Orphan drug evaluation

Tovecimig

Every factual statement is a verbatim quote from the source cited beneath it; the evidence grades, the risk of bias and applicability ratings, and the authorization criteria are the reviewer’s, each traceable to the section that supports it. · 31 sources

Evaluation section

Field	Value
Drug	Tovecimig (CTX-009 and ABL001)
Indication reviewed	Second-line advanced biliary tract cancer
Generic name	Tovecimig
Brand name (manufacturer)	No brand name assigned (Compass Therapeutics)
Therapeutic category	Bispecific antibodies targeting DLL4 and VEGF-A
Dosage form and route	Solution for intravenous infusion
Orphan designation	Granted April 2026 by the Food and Drug Administration, for biliary tract cancer
Regulatory status	Not approved in any country. Fast Track designation granted April 2024; biologics license application planned for the fourth quarter of 2026
Date of review	September 2026
End date of literature search	September 21, 2026
Manufacturer dossier received	No
Prepared by	To be completed by the reviewing plan
Review status	Draft for pharmacy and therapeutics committee review

Purpose for review

Scope of this review

To review the evidence for the safety and effectiveness of tovecimig with paclitaxel in adults with advanced biliary tract cancer that has progressed after first-line gemcitabine and platinum chemotherapy.
To set out the clinical conditions under which tovecimig would be authorized, for review against the labeling when it issues.
Tovecimig is not approved in any country, so this review prepares for a decision rather than recording one. (see 7.3)

Plain language summary

Biliary tract cancer is a cancer of the bile ducts, the gallbladder, and the duct where bile reaches the small intestine. It is uncommon, and about 26,500 people are diagnosed with it in the United States each year. (see 6)
Most people are diagnosed once the cancer has spread and cannot be removed by surgery. The first treatment is chemotherapy with gemcitabine and a platinum drug. When that stops working, only about 15 to 25 out of every 100 people are well enough to receive a second course of treatment. (see 6)
For most people there is no treatment approved by the Food and Drug Administration (FDA) for that second course. The chemotherapy used instead shrinks the tumor in about 5 out of 100 people, and people live about six months on average. (see 6)
Tovecimig is an experimental antibody that blocks two of the signals a tumor uses to grow its own blood supply. It is given into a vein every two weeks, together with the chemotherapy drug paclitaxel. It is not approved, and the manufacturer plans to apply to the FDA at the end of 2026. (see 7.1, 7.2, 7.3)
In a trial of 168 people, tumors shrank in 18 out of 100 people given tovecimig with paclitaxel, against 5 out of 100 given paclitaxel alone. The time before the cancer grew again was longer: 4.7 months against 2.6 months. (see 8.1)
People given tovecimig did not live longer. Average survival was 8.9 months with tovecimig and 9.4 months without it, a difference small enough to be chance. (see 8.1)
The most common side effect was high blood pressure, in 69 out of 100 people given tovecimig against 19 out of 100 given chemotherapy alone, and it was severe in about half of them. Tiredness and low white blood cell counts were also more common. (see 8.1, 10)
The evidence is of low quality. It comes from one trial that has not yet been published in a medical journal, in which the doctors and the participants knew which treatment was being given. (see 4, 8.1)

Research questions

What is the effectiveness of tovecimig with paclitaxel in adults with advanced biliary tract cancer that has progressed after first-line gemcitabine and platinum chemotherapy?
What are the harms of tovecimig with paclitaxel in that population?
Are there subgroups, defined by age, disease severity, tumor site, molecular alteration, demographics, or line of therapy, in which tovecimig is more effective or associated with fewer harms?

Conclusions

Effectiveness

There is low-quality evidence that tovecimig with paclitaxel raised the objective response rate over paclitaxel alone: 18.0% (20 of 111) against 5.3% (3 of 57) by blinded independent central review, p=0.0228. No confidence interval for the difference is reported. (see 8.1)
There is low-quality evidence that progression-free survival was longer: median 4.7 months against 2.6 months, hazard ratio 0.44, p<0.0001. (see 8.1)
Overall survival did not differ: median 8.9 months against 9.4 months, hazard ratio 1.05, p=0.78. The sponsor's crossover-adjusted analysis states that its assumptions were not met and that the result is largely uninterpretable, so the trial supports no conclusion that tovecimig extends survival. (see 8.1)
The response rate is a surrogate for clinical benefit, and overall survival, the outcome it stands in for, was null in the same trial. The grade is held at low on that ground and on the trial being open-label and unpublished. (see 8.1)

Harms

There is low-quality evidence of substantially more hypertension with tovecimig: 69% against 19% at any grade, and 52% against 6% at grade 3 or higher. Fatigue (67% against 45%) and neutropenia (55% against 38%) were also more frequent. (see 8.1, 10)
There is insufficient evidence on treatment discontinuation, serious adverse events, and deaths in the randomized trial. None of the three is reported in the sources available, and the reported safety population is 108 of 111 and 53 of 57 randomized. (see 8.1)
There is insufficient evidence on long-term harms. The randomized comparison is unpublished, and no exposure beyond the trial exists. (see 8.1)

Subgroups

There is insufficient evidence for any subgroup in which tovecimig is more effective or safer. No prespecified subgroup analysis of the randomized trial is reported. (see 8.1)
In the single-arm ABL001-P1bC cohort of 24 participants, the response rate was 63.6% in the second-line participants and 15.4% in the third-line participants. A single-arm cohort of this size supports no conclusion about line of therapy. (see 8.2)

Recommendations

Defer a formulary decision until the Food and Drug Administration acts on the planned biologics license application and the labeling is available. (see 7.3)
Where authorization is prepared in advance of that, apply the criteria at 11, which confine use to the population the randomized trial enrolled. (see 11)
Require blood pressure measurement at baseline and before each dose, given the frequency and the severity of hypertension in the randomized trial. (see 8.1, 10)
Reassess when the complete COMPANION-002 dataset is published. It was selected for oral presentation in October 2026, and the trial is otherwise unpublished. (see 7.3, 8.1)

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)
“CCA is the second most common primary hepatic malignancy after hepatocellular carcinoma (HCC), comprising approximately 15% of all primary liver tumours and 3% of gastrointestinal cancers” (opens the source at this quote in a new tab)

“Cholangiocarcinoma (CCA) is a highly lethal, epithelial cell malignancy that occurs anywhere along the biliary tree and/or within the hepatic parenchyma.” (opens the source at this quote in a new tab)
“These cancers are heterogeneous and are best classified according to the primary, anatomic subtype as intrahepatic CCA (iCCA), perihilar CCA (pCCA) or distal CCA (dCCA)” (opens the source at this quote in a new tab)
“Most CCAs are adenocarcinomas and other histological subtypes, such as adenosquamous carcinoma or clear cell carcinoma, are encountered rarely” (opens the source at this quote in a new tab)

Incidence: new cases, deaths, and age-adjusted rates 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)
“CCA incidence increased with age, with greatest increase among younger patients (18-44 years, 81.0%).” (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)
“The overall age-adjusted incidence of CCA from 2001 to 2017 increased with patient’s age (18-44 years, 0.27; 45-64 years, 3.10; 65-84 years, 14.19; ≥85 years, 22.05)” (opens the source at this quote in a new tab)
“The overall incidence of CCA from 2001 to 2017 was 4.40 in men vs 3.08 in women” (opens the source at this quote in a new tab)

Prevalence and lifetime risk of a diagnosis in the United States

“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)

Proportion of participants who reach a second line of therapy

“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)

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)

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%”

“For liver and intrahepatic bile duct cancer, 44.7% are diagnosed at the local stage. The 5-year relative survival for localized liver and intrahepatic bile duct cancer is 37.4%.” (opens the source at this quote in a new tab)

“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)

Diagnosis: molecular profiling before non-surgical treatment, and its yield

“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)

“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)

“Reportable genomic alterations were detected in 88 patients (96.7%), whereas no reportable alteration was detected in three patients (3.3%).” (opens the source at this quote in a new tab)
“Potentially actionable genomic alterations were identified in 21 patients (23.1%). Expert panel-based therapeutic options were identified in 15 patients (16.5%), and genomically matched therapy was introduced in 7 patients (7.7%).” (opens the source at this quote in a new tab)
“Site-specific frequencies of potentially actionable alterations were highest in iCCA (17/46, 37.0%), followed by GBC (4/24, 16.7%), whereas no potentially actionable genomic alteration was identified in eCCA or ampullary tumors using this definition.” (opens the source at this quote in a new tab)

Molecular subtypes that direct second-line therapy, and the share of participants with no targetable alteration

“Ivosidenib is recommended for the treatment of patients with CCA and IDH1 mutations who have progressed after ≥1 prior line of systemic therapy” (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” (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” (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” (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)

Second-line standard of care: FOLFOX, and the survival observed in ABC-06

“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)

Limitations of current therapy: no approved second-line option for most participants

“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.” (opens the source at this quote in a new tab)
“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)

“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)

“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)

“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)

“Although recent advances have improved clinical outcomes in patients with advanced BTC, median overall survival remains around 1 year, underscoring the need for further therapeutic innovation.” (opens the source at this quote in a new tab)
“Several targeted agents have demonstrated clinically meaningful efficacy in phase 2-3 trials and are recommended as subsequent-line therapy for biomarker-selected disease, including FGFR2 gene rearrangements, IDH1 mutations, and HER2 amplification.” (opens the source at this quote in a new tab)

“Despite incremental advancements, a breakthrough in advanced BTC treatment remains elusive.” (opens the source at this quote in a new tab)

Drug information

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)

“The ABL001 bispecific antibody consists of an anti-VEGF antibody (bevacizumab-like) backbone C-terminally linked with a DLL4-targeting single-chain variable fragment which shows potent binding affinity to VEGF” (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)

Preclinical antitumor activity and effect on tumor vasculature

“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)

“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)

Dosing, administration, and monitoring

Dose and schedule as administered in COMPANION-002

“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 as recorded in the trial 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 as administered 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)

Dose range evaluated in the phase 1 dose escalation and the basis for the 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 population pharmacokinetic 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)

Availability during development: trial sites and enrollment

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

Expanded access program

No evidence found.

Premedication, dose modification, and dosing in organ impairment

No evidence found.

Regulatory history

Investigational status: tovecimig holds 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 phase of development: 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”

Prior clinical development completed in South Korea and the decision to advance directly to a randomized phase 2/3 study

“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)

United States: Fast Track designation granted April 2024

“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 granted April 2026

“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)

Planned regulatory submission: biologics license application in 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)

Anticipated approval and launch

“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)

Post-marketing obligations and post-approval monitoring required by the FDA

Not applicable.

Cost of therapy

No evidence found.

Clinical efficacy and safety

COMPANION-002

Trial design and duration

“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)

“COMPANION-002 is a multicenter, randomized, phase II/III study evaluating the efficacy and safety of CTX-009 in combination with paclitaxel as second-line treatment for patients with advanced or metastatic BTC.” (opens the source at this quote in a new tab)

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

“A blinded independent review committee will be used to assess the primary study endpoint.” (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. 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)

“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)

“An independent Data Monitoring Committee (DMC) has reviewed safety data at four separate (pre-specified) DMC meetings and, after each meeting, recommended continuation of the study without modification.” (opens the source at this quote in a new tab)

Milestone	Registry record
Study start (actual)	“2023-01-09”
Primary completion (estimated)	“2027-08-31”
Study completion (estimated)	“2027-08-31”
Enrollment (actual)	“168”
Recruitment status	“Active, not recruiting”
Last update posted	“2026-09-02”

“Data cutoff from COMPANION - 002 as of March 2025.” (opens the source at this quote in a new tab)
“Data cutoff from COMPANION - 002 as of April 2026.” (opens the source at this quote in a new tab)

“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)

Intervention

“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)

Intervention	Registry description
CTX-009	“IV infusion on day 1 and 14 of every 28 day cycle”
Paclitaxel	“IV infusion on day 1, 8, and 15 of every 28 day cycle”

Comparator

“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 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)

Participants

“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)

“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)

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”

“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)

“Not Evaluable: patients who did not receive a Week-8 scan.” (opens the source at this quote in a new tab)

Key inclusion criteria

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.)”

Key exclusion criteria

“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)
“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)

Baseline disease severity and population characteristics

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

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)”

Setting

“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)

“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)

Endpoints

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”

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”

“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)

“In a phase II study of patients with advanced biliary tract cancer who had received one or two prior therapies, CTX-009 with paclitaxel demonstrated a 37.5% overall response rate (ORR).” (opens the source at this quote in a new tab)
“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)

“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. The combinations of therapeutics used in this setting, which are not labeled for this indication, generally have an ORR of ~5% or less and patients face a median overall survival of approximately six months.” (opens the source at this quote in a new tab)
“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)

Magnitude of benefit and clinical relevance of results

“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)
“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)

“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	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%)”

“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)
“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)
“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)

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”

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

Safety signals

“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)

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)”	“-”

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

“An independent Data Monitoring Committee (DMC) has reviewed safety data at four separate (pre-specified) DMC meetings and, after each meeting, recommended continuation of the study without modification.” (opens the source at this quote in a new tab)

Subgroup analyses

“An additional, pre-specified secondary endpoint analyzed PFS in the patients in the paclitaxel arm who crossed over to receive tovecimig plus paclitaxel.” (opens the source at this quote in a new tab)
“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)
“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)
“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)

“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)

Risk of bias

Domain	Rating	Basis
Selection bias	Low	Participants were randomized 2:1 with stratification by stage, anatomic subtype, and performance status, and the sponsor reports baseline characteristics were well balanced, which the reported demographic table supports.
Performance bias	High	The trial is open-label, so participants and treating investigators knew the assignment, and control-arm participants could elect crossover at progression.
Detection bias	Low	The primary endpoint and progression were assessed by blinded independent central radiology review, and the registry records masking of the outcomes assessor.
Attrition bias	Unclear	Treatment discontinuation, withdrawal, and follow-up counts are not reported, and 14.4% of the tovecimig arm and 15.8% of the control arm were not evaluable for response because no week-8 scan was obtained.
Reporting bias	High	Results are available only from sponsor announcements and a corporate presentation filed with the Securities and Exchange Commission, and the registered endpoints of disease control rate, duration of response, and EORTC QLQ-C30 quality of life, together with deaths, serious adverse events, and discontinuations, are unreported.
Other bias	High	The trial is sponsor-designed, sponsor-funded, and sponsor-reported, 54% of the control arm crossed over to the experimental regimen, and the benefit narrative rests partly on post hoc subsets and on a prespecified crossover adjustment whose assumptions the sponsor states were not met.

Applicability

Element	Assessment
Patient	The enrolled population is the second-line population a plan would treat, adults with histologically or cytologically confirmed biliary tract cancer progressing after gemcitabine and platinum, but it is restricted to performance status 0 or 1, total bilirubin at or below 1.5 times the upper limit of normal, no percutaneous transhepatic biliary drain, and no eligibility for an approved targeted therapy, so it excludes the frailer and the biliary-obstructed patients a committee will see.
Intervention	The regimen is tovecimig 10 mg/kg intravenously twice per 28-day cycle with paclitaxel 80 mg/m2 on days 1, 8, and 15, the same dose carried forward from the single-arm phase 2 cohort rather than from a dose-ranging study, and the registry and the sponsor announcements state different tovecimig days, day 1 and 14 against days 1 and 15.
Comparator	Paclitaxel monotherapy is one of the unlabeled regimens used in this setting, which the sponsor states generally produce a response rate of about 5% or less, so the comparator reflects current practice but is not an approved standard, and no comparison against gemcitabine-platinum rechallenge, FOLFOX, or liposomal irinotecan was made.
Outcomes	The primary endpoint is a radiographic response rate rather than survival, overall survival was not improved in the intent-to-treat analysis, and duration of response, disease control rate, and the prespecified EORTC QLQ-C30 quality-of-life endpoint are unreported, so the outcomes that matter most to a patient are either unmeasured or unmet.
Setting	All 34 sites are in the United States, and the enrolled population is 75.7% and 70.2% White by arm, so the care setting matches a United States plan population while the racial distribution may not match every plan.

Evidence limitations

The primary endpoint is objective response rate, a radiographic measure, and no source in this document states what that response rate predicts for survival in this population (see 8.1).
Overall survival, a secondary endpoint, was not improved, at 8.9 months against 9.4 months with a hazard ratio of 1.05 and p=0.78 (see 8.1).
Fifty-four percent of the control arm (31 of 57) crossed over to tovecimig, so 85% of all randomized participants received it and the control arm is not a tovecimig-naive comparator for survival (see 8.1).
The prespecified rank-preserving structural failure time adjustment gave a hazard ratio of 1.13 with p=0.65, and the sponsor states its assumptions were not met and its results are largely uninterpretable (see 8.1).
The crossover comparisons that favor tovecimig are post hoc analyses of non-randomized subsets that differed from one another, since crossover participants had progressed faster on paclitaxel alone, at 1.9 against 3.6 months (see 8.1).
The trial was powered to detect a 23 percentage-point absolute difference in response rate, and the observed difference was about 12 percentage points (see 8.1).
No peer-reviewed publication or congress presentation of the complete dataset exists, so the results rest on sponsor announcements and a corporate presentation filed with the Securities and Exchange Commission (see 8.1).
Participant disposition, deaths, serious adverse events, discontinuations due to adverse events, disease control rate, duration of response, and quality of life are unreported (see 8.1).
Safety was reported for 108 and 53 participants rather than the 111 and 57 randomized, and no reason for the difference is given (see 8.1).
Grade 3 or higher hypertension occurred in 52% of the tovecimig arm against 6% of the control arm, a difference a committee would have to manage with antihypertensive monitoring (see 8.1).
Eligibility excluded participants who could receive an approved molecularly targeted therapy after first-line chemotherapy, so the result applies to the population without an actionable alteration rather than to all second-line biliary tract cancer (see 8.1).

ABL001-P1bC

Trial design and duration

“This study is a Phase 1b/2 multi-center study to assess the safety, tolerability, pharmacokinetics of CTX-009 (ABL001) in combination with Irinotecan or Paclitaxel in patients with advanced or metastatic solid tumors.” (opens the source at this quote in a new tab)

Design feature	Registry record
Primary purpose	“Treatment”
Allocation	“Non-Randomized”
Interventional model	“Parallel Assignment”
Masking	“None (Open Label)”

“Indication of phase 1b study is the advanced or metastatic solid tumors (including, but not limited to, colorectal cancer, gastric cancer, and ovarian cancer).” (opens the source at this quote in a new tab)
“Indication of phase 2 study is unresectable advanced, metastatic or recurrent biliary tract cancer (BTC) (including intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, gallbladder cancer, and ampullary carcinoma).” (opens the source at this quote in a new tab)

“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)
“Overall, 24 pts have been enrolled (IHCC: 9, EHCC: 3, GB: 7, AoV: 5) and as of the data cut-off date (August 12, 2022), the median follow-up duration was 11.8 months (m) (range: 1.6-16.4) and 3 pts remained on treatment.” (opens the source at this quote in a new tab)

“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)

Milestone	Registry record
Study start (actual)	“2020-06-22”
Primary completion (actual)	“2024-01-08”
Study completion (actual)	“2025-01-09”
Enrollment (actual)	“41”
Recruitment status	“Terminated”
Reason stopped	“Change of Development Plan”

Intervention

“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)

Intervention	Registry description
CTX-009 (ABL001)	“CTX-009 (ABL001) will be administered biweekly.”
Paclitaxel	“Paclitaxel will be administered weekly.”
Irinotecan	“Irinotecan will be administered biweekly.”

Comparator

“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)

Design feature	Registry record
Allocation	“Non-Randomized”
Masking	“None (Open Label)”

Participants

“41” (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)

“In the Phase 1b study, there were four patients enrolled with cholangiocarcinoma. Two of these four patients had deep, durable, and confirmed responses.” (opens the source at this quote in a new tab)

“Six pts (25.0%) experienced treatment-emergent AEs (confusional state, pulmonary embolism, blood creatinine increased, pneumonia, biliary fistula, and large intestine perforation) that led to discontinuation of the study treatment.” (opens the source at this quote in a new tab)

Key inclusion criteria

Criterion	Quoted registry text
Phase 2 diagnosis	“P2 only: Patients with histologically or cytologically confirmed unresectable advanced, metastatic, or recurrent biliary tract cancers (including intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, gallbladder cancer, ampullary carcinoma)”
Phase 2 prior therapy	“P2 only: Patients who have shown disease progress or recurrence of disease after receiving first-line or second-line systemic chemotherapy, including treatment with gemcitabine in combination with a platinum agent”
Age	“Patients aged 19 years or older”
Measurable disease	“At least one lesion measurable defined by response evaluation criteria in solid tumors (RECIST) version 1.1.”
Performance status	“ECOG performance status 0 or 1”

Key exclusion criteria

“History of cardiac illness: New York Heart Association (NYHA) class ≥ II congestive heart failure (CHF), uncontrolled hypertension, hypertension crisis, pulmonary hypertension, myocardial infarction, uncontrolled arrhythmia, unstable angina” (opens the source at this quote in a new tab)
“Symptomatic or uncontrolled central nervous system (CNS) metastasis” (opens the source at this quote in a new tab)
“Administration of antiplatelets or anticoagulants within 2 weeks prior to screening” (opens the source at this quote in a new tab)
“Requiring continuous treatment with systemic NSAIDs or systemic corticosteroids” (opens the source at this quote in a new tab)

Baseline disease severity and population characteristics

“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)

Setting

“This study has 4 locations” (opens the source at this quote in a new tab)
“South Korea” (opens the source at this quote in a new tab)

Endpoints

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”

“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)

“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)

Magnitude of benefit and clinical relevance of results

“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)

“In a phase II study of patients with advanced biliary tract cancer who had received one or two prior therapies, CTX-009 with paclitaxel demonstrated a 37.5% overall response rate (ORR).” (opens the source at this quote in a new tab)

Safety signals

“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)
“Six pts (25.0%) experienced treatment-emergent AEs (confusional state, pulmonary embolism, blood creatinine increased, pneumonia, biliary fistula, and large intestine perforation) that led to discontinuation of the study treatment.” (opens the source at this quote in a new tab)

“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)
“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)

Subgroup analyses

“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)

Risk of bias

Domain	Rating	Basis
Selection bias	High	The phase 2 cohort is single-arm and non-randomized, it was added after two of three or four participants with cholangiocarcinoma responded in the preceding phase 1b study, and it has no concurrent control.
Performance bias	High	The study is open-label with no comparator, so every participant and investigator knew the treatment given.
Detection bias	High	The reported response rate was determined by investigator assessment rather than by the independent radiology review named in the registered primary outcome measure.
Attrition bias	Unclear	Beyond the three participants remaining on treatment at the August 12, 2022 cut-off and six who discontinued for a treatment-emergent adverse event, disposition is not reported, and the study was terminated for a change of development plan.
Reporting bias	High	The cohort is reported only in a congress abstract, a trial design publication, and a corporate filing, with no full publication, no baseline demographic table, no quality-of-life result, and two different median durations of response for the same cohort, 9.4 months and 6.9 months.
Other bias	High	The study was sponsor-funded and sponsor-reported, the second stage of the Simon two-stage design was never conducted, and the cohort therefore never reached its planned size.

Applicability

Element	Assessment
Patient	The 24 participants had biliary tract cancer in the second or third line, so fewer than half (11 of 24) match the second-line population under review, and all were enrolled in South Korea at 19 years of age or older with performance status 0 or 1.
Intervention	The regimen, CTX-009 10 mg/kg intravenously every two weeks with paclitaxel 80 mg/m2 on days 1, 8, and 15 of a four-week cycle, is the regimen taken into COMPANION-002, so the dose studied is the dose that would be used.
Comparator	There is none: the phase 2 cohort is single-arm, so the 37.5% response rate cannot be compared with what paclitaxel alone or any other second-line regimen would have produced in the same participants.
Outcomes	The primary outcome is an investigator-assessed response rate, median overall survival had not been reached at a median follow-up of 11.8 months, the two sources disagree on median duration of response, and no quality-of-life or functional outcome was reported.
Setting	All four sites are in South Korea, so the care setting, the supportive-care practices, and the racial composition differ from a United States plan population.

Evidence limitations

The phase 2 cohort is single-arm and open-label, so its 37.5% response rate has no concurrent control and carries no comparative estimate of benefit (see 8.2).
Only 24 participants were enrolled and only 11 of them in the second line, so the second-line response rate of 63.6% rests on seven responses in eleven participants (see 8.2).
The response rate differed markedly by line of therapy, 63.6% in the second line against 15.4% in the third line, so the pooled estimate depends on the mix of lines enrolled (see 8.2).
Responses were assessed by investigator review rather than by the independent radiology review specified as the registered primary outcome measure (see 8.2).
The congress abstract and the trial design publication report different median durations of response for the same cohort, 9.4 months and 6.9 months (see 8.2).
Median overall survival had not been reached at the August 12, 2022 data cut-off, with a median follow-up of 11.8 months, so no survival estimate is available (see 8.2).
All four sites are in South Korea, so the estimate was not obtained in a United States population (see 8.2).
Treatment-related adverse events of grade 3 or higher occurred in 75% of participants, including one grade 5 pneumonia, and six participants (25.0%) discontinued for a treatment-emergent adverse event (see 8.2).
The study was terminated for a change of development plan and the second stage of the Simon two-stage design was never conducted, so the cohort was never expanded to its planned size (see 8.2).
No baseline demographic table, quality-of-life outcome, or peer-reviewed full report of the cohort has been published (see 8.2).

Comparative evidence table

Trials of tovecimig in advanced biliary tract cancer

Reference and study design	Regimens and duration	Patient population	N	Efficacy endpoints	ARR/NNT	Safety outcomes	ARR/NNH
Randomized; Parallel Assignment; Single (Outcomes Assessor); A blinded independent review committee will be used to assess the primary study endpoint.; COMPANION-002 is a multicenter, randomized, phase II/III study evaluating the efficacy and safety of CTX-009 in combination with paclitaxel as second-line treatment for patients with advanced or metastatic BTC.; Data cutoff from COMPANION - 002 as of April 2026.	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.; 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.	Histologically or cytologically confirmed unresectable advanced, metastatic, or recurrent biliary tract cancers (including intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, gallbladder cancer, and ampullary carcinoma); 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.; 18 years of age or older; Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1; Total bilirubin ≤ 1.5 X ULN; 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.; 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); Patients with percutaneous transhepatic biliary drains (PTBD); Baseline characteristics were well balanced	The study enrolled 168 adult patients, randomized in a 2:1 ratio to receive tovecimig plus paclitaxel (n=111) or paclitaxel alone (n=57).; 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.	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%.; With this change, the p-value improved to 0.0228 compared to paclitaxel alone (ORR of 5.3% in the paclitaxel arm).; 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.; 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).; 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.	12.7%/8	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%).; Safety profile generally consistent with previously reported data	46%/3

Abbreviations: ARR = absolute risk reduction; BICR = blinded independent central review; BTC = biliary tract cancer; CTX-009 = tovecimig; DBP = diastolic blood pressure; ECOG = Eastern Cooperative Oncology Group; HR = hazard ratio; ITT = intent-to-treat; kg = kilogram; m2 = square meter; mg = milligram; mmHg = millimeters of mercury; N = number of participants in the population; n = number of participants in the arm; NNH = number needed to harm; NNT = number needed to treat; ORR = overall response rate; OS = overall survival; p = probability value; PFS = progression-free survival; PTBD = percutaneous transhepatic biliary drain; RECIST = Response Evaluation Criteria in Solid Tumors; RPSFT = rank-preserving structural failure time; SBP = systolic blood pressure; ULN = upper limit of normal

Reference and study design	Regimens and duration	Patient population	N	Efficacy endpoints	ARR/NNT	Safety outcomes	ARR/NNH
This study is a Phase 1b/2 multi-center study to assess the safety, tolerability, pharmacokinetics of CTX-009 (ABL001) in combination with Irinotecan or Paclitaxel in patients with advanced or metastatic solid tumors.; Non-Randomized; None (Open Label); 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.; 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.	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).	P2 only: Patients with histologically or cytologically confirmed unresectable advanced, metastatic, or recurrent biliary tract cancers (including intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, gallbladder cancer, ampullary carcinoma); P2 only: Patients who have shown disease progress or recurrence of disease after receiving first-line or second-line systemic chemotherapy, including treatment with gemcitabine in combination with a platinum agent; Patients aged 19 years or older; ECOG performance status 0 or 1; History of cardiac illness: New York Heart Association (NYHA) class ≥ II congestive heart failure (CHF), uncontrolled hypertension, hypertension crisis, pulmonary hypertension, myocardial infarction, uncontrolled arrhythmia, unstable angina; Symptomatic or uncontrolled central nervous system (CNS) metastasis; 11 pts were treated in 2L and 13 pts treated in 3L.; 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.; South Korea	Overall, 24 pts have been enrolled (IHCC: 9, EHCC: 3, GB: 7, AoV: 5) and as of the data cut-off date (August 12, 2022), the median follow-up duration was 11.8 months (m) (range: 1.6-16.4) and 3 pts remained on treatment.	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).; 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%.	NA	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%).; Six pts (25.0%) experienced treatment-emergent AEs (confusional state, pulmonary embolism, blood creatinine increased, pneumonia, biliary fistula, and large intestine perforation) that led to discontinuation of the study treatment.	NA

Abbreviations: 2L = second line; 3L = third line; ABL001 = tovecimig; AE = adverse event; AoV = ampulla of Vater; ARR = absolute risk reduction; BTC = biliary tract cancer; CHF = congestive heart failure; CI = confidence interval; CNS = central nervous system; CTX-009 = tovecimig; DOR = duration of response; ECOG = Eastern Cooperative Oncology Group; EHCC = extrahepatic cholangiocarcinoma; GB = gallbladder; IHCC = intrahepatic cholangiocarcinoma; IV = intravenous; kg = kilogram; m = month; m2 = square meter; mg = milligram; N = number of participants in the population; n = number of participants in the subgroup; NA = not applicable; NE = not estimable; NNH = number needed to harm; NNT = number needed to treat; NYHA = New York Heart Association; ORR = overall response rate; OS = overall survival; P2 = phase 2 portion of the study; PFS = progression-free survival; PR = partial response; pts = patients; q4-weekly = every four weeks; TRAE = treatment-related adverse event; TTF = time to treatment failure

Adverse events

Treatment-emergent adverse events occurring in at least 20% of participants in COMPANION-002, in the treated population

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)”	“-”

Abbreviations: n = number of participants with the event; N = number of participants in the population

Prior authorization criteria

Goal

To set out the clinical conditions under which tovecimig with paclitaxel would be authorized in second-line advanced biliary tract cancer, for review against the labeling when it issues. (see 7.3)
To confine use to the population in which the randomized trial observed an effect. (see 8.1)

Length of authorization

Initial authorization covers 6 months, which spans the median progression-free survival observed in the randomized trial, 4.7 months. (see 8.1)
Renewal covers 6 months at a time, on documented absence of progression. (see 8.1)

Approval criteria

#	Question	If yes	If no
1	What diagnosis is being treated?	Record the diagnosis code.
2	Is this a renewal of a previous approval?	Go to renewal criteria.	Go to 3.
3	Is the request for tovecimig in combination with paclitaxel? (see 7.2, 8.1)	Go to 4.	Does not meet criteria.
4	Is the patient 18 years of age or older? (see 8.1)	Go to 5.	Does not meet criteria.
5	Is there histological or cytological confirmation of unresectable advanced, metastatic, or recurrent biliary tract cancer, meaning intrahepatic or extrahepatic cholangiocarcinoma, gallbladder cancer, or ampullary cancer? (see 8.1)	Go to 6.	Does not meet criteria.
6	Is there radiologically documented progression during or after first-line gemcitabine with a platinum agent? (see 8.1)	Go to 7.	Does not meet criteria.
7	Is there at least one measurable lesion by RECIST v1.1? (see 8.1)	Go to 8.	Does not meet criteria.
8	Is the ECOG performance status 0 or 1? (see 8.1)	Go to 9.	Does not meet criteria.
9	Has molecular profiling been performed, and does the result leave the patient ineligible for a targeted therapy labeled for the alteration identified? (see 8.1)	Go to 10.	Does not meet criteria.
10	Are the baseline laboratory values within the trial's limits: total bilirubin no more than 1.5 times the upper limit of normal, creatinine clearance at least 30 mL/min, and urine protein no more than 1+? (see 8.1)	Go to 11.	Does not meet criteria.
11	Is the requested dose 10 mg/kg intravenously on days 1 and 15 of each 28-day cycle? (see 7.2)	Go to 12.	Does not meet criteria.
12	Is there a documented plan to measure blood pressure at baseline and before each dose? (see 8.1, 10)	Approve for 6 months.	Does not meet criteria.

Criteria not written

No criterion names a prescriber specialty or a care setting. No quote in this document establishes either, and a criterion no quote supports is not written.
No criterion names a tumor site within the biliary tract, because the trial's eligibility criteria admitted all four sites. (see 8.1)
No criterion sets a response or a laboratory target for continuing therapy, because the trial reports no such threshold. (see 8.1)

Renewal criteria

#	Question	If yes	If no
1	Is the request to continue tovecimig with paclitaxel for the same indication?	Go to 2.	Does not meet criteria.
2	Is there imaging within the past 12 weeks showing no progression by RECIST v1.1? (see 8.1)	Go to 3.	Does not meet criteria.
3	Has blood pressure been measured before each dose, with any grade 3 or higher hypertension addressed? (see 8.1, 10)	Approve for 6 months.	Does not meet criteria.

Evaluation section

1Purpose for review

Scope of this review

2Plain language summary

Plain language summary

3Research questions

Research questions

4Conclusions

Effectiveness

Harms

Subgroups

5Recommendations

Recommendations

6Background

Definition: biliary tract cancer and the anatomical subtypes of cholangiocarcinoma

Incidence: new cases, deaths, and age-adjusted rates in the United States

Prevalence and lifetime risk of a diagnosis in the United States

Proportion of participants who reach a second line of therapy

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

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

Diagnosis: molecular profiling before non-surgical treatment, and its yield

Molecular subtypes that direct second-line therapy, and the share of participants with no targetable alteration

Second-line standard of care: FOLFOX, and the survival observed in ABC-06

Limitations of current therapy: no approved second-line option for most participants

7Drug information

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 and effect on tumor vasculature

Dose and schedule as administered in COMPANION-002

Route and schedule as recorded in the trial registry

Infusion preparation and duration as administered in the phase 1 study

Dose range evaluated in the phase 1 dose escalation and the basis for the starting dose

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

Alternative dosing strategies supported by population pharmacokinetic simulation

Availability during development: trial sites and enrollment

Expanded access program

Premedication, dose modification, and dosing in organ impairment

Investigational status: tovecimig holds no marketing approval

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

Prior clinical development completed in South Korea and the decision to advance directly to a randomized phase 2/3 study

United States: Fast Track designation granted April 2024

United States: orphan drug designation granted April 2026

Planned regulatory submission: biologics license application in the fourth quarter of 2026

Presentation of the complete dataset

Anticipated approval and launch

Post-marketing obligations and post-approval monitoring required by the FDA

8Clinical efficacy and safety

Trial design and duration

Intervention

Comparator

Participants

Key inclusion criteria

Key exclusion criteria

Baseline disease severity and population characteristics

Setting

Endpoints

Magnitude of benefit and clinical relevance of results

Safety signals

Subgroup analyses

Risk of bias

Applicability

Evidence limitations

Trial design and duration

Intervention

Comparator

Participants

Key inclusion criteria

Key exclusion criteria

Baseline disease severity and population characteristics

Setting

Endpoints

Magnitude of benefit and clinical relevance of results

Safety signals

Subgroup analyses

Risk of bias

Applicability

Evidence limitations

9Comparative evidence table

Purpose for review

Plain language summary

Research questions

Conclusions

Recommendations

Background

Drug information

Clinical efficacy and safety

Comparative evidence table

Adverse events

Prior authorization criteria

References