Tovecimig (CTX-009)

Biliary tract cancer is an adenocarcinoma of the biliary epithelium comprising intrahepatic cholangiocarcinoma, extrahepatic (perihilar and distal) cholangiocarcinoma, gallbladder cancer, and carcinoma of the ampulla of Vater, and accounts for less than 1% of cancers worldwide. 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, and Compass Therapeutics estimates approximately 26,500 people newly diagnosed with biliary tract cancer in the United States each year and over 200,000 worldwide. Age-adjusted cholangiocarcinoma incidence in the Surveillance, Epidemiology, and End Results program was 3.65 per 100 000 person-years from 2001 to 2017 and rose 43.8% over that period, driven by a 148.8% rise in intrahepatic disease against a 7.5% rise in extrahepatic disease. No registry reports the incidence of the second-line population directly. ABC-06 reported that 15% to 25% of participants receive second-line therapy, and in a United States commercial-claims cohort of 413 participants with advanced disease, 46% initiated a second line and 16.5% a third line; in a separate cohort, 514 of 1,298 participants (39.6%) died without receiving second-line therapy.

Survival is short and falls further after first-line progression. Five-year relative survival for liver and intrahepatic bile duct cancer is 21.9% overall, 13.4% for regional and 3.6% for distant disease, and median overall survival from diagnosis across 40,030 cholangiocarcinoma cases was 8 months. First-line chemoimmunotherapy extends survival modestly: median overall survival was 12.9 months with durvalumab plus gemcitabine and cisplatin versus 11.3 months with placebo plus chemotherapy in the TOPAZ-1 three-year update, and 12.7 versus 10.9 months in KEYNOTE-966. After progression, ABC-06 randomized 162 participants and reported median overall survival of 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), 12-month survival of 25.9% and 11.4%, median progression-free survival of 4.0 months, and an objective response in 4 of 81 participants (5%). Grade 3 to 5 adverse events occurred in 56 of 81 participants (69%) receiving FOLFOX, including three chemotherapy-related deaths. Baseline tumour marker elevation stratifies the population sharply, with median overall survival falling from 8.9 months when none of CA19-9, CEA, and CA125 was elevated to 3.2 months when all three were.

No systemic regimen is approved by the FDA for second-line advanced biliary tract cancer. Guideline-recommended targeted options address FGFR2 fusions, IDH1 mutations, HER2 overexpression or amplification, BRAF V600E mutations, NTRK and RET fusions, and mismatch repair deficient or tumour mutational burden-high disease, but the COMPANION-002 investigators 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, and the sponsor states that approximately 85% of participants have no actionable mutation with an approved targeted therapy. Comprehensive genomic profiling of 91 biliary tract tumours at a single centre produced potentially actionable findings in 21 participants (23.1%) and genomically matched therapy in 7 (7.7%). The Pan-Asian adaptation of the ESMO guideline downgraded the second-line chemotherapy recommendation from level of evidence I to II and from grade A to B, citing the limited survival benefit and ABC-06 being the only positive phase 3 trial in the setting. Randomized evidence for liposomal irinotecan is inconsistent, with median blinded independent central review progression-free survival of 7.1 versus 1.4 months in NIFTY against 2.6 versus 2.3 months in NALIRICC, and 3.6 versus 1.8 months in a pooled analysis of 278 participants. The sponsor states that the regimens 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.

Humanistic and economic burden are substantial. In ABC-06 there was 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 the EQ-5D utility value fell from 0.75 at baseline to 0.62 at month 4 in the active symptom control arm while declining less with FOLFOX. Long-term morbidity is dominated by recurrent biliary obstruction and infection: in a single-centre series of 171 participants receiving a palliative biliary stent, complications occurred in 91 (53%), cholangitis was the most frequent, and median survival was 75.5 days. In a United States claims cohort, 69.5% of participants had an all-cause inpatient hospitalization with a mean stay of 7 days per visit. Mean per-patient-per-month all-cause costs were $18,274 overall and rose with each line, from $19,589 in first line to $22,617 in second line and $33,534 in third line. Among working-age participants with cholangiocarcinoma, mean all-cause days absent per patient per month were 6.0 for intrahepatic and 4.3 for extrahepatic disease, and median indirect costs per patient per month from absenteeism, short-term disability, and long-term disability were $622, $635, and $690 for intrahepatic disease.