phase 2/3 trial

“Tovecimig (CTX-009), our bispecific antibody targeting DLL4 and VEGF-A, is currently being evaluated in a randomized Phase 2/3 trial in the United States in combination with paclitaxel in patients with biliary tract cancer (“BTC”) who received one prior treatment regimen.” (opens the source at this quote in a new tab)

Dosing and administration

COMPANION-002 regimen: tovecimig dose and schedule with the paclitaxel backbone

“All patients were dosed with 80 mg/m2 of paclitaxel on days 1, 8 and 15 of every 28-day cycle. Patients in the tovecimig arm were also dosed with 10 mg/kg of tovecimig on days 1 and 15 of each 28-day cycle.” (opens the source at this quote in a new tab)

“CTX-009 will be administered at 10 mg/kg on Day 1 and Day 15 of every 28-day cycle. Paclitaxel will be administered 80 mg/m2 on Day 1, Day 8 and Day 15 of every 28-day cycle.” (opens the source at this quote in a new tab)

Route and schedule recorded in the registry

Field	Quoted record
Experimental arm	“CTX-009 plus Paclitaxel”
CTX-009 administration	“IV infusion on day 1 and 14 of every 28 day cycle”
Paclitaxel administration	“IV infusion on day 1, 8, and 15 of every 28 day cycle”

Infusion preparation and duration in the phase 1 study

“Patients received an intravenous infusion of ABL001/CTX‐009 diluted in 0.9% normal saline (250 mL) over 1 h. ABL001/CTX‐009 was administered in a 2‐week cycle, with the exception of the second dose, which had a 3‐week interval. Administration continued until unacceptable toxicity or disease progression was identified according to RECIST version 1.1.” (opens the source at this quote in a new tab)

Basis for the paclitaxel backbone

“Paclitaxel was chosen based on the safety and efficacy data from this phase Ib study.” (opens the source at this quote in a new tab)

Phase 1 dose escalation range and starting dose

“The study was designed in a classical 3+3 dose-escalation schema where ABL001 is administered by IV across nine dose cohorts ranging from 0.3, 1, 2.5, 5, 7.5, 10, 12.5, 15, to 17.5 mg/kg biweekly” (opens the source at this quote in a new tab)

“The initial dose of 0.3 mg/kg was determined based on the no observed adverse effect level (NOAEL) 10 mg/kg in the monkey model, converted to human equivalent dose with the safety factor of 10.” (opens the source at this quote in a new tab)

Dose levels at which responses were observed in the phase 1 study

“All responses were seen at dose levels above 10 mg/kg, and all confirmed responses were seen at the 10 mg/kg or 12.5 mg/kg dose levels” (opens the source at this quote in a new tab)

Alternative dosing strategies supported by simulation

“Based on the simulation results, ABL001/CTX‐009 can be administered as a fixed dose and with a longer dosing interval for follow‐up studies.” (opens the source at this quote in a new tab)
“Simulation results comparing fixed dosing (700 mg) and weight‐base dosing (10 mg/kg) showed comparable PK properties of ABL001/CTX‐009, supporting the suitability of a non‐weight‐based dosing of ABL001/CTX‐009.” (opens the source at this quote in a new tab)

Premedication, dose modification, and dosing in organ impairment

No evidence found.

Clinical efficacy summary

COMPANION-002

Design and population

Registered purpose of the trial

“This is a multi-center, open-label, randomized, phase 2/3 trial of the bispecific antibody CTX-009 plus paclitaxel versus paclitaxel in patients with previously treated, unresectable advanced or metastatic biliary tract cancers.” (opens the source at this quote in a new tab)

Registered design details

Design feature	Registry record
Primary purpose	“Treatment”
Allocation	“Randomized”
Interventional model	“Parallel Assignment”
Masking	“Single (Outcomes Assessor)”

Blinded independent central review of the primary endpoint

“A blinded independent review committee will be used to assess the primary study endpoint.” (opens the source at this quote in a new tab)

Randomization ratio and stratification factors

“Patients are randomized to a 2:1 ratio, and crossover is allowed to the experimental arm at the time of progression in the control arm for patients that continue to meet eligibility criteria. Stratification factors include stage (locally advanced vs metastatic), anatomic subtype of the primary tumor (intrahepatic cholangiocarcinoma vs other) and ECOG performance status (0 or 1).” (opens the source at this quote in a new tab)

Crossover from the control arm

“Patients randomized to receive paclitaxel only have the option to crossover to the CTX-009 plus paclitaxel arm after documented disease progression per RECIST v1.1.” (opens the source at this quote in a new tab)

“Patients in the paclitaxel-only arm who progressed could cross over to the tovecimig plus paclitaxel arm after centrally confirmed progression if they also still met the enrollment criteria for the study.” (opens the source at this quote in a new tab)

Registered sites

“This study has 34 locations” (opens the source at this quote in a new tab)
“United States” (opens the source at this quote in a new tab)

Completion of enrollment

“The trial was fully enrolled in August 2024 with 168 patients randomized in a 2:1 ratio to receive tovecimig plus paclitaxel (n=111) or paclitaxel alone (n=57).” (opens the source at this quote in a new tab)

Planned and randomized sample size

“The planned sample size is approximately 150 patients. This is a multicenter study with 32 study sites.” (opens the source at this quote in a new tab)

“The study enrolled 168 adult patients, randomized in a 2:1 ratio to receive tovecimig plus paclitaxel (n=111) or paclitaxel alone (n=57).” (opens the source at this quote in a new tab)

Populations analyzed for efficacy and for safety

Analysis set	Tovecimig plus paclitaxel	Paclitaxel
Intent-to-treat population, efficacy analyses	“n=111”	“n=57”
Population reported for treatment-emergent adverse events	“n=108”	“n=53”

Dosing of both arms as reported by the sponsor

“All patients were dosed with 80 mg/m2 of paclitaxel on days 1, 8 and 15 of every 28-day cycle. Patients in the tovecimig arm were also dosed with 10 mg/kg of tovecimig on days 1 and 15 of each 28-day cycle.” (opens the source at this quote in a new tab)

Key inclusion criteria: registry record

Criterion	Quoted registry text
Age	“18 years of age or older”
Diagnosis	“Histologically or cytologically confirmed unresectable advanced, metastatic, or recurrent biliary tract cancers (including intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, gallbladder cancer, and ampullary carcinoma)”
Prior therapy	“Patients must have radiologically documented progression after a prior gemcitabine and platinum containing chemotherapy regimen as first line therapy for locally advanced unresectable or metastatic disease.”
Measurable disease	“At least one lesion measurable as defined by RECIST v1.1”
Performance status	“Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1”
Life expectancy	“Predicted life expectancy of at least 12 weeks”
Hepatic function	“Total bilirubin ≤ 1.5 X ULN”
Renal function	“Estimated creatinine clearance ≥ 30 mL/min based on Cockcroft-Gault”
Proteinuria	“Urine protein ≤ 1+ by Dipstick (Only when urinalysis shows a protein dipstick result of > 1 positive (+), the total protein volume (<1.0 g/24hr) can be confirmed with a 24-hour urine test.)”

Exclusion of participants eligible for an approved targeted therapy

“Patients who are eligible to be treated with a molecularly targeted therapy on a labelled regimen after receiving first-line chemotherapy. Patients who received a molecularly targeted therapy as part of their first line treatment may be eligible, as determined by the Sponsor Medical Monitor.” (opens the source at this quote in a new tab)

Balance of baseline characteristics between arms

“Baseline characteristics were well balanced” (opens the source at this quote in a new tab)

Baseline demographics and disease characteristics, n (%) unless stated

Characteristic	Tovecimig plus paclitaxel (n=111)	Paclitaxel (n=57)
Median age, years	“65.0”	“63.0”
Male	“53 (47.7)”	“24 (42.1)”
Female	“58 (52.3)”	“33 (57.9)”
Asian	“17 (15.3)”	“10 (17.5)”
White	“84 (75.7)”	“40 (70.2)”
African American	“4 (3.6)”	“6 (10.5)”
Unknown or other race	“6 (5.4)”	“1 (1.8)”
Intrahepatic primary location	“62 (55.9)”	“30 (52.6)”
Other primary location (extrahepatic, gallbladder, ampullary)	“49 (44.1)”	“27 (47.4)”
ECOG performance status 0	“53 (47.7)”	“27 (47.4)”
ECOG performance status 1	“58 (52.3)”	“30 (52.6)”
Locally advanced disease	“12 (10.8)”	“5 (8.8)”
Metastatic disease	“99 (89.2)”	“52 (91.2)”

Endpoints

Registered primary outcome measure

Outcome measure	Measure description	Time frame
“Best Overall Response”	“Percentage of patients whose Best Overall Response (BOR) is assessed as Complete Response (CR) or Partial Response (PR) as assessed by RECIST 1.1”	“From randomization to treatment discontinuation for any reason, average 6 months”

Registered secondary outcome measures

Outcome measure	Measure description	Time frame
“Progression Free Survival”	“Time from randomization until the date of objective PD (as assessed by RECIST 1.1) or the date of death (by any cause in the absence of disease progression)”	“From randomization to first documented objective PD or death if PD does not occur, average 6 months”
“Duration of Response”	“The time between the date of the radiological evaluation that first confirmed CR or PR and the date of the radiation evaluation that first confirmed Progressive Disease (PD)”	“From first confirmed CR or PR to confirmed PD, average 6 months”
“Overall Survival”	“Time from randomization until the date of death by any cause. Patients who are still alive at the time of the analysis, or who have become lost to follow-up or withdrawn consent will be censored at their last date known to be alive”	“From randomization to death from any cause, average 12 months”
“Disease Control Rate”	“Percentage of patients whose BOR is assessed as CR, PR, or Stable Disease (SD)”	“From randomization to treatment discontinuation for any reason, average 6 months”
“Incidence of Treatment Emergent Adverse Events (TEAEs) and changes in clinical abnormalities”	“Incidence of Treatment Emergent Adverse Events (TEAEs) and changes in clinical abnormalities for all randomized patients who received at least one dose of study treatment (either CTX-009 or paclitaxel)”	“From randomization to 60 days after the last dose of study treatment, average 7 months”

Endpoint definitions in the trial design publication, including the quality-of-life instrument

“The primary end point is ORR per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) by independent central review (ICR). The secondary end points are progression free survival, duration of response, overall survival, disease control rate, safety and quality of life measured with EORTC QLQ-C30.” (opens the source at this quote in a new tab)

Power and treatment-effect assumption

“This study was designed to detect a 23% absolute difference in response rate between the two arms, with 90% power and a two-sided alpha of 0.05.” (opens the source at this quote in a new tab)

Event threshold triggering the time-to-event analyses

“The trial requires a threshold of events in 80% of patients to trigger the secondary endpoint analyses.” (opens the source at this quote in a new tab)

“In the Phase 2/3 trial, the prespecified event threshold of 80% overall survival (OS) events was reached in Q1 2026; therefore, the analyses of progression-free survival (PFS) and OS are expected to be reported in April 2026.” (opens the source at this quote in a new tab)

Efficacy results

Primary endpoint: objective response rate as first reported

“17.1% ORR for tovecimig in combination with paclitaxel (19 of 111 patients) including one complete response, compared to 5.3% for paclitaxel alone (3 of 57 patients), in patients with BTC in the second line setting” (opens the source at this quote in a new tab)
“This 11.8% relative improvement in ORR for those receiving the combination was statistically significant (p=0.031).” (opens the source at this quote in a new tab)

Primary endpoint: objective response rate in the final analysis

“In the final data analysis, the overall response rate (ORR), the primary endpoint in the study, improved to 18.0% (20/111 patients) in the tovecimig combination arm from a previously reported 17.1%.” (opens the source at this quote in a new tab)
“With this change, the p-value improved to 0.0228 compared to paclitaxel alone (ORR of 5.3% in the paclitaxel arm).” (opens the source at this quote in a new tab)

Best overall response by blinded independent central review, intent-to-treat population

Best overall response	Tovecimig plus paclitaxel (n=111)	Paclitaxel (n=57)
Overall response rate (complete plus partial response)	“19 (17.1%)”	“3 (5.3%)”
Complete response	“1 (0.9%)”	“0 (0.0%)”
Partial response	“18 (16.2%)”	“3 (5.3%)”
Stable disease	“49 (44.1%)”	“19 (33.3%)”
Non-complete response / non-progressive disease	“9 (8.1%)”	“2 (3.5%)”
Progressive disease	“18 (16.2%)”	“24 (42.1%)”
Not evaluable	“16 (14.4%)”	“9 (15.8%)”

Central confirmation of responses

“The difference in ORR between the two treatment arms, the primary endpoint of the study, was statistically significant (p=0.031), and all responses have been confirmed by blinded independent central radiology review.” (opens the source at this quote in a new tab)

Key secondary endpoint: progression-free survival

“Tovecimig in combination with paclitaxel demonstrated a statistically significant improvement in median PFS of 4.7 months compared to 2.6 months for paclitaxel alone (HR=0.44, p<0.0001). Progression was confirmed in each case by BICR.” (opens the source at this quote in a new tab)

Key secondary endpoint: overall survival in the intent-to-treat population

“In the ITT OS analysis, tovecimig in combination with paclitaxel had a median OS of 8.9 months compared to 9.4 months for the control arm, which included 26 patients (46%) who received paclitaxel alone and 31 patients (54%) who crossed over to receive tovecimig in combination with paclitaxel (HR=1.05, p=0.78).” (opens the source at this quote in a new tab)

Efficacy summary with hazard ratios and two-sided p values

Endpoint	Tovecimig plus paclitaxel (n=111)	Paclitaxel (n=57)	Hazard ratio	Two-sided p value
Overall response rate	“19 (17.1%)”	“3 (5.3%)”	Not reported	“p=0.031”
Progression-free survival, months	“4.7”	“2.6”	“0.44”	“p<0.0001”
Overall survival, intent-to-treat, months	“8.9”	“9.4”	“1.05”	“p=0.78”
Overall survival, crossover-adjusted by rank-preserving structural failure time, months	“8.9”	“9.4”	“1.13”	“p=0.65”

Prespecified secondary analysis of progression-free survival before and after crossover

“In this analysis, the pre-crossover PFS (PFS1) on paclitaxel alone was compared to PFS with tovecimig post-crossover (PFS2) in the same crossover patients (n=31). In this subset, tovecimig demonstrated a statistically significant improvement with median PFS2 of 3.5 months after treatment with tovecimig compared to median PFS1 of 1.9 months for paclitaxel (HR=0.36, p=0.0016).” (opens the source at this quote in a new tab)

Post hoc analysis of overall survival within the control arm

“In an analysis of OS in all patients randomized to the paclitaxel control arm (n=57), crossover patients who subsequently received tovecimig demonstrated a statistically significant improvement in median OS of 12.8 months compared to 6.1 months for non-crossover patients who received only paclitaxel (HR=0.54, p=0.04).” (opens the source at this quote in a new tab)

Post hoc analysis of progression-free survival within the control arm

“Another analysis of these same patients randomized to the paclitaxel control arm (n=57) demonstrated that the crossover patients initially progressed faster on paclitaxel monotherapy compared to the non-crossover patients, with a median PFS of 1.9 months versus 3.6 months (HR=2.31, p=0.007).” (opens the source at this quote in a new tab)

Post hoc pooled overall survival of all participants who received tovecimig

“For all patients treated with tovecimig, including both crossover patients and patients initially randomized to the tovecimig combination arm (n=142), the pooled median OS was 9.8 months. The median OS for patients randomized to the paclitaxel alone who did not crossover (n=26) was 6.1 months.” (opens the source at this quote in a new tab)

Duration of response

“The complete dataset, including Duration of Response (DoR), will be presented at a medical conference later this year.” (opens the source at this quote in a new tab)

Limitations

Crossover as the stated reason the overall survival endpoint was not met

“Tovecimig did not meet the OS secondary endpoint due to high crossover from the control arm (31 of 57 patients, or 54%) and prolonged survival of those crossover patients after receiving tovecimig, as further described below. As a result of this crossover, 85% (142 of 168) of patients in the study received tovecimig plus paclitaxel with a pooled OS in the study of 8.9 months.” (opens the source at this quote in a new tab)

Stated non-fulfilment of the crossover-adjusted analysis assumptions

“In the rank-preserving structural failure time (RPSFT) OS analysis, the combination also had a median OS of 8.9 months compared to 9.4 months for paclitaxel alone (HR=1.13, p=0.65). Though the RPSFT analysis is intended to adjust for crossover, its validity depends on certain assumptions that were not met in this study and thus its results here are largely uninterpretable.” (opens the source at this quote in a new tab)

Prespecified status of the analysis whose assumptions were not met

“Although this was a prespecified analysis, statistical assumptions for the RPSFT were not met.” (opens the source at this quote in a new tab)

ABL001-P1bC

Design and population

Single-arm phase 2 design in the second- and third-line setting

“This open-label, multi-center, single-arm Phase 2 study investigated pts with unresectable advanced, metastatic or recurrent BTC in advanced 2L or 3L setting.” (opens the source at this quote in a new tab)

Origin of the biliary tract cancer cohort

“A phase Ib study conducted in South Korea, evaluated CTX-009 in combination with either irinotecan or paclitaxel in patients with metastatic or advanced solid tumors. Two out of three patients with cholangiocarcinoma who received CTX-009 in combination with paclitaxel achieved confirmed PRs. This observation in the phase Ib study led to the addition of a phase II cohort that enrolled patients with BTC who were treated in the second- or third-line setting.” (opens the source at this quote in a new tab)

Participants enrolled, anatomic subtype, and line of therapy

“11 pts were treated in 2L and 13 pts treated in 3L.” (opens the source at this quote in a new tab)

“A total of 24 patients were enrolled: nine (37%) with intrahepatic cholangiocarcinoma, three (13%) with extrahepatic cholangiocarcinoma, seven (29%) with gallbladder cancer and five (21%) with ampullary carcinoma.” (opens the source at this quote in a new tab)

Dosing regimen

“Eligible pts were treated with CTX-009 (10 mg/kg IV biweekly) in combination with paclitaxel (80 mg/m2 IV on Day 1, 8, 15 q4-weekly).” (opens the source at this quote in a new tab)

Simon two-stage adaptive design

“This Phase 2 trial utilized a Simon Two-Stage adaptive design where the criteria to advance to the second stage of the trial was three PRs observed in 21 evaluable patients.” (opens the source at this quote in a new tab)

Endpoints

Registered primary outcome measures

Outcome measure	Measure description	Time frame
“P1b: Proportion of subjects with Dose-Limiting Toxicity (DLT)”	“Number of subjects who experience DLT events during 28 days after first administration of CTX-009 (ABL001) and Irinotecan/Paclitaxel, divided by the number of DLT-evaluable subjects”	“From Day 1 until disease progression or Day 28, whichever came first”
“P2: Objective response rate (ORR) of CTX-009 (ABL001) in combination with paclitaxel in patients with BTC”	“The proportion of subjects whose best overall response (BOR) is assessed to be complete response (CR) or partial response (PR) as per Independent Radiology Center's review”	“Up to approximately 24 months”

Primary and secondary objectives as reported at the congress

“The primary objective was to assess the objective response rate (ORR) based on RECIST v1.1. Secondary endpoints included time to treatment failure (TTF), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety.” (opens the source at this quote in a new tab)

Efficacy results

Response and survival outcomes as reported at the congress

“There were 9 confirmed PRs by investigator’s assessment and ORR was 37.5% (95% CI: 18.8-59.4; 2L: 63.6%, 3L: 15.4%). Median DOR and PFS were 9.4 m (95% CI: 3.5–NE) and 9.4 m (95% CI: 5.4-11.1), respectively. Median TTF was 5.9 m (95% CI: 3.9-9.8) and median OS has not been reached (95% CI: 11.0–NE); the OS rate at 12 m was 53.0% (95% CI: 29.8–71.7).” (opens the source at this quote in a new tab)

Response and survival outcomes as summarized in the trial design publication

“The primary end point of the phase II study was overall response rate (ORR) and the ORR was 37.5% (n = 9/24 patients). Among 11 patients treated in the second-line, the ORR was 63.6% (n = 7/11) versus 15% (n = 2/13) among patients treated in the third-line setting. The median duration of response was 6.9 months, and responses were seen in patients with all anatomic subtypes of BTC, including ampullary cancer. The median progression-free survival was 9.4 months and the survival rate at 1 year was 53%.” (opens the source at this quote in a new tab)

Limitations

No evidence found.

2024-0279

Design and population

Safety lead-in followed by expansion

“Safety Lead-in: CTX-009+ Durvalumab+Gemcitabine+cisplatin” (opens the source at this quote in a new tab)
“Expansion: CTX-009+ Durvalumab+Gemcitabine+cisplatin” (opens the source at this quote in a new tab)

Study dates, status, and site

Milestone	Registry record
Study start (actual)	“2025-01-22”
Primary completion (estimated)	“2027-05-01”
Enrollment (estimated)	“50”
Recruitment status	“Recruiting”
Last update posted	“2026-09-09”

Key inclusion criteria

Criterion	Quoted registry text
Age	“Age ≥ 18 years.”
Diagnosis and prior therapy	“Histologically or cytologically confirmed (outside pathology reports will be accepted) unresectable advanced, metastatic, or recurrent BTC at the time of enrollment that has not been previously treated in the metastatic setting.”
Performance status	“ECOG performance status ≤2”

Sponsor description of the investigator-sponsored trial

“The investigator sponsored trial (IST) of tovecimig in combination with the current first-line, standard-of-care regimen of gemcitabine, cisplatin, and durvalumab in patients with BTC (NCT06548412) is ongoing with expansion to additional sites expected.” (opens the source at this quote in a new tab)

Endpoints

Registered primary outcome measure

Outcome measure	Measure description	Time frame
“Safety and Adverse Events (AEs)”	“Incidence of Adverse Events, Graded According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version (v) 5.0”	“Through study completion; an average of 1 year”

Primary and secondary objectives

“Assess tolerability/safety of this combination and determine the maximum tolerated dose (MTD) of CTX-009.” (opens the source at this quote in a new tab)
“Assess 6 month progression-free survival to the combination therapy according to RECIST 1.1” (opens the source at this quote in a new tab)

Efficacy results

No evidence found.

Limitations

No evidence found.

NOV150101-101

Design and population

Open-label dose escalation and dose expansion design

“The purpose of this open-label, dose escalation-dose expansion, Phase 1 clinical trial is to evaluate the safety, pharmacokinetics and anti-tumor activity and determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of NOV1501 (ABL001).” (opens the source at this quote in a new tab)

Dose cohorts and expansion dose levels

“The dose escalation phase had 9 dose cohorts from 0.3 to 17.5 mg/kg (IV every 2 weeks), using a traditional 3+3 design. The study was expanded at dose levels of 7.5, 10, 12.5 and 15 mg/kg. Archived tumor tissue samples were collected to assess DLL4 expression levels using an immunohistochemistry (IHC) method.” (opens the source at this quote in a new tab)

Route, infusion duration, and dosing interval

“Patients received an intravenous infusion of ABL001/CTX‐009 diluted in 0.9% normal saline (250 mL) over 1 h. ABL001/CTX‐009 was administered in a 2‐week cycle, with the exception of the second dose, which had a 3‐week interval. Administration continued until unacceptable toxicity or disease progression was identified according to RECIST version 1.1.” (opens the source at this quote in a new tab)

Participants enrolled by study part

“A total of 45 patients (31 patients in the dose escalation phase and 14 patients in the dose expansion phase) were enrolled in the study.” (opens the source at this quote in a new tab)

Prior therapy, performance status, and tumor types

“The patients were heavily pretreated and received a median of 4 lines of prior therapies. 86.7% of the patients were ECOG 1. Gastric cancer (n=19) and colorectal cancer (n=18) were the most common tumors.” (opens the source at this quote in a new tab)

Endpoints

Registered primary outcome measure

Outcome measure	Measure description	Time frame
“Number and percentage of subjects with adverse events (AEs), serious adverse events (SAEs), and dose-limiting toxicities (DLTs)”	“The maximum tolerated dose/maximum administered dose will be determined by the number of participant experiencing DLTs. The safety profile will be assessed through number of participants experiencing AEs, SAEs, abnormal laboratory parameters, vital signs and electrocardiogram (ECG) results.”	“From time of 1st administration of ABL001 until day 21.”

Efficacy results

Responses, dose levels at which they occurred, and DLL4 expression

“Of the 39 evaluable patients, there were 4 partial responses (PRs) and 3 of those responses were confirmed by RECIST. Responses began to appear at the 10 mg/kg dose level. The 3 confirmed partial responses included 2 colorectal cancer patients at 10 mg/kg and 1 gastric cancer patient at 12.5 mg/kg. All 3 patients with PRs exhibited high DLL4 expression by IHC on archived tumor tissue samples. The unconfirmed PR was in a patient with gastric cancer dosed at 15 mg/kg who was also DLL4 IHC positive.” (opens the source at this quote in a new tab)

Response and disease control at the recommended phase 2 doses

“The recommended Phase 2 doses (RP2Ds) were determined to be 10 mg/kg and 12.5 mg/kg and the Overall Response Rate (ORR) at the RP2D was 18.8% (3/16) and the Disease Control Rate (DCR) was 62.5% (11/16).” (opens the source at this quote in a new tab)

Limitations

No evidence found.

Clinical guidelines

Guidelines make no recommendation for tovecimig; the ESMO Clinical Practice Guideline (2023) states an urgent need for new therapies in this setting

“Nearly 40% of patients with BTC harbour genetic alterations which are potential targets for precision medicine.” (opens the source at this quote in a new tab)
“There remains, therefore, an urgent need to develop new therapies, particularly for patients who lack a targetable genomic alteration.” (opens the source at this quote in a new tab)

ESMO Clinical Practice Guideline (2023): second-line systemic therapy after cisplatin and gemcitabine

“FOLFOX is the SoC in the second-line setting after cisplatin–gemcitabine [I, A; ESMO-MCBS v1.1 score: 1; no specific licensed indication in BTC].” (opens the source at this quote in a new tab)
“Second-line ChT has previously been used ad hoc by clinicians with limited knowledge of the magnitude of benefit.” (opens the source at this quote in a new tab)
“Evidence for irinotecan-based therapies is currently limited.” (opens the source at this quote in a new tab)

ESMO Clinical Practice Guideline (2023): tissue acquisition and the composition of the molecular testing panel

“A core biopsy should be obtained for diagnostic pathology and molecular profiling before any nonsurgical treatment [III, A].” (opens the source at this quote in a new tab)
“In patients with d/pCCA without extraductal metastasis, PTC- or ERCP-guided biopsies should be carried out to obtain adequate tissue for diagnostic pathology and molecular profiling [III, A].” (opens the source at this quote in a new tab)
“Parallel sequencing of several genes using focused next-generation sequencing (NGS) is preferred over single gene testing.” (opens the source at this quote in a new tab)
“Currently, the gene panel should include the respective coding DNA regions (target regions) of isocitrate dehydrogenase 1 (IDH1), human epidermal growth factor receptor 2 (HER2)/neu [v-erb-b2 avian erythroblastic leukaemia viral oncogene homologue 2 (ERBB2)] and BRAF to test for hotspot mutations, but the rapidly evolving landscape of drug targets and predictive biomarkers may soon necessitate larger panels.” (opens the source at this quote in a new tab)

Pan-Asian adapted ESMO Clinical Practice Guidelines (2024): first-line alternatives, second-line chemotherapy, molecularly directed therapy, locoregional therapy, and supportive care

“Oxaliplatin or carboplatin may be substituted for cisplatin when renal or auditory function is of concern, while gemcitabine plus S-1 can be an option for patients who present with or are susceptible to peripheral sensory neuropathy [II, B]” (opens the source at this quote in a new tab)
“Gemcitabine monotherapy may be used in patients with a PS of 2 [IV, B]” (opens the source at this quote in a new tab)
“FOLFOX is the standard of care in the second-line setting after cisplatin-gemcitabine-based treatment” (opens the source at this quote in a new tab)
“Irinotecan monotherapy or irinotecan- or liposomal irinotecan-based combination therapy may be considered [III, B]” (opens the source at this quote in a new tab)
“Furthermore, FOLFOX treatment showed a limited survival benefit compared with active symptom control (6.2 months for FOLFOX versus 5.3 months for active symptom control).” (opens the source at this quote in a new tab)
“Moreover, because the ABC-06 trial is the only positive phase III trial for the second-line treatment of BTC, the LoE was also downgraded from ‘I’ to ‘II’.” (opens the source at this quote in a new tab)
“Ivosidenib is recommended for the treatment of patients with CCA and IDH1 mutations who have progressed after ≥1 prior line of systemic therapy [I, A; ESMO-MCBS v1.1 score: 2; ESCAT score: I-A; FDA approved, not EMA approved]” (opens the source at this quote in a new tab)
“FGFR inhibitors are recommended for the treatment of patients with FGFR2 fusions who have progressed after ≥1 prior line of systemic therapy [III, A; ESMO-MCBS v1.1 score: 3; ESCAT score: I-B]” (opens the source at this quote in a new tab)
“HER2-directed therapies can be considered in patients with HER2 overexpression/amplification who have progressed on or are intolerant to prior treatment [III, A; ESCAT score: I-C]” (opens the source at this quote in a new tab)
“Dabrafenib-trametinib is recommended for the treatment of patients with BRAFV600E mutations who have progressed after ≥1 prior line of systemic therapy [III, A; ESMO-MCBS v1.1 score: 3; ESCAT score: I-B; FDA approved, not EMA approved]” (opens the source at this quote in a new tab)
“NTRK inhibitors are recommended in patients with NTRK fusions who have progressed on or are intolerant to prior treatment [III, A; ESCAT score: I-C]” (opens the source at this quote in a new tab)
“Selpercatinib can be considered in patients with RET fusions who have progressed on or are intolerant to prior treatment [III; A; ESMO-MCBS v1.1 score for solid tumours with a RET fusion: 3; ESCAT score: I-C; FDA approved, not EMA approved]” (opens the source at this quote in a new tab)
“Pembrolizumab is recommended in patients with MSI-H/dMMR who have progressed on or are intolerant to prior non-immune checkpoint inhibitor-containing treatment [III, A; ESMO-MCBS v1.1 score: 3; ESCAT score: I-C]” (opens the source at this quote in a new tab)
“Pembrolizumab can be considered in patients with TMB-H tumours who have progressed on or are intolerant to prior non-immune checkpoint inhibitor-containing treatment [IV; A; ESMO-MCBS v1.1 score for pembrolizumab in TMB-H solid tumours: 3; ESCAT Score: I-C]” (opens the source at this quote in a new tab)
“Local ablation could be considered as an option for patients with iCCA ≤3 cm who have contraindications or are otherwise unfit for surgery [III, B]” (opens the source at this quote in a new tab)
“SBRT can be considered for patients with iCCA in case of contraindication to surgery for liver-limited disease in the palliative setting [III, C]” (opens the source at this quote in a new tab)
“Intraarterial therapies, in combination with systemic ChT, can be an option for patients with liver-limited iCCA and discussed by the MDTB according to local availability [III, C]” (opens the source at this quote in a new tab)
“In patients with biliary obstruction, biliary drainage and subsequent treatment should be carried out; when endoscopic access is not possible, percutaneous transhepatic drainage is recommended [IV, A]” (opens the source at this quote in a new tab)
“Sepsis secondary to biliary obstruction is common and should be treated promptly [IV, A]” (opens the source at this quote in a new tab)
“Patients should be advised of the likely duration of stent patency and of symptoms and signs which are indicative of biliary obstruction or infection [V, A]” (opens the source at this quote in a new tab)

Pan-Asian adapted ESMO Clinical Practice Guidelines (2024): imaging, biomarkers, and molecular analysis that define the treated population

“Molecular analysis is recommended in advanced disease considered suitable for systemic treatment [I, A]” (opens the source at this quote in a new tab)
“Elevated CA 19-9 is associated with poorer prognosis and can be useful for assessing response to treatment [III, C]” (opens the source at this quote in a new tab)
“Thoraco-abdomino-pelvic CT remains the reference examination for lymph node and metastatic extension [III, A]” (opens the source at this quote in a new tab)
“FDG-PET is not recommended for imaging of the primary tumour. However, it may be considered where there is clinical suspicion of nodal metastases, distant metastases and disease recurrence [III, C; consensus = 100%].” (opens the source at this quote in a new tab)
“Radiological imaging should be carried out before ERCP or PTC in patients with jaundice [III, A]” (opens the source at this quote in a new tab)

ESMO Clinical Practice Guideline interim update (2025): first-line chemoimmunotherapy and biomarker-directed later-line therapy

“Cisplatin–gemcitabine–durvalumab and cisplatin–gemcitabine–pembrolizumab are recommended as first-line therapy [I, A].” (opens the source at this quote in a new tab)
“Cisplatin–gemcitabine combined with either pembrolizumab or durvalumab is a viable option for first-line treatment.” (opens the source at this quote in a new tab)
“At present, there are no discernible clinical, biochemical or molecular biomarkers, nor any notable differences in efficacy or toxicity, favouring one immune checkpoint inhibitor over the other.” (opens the source at this quote in a new tab)
“Higher rates of treatment-related toxicity are observed with the addition of a third cytotoxic agent to gemcitabine–cisplatin in all of these regimens.” (opens the source at this quote in a new tab)
“Futibatinib [ESMO-Magnitude of Clinical Benefit (MCBS) v1.1 score: 3] and pemigatinib (ESMO-MCBS v1.1 score: 2) are recommended in patients with FGFR2 fusions or rearrangements who have progressed after one or more prior lines of systemic therapy [III, A; ESCAT score: I-B].” (opens the source at this quote in a new tab)
“These findings led to both the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) approval of pemigatinib and futibatinib.” (opens the source at this quote in a new tab)
“Zanidatamab is recommended in patients with previously treated HER2-positive disease [III, A; ESMO-MCBS v1.1 score: 3; ESCAT score: I-C; FDA approved, not EMA approved].” (opens the source at this quote in a new tab)
“Trastuzumab deruxtecan should be considered in patients with HER2 overexpression and/or HER2 amplification who have progressed on or are intolerant to prior treatment [III, A; ESMO-MCBS v1.1 score: 3; ESCAT score: I-C; FDA approved, not EMA approved].” (opens the source at this quote in a new tab)
“Zanidatamab is now FDA approved for previously treated, unresectable or metastatic HER2-positive BTC.” (opens the source at this quote in a new tab)
“HER2 alterations, comprising amplifications and mutations, as well as human epidermal growth factor receptor 2 (HER2) protein overexpression, can be found in ∼5%-10% of BTC cases, with a higher prevalence observed in extrahepatic CCA and gallbladder carcinoma.” (opens the source at this quote in a new tab)
“Most clinical trials focus on patients with HER2 overexpression and HER2 amplification, yet there are currently no standardised criteria for assessing HER2 status in BTC and no specific test can be recommended.” (opens the source at this quote in a new tab)
“Entrectinib (ESMO-MCBS v1.1 score: 3), larotrectinib (ESMO-MCBS v1.1 score: 3) and repotrectinib (not EMA or FDA approved) are recommended in patients with NTRK fusions who have progressed on or are intolerant to prior treatment [III, A; ESCAT score: I-C].” (opens the source at this quote in a new tab)
“Selpercatinib should be considered in patients with RET fusions who have progressed on or are intolerant to prior treatment [III, A; ESMO-MCBS v1.1 score: 3; ESCAT score: I-C].” (opens the source at this quote in a new tab)
“NTRK fusions occur in <0.1% of BTC cases.” (opens the source at this quote in a new tab)
“Because of the very low prevalence of these alterations, the respective inhibitors have only been evaluated in basket trials.” (opens the source at this quote in a new tab)

Safety summary

Contraindications

No approved labeling and therefore no labeled contraindications: tovecimig is an investigational product whose biologics license application is planned

“Tovecimig (formerly known as CTX-009) is an investigational bispecific antibody that is designed to simultaneously block the DLL4 and VEGF-A signaling pathways, which are critical to angiogenesis and tumor vascularization.” (opens the source at this quote in a new tab)

“Planning to file BLA based on data with potential approval in 2H 2027” (opens the source at this quote in a new tab)

Cardiovascular, hemorrhagic, and gastrointestinal conditions excluded from COMPANION-002

“Congestive heart failure (CHF) that corresponds to Class II or a higher class under New York Heart Association (NYHA) classification, or less than 50% of left ventricular ejection fraction (LVEF)” (opens the source at this quote in a new tab)
“Uncontrolled hypertension (SBP/DBP >140/90 mmHg) (e.g., patient with SBP/DBP >140/90 mmHg despite the best care including optimizing the anti-hypertensive medication regimen)” (opens the source at this quote in a new tab)
“Patients with any history of hypertensive crisis or pre-existing hypertensive encephalopathy” (opens the source at this quote in a new tab)
“Active hemorrhage, hemorrhagic diathesis, coagulopathy or tumor in great arteries” (opens the source at this quote in a new tab)
“History of clinically significant gastroenterological disease, such as peptic ulcer, GI bleeding, GI or non-GI fistula, perforation, abdominal abscess, clinical symptoms, and signs of GI obstruction, need for parenteral hydration or nutrition, or inflammatory bowel disease (IBD)” (opens the source at this quote in a new tab)
“Pre-existing hemoptysis (≥ 1/2 teaspoon of bright red blood per episode) within 28 days prior to screening” (opens the source at this quote in a new tab)
“Patients with percutaneous transhepatic biliary drains (PTBD)” (opens the source at this quote in a new tab)

Boxed warning

No approved labeling and therefore no boxed warning: tovecimig is an investigational product whose biologics license application is planned

“Tovecimig (formerly known as CTX-009) is an investigational bispecific antibody that is designed to simultaneously block the DLL4 and VEGF-A signaling pathways, which are critical to angiogenesis and tumor vascularization.” (opens the source at this quote in a new tab)

“Planning to file BLA based on data with potential approval in 2H 2027” (opens the source at this quote in a new tab)

Warnings and precautions

No approved labeling and therefore no labeled warnings and precautions: tovecimig is an investigational product whose biologics license application is planned

“Tovecimig (formerly known as CTX-009) is an investigational bispecific antibody that is designed to simultaneously block the DLL4 and VEGF-A signaling pathways, which are critical to angiogenesis and tumor vascularization.” (opens the source at this quote in a new tab)

“Planning to file BLA based on data with potential approval in 2H 2027” (opens the source at this quote in a new tab)

Independent safety monitoring in COMPANION-002

“Safety Monitoring : An independent Data Safety Monitoring Committee reviewed safety data at four separate (pre - specified) meetings and recommended continuation of the study with no modification after each meeting.” (opens the source at this quote in a new tab)

Adverse event grading and safety follow-up specified in COMPANION-002

“Safety will be monitored throughout the study and for 30 days after the end of treatment. Adverse events will be assessed as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0.” (opens the source at this quote in a new tab)

Class-related events reported with other DLL4 and VEGF bispecific antibodies

“The treatment related adverse events (≥15% of patients) were hypertension (57.6%), headache (28.8%), fatigue (25.8%), and pulmonary hypertension (18.2%). Pulmonary hypertension was mostly asymptomatic at doses ≤5 mg/kg (6 Gr1, 1 Gr2), but was more severe at higher doses (4 Gr2, 1 Gr3).” (opens the source at this quote in a new tab)
“Twelve patients experienced pulmonary hypertension (6 asymptomatic Grade 1, 5 Grade 2 and 1 Grade 3) that was reversible upon drug discontinuation.” (opens the source at this quote in a new tab)
“Left-sided heart failure was the primary toxicity which limited the therapeutic index of the anti-DLL4 agents. Importantly, no cases of left-sided heart failure were observed in this study of dual DLL4/VEGF inhibition.” (opens the source at this quote in a new tab)
“There were 19 (28.8%) patients that had navicixizumab withdrawn because of an adverse event. The most common adverse event that resulted in navicixizumab being withdrawn were: pulmonary hypertension (7 [10.6%] patients); hypertension (4 [6.1%] patients); and infusion-related reactions, fatigue, and increased BNP (2 [3.0%] patients each).” (opens the source at this quote in a new tab)
“Single agent activity has been observed with anti-DLL4 therapy, but treatment duration was limited by cardiotoxicity that is believed to be due to the increased vascular sprouting which occurs when DLL4 is inhibited, but VEGF is not inhibited” (opens the source at this quote in a new tab)

“A TRAE of special interest was gastrointestinal perforation, occurring in 2 patients (3.6%; 1 with ovarian and 1 with prostate cancer) and resulting in 1 death.” (opens the source at this quote in a new tab)

Hypertension management protocol and cardiac monitoring in the navicixizumab phase 1a study

“This dose level was expanded to 6 patients; of these, 4 patients discontinued from the study due to hypertension. As a result, a standardized protocol for hypertension management was established (initially using amlodipine or nifedipine at starting doses of 5 and 30 mg daily, when blood pressure was >140/90; ACE inhibitors or beta-blockers were added afterwards as needed) and 6 more patients were treated at 2.5 mg/kg without having to be withdrawn for hypertension.” (opens the source at this quote in a new tab)
“Patients with ≥ Grade 2 pulmonary hypertension were referred to a cardiologist or pulmonologist to determine what if any further evaluations and/or treatment for their pulmonary hypertension were warranted.” (opens the source at this quote in a new tab)
“Six patients had a BNP level > 250 pg/mL. Five of these patients had pulmonary hypertension which presumably caused the BNP elevation and 1 patient had a reduction in left ventricular ejection fraction (from 55 to 40%) without pulmonary hypertension.” (opens the source at this quote in a new tab)

Common adverse reactions

COMPANION-002: overall safety conclusion and most frequent events

“Tovecimig was generally well tolerated and the safety profile was consistent with previously reported data from prior studies, with no new safety signals. The most commonly reported treatment emergent adverse events in the tovecimig combination arm were hypertension (69%) and fatigue (67%). The most common related treatment-emergent adverse events of Grade 3 or higher included hypertension (44%) and neutropenia (36%).” (opens the source at this quote in a new tab)

COMPANION-002: treatment-emergent adverse events reported in at least 20% of participants, n (%), with the paclitaxel comparator arm

Adverse event	Tovecimig plus paclitaxel (n=108), any grade	Tovecimig plus paclitaxel (n=108), grade 3 or higher	Paclitaxel (n=53), any grade	Paclitaxel (n=53), grade 3 or higher
Hypertension	“75 (69)”	“56 (52)”	“10 (19)”	“3 (6)”
Fatigue	“72 (67)”	“16 (15)”	“24 (45)”	“3 (6)”
Neutropenia	“59 (55)”	“40 (37)”	“20 (38)”	“14 (26)”
Diarrhea	“51 (47)”	“6 (6)”	“15 (28)”	“1 (2)”
Anemia	“48 (44)”	“23 (21)”	“17 (32)”	“5 (9)”
Decreased appetite	“44 (41)”	“2 (2)”	“11 (21)”	“-”
Nausea	“43 (40)”	“2 (2)”	“17 (32)”	“-”
Proteinuria	“37 (34)”	“3 (3)”	“5 (9)”	“-”
Vomiting	“36 (33)”	“1 (1)”	“13 (25)”	“1 (2)”
Abdominal pain	“35 (32)”	“9 (8)”	“13 (25)”	“4 (8)”
Dyspnea	“32 (30)”	“5 (5)”	“13 (25)”	“-”
Epistaxis	“32 (30)”	“-”	“4 (8)”	“-”
Alopecia	“32 (30)”	“-”	“28 (53)”	“-”
Thrombocytopenia	“33 (31)”	“7 (7)”	“6 (11)”	“-”
Peripheral edema	“35 (32)”	“-”	“7 (13)”	“-”
Peripheral neuropathy	“29 (27)”	“2 (2)”	“13 (25)”	“1 (2)”
Constipation	“30 (28)”	“-”	“8 (15)”	“-”
Headache	“25 (23)”	“-”	“7 (13)”	“-”
Arthralgia	“25 (23)”	“-”	“6 (11)”	“-”

COMPANION-002: consistency of the safety profile across data cuts

“Safety profile generally consistent with previously reported data” (opens the source at this quote in a new tab)

Single-arm phase 1b/2 in South Korea: treatment-related adverse events

“Treatment-related adverse events (TRAEs) of any grade were reported in 100% of pts and TRAEs of ≥ grade 3 were reported in 75% of pts (including one grade 5 pneumonia). The most frequent TRAEs of ≥ grade 3 were neutropenia (50.0%), hypertension (16.7%), anemia (12.5%), and thrombocytopenia (8.3%).” (opens the source at this quote in a new tab)

Single-arm phase 1b/2 in South Korea: treatment-emergent adverse events regardless of relationship

“Of the 24 patients enrolled in the trial, all patients had at least one treatment emergent adverse event (“TEAE”). Grade 3 or greater TEAEs were reported in 95.8% of patients regardless of the relationship to tovecimig or paclitaxel, including decreased neutrophil count (83.3%), hypertension (16.7%), anemia (20.8%), and decreased platelet count (12.5%).” (opens the source at this quote in a new tab)

Single-arm phase 1b/2 in South Korea: adverse events of special interest

“Grade 3 or greater adverse events that were designated to be of special interest (“AESIs”) by the trial investigators were hemoptysis or hemorrhage (12.5%) and GI or tumor perforation (8.3%), with 0% for pulmonary hypertension, wound healing complication and cardiac failure.” (opens the source at this quote in a new tab)

Phase 1 monotherapy dose escalation: dose-limiting toxicities and treatment-emergent adverse events

“No dose limiting toxicities (DLTs) were observed. The most common Treatment-Emergent Adverse Events (TEAEs) reported in ≥10% patients were hypertension (37.8%), headache (22.2%), anemia (13.3%), asthenia (13.3%) and fatigue (11.1%). Grade 3 or greater TEAEs reported in ≥5% patients were hypertension (15.6%) and anemia (6.7%). The most common Treatment Related Adverse Events (TRAEs) reported in ≥10% patients were hypertension (37.8%) and headache (15.6%).” (opens the source at this quote in a new tab)

Phase 1 monotherapy dose escalation: tolerability across the dose range

“ABL001/CTX‐009 showed favorable tolerability in the dose range from 0.3 to 17.5 mg/kg in this first‐in‐human study in patients with advanced solid tumors.” (opens the source at this quote in a new tab)

Phase 2 monotherapy in colorectal cancer: hypertension

“Tovecimig’s safety profile was generally consistent with prior studies with hypertension as the most common treatment-emergent adverse event, all of which occurred in patients with a prior history of hypertension.” (opens the source at this quote in a new tab)

Drug interactions

Protocol restrictions on anticoagulants, antiplatelet agents, and prior anticancer therapy

“Current or recent (within 10 days prior to study treatment) use of full-dose oral or parenteral anticoagulants or thrombolytic agents for therapeutic (as opposed to prophylactic) purpose will be excluded” (opens the source at this quote in a new tab)
“Patients with current or recent (within 10 days of study treatment) use of aspirin (>81 mg/day), or other NSAIDs, or other antiplatelets (i.e., dipyridamole, ticlopidine, clopidogrel and cilostazol) will be excluded” (opens the source at this quote in a new tab)
“Less than 2 weeks have elapsed since patients had chemotherapy or hormone therapy” (opens the source at this quote in a new tab)

Covariates tested in the population pharmacokinetic analysis

“Except for body weight, no other covariate was determined as significant to the PK properties of ABL001/CTX‐009, and the body weight was assessed as a significant covariate for V1 by leading to the largest decrease in the OFV and was added as a covariate on V1 as below:” (opens the source at this quote in a new tab)

Preclinical interaction with cytotoxic chemotherapy through tumor vessel normalization

“Anti-VEGF therapy is known to normalize tumor blood vessels, leading to a more efficient delivery of cytotoxic anti-cancer agents into tumor tissues” (opens the source at this quote in a new tab)
“Moreover, because the VEGF-binding part of ABL001 is composed of the same IgG backbone and sequence as bevacizumab, ABL001 may have similar activity and function as bevacizumab in tumor vessels, resulting in a more effective delivery of anti-cancer agents, such as paclitaxel or irinotecan.” (opens the source at this quote in a new tab)

Dedicated clinical drug interaction studies

No evidence found.

Special populations

Eligibility restrictions applied in COMPANION-002

Criterion	Quoted record
Minimum age	“18 Years”
Performance status	“Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1”
Life expectancy	“Predicted life expectancy of at least 12 weeks”
Hematologic function	“Hemoglobin ≥ 9.0 g/dL”
Hepatic function	“Total bilirubin ≤ 1.5 X ULN”
Renal function	“Estimated creatinine clearance ≥ 30 mL/min based on Cockcroft-Gault”
Proteinuria	“Urine protein ≤ 1+ by Dipstick”
Biliary drainage	“Patients with percutaneous transhepatic biliary drains (PTBD)”
Cardiovascular disease	“Uncontrolled arrhythmia”
Pulmonary hypertension	“Pulmonary hypertension”
Central nervous system metastases	“Symptomatic or uncontrolled central nervous system (CNS) metastasis”
Hemorrhage	“Active hemorrhage, hemorrhagic diathesis, coagulopathy or tumor in great arteries”
Pulmonary disease	“Interstitial lung disease or pulmonary fibrosis”
Paclitaxel tolerance	“Patients with contraindications to paclitaxel therapy”
Electrocardiogram	“QT interval (Fridericia's formula) (QTcF) interval > 450msec at the time of screening”
Pregnancy and lactation	“Pregnant or lactating patients, or patients planning to become pregnant during the clinical study”
Hypersensitivity	“History of hypersensitivity reactions to any components of the investigational product or other drugs of the same class (humanized/human monoclonal antibody drugs) or paclitaxel”

Contraception requirements

“Female patients must be surgically sterile (or have a monogamous partner who is surgically sterile), or be at least 2 years postmenopausal, or commit to use two acceptable forms of birth control (defined as the use of an IUD, a barrier method with spermicide, condoms, or any form of hormonal contraceptives) or abstinence for the duration of the study and for 6 months following the last dose of study treatment. Male patients must be sterile (biologically or surgically) or commit to the use of a reliable method of birth control (condoms with spermicide) for the duration of the study and for 6 months following the last dose of study treatment” (opens the source at this quote in a new tab)

Age, sex, and race of participants randomized in COMPANION-002

Characteristic	Tovecimig plus paclitaxel (n=111)	Paclitaxel (n=57)
Median age, years	“65.0”	“63.0”
Male, n (%)	“53 (47.7)”	“24 (42.1)”
Female, n (%)	“58 (52.3)”	“33 (57.9)”
Asian, n (%)	“17 (15.3)”	“10 (17.5)”
White, n (%)	“84 (75.7)”	“40 (70.2)”
African American, n (%)	“4 (3.6)”	“6 (10.5)”
Unknown or other, n (%)	“6 (5.4)”	“1 (1.8)”

Age and organ-function eligibility in the phase 1 study

“Adult patients (aged ≥19 years) with confirmed of any progressive locally advanced or metastatic solid tumors that had relapsed or were refractory to the standard therapy were enrolled.” (opens the source at this quote in a new tab)
“Patients who had clinically significant cardiovascular disease, including pulmonary hypertension and myocardial infarction, hypersensitivity to humanized/human mAb, or who previously received anti‐DLL4 antibody were excluded.” (opens the source at this quote in a new tab)

Pediatric use, pregnancy and lactation, and dedicated renal or hepatic impairment pharmacokinetic studies

No evidence found.

Comparators and place in therapy

Absence of an approved systemic therapy in the second line outside biomarker-directed agents

“The only FDA approved therapies for second line treatment of BTC are targeted therapies that address specific tumor mutations or solid tumors that are microsatellite instability high. For example, in November 2024, Jazz Pharmaceuticals received FDA approval of Ziihera (zanidatamab-hrii) for previously treated, unresectable, or metastatic human epidermal growth factor receptor (“HER2”) positive (IHC 3+) biliary tract cancer, which may be beneficial to the small subset of patients in whom HER2 is amplified overexpressed.” (opens the source at this quote in a new tab)

“For the vast majority of patients with BTC whose tumors do not harbor an actionable mutation with an approved targeted therapy, there is currently no FDA-approved treatment in the second line setting. The therapeutics most commonly used in this setting, which are not labeled or approved by the FDA for the treatment of patients with BTC, generally have an ORR of ~5% or less and patients face a median OS of approximately six months.” (opens the source at this quote in a new tab)

FOLFOX: guideline standing and reported outcomes in the second line

“FOLFOX is the standard of care in the second-line setting after cisplatin-gemcitabine-based treatment” (opens the source at this quote in a new tab)
“Irinotecan monotherapy or irinotecan- or liposomal irinotecan-based combination therapy may be considered [III, B]” (opens the source at this quote in a new tab)

“For patients who progressed after frontline therapy and lack actionable alterations, fluoropyrimidine plus oxaliplatin and fluoropyrimidine plus liposomal irinotecan are recommended second-line options, supported by ABC-06 and NIFTY, respectively.” (opens the source at this quote in a new tab)
“The primary endpoint, median OS, was significantly improved with ASC plus FOLFOX over ASC alone (Table 1B). The median PFS was 4.0 months, and the ORR was 4.9% in the FOLFOX arm.” (opens the source at this quote in a new tab)

“FOLFOX is the SoC in the second-line setting after cisplatin–gemcitabine [I, A; ESMO-MCBS v1.1 score: 1; no specific licensed indication in BTC].” (opens the source at this quote in a new tab)
“Second-line ChT has previously been used ad hoc by clinicians with limited knowledge of the magnitude of benefit.” (opens the source at this quote in a new tab)
“Evidence for irinotecan-based therapies is currently limited.” (opens the source at this quote in a new tab)

“Overall survival was significantly longer in the ASC plus FOLFOX group than in the ASC alone group, with a median overall survival of 6·2 months (95% CI 5·4–7·6) in the ASC plus FOLFOX group versus 5·3 months (4·1–5·8) in the ASC alone group (adjusted hazard ratio 0·69 [95% CI 0·50–0·97]; p=0·031).” (opens the source at this quote in a new tab)
“Objective response was observed in four (5%) of 81 patients in the ASC plus FOLFOX group: one (1%) patient had a complete response and three (4%) patients had a partial response.” (opens the source at this quote in a new tab)
“Grade 3–5 adverse events were reported in 42 (52%) of 81 patients in the ASC alone group and 56 (69%) of 81 patients in the ASC plus FOLFOX group, including three chemotherapy-related deaths (one each due to infection, acute kidney injury, and febrile neutropenia).” (opens the source at this quote in a new tab)
“Based on these findings, FOLFOX should become standard-of-care chemotherapy in second-line treatment for advanced biliary tract cancer and the reference regimen for further clinical trials.” (opens the source at this quote in a new tab)

“For reference, one regimen that has been studied in patients with advanced BTC is the three-drug combination FOLFOX. FOLFOX demonstrated an ORR of 4.9%, a median PFS of 4.0 months, and a median OS of 6.2 months in a randomized study against best supportive care.” (opens the source at this quote in a new tab)

“2L treatment options are ineffective – FOLFOX in this setting has a 5% ORR and a median OS of 6.1 months” (opens the source at this quote in a new tab)

Downgraded strength of the second-line chemotherapy recommendation

“Furthermore, FOLFOX treatment showed a limited survival benefit compared with active symptom control (6.2 months for FOLFOX versus 5.3 months for active symptom control).” (opens the source at this quote in a new tab)
“Moreover, because the ABC-06 trial is the only positive phase III trial for the second-line treatment of BTC, the LoE was also downgraded from ‘I’ to ‘II’.” (opens the source at this quote in a new tab)

Liposomal irinotecan-based regimens: NIFTY, NALIRICC, and pooled individual patient data

“At a median follow-up of 11·8 months (IQR 7·7-18·7), the median BICR-assessed progression-free survival was significantly longer in the liposomal irinotecan plus fluorouracil and leucovorin group (7·1 months, 95% CI 3·6-8·8) than in the fluorouracil and leucovorin group (1·4 months, 1·2-1·5; hazard ratio 0·56, 95% CI 0·39-0·81; p=0·0019).” (opens the source at this quote in a new tab)
“Liposomal irinotecan plus fluorouracil and leucovorin could be considered a standard-of-care second-line therapy for advanced biliary tract cancer.” (opens the source at this quote in a new tab)
“The discordance rate for the date of tumour progression between the investigator and the BICR assessments was 30% (52 of 174; appendix 2 pp 5–8).” (opens the source at this quote in a new tab)
“the possibility of overestimation in the median progression-free survival by BICR assessment cannot be excluded.” (opens the source at this quote in a new tab)

“Median progression-free survival was 2·6 months (95% CI 1·7-3·6) in the nanoliposomal irinotecan group and 2·3 months (1·6-3·4) in the control group (hazard ratio [HR] 0·87 [0·56-1·35]).” (opens the source at this quote in a new tab)
“The addition of nanoliposomal irinotecan to fluorouracil plus leucovorin did not improve progression-free survival or overall survival and was associated with higher toxicity compared with fluorouracil plus leucovorin.” (opens the source at this quote in a new tab)

“Differences in sample size (174 vs. 100), iCCA proportion (64% vs. 43%), ethnicity (Asian vs. White), and more frequent early treatment discontinuations due to toxicity in NALIRICC may have contributed to the discordant results [28].” (opens the source at this quote in a new tab)

“Current standard of care for second-line therapy in patients with advanced biliary tract cancer (BTC) is FOLFOX.” (opens the source at this quote in a new tab)
“The nal-IRI plus 5-FU/LV group showed significantly longer median PFS (3.6 months [95% CI 2.7-4.4] vs. 1.8 months [95% CI 1.5-2.6]; hazard ratio 0.65, p <0.001).” (opens the source at this quote in a new tab)
“There was no statistically significant difference in OS (median 8.1 vs. 6.1 months, HR 0.77, p = 0.051).” (opens the source at this quote in a new tab)
“However, nal-IRI plus 5-FU/LV may be considered a viable alternative to second-line FOLFOX for patients of East Asian ethnicity or those deemed unfit for FOLFOX (e.g. due to severe peripheral neuropathy caused by prior platinum-based therapy).” (opens the source at this quote in a new tab)

Taxane-based chemotherapy in later-line practice and the rationale for the paclitaxel comparator

“Treatment distribution was as follows: FOLFIRI (n = 51, 20%), paclitaxel (n = 43, 17%), combinations of 5-FU cisplatin/FOLFOX (n = 32, 13%), molecularly targeted therapy (n = 65, 25%) and others (n = 63, 25%).” (opens the source at this quote in a new tab)
“OS was 13 months with paclitaxel and 7 months with FOLFIRI (P = 0.03).” (opens the source at this quote in a new tab)

“Second-line options for biliary tract cancer (BTC) are limited. While nab-paclitaxel has demonstrated certain antitumor activity, evidence remains scarce.” (opens the source at this quote in a new tab)
“Among 84 patients (41 in the chemo-anti-PD-(L)1 group and 43 in the chemotherapy group), the median OS was 15.17 months (95% confidence interval (CI), 12.63-21.43), median PFS was 5.40 months (95% CI, 3.23-8.03), objective response rate (ORR) was 21.43% (95% CI, 13.22-31.74), and disease control rate (DCR) was 60.71% (95% CI, 49.45-71.20).” (opens the source at this quote in a new tab)

“Paclitaxel was chosen based on the safety and efficacy data from this phase Ib study.” (opens the source at this quote in a new tab)
“The primary end point of the phase II study was overall response rate (ORR) and the ORR was 37.5% (n = 9/24 patients).” (opens the source at this quote in a new tab)
“Among 11 patients treated in the second-line, the ORR was 63.6% (n = 7/11) versus 15% (n = 2/13) among patients treated in the third-line setting.” (opens the source at this quote in a new tab)

Tovecimig plus paclitaxel compared with paclitaxel alone in COMPANION-002

“In the final data analysis, the overall response rate (ORR), the primary endpoint in the study, improved to 18.0% (20/111 patients) in the tovecimig combination arm from a previously reported 17.1%.” (opens the source at this quote in a new tab)

“Tovecimig (a DLL4 x VEGF-A bispecific antibody) in combination with paclitaxel demonstrated a highly statistically significant improvement versus paclitaxel alone in the key secondary endpoint of median progression-free survival (PFS) of 4.7 months versus 2.6 months, providing a 56% reduction in the risk of progression (hazard ratio=0.44, p<0.0001).” (opens the source at this quote in a new tab)

Share of patients eligible for a biomarker-directed option

“For the approximately 85% of patients with BTC whose tumors do not harbor an actionable mutation with an approved targeted therapy, there is currently no FDA-approved treatment in the second line setting.” (opens the source at this quote in a new tab)

“Nearly 40% of patients with BTC harbour genetic alterations which are potential targets for precision medicine.” (opens the source at this quote in a new tab)
“There remains, therefore, an urgent need to develop new therapies, particularly for patients who lack a targetable genomic alteration.” (opens the source at this quote in a new tab)

“A treatment option is urgently needed for patients with tumors without an obvious actionable alteration.” (opens the source at this quote in a new tab)
“While several targeted therapies have gained approval for addressing gene alterations that are relevant in BTC, only a minority of BTCs harbor these alterations.” (opens the source at this quote in a new tab)
“In a randomized study in the second-line setting, the three drug combination regimen FOLFOX improved median overall survival by 0.9 months compared with best supportive care” (opens the source at this quote in a new tab)

FGFR2 fusion-directed inhibitors: prevalence, recommendations, and reported outcomes

“Fibroblast growth factor receptor 2 (FGFR2) fusions or rearrangements occur in up to 14% of patients with intrahepatic cholangiocarcinoma.” (opens the source at this quote in a new tab)
“Exploratory ctDNA analysis identified FGFR2 fusions or rearrangements in 83 of the 95 patients (87%) evaluated” (opens the source at this quote in a new tab)

“Futibatinib [ESMO-Magnitude of Clinical Benefit (MCBS) v1.1 score: 3] and pemigatinib (ESMO-MCBS v1.1 score: 2) are recommended in patients with FGFR2 fusions or rearrangements who have progressed after one or more prior lines of systemic therapy [III, A; ESCAT score: I-B].” (opens the source at this quote in a new tab)
“These findings led to both the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) approval of pemigatinib and futibatinib.” (opens the source at this quote in a new tab)

“FGFR inhibitors are recommended for the treatment of patients with FGFR2 fusions who have progressed after ≥1 prior line of systemic therapy [III, A; ESMO-MCBS v1.1 score: 3; ESCAT score: I-B]” (opens the source at this quote in a new tab)

“The ORR in cohort A was 37.0% (95% confidence interval 27.9% to 46.9%); complete and partial responses were observed in 3 and 37 patients, respectively.” (opens the source at this quote in a new tab)
“Median DOR was 9.1 (6.0-14.5) months; median PFS and OS were 7.0 (6.1-10.5) months and 17.5 (14.4-22.9) months, respectively.” (opens the source at this quote in a new tab)
“The most common TEAEs of any grade were hyperphosphatemia (58.5%), alopecia (49.7%), and diarrhea (47.6%).” (opens the source at this quote in a new tab)

“A total of 43 of 103 patients (42%; 95% confidence interval, 32 to 52) had a response, and the median duration of response was 9.7 months.” (opens the source at this quote in a new tab)
“At a median follow-up of 17.1 months, the median progression-free survival was 9.0 months and overall survival was 21.7 months.” (opens the source at this quote in a new tab)
“Common treatment-related grade 3 adverse events were hyperphosphatemia (in 30% of the patients), an increased aspartate aminotransferase level (in 7%), stomatitis (in 6%), and fatigue (in 6%).” (opens the source at this quote in a new tab)
“Overall, treatment-related adverse events led to dose interruptions in 52 patients (50%) and dose reductions in 56 patients (54%).” (opens the source at this quote in a new tab)

“Cholangiocarcinoma is a rare, aggressive cancer often driven by FGFR2 fusions, which are targetable with inhibitors such as pemigatinib and futibatinib. However, resistance frequently develops due to acquired FGFR2 mutations.” (opens the source at this quote in a new tab)
“Among 51 patients included in the efficacy evaluable set, the objective response rate was 6·3% (95% CI 0·2-30·2; one confirmed partial response) in cohort A1, 30·0% (6·7-65·3; three confirmed partial responses) in cohort A2, 23·1% (5·0-53·8; three confirmed partial responses) in cohort B, and 0% in cohort C.” (opens the source at this quote in a new tab)

IDH1 inhibition: recommendation and ClarIDHy results

“Ivosidenib is recommended for the treatment of patients with CCA and IDH1 mutations who have progressed after ≥1 prior line of systemic therapy [I, A; ESMO-MCBS v1.1 score: 2; ESCAT score: I-A; FDA approved, not EMA approved]” (opens the source at this quote in a new tab)

“Progression-free survival was significantly improved with ivosidenib compared with placebo (median 2·7 months [95% CI 1·6-4·2] vs 1·4 months [1·4-1·6]; hazard ratio 0·37; 95% CI 0·25-0·54; one-sided p<0·0001).” (opens the source at this quote in a new tab)

“Median OS was 10.3 months (95% CI, 7.8-12.4 months) with ivosidenib vs 7.5 months (95% CI, 4.8-11.1 months) with placebo (hazard ratio, 0.79 [95% CI, 0.56-1.12]; 1-sided P = .09).” (opens the source at this quote in a new tab)
“When adjusted for crossover, median OS with placebo was 5.1 months (95% CI, 3.8-7.6 months; hazard ratio, 0.49 [95% CI, 0.34-0.70]; 1-sided P < .001).” (opens the source at this quote in a new tab)

HER2-directed therapy: alteration frequency, recommendations, and reported outcomes

“HER2 alterations, comprising amplifications and mutations, as well as human epidermal growth factor receptor 2 (HER2) protein overexpression, can be found in ∼5%-10% of BTC cases, with a higher prevalence observed in extrahepatic CCA and gallbladder carcinoma.” (opens the source at this quote in a new tab)
“Most clinical trials focus on patients with HER2 overexpression and HER2 amplification, yet there are currently no standardised criteria for assessing HER2 status in BTC and no specific test can be recommended.” (opens the source at this quote in a new tab)

“Between Sept 15, 2020, and March 16, 2022, 847 patients were pre-screened for HER2 amplification and 171 (20%) had HER2-amplified tumours, of which 131 (77%) entered study screening and 87 (66%) were enrolled.” (opens the source at this quote in a new tab)
“HER2 gene amplification status was determined by the VENTANA HER2 Dual ISH DNA Probe Cocktail assay (Ventana Medical Systems, Tuscon, AZ, USA). HER2 gene status was classified as non-amplified (HER2/Chr17 ratio <2·0) or amplified (HER2/Chr17 ratio ≥2·0).” (opens the source at this quote in a new tab)

“Zanidatamab is recommended in patients with previously treated HER2-positive disease [III, A; ESMO-MCBS v1.1 score: 3; ESCAT score: I-C; FDA approved, not EMA approved].” (opens the source at this quote in a new tab)
“Trastuzumab deruxtecan should be considered in patients with HER2 overexpression and/or HER2 amplification who have progressed on or are intolerant to prior treatment [III, A; ESMO-MCBS v1.1 score: 3; ESCAT score: I-C; FDA approved, not EMA approved].” (opens the source at this quote in a new tab)
“Zanidatamab is now FDA approved for previously treated, unresectable or metastatic HER2-positive BTC.” (opens the source at this quote in a new tab)

“HER2-directed therapies can be considered in patients with HER2 overexpression/amplification who have progressed on or are intolerant to prior treatment [III, A; ESCAT score: I-C]” (opens the source at this quote in a new tab)

“Confirmed objective responses by independent central review were observed in 33 patients in cohort 1 (41·3% [95% CI 30·4-52·8]).” (opens the source at this quote in a new tab)
“The median duration of response for the 33 patients in cohort 1 with a confirmed objective response was 12·9 months (95% CI 6·0–not estimable; range 1·5–16·9+) with 16 (49%) patients having ongoing responses at the time of the data cutoff (figure 2B; appendix p 5). No responses to zanidatamab were observed in cohort 2.” (opens the source at this quote in a new tab)
“The median progression-free survival by independent central review in cohort 1 was 5·5 months (95% CI 3·7–7·2; range 0·3–18·5+; table 2; appendix p 6). Overall survival at 9 months was 69·9% (95% CI 57·8–79·1) for cohort 1; median overall survival data were immature at the time of data cutoff.” (opens the source at this quote in a new tab)
“16 patients (18%) had grade 3 treatment-related adverse events; of these, diarrhoea (four [5%] patients), ejection fraction decreased (three [3%]), and anaemia (two [2%]) occurred in more than one patient. No grade 4 or grade 5 treatment-related adverse events were reported.” (opens the source at this quote in a new tab)

“In patients with central HER2 IHC 3+ expression (n = 75), the ORR was 61.3% (95% CI, 49.4 to 72.4), the median DOR was 22.1 months (95% CI, 9.6 to not reached), the median PFS was 11.9 months (95% CI, 8.2 to 13.0), and the median OS was 21.1 months (95% CI, 15.3 to 29.6).” (opens the source at this quote in a new tab)
“Grade ≥3 drug-related adverse events were observed in 40.8% of patients; 10.5% experienced adjudicated drug-related interstitial lung disease (ILD), with three deaths.” (opens the source at this quote in a new tab)

“The cORR was 46.7% (90% CI, 30.8 to 63.0), with a disease control rate of 76.7% (90% CI, 60.6 to 88.5).” (opens the source at this quote in a new tab)
“The median duration of response and progression-free survival were 6.0 months (90% CI, 5.5 to 6.9) and 5.5 months (90% CI, 3.9 to 8.1), respectively.” (opens the source at this quote in a new tab)
“At data cutoff, 15 patients (50.0%) had died, and the estimated 12-month overall survival rate was 53.6% (90% CI, 36.8 to 67.8).” (opens the source at this quote in a new tab)

Tumor-agnostic targeted and immune therapies: target frequency and recommendations

“Disease-agnostic approved agents are available for tumors with BRAF V600E mutations (4–5% frequency in BTC), NTRK fusions (<1%), RET fusions (<1%), and/or microsatellite instability (1–2%)” (opens the source at this quote in a new tab)

“NTRK fusions occur in <0.1% of BTC cases.” (opens the source at this quote in a new tab)
“Because of the very low prevalence of these alterations, the respective inhibitors have only been evaluated in basket trials.” (opens the source at this quote in a new tab)

“Dabrafenib-trametinib is recommended for the treatment of patients with BRAFV600E mutations who have progressed after ≥1 prior line of systemic therapy [III, A; ESMO-MCBS v1.1 score: 3; ESCAT score: I-B; FDA approved, not EMA approved]” (opens the source at this quote in a new tab)
“NTRK inhibitors are recommended in patients with NTRK fusions who have progressed on or are intolerant to prior treatment [III, A; ESCAT score: I-C]” (opens the source at this quote in a new tab)
“Selpercatinib can be considered in patients with RET fusions who have progressed on or are intolerant to prior treatment [III; A; ESMO-MCBS v1.1 score for solid tumours with a RET fusion: 3; ESCAT score: I-C; FDA approved, not EMA approved]” (opens the source at this quote in a new tab)
“Pembrolizumab is recommended in patients with MSI-H/dMMR who have progressed on or are intolerant to prior non-immune checkpoint inhibitor-containing treatment [III, A; ESMO-MCBS v1.1 score: 3; ESCAT score: I-C]” (opens the source at this quote in a new tab)
“Pembrolizumab can be considered in patients with TMB-H tumours who have progressed on or are intolerant to prior non-immune checkpoint inhibitor-containing treatment [IV; A; ESMO-MCBS v1.1 score for pembrolizumab in TMB-H solid tumours: 3; ESCAT Score: I-C]” (opens the source at this quote in a new tab)

“Entrectinib (ESMO-MCBS v1.1 score: 3), larotrectinib (ESMO-MCBS v1.1 score: 3) and repotrectinib (not EMA or FDA approved) are recommended in patients with NTRK fusions who have progressed on or are intolerant to prior treatment [III, A; ESCAT score: I-C].” (opens the source at this quote in a new tab)
“Selpercatinib should be considered in patients with RET fusions who have progressed on or are intolerant to prior treatment [III, A; ESMO-MCBS v1.1 score: 3; ESCAT score: I-C].” (opens the source at this quote in a new tab)

“An investigator-assessed overall response was achieved by 22 (51%, 95% CI 36-67) of 43 patients.” (opens the source at this quote in a new tab)
“An independent reviewer-assessed overall response was achieved by 20 (47%, 95% CI 31-62) of 43 patients.” (opens the source at this quote in a new tab)
“The median duration of response in 22 patients with an investigator-assessed overall response was 9 months (95% CI 6–14).” (opens the source at this quote in a new tab)
“Median progression-free survival by investigator assessment was 9 months (95% CI 5–10; figure 2A). Overall survival was 84% (95% CI 69–92) at 6 months, 56% (38–71) at 12 months, and 36% (19–53) at 24 months.” (opens the source at this quote in a new tab)
“15 (35%) patients had adverse events that led to dose reduction, 24 (56%) patients had adverse events that led to dose interruption” (opens the source at this quote in a new tab)

Line of therapy and eligibility without positive biomarker selection

“Patients who are eligible to be treated with a molecularly targeted therapy on a labelled regimen after receiving first-line chemotherapy.” (opens the source at this quote in a new tab)
“Stratification factors include stage (locally advanced vs metastatic), anatomic subtype of the primary tumor (intrahepatic cholangiocarcinoma vs other) and ECOG performance status (0 or 1).” (opens the source at this quote in a new tab)
“Patients are randomized to a 2:1 ratio, and crossover is allowed to the experimental arm at the time of progression in the control arm for patients that continue to meet eligibility criteria.” (opens the source at this quote in a new tab)

Care setting and administration schedule anticipated for tovecimig

Field	Registry record
Official title	“A Phase 2/3 Randomized, Controlled Study of CTX-009 in Combination With Paclitaxel Versus Paclitaxel Alone in Adult Patients With Unresectable Advanced, Metastatic or Recurrent Biliary Tract Cancers Who Have Received One Prior Systemic Chemotherapy Regimen”
Intervention description, CTX-009	“IV infusion on day 1 and 14 of every 28 day cycle”
Intervention description, paclitaxel	“IV infusion on day 1, 8, and 15 of every 28 day cycle”
Comparator arm description	“Patients randomized to receive paclitaxel only have the option to crossover to the CTX-009 plus paclitaxel arm after documented disease progression per RECIST v1.1.”
Overall status	“Active, not recruiting”

“The study enrolled 168 adult patients, randomized in a 2:1 ratio to receive tovecimig plus paclitaxel (n=111) or paclitaxel alone (n=57). All patients were dosed with 80 mg/m2 of paclitaxel on days 1, 8 and 15 of every 28-day cycle. Patients in the tovecimig arm were also dosed with 10 mg/kg of tovecimig on days 1 and 15 of each 28-day cycle.” (opens the source at this quote in a new tab)
“Patients in the paclitaxel-only arm who progressed could cross over to the tovecimig plus paclitaxel arm after centrally confirmed progression if they also still met the enrollment criteria for the study.” (opens the source at this quote in a new tab)

Absence of a direct head-to-head comparison against an active second-line regimen

No evidence found.

Conclusion

Unmet need in the population that would receive tovecimig

“Nearly 40% of patients with BTC harbour genetic alterations which are potential targets for precision medicine.” (opens the source at this quote in a new tab)
“There remains, therefore, an urgent need to develop new therapies, particularly for patients who lack a targetable genomic alteration.” (opens the source at this quote in a new tab)

Strongest reported efficacy result: objective response rate in the final analysis of COMPANION-002

“In the final data analysis, the overall response rate (ORR), the primary endpoint in the study, improved to 18.0% (20/111 patients) in the tovecimig combination arm from a previously reported 17.1%.” (opens the source at this quote in a new tab)
“With this change, the p-value improved to 0.0228 compared to paclitaxel alone (ORR of 5.3% in the paclitaxel arm).” (opens the source at this quote in a new tab)

Supporting result: progression-free survival

“Tovecimig in combination with paclitaxel demonstrated a statistically significant improvement in median PFS of 4.7 months compared to 2.6 months for paclitaxel alone (HR=0.44, p<0.0001). Progression was confirmed in each case by BICR.” (opens the source at this quote in a new tab)

Constraint on those results: the overall survival endpoint was not met and the crossover-adjusted analysis is stated to be uninterpretable

“In the ITT OS analysis, tovecimig in combination with paclitaxel had a median OS of 8.9 months compared to 9.4 months for the control arm, which included 26 patients (46%) who received paclitaxel alone and 31 patients (54%) who crossed over to receive tovecimig in combination with paclitaxel (HR=1.05, p=0.78).” (opens the source at this quote in a new tab)
“In the rank-preserving structural failure time (RPSFT) OS analysis, the combination also had a median OS of 8.9 months compared to 9.4 months for paclitaxel alone (HR=1.13, p=0.65). Though the RPSFT analysis is intended to adjust for crossover, its validity depends on certain assumptions that were not met in this study and thus its results here are largely uninterpretable.” (opens the source at this quote in a new tab)

Safety statement that most constrains use

“Tovecimig was generally well tolerated and the safety profile was consistent with previously reported data from prior studies, with no new safety signals. The most commonly reported treatment emergent adverse events in the tovecimig combination arm were hypertension (69%) and fatigue (67%). The most common related treatment-emergent adverse events of Grade 3 or higher included hypertension (44%) and neutropenia (36%).” (opens the source at this quote in a new tab)

Regulatory standing: designations granted and a submission not yet filed

“today announced that the U.S. Food and Drug Administration (FDA) has granted Fast Track Designation (FTD) to CTX-009, the Company’s bispecific DLL4/VEGF-A antibody, in combination with paclitaxel for the treatment of patients with metastatic or locally advanced BTC that have been previously treated.” (opens the source at this quote in a new tab)

“Planning to file BLA based on data with potential approval in 2H 2027” (opens the source at this quote in a new tab)

Current status of the product

“Tovecimig (formerly known as CTX-009) is an investigational bispecific antibody that is designed to simultaneously block the DLL4 and VEGF-A signaling pathways, which are critical to angiogenesis and tumor vascularization.” (opens the source at this quote in a new tab)
“Tovecimig (CTX-009), our bispecific antibody targeting DLL4 and VEGF-A, is currently being evaluated in a randomized Phase 2/3 trial in the United States in combination with paclitaxel in patients with biliary tract cancer (“BTC”) who received one prior treatment regimen.” (opens the source at this quote in a new tab)

Monograph section

1Introduction

Definition: biliary tract cancer and the anatomical subtypes of cholangiocarcinoma

Incidence in the United States

Prevalence and the proportion of participants who reach second-line therapy

The second-line population: progression after first-line chemotherapy and immunotherapy

Signs and symptoms

Natural history: late presentation, stage at diagnosis, and survival from diagnosis

Survival after progression on first-line therapy

Burden: quality of life, healthcare costs, and work loss

Investigational status: tovecimig is a product candidate with no marketing approval

Current development phase: randomized phase 2/3 COMPANION-002 trial

Trial sites and enrollment

Prior clinical development completed in South Korea

Investigator-sponsored trials in progress

United States: Fast Track designation

United States: orphan drug designation

Regulatory submission: BLA planned for the fourth quarter of 2026

Presentation of the complete dataset

Launch: anticipated in 2027

2Pharmacology and usage

Dual target: DLL4 and VEGF-A

Molecular format: anti-VEGF antibody backbone linked to DLL4-binding single-chain variable fragments

Rationale for adding DLL4 blockade to VEGF blockade

Target biology in biliary tract cancer

Preclinical antitumor activity in gastric and colon cancer xenograft models

Effect on tumor vasculature and on target expression in tumor endothelium

Clinical pharmacodynamic or target-engagement biomarkers

Population pharmacokinetic model in patients with solid tumors

Model parameter estimates

Elimination half-life and time to steady state

Simulated exposure: fixed dosing compared with weight-based dosing and alternative intervals

Immunogenicity and pharmacokinetics in organ impairment

3Indications

Investigational product with no approved indication: population under study in COMPANION-002

Investigational use covered by the FDA Fast Track designation

Investigational use covered by the FDA orphan drug designation

Investigational setting: size of the second-line population without an approved targeted option

Investigational product currently under evaluation in a randomized phase 2/3 trial

4Dosing and administration

COMPANION-002 regimen: tovecimig dose and schedule with the paclitaxel backbone

Route and schedule recorded in the registry

Infusion preparation and duration in the phase 1 study

Basis for the paclitaxel backbone

Phase 1 dose escalation range and starting dose

Dose levels at which responses were observed in the phase 1 study

Alternative dosing strategies supported by simulation

Premedication, dose modification, and dosing in organ impairment

5Clinical efficacy summary

Registered purpose of the trial

Registered design details

Blinded independent central review of the primary endpoint

Randomization ratio and stratification factors

Crossover from the control arm

Registered sites

Completion of enrollment

Planned and randomized sample size

Populations analyzed for efficacy and for safety

Dosing of both arms as reported by the sponsor

Key inclusion criteria: registry record

Exclusion of participants eligible for an approved targeted therapy

Balance of baseline characteristics between arms

Baseline demographics and disease characteristics, n (%) unless stated

Registered primary outcome measure

Registered secondary outcome measures

Endpoint definitions in the trial design publication, including the quality-of-life instrument

Power and treatment-effect assumption

Event threshold triggering the time-to-event analyses

Primary endpoint: objective response rate as first reported

Primary endpoint: objective response rate in the final analysis

Best overall response by blinded independent central review, intent-to-treat population

Central confirmation of responses

Key secondary endpoint: progression-free survival

Key secondary endpoint: overall survival in the intent-to-treat population

Efficacy summary with hazard ratios and two-sided p values

Prespecified secondary analysis of progression-free survival before and after crossover

Post hoc analysis of overall survival within the control arm

Post hoc analysis of progression-free survival within the control arm

Post hoc pooled overall survival of all participants who received tovecimig

Duration of response

Introduction

Pharmacology and usage

Indications

Dosing and administration

Clinical efficacy summary

Clinical guidelines

Safety summary