Tovecimig

Tovecimig (CTX-009, ABL001, NOV1501, TR009) is investigational and holds no marketing authorization in any jurisdiction. The registrational study in second-line advanced biliary tract cancer is COMPANION-002 (NCT05506943), a randomized, open-label phase 2/3 trial of tovecimig plus paclitaxel versus paclitaxel alone that enrolled 168 participants at 34 sites in the United States and is listed as active, not recruiting, with an estimated primary completion date of 31 August 2027. The trial met its primary endpoint of objective response rate, reported in April 2025 as 17.1% versus 5.3% (p=0.031) and revised in the final analysis to 18.0% versus 5.3% (p=0.0228); median progression-free survival was 4.7 months versus 2.6 months (hazard ratio 0.44, p<0.0001), and the overall survival endpoint was not met.

The FDA granted Fast Track designation to CTX-009 in combination with paclitaxel in April 2024 for previously treated metastatic or locally advanced biliary tract cancer, and orphan drug designation for biliary tract cancer in April 2026. In its report for the second quarter of 2026, filed 6 August 2026, Compass Therapeutics stated that it expected FDA feedback on the COMPANION-002 data during the third quarter of 2026 before a biologics license application filing later in 2026. The July 2026 corporate presentation places the FDA meeting in the third quarter of 2026, the start of the biologics license application filing in late 2026, and potential approval and launch in 2027, with approval anticipated in the second half of 2027. No submission outside the United States has been announced. The complete COMPANION-002 dataset was selected for oral presentation at the 2026 European Society for Medical Oncology Congress in October 2026.

Earlier development was conducted in South Korea: a phase 1 monotherapy dose escalation and expansion study (NCT03292783), a phase 1b combination study, and a single-arm phase 2 study of tovecimig plus paclitaxel in biliary tract cancer. Investigator-sponsored trials are ongoing in first-line biliary tract cancer with gemcitabine, cisplatin and durvalumab (NCT06548412), in second-line colorectal cancer with FOLFIRI (NCT07662031), and in second-line glioblastoma with CTX-471 (NCT07392957). A company-sponsored phase 2 basket study in DLL4-positive tumors was planned for initiation in mid-2026.

Tovecimig has no approved indication. The indication under development is unresectable advanced, metastatic or recurrent biliary tract cancer, including intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, gallbladder cancer and ampullary carcinoma, in adults who have progressed after one prior gemcitabine- and platinum-containing chemotherapy regimen. The FDA Fast Track designation covers CTX-009 in combination with paclitaxel for previously treated metastatic or locally advanced biliary tract cancer, and the April 2026 orphan drug designation covers biliary tract cancer. COMPANION-002 excludes participants who are eligible for an approved molecularly targeted therapy on a labeled regimen after first-line chemotherapy, so the target population is the subgroup without an actionable alteration; the sponsor states that all targeted therapies together are appropriate for approximately 10% to 15% of patients with biliary tract cancer and estimates more than 15,000 patients per year in the United States as potentially eligible. No biomarker selection for DLL4 or VEGF-A expression is required for enrollment in COMPANION-002. Tovecimig is also being studied in first-line biliary tract cancer, colorectal cancer, glioblastoma, and a planned basket study of DLL4-positive tumors.

No prescribing information, boxed warning, contraindication, or risk evaluation and mitigation strategy exists, because tovecimig is investigational. In COMPANION-002, the most common treatment-emergent adverse events in the tovecimig combination arm were hypertension (69%) and fatigue (67%), and the most common related treatment-emergent adverse events of grade 3 or higher were hypertension (44%) and neutropenia (36%). In the single-arm phase 2 study of tovecimig plus paclitaxel in South Korea, all 24 participants had at least one treatment-emergent adverse event and grade 3 or higher events were reported in 95.8%, including decreased neutrophil count in 83.3%, anemia in 20.8%, hypertension in 16.7% and decreased platelet count in 12.5%; grade 3 or higher adverse events of special interest were hemoptysis or hemorrhage in 12.5% and gastrointestinal or tumor perforation in 8.3%, with no pulmonary hypertension, wound healing complication or cardiac failure. In the phase 1 monotherapy dose escalation study of 45 participants, the most frequent treatment-emergent adverse events were hypertension (37.8%), headache (22.2%), asthenia (13.3%), anemia (13.3%) and fatigue (11.1%), no dose-limiting toxicity occurred, and the maximum tolerated dose was not reached at 17.5 mg/kg. In the phase 2 monotherapy study in colorectal cancer, hypertension was the most common treatment-emergent adverse event and occurred only in participants with a prior history of hypertension. An independent data safety monitoring committee reviewed COMPANION-002 safety data at four prespecified meetings and recommended continuation without modification each time. Adverse events reported with other DLL4 and VEGF bispecific antibodies include pulmonary hypertension and gastrointestinal perforation.

The phase 1 first-in-human monotherapy study in South Korea used a 3 plus 3 design across nine dose levels from 0.3 to 17.5 mg/kg given every 2 weeks; no dose-limiting toxicity occurred and the maximum tolerated dose was not reached. The starting dose of 0.3 mg/kg was derived from a no observed adverse effect level of 10 mg/kg in cynomolgus monkeys, converted to a human equivalent dose with a safety factor of 10. All responses in the phase 1 study occurred at dose levels above 10 mg/kg and all confirmed responses at 10 mg/kg or 12.5 mg/kg. The dose taken into the phase 2 study in biliary tract cancer and into COMPANION-002 is 10 mg/kg intravenously on days 1 and 15 of each 28-day cycle, given with paclitaxel 80 mg/m2 on days 1, 8 and 15. Population pharmacokinetic simulations indicate that a fixed dose of 700 mg gives exposure comparable with 10 mg/kg, and that 15 mg/kg every 3 weeks gives an average steady-state concentration comparable with 10 mg/kg every 2 weeks. No labeled dose, dose-modification table, or dosing recommendation for organ impairment exists.

Tovecimig is available only through clinical trials. COMPANION-002 enrolled 168 participants at 34 sites in the United States, is listed as active, not recruiting, and the registry record states that expanded access is not available. Additional access is through investigator-sponsored trials in first-line biliary tract cancer, colorectal cancer, and glioblastoma. Compass Therapeutics holds exclusive global rights outside South Korea, where rights are held by Handok, and Chinese rights are held by Elpiscience; the company states that it may commercialize independently by building an internal sales and marketing organization or through collaborations. The company reported pre-commercialization expenses beginning in 2026 and describes building a commercial organization to support tovecimig in biliary tract cancer. No distribution model, specialty pharmacy arrangement, site-of-care restriction, or expanded access program has been described.

No systemic therapy is approved by the FDA for second-line biliary tract cancer other than biomarker-directed agents, which the sponsor states are appropriate for approximately 10% to 15% of patients. The regimens most commonly used off-label in this setting are reported to produce objective response rates of about 5% or less and a median overall survival of approximately 6 months; FOLFOX, the regimen tested against best supportive care in a randomized study, produced an objective response rate of 4.9%, a median progression-free survival of 4.0 months and a median overall survival of 6.2 months. In COMPANION-002 the objective response rate with tovecimig plus paclitaxel was 18.0% (20 of 111 participants) compared with 5.3% (3 of 57) with paclitaxel alone (p=0.0228) in the final analysis, and median progression-free survival was 4.7 months compared with 2.6 months (hazard ratio 0.44, p<0.0001). No head-to-head study against another agent has been conducted.

Two other bispecific antibodies targeting DLL4 and VEGF have been tested in first-in-human studies. Navicixizumab (OMP-305B83) was given to 66 participants with refractory solid tumors at 0.5 to 12.5 mg/kg every 3 weeks; the maximum tolerated dose was not reached, 7.5 mg/kg was selected for expansion, treatment-related adverse events in at least 15% of participants were hypertension (57.6%), headache (28.8%), fatigue (25.8%) and pulmonary hypertension (18.2%), the half-life was 11.4 days, anti-drug antibodies formed in 29%, and 4 participants had a partial response. Dilpacimab (ABT-165), a dual-variable domain immunoglobulin, was given to 55 participants at 1.25 to 7.5 mg/kg on days 1 and 15 of 28-day cycles; the most common treatment-related adverse events were hypertension (60.0%), headache (30.9%) and fatigue (21.8%), gastrointestinal perforation occurred in 2 participants (3.6%) with one death, the half-life ranged from 4.9 to 9.5 days, the recommended phase 2 dose was 3.75 mg/kg, and 10.9% of participants had a partial response. Neither agent has reported a randomized trial in biliary tract cancer. Tovecimig differs from both in molecular format, being an anti-VEGF IgG backbone with C-terminal anti-DLL4 single-chain variable fragments, and in dose, at 10 mg/kg every 2 weeks. Pulmonary hypertension, reported in 18.2% of participants receiving navicixizumab, was not reported among grade 3 or higher adverse events of special interest in the phase 2 study of tovecimig plus paclitaxel.

Biliary tract cancer is an adenocarcinoma arising from the epithelium of the biliary tree and comprises intrahepatic cholangiocarcinoma, extrahepatic (perihilar and distal) cholangiocarcinoma, gallbladder cancer, and carcinoma of the ampulla of Vater. Cholangiocarcinoma is subdivided anatomically: intrahepatic cholangiocarcinoma arises above the second-order bile ducts, and the insertion of the cystic duct separates perihilar from distal cholangiocarcinoma. In the United States, perihilar disease accounts for approximately 50% to 60% of cholangiocarcinomas, distal disease for 20% to 30%, and intrahepatic disease for 10% to 20%. Biliary tract cancers account for less than 1% of all cancers worldwide.

Second-line advanced biliary tract cancer is the disease state of participants with locally advanced or metastatic biliary tract cancer whose disease has progressed after first-line systemic therapy, historically cisplatin and gemcitabine and now cisplatin, gemcitabine, and an anti-PD-L1 or anti-PD-1 antibody. In the ABC-06 randomized trial, the primary tumour sites among 162 participants enrolled after progression on cisplatin and gemcitabine were intrahepatic cholangiocarcinoma (72 of 162, 44%), extrahepatic cholangiocarcinoma (45, 28%), gallbladder (34, 21%), and ampullary cancer (11, 7%).

Most risk factors share chronic inflammation of the biliary epithelium and bile stasis. Reported associations include choledochal cyst, Caroli disease, primary sclerosing cholangitis, choledocholithiasis and cholelithiasis, cirrhosis, chronic hepatitis B and C, inflammatory bowel disease, chronic pancreatitis, type 2 diabetes, non-alcoholic fatty liver disease, and, in endemic regions of Southeast Asia, infection with the liver flukes Opisthorchis viverrini and Clonorchis sinensis. In most countries the majority of cases remain sporadic with no identifiable risk factor.

No registry reports the incidence of second-line advanced biliary tract cancer directly; it is estimated from the incidence of biliary tract cancer and the proportion of participants who reach a second line of therapy. For 2026, the American Cancer Society estimates 42,340 new cases of liver and intrahepatic bile duct cancer and 12,640 new cases of gallbladder and other biliary cancer in the United States. Compass Therapeutics estimates approximately 26,500 people newly diagnosed with biliary tract cancer in the United States each year and over 200,000 worldwide.

In the Surveillance, Epidemiology, and End Results program, the overall age-adjusted incidence of cholangiocarcinoma from 2001 to 2017 was 3.65 per 100 000 person-years and rose 43.8% over that period, driven by a 148.8% rise in intrahepatic cholangiocarcinoma against a 7.5% rise in extrahepatic cholangiocarcinoma. In North American Association of Central Cancer Registries data for 1999 to 2013, intrahepatic and extrahepatic cholangiocarcinoma rates increased by 3.2% and 1.8% per year while gallbladder cancer rates declined among women and among people aged 45 years or older. Globally, GLOBOCAN 2024 estimated 126,384 new gallbladder cancers and 843,045 new cancers of the liver and intrahepatic bile duct.

Only a subset of the incident population reaches second-line treatment. ABC-06 reported that 15% to 25% of participants receive second-line therapy, and a United States commercial-claims cohort of 413 participants with advanced biliary tract cancer found that 46% initiated a second line and 16.5% a third line.

Prevalence of biliary tract cancer is low relative to incidence because survival is short. SEER estimated 116,514 people living with liver and intrahepatic bile duct cancer in the United States in 2023, and the lifetime risk of a diagnosis of liver and intrahepatic bile duct cancer is approximately 1.1 percent. A SEER analysis of 40,030 cholangiocarcinoma cases reported a 16-year limited-duration prevalence for cholangiocarcinoma of 5.92, higher for extrahepatic (4.23) than intrahepatic (1.69) disease, with the intrahepatic figure rising across successive periods from 0.60 in 2001 to 2006 to 1.37 in 2013 to 2017.

The prevalent second-line population is smaller still, because median overall survival from second-line randomization was 6.2 months with FOLFOX and 5.3 months with active symptom control alone in ABC-06. Approximately 60% of participants with advanced biliary tract cancer have no targetable alteration and are therefore candidates for non-targeted second-line therapy; the manufacturer places the share with targeted mutations at approximately 15% to 20%.

Biliary tract cancer is usually detected late and is rarely curable. SEER records 21.9% five-year relative survival for liver and intrahepatic bile duct cancer overall, falling to 13.4% for regional and 3.6% for distant disease. Across 40,030 SEER cholangiocarcinoma cases diagnosed from 2001 to 2017, median overall survival from diagnosis was 8 months overall, 6 months for intrahepatic and 9 months for extrahepatic disease.

In the first-line advanced setting, the TOPAZ-1 three-year update reported median overall survival of 12.9 months with durvalumab plus gemcitabine and cisplatin versus 11.3 months with placebo plus chemotherapy, and 36-month overall survival of 14.6% versus 6.9%. KEYNOTE-966 reported median overall survival of 12.7 months with pembrolizumab plus gemcitabine and cisplatin versus 10.9 months with chemotherapy alone.

After progression on first-line therapy, survival is measured in months. In ABC-06, median overall survival was 6.2 months with active symptom control plus FOLFOX versus 5.3 months with active symptom control alone (adjusted hazard ratio 0.69, 95% CI 0.50 to 0.97, p=0.031), with 12-month survival of 25.9% and 11.4%. Median progression-free survival with FOLFOX was 4.0 months. Baseline tumour marker elevation stratifies this population sharply: median overall survival fell from 8.9 months when none of CA19-9, CEA, and CA125 was elevated to 3.2 months when all three were. In a United States claims cohort of 413 participants receiving systemic therapy for advanced biliary tract cancer, median overall survival was 11.5 months from index and 13.3 months from first presumed diagnosis, and all-cause mortality was 53%.

Biliary tract cancers arise from cholangiocytes and related biliary epithelium, and can also develop from peribiliary glands and hepatocytes depending on the underlying liver disease and location. Chronic inflammation and bile stasis drive cholangiocarcinogenesis through pro-inflammatory cytokines, growth factors, and bile acids in the tumour microenvironment. The tumours are highly desmoplastic, with a reactive stroma of cancer-associated fibroblasts that secrete paracrine factors promoting proliferation, chemotaxis, and angiogenesis, including VEGF-A and VEGF-C.

Genomic alterations track with anatomic subtype. FGFR2 fusions and IDH1 and IDH2 mutations occur almost exclusively in intrahepatic disease, while PRKACA and PRKACB fusions and ELF3 mutations characterize extrahepatic tumours. In a real-world comprehensive genomic profiling series of 91 biliary tract tumours, the most frequently altered genes were TP53 (51 of 91, 56.0%), KRAS (21 of 91, 23.1%), CDKN2A (18 of 91, 19.8%), SMAD4 (14 of 91, 15.4%), and ARID1A or PBRM1 (12 of 91, 13.2%).

Angiogenesis is a relevant pathway for the disease and for the mechanism of tovecimig. Transcriptomic stratification of cholangiocarcinoma identified VEGF signalling among the main oncogenic networks in participants with poor overall survival. In intrahepatic cholangiocarcinoma, NOTCH1, HES1, MMP13, DLL4, and VEGFA were significantly upregulated in tumours compared with adjacent non-tumorous tissue, and selective NOTCH1 inhibition downregulated VEGFA, HES1, and MMP13 and inhibited vessel formation in an in vitro angiogenesis model.

Diagnosis rests on cross-sectional imaging followed by tissue confirmation, with the route to tissue determined by anatomic subtype. Contrast-enhanced CT and MRI are the reference imaging modalities; magnetic resonance cholangiopancreatography is used for perihilar and distal disease and endoscopic retrograde cholangiography provides biliary brushings for cytology and fluorescence in situ hybridization. Biliary cytology has low sensitivity for perihilar disease (43% in one meta-analysis) and FISH is more sensitive (65% versus 19% in one series). CA19-9 is the principal serum biomarker but lacks specificity. Histopathological or cytological confirmation is mandatory because no radiological pattern is specific for cholangiocarcinoma.

For the second-line setting, molecular profiling determines whether a targeted option exists. The Pan-Asian adapted ESMO guideline recommends a core biopsy for diagnostic pathology and molecular profiling before any non-surgical treatment and molecular analysis in advanced disease considered suitable for systemic treatment, and recommends ivosidenib for IDH1 mutations, FGFR inhibitors for FGFR2 fusions, pembrolizumab for MSI-H or dMMR tumours, and dabrafenib with trametinib for BRAF V600E tumours after at least one prior line. In a real-world series of 91 biliary tract tumours, comprehensive genomic profiling identified potentially actionable alterations in 21 participants (23.1%), yielded expert panel therapeutic options in 15 (16.5%), and led to genomically matched therapy in 7 (7.7%).

Long-term morbidity in advanced biliary tract cancer is dominated by recurrent biliary obstruction and its management, by infection, and by functional decline after progression on first-line therapy. Active symptom control in the second-line setting is defined to include biliary drainage, antibiotics, analgesia, steroids, anti-emetics, palliative radiotherapy, and transfusion of blood products. In a single-centre series of 171 participants who received a palliative biliary stent, complications occurred in 91 (53%) and cholangitis was the most frequent, in 48 (53%) of those with complications; median survival was 75.5 days. In a United States claims cohort, 69.5% of participants had an all-cause inpatient hospitalization and 65.6% a biliary-tract-cancer-related hospitalization, with a mean stay of 7 days per visit and the largest share of inpatient visits occurring during third-line therapy. Rapid decline in performance status after first-line progression limits how many participants can be treated at all.

Robust health-related quality-of-life data in cholangiocarcinoma are sparse, which the authors of a disease primer attribute to low incidence, high lethality, limited trial enrollment until recently, and a historical lack of dedicated measurement tools. The EORTC QLQ-BIL21 was validated in 172 participants with cholangiocarcinoma and 91 with gallbladder cancer and measures eating, jaundice, tiredness, pain, and anxiety symptoms alongside the generic QLQ-C30.

In the second-line setting, the ABC-06 quality-of-life analysis found no difference between arms in time to deterioration of the global health scale (adjusted hazard ratio 0.97, 95% CI 0.48 to 1.97, P = 0.937) and found that adding FOLFOX did not worsen global, physical, social, or symptom scores, whereas the active-symptom-control arm declined across several domains including the EQ-5D utility value, which fell from 0.75 at baseline to 0.62 at month 4. In the first-line setting, neither durvalumab nor pembrolizumab added to gemcitabine and cisplatin worsened patient-reported outcomes: median time to deterioration of global health status or quality of life was 7.4 months versus 6.7 months in TOPAZ-1, and estimates were similar between arms in KEYNOTE-966.

In a United States commercially insured cohort of participants with advanced biliary tract cancer treated before immuno-oncology regimens were approved, mean per-patient-per-month all-cause costs were $18,274 overall, of which approximately 84% ($15,296) were biliary-tract-cancer-related. Costs rose with each line of therapy, from $19,589 in first line to $22,617 in second line and $33,534 in third line. Outpatient and inpatient utilization were the main cost drivers, and approximately 70% of participants had at least one inpatient visit. Earlier estimates cited in the same study were $7,743 per-patient-per-month for advanced cholangiocarcinoma-associated costs after first-line failure and $20,696 per-patient-per-month for all-cause biliary tract cancer management. In a separate claims analysis of participants receiving pemigatinib, mean per-patient-per-month medical costs were $13,444 for those with a prior cancer-of-unknown-primary diagnosis and $9,881 for those without.

Cholangiocarcinoma imposes measurable work loss and indirect costs on working-age households. In a United States retrospective claims analysis of 1,065 participants with cholangiocarcinoma who had work absence and disability benefits eligibility, mean all-cause days absent per patient per month for illness were 6.0 for intrahepatic and 4.3 for extrahepatic disease, and 12.9% and 6.6% respectively had at least one cholangiocarcinoma-related short-term disability claim. Median indirect costs per patient per month from absenteeism, short-term disability, and long-term disability were $622, $635, and $690 for intrahepatic disease and $304, $589, and $465 for extrahepatic disease. A patient and advocate writing in a disease primer describes declining a first-line clinical trial because insurance would not cover the associated standard-of-care costs and she did not want to put her family in financial distress, and describes travel for trial participation as a source of financial burden.

Second-line treatment selection in biliary tract cancer depends on molecular profiling, because approved second-line targeted options are restricted to IDH1 mutations, FGFR2 fusions, MSI-H or dMMR tumours, and BRAF V600E tumours, and the Pan-Asian adapted ESMO guideline recommends molecular analysis in advanced disease considered suitable for systemic treatment. The economic return on that testing is limited by yield: in 91 biliary tract tumours profiled at a single centre, comprehensive genomic profiling produced potentially actionable findings in 23.1% and genomically matched therapy in 7.7%. The cost of failing to establish a primary site is measurable. Among 221 participants with cholangiocarcinoma initiating pemigatinib, those with a prior cancer-of-unknown-primary diagnosis had higher ambulatory resource use (8.2 versus 5.5 visits per patient per month), higher ambulatory costs ($8,584 versus $5,308), mean medical costs of $13,444 versus $9,881 per patient per month, and shorter median overall survival (10.2 versus 30.7 months); the authors conclude that reflexive genomic testing should be encouraged for all participants with cancer of unknown primary.

No systemic regimen is approved by the FDA for second-line advanced biliary tract cancer, and the sponsor of COMPANION-002 states that the therapeutics most commonly used in this setting are not labeled or approved for it, generally produce an objective response rate of about 5% or less, and are associated with a median overall survival of approximately six months. First-line chemoimmunotherapy improves survival only modestly: the hazard ratio for overall survival was 0.80 with durvalumab added to gemcitabine and cisplatin and 0·83 with pembrolizumab added to gemcitabine and cisplatin, with median overall survival of 12·7 versus 10·9 months in KEYNOTE-966, and a 2026 review states that median overall survival remains around 1 year.

The second-line evidence base rests on one positive phase 3 trial. In ABC-06, 162 participants were randomized, median overall survival was 6·2 months with active symptom control plus FOLFOX versus 5·3 months with active symptom control alone, and an objective response occurred in 4 of 81 participants (5%). The Pan-Asian adaptation of the ESMO guideline downgraded the level of evidence from I to II and the grade of recommendation from A to B, noting the limited survival benefit and the absence of Asian participants. Randomized evidence for liposomal irinotecan is inconsistent: NIFTY reported a median blinded independent central review progression-free survival of 7·1 versus 1·4 months, whereas NALIRICC reported 2·6 versus 2·3 months with a hazard ratio of 0·87 and no overall survival benefit, and a pooled analysis of the two trials (278 participants) found a median progression-free survival of 3.6 versus 1.8 months. A meta-analysis of 17 randomized trials in 4,584 participants concluded that a breakthrough in advanced biliary tract cancer treatment remains elusive.

Biomarker-directed options apply to a minority. Guideline-recommended targeted therapies address FGFR2 fusions or rearrangements, IDH1 mutations, HER2 overexpression or amplification, BRAF V600E mutations, NTRK fusions, RET fusions, and mismatch repair deficient or tumor mutational burden-high disease, but the COMPANION-002 investigators state that only a minority of biliary tract cancers harbor these alterations and report frequencies of 4% to 5% for BRAF V600E, less than 1% for NTRK fusions, less than 1% for RET fusions, and 1% to 2% for microsatellite instability, while the sponsor states that approximately 85% of participants have no actionable mutation with an approved targeted therapy. Where targeted agents do apply, benefit is time-limited: ivosidenib improved median progression-free survival from 1·4 to 2·7 months and did not reach statistical significance for overall survival in the intention-to-treat analysis, FGFR inhibition is followed by acquired FGFR2 resistance mutations, and a next-generation FGFR inhibitor produced an objective response rate of 6·3% in tumors with primary FGFR inhibitor resistance. No standardized criteria exist for assessing HER2 status in biliary tract cancer and no specific test can be recommended.

Toxicity and delivery constrain use. Grade 3 to 5 adverse events occurred in 56 of 81 participants (69%) receiving active symptom control plus FOLFOX, including three chemotherapy-related deaths; the addition of a third cytotoxic agent to gemcitabine and cisplatin increases treatment-related toxicity and did not improve overall survival in SWOG S1815; trastuzumab deruxtecan caused adjudicated drug-related interstitial lung disease in 10.5% of participants with three deaths; and pemigatinib caused hyperphosphatemia in 58.5% of participants. Locoregional options are confined to liver-limited or unresectable non-metastatic disease rather than the second-line metastatic setting, and intra-arterial therapy availability varies by region.

Tovecimig is investigational and has no marketing authorization. Its anticipated population is the population enrolled in COMPANION-002: adults with unresectable advanced, metastatic, or recurrent biliary tract cancer, including intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, gallbladder cancer, and ampullary carcinoma, who have radiologically documented progression after one prior gemcitabine and platinum containing regimen and who have an Eastern Cooperative Oncology Group performance status of 0 or 1. The trial randomized 168 participants 2:1 to tovecimig plus paclitaxel or paclitaxel alone and allowed crossover after centrally confirmed progression.

No positive biomarker is required for selection. Molecular testing is nonetheless relevant to eligibility, because the trial excluded participants who were eligible for a molecularly targeted therapy on a labelled regimen after first-line chemotherapy. The sponsor frames the target population as the approximately 85% of participants whose tumors do not harbor an actionable mutation with an approved targeted therapy, for whom there is no FDA-approved second-line treatment. In current guidelines that population receives FOLFOX, with irinotecan-based or liposomal irinotecan-based regimens as alternatives, so tovecimig plus paclitaxel would enter second-line treatment as an alternative to fluoropyrimidine-based chemotherapy rather than displacing a biomarker-directed option.

The regimen is entirely parenteral and requires an infusion setting. Paclitaxel 80 mg/m2 is given intravenously on days 1, 8, and 15 of each 28-day cycle, and tovecimig 10 mg/kg is given intravenously on days 1 and 15 of each 28-day cycle, so participants attend three infusion visits per 28-day cycle. Regulatory status as of September 2026 is pre-submission: the sponsor reported in August 2026 that it expected FDA feedback in the third quarter of 2026 and planned to include the COMPANION-002 data in a Biologics License Application later in 2026, with the full dataset selected for oral presentation at the October 2026 ESMO Congress.

COMPANION-002 prespecified three stratification factors that define the subgroups in which effect modification would be examined: stage (locally advanced versus metastatic), anatomic subtype of the primary tumor (intrahepatic cholangiocarcinoma versus other), and Eastern Cooperative Oncology Group performance status (0 or 1). No subgroup analysis by tumor site, prior therapy, or geography has been reported in the sponsor's disclosures of the primary and key secondary endpoints, and the full dataset was scheduled for presentation in October 2026, so subgroup results are not yet available.

The heterogeneity that the sponsor has reported concerns crossover rather than baseline characteristics. Of 57 participants randomized to paclitaxel alone, 31 (54%) crossed over after centrally confirmed progression. Within that control arm, participants who crossed over had a median overall survival of 12.8 months versus 6.1 months for those who did not (hazard ratio 0.54, p=0.04), despite having progressed faster on initial paclitaxel monotherapy (median progression-free survival 1.9 versus 3.6 months, hazard ratio 2.31, p=0.007). In the same 31 participants, median progression-free survival after crossover was 3.5 months compared with 1.9 months before crossover (hazard ratio 0.36, p=0.0016). These are post hoc or within-participant comparisons in a non-randomized subset, and the sponsor states that the rank-preserving structural failure time adjustment for crossover rested on assumptions that were not met and is largely uninterpretable.

No predictive biomarker for DLL4 or VEGF-A blockade has been established in biliary tract cancer. The COMPANION-002 investigators describe DLL4 as highly expressed in biliary tract cancer with up-regulation associated with poor survival, and VEGF-A overexpression as correlating with stage, presence of metastases, and prognosis, but these are prognostic observations and the trial did not select participants by DLL4 or VEGF-A expression. By contrast, the comparator landscape is strongly biomarker-defined: response rates differ from 37.0% with pemigatinib and 42% with futibatinib in FGFR2 fusion-positive disease, to 41·3% with zanidatamab and 46.7% with tucatinib plus trastuzumab in HER2-positive disease, to 61.3% with trastuzumab deruxtecan in centrally confirmed HER2 immunohistochemistry 3+ tumors, to 51% with dabrafenib plus trametinib in BRAF V600E-mutated disease, against 5% with FOLFOX in unselected second-line participants.

Modifiers observed in the comparator trials are mainly clinical rather than molecular. In ABC-06 the survival benefit of FOLFOX was independent of platinum sensitivity, subgroups with suspected poorer prognosis appeared to benefit most, and the benefit appeared weaker in the extrahepatic cholangiocarcinoma subgroup, though the investigators state that the subgroup analyses were insufficiently powered. In SWOG S1815, the addition of nab-paclitaxel improved progression-free survival more in gallbladder carcinoma than in intrahepatic or extrahepatic cholangiocarcinoma (interaction P = .01) without a corresponding overall survival interaction. In the ABC-06 biomarker analysis, median overall survival fell from 8.9 months when no tumor marker was elevated to 3.2 months when carbohydrate antigen 19-9, carcinoembryonic antigen, and cancer antigen 125 were all elevated.

Three strands of care management apply. First, molecular profiling determines whether a participant belongs to the biomarker-directed pathway or to the chemotherapy pathway that tovecimig targets; guidelines recommend profiling when first-line systemic treatment is initiated, and COMPANION-002 excluded participants eligible for a labelled targeted regimen. Second, biliary tract cancer requires ongoing biliary and infection management independent of systemic therapy: guidelines recommend biliary drainage with percutaneous transhepatic drainage when endoscopic access is not possible, prompt treatment of sepsis secondary to biliary obstruction, patient education on stent patency and on the signs of obstruction or infection, and follow-up every 8 to 12 weeks with computed tomography or magnetic resonance imaging supplemented by carbohydrate antigen 19-9 or carcinoembryonic antigen when secreted. COMPANION-002 required adequate biliary excretion at entry and excluded participants with percutaneous transhepatic biliary drains.

Third, the adverse event profile of tovecimig plus paclitaxel defines the monitoring program. The most common treatment-emergent adverse events in the combination arm were hypertension (69%) and fatigue (67%), and the most common related grade 3 or higher events were hypertension (44%) and neutropenia (36%), which indicates a need for blood pressure measurement at every visit with antihypertensive management, and for complete blood counts before each weekly paclitaxel dose. The angiogenesis-directed mechanism is reflected in the trial's entry requirements and exclusions, which covered urine protein by dipstick with 24-hour confirmation, uncontrolled hypertension, hemorrhage-related and gastroenterological disease, and current or recent therapeutic anticoagulation or antiplatelet use, so proteinuria, bleeding risk, and concomitant anticoagulation require assessment before and during treatment. In the earlier phase 2 study of the same combination the most frequent grade 3 or higher events were neutropenia (50.0%), hypertension (16.7%), anemia (12.5%), and thrombocytopenia (8.3%).

COMPANION-002 defines the outcomes tovecimig plus paclitaxel is expected to achieve. The primary endpoint is the proportion of participants whose best overall response is complete or partial response by RECIST version 1.1, and the secondary endpoints are progression-free survival, duration of response, overall survival, disease control rate, and treatment-emergent adverse events.

On the primary endpoint, the final analysis reported an objective response rate of 18.0% (20 of 111 participants) with tovecimig plus paclitaxel versus 5.3% with paclitaxel alone (p=0.0228), revised from the 17.1% versus 5.3% (p=0.031) reported at the April 2025 top-line analysis after one participant was adjudicated by blinded independent central review as a partial response. Progressive disease as best overall response occurred in 16.2% of the combination arm versus 42.1% of the control arm. On the key secondary endpoint, median progression-free survival by blinded independent central review was 4.7 months versus 2.6 months (hazard ratio 0.44, p<0.0001). Overall survival did not reach statistical significance: median overall survival was 8.9 months with the combination and 9.4 months in the control arm (hazard ratio 1.05, p=0.78), which the sponsor attributes to 31 of 57 control participants (54%) crossing over, with the result that 142 of 168 participants (85%) received tovecimig and the pooled median overall survival across the study was 8.9 months.

These values are to be read against the benchmarks the sponsor and the guideline evidence describe for second-line treatment: an objective response rate of approximately 5% or less and a median overall survival of approximately six months with the regimens most commonly used off-label; a median overall survival of 6·2 months with FOLFOX versus 5·3 months with active symptom control and an objective response in 4 of 81 participants (5%) in ABC-06; and a median blinded independent central review progression-free survival of 7·1 months with liposomal irinotecan plus fluorouracil and leucovorin in NIFTY against 2·6 months in NALIRICC. Duration of response has not been reported, and no health-related quality of life outcome for tovecimig has been reported in the cited sources. The complete dataset was scheduled for oral presentation at the October 2026 ESMO Congress.