Tovecimig (CTX-009)

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.