Summary: survival across the disease course and in the second-line setting

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%.

Natural history: asymptomatic early disease and late presentation

“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)

Survival: SEER stage distribution and five-year relative survival, liver and intrahepatic bile duct cancer

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)

Survival: median overall survival by cholangiocarcinoma subtype in SEER

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

Survival: first-line overall survival with durvalumab plus chemotherapy, TOPAZ-1 three-year update

“After a median 41.3 (95% CI 39.3-44.1) months' follow-up in all participants, median OS (95% CI) for durvalumab+GemCis vs. placebo+GemCis was 12.9 (11.6-14.1) vs. 11.3 (10.1-12.5) months (hazard ratio, 0.74 [95% CI 0.63-0.87]); 36-month OS rate was 14.6% vs. 6.9%, respectively.” (opens the source at this quote in a new tab)
“The 36-month Kaplan-Meier OS rate for the durvalumab arm was more than double that of the placebo arm, and the OS rate ratio for durvalumab vs. placebo increased over time (12 months: 1.15; 24 months: 1.75; 36 months: 2.12).” (opens the source at this quote in a new tab)
“In total, 88/685 (12.8%) participants were eLTS, with more eLTS in the durvalumab arm (58/341 [17.0%]) vs. the placebo arm (30/344 [8.7%]).” (opens the source at this quote in a new tab)

Survival: first-line overall survival with pembrolizumab plus chemotherapy, KEYNOTE-966

“Median overall survival was 12·7 months (95% CI 11·5-13·6) in the pembrolizumab group versus 10·9 months (9·9-11·6) in the placebo group (hazard ratio 0·83 [95% CI 0·72-0·95]; one-sided p=0·0034 [significance threshold, p=0·0200]).” (opens the source at this quote in a new tab)

Survival: second-line overall survival in ABC-06

“Median overall survival was 6·2 months (95% CI 5·4–7·6) in the ASC plus FOLFOX group versus 5·3 months (4·1–5·8) in the ASC alone group (adjusted HR 0·69 [95% CI 0·50–0·97], p=0·031; figure 2).” (opens the source at this quote in a new tab)
“The overall survival rate in the ASC alone group was 35·5% (95% CI 25·2–46·0) at 6 months and 11·4% (5·6–19·5) at 12 months, compared with 50·6% (39·3–60·9) at 6 months and 25·9% (17·0–35·8) at 12 months in the ASC plus FOLFOX group.” (opens the source at this quote in a new tab)
“Median progression-free survival was 4·0 months (95% CI 3·2–5·0; appendix p 4).” (opens the source at this quote in a new tab)
“The progression-free survival rate was 66·7% (95% CI 55·3–75·8) at 3 months, 32·1% (22·3–42·3) at 6 months, and 8·6% (3·8–16·0) at 12 months.” (opens the source at this quote in a new tab)

Survival: prognostic value of baseline tumour markers in the second-line setting

“Baseline CA19-9 data were available for 135 of 162 patients: 92 (68.1%) high, 43 (31.9%) low. High baseline CA19-9 was associated with shorter unadjusted OS [4.4 versus 6.4 months; hazard ratio (HR) 1.97, 95% confidence interval (CI) 1.33-2.93, P < 0.001] and unadjusted PFS (3.2 versus 5.0 months; HR 1.53, 95% CI 1.05-2.23, P = 0.027) in the FOLFOX arm.” (opens the source at this quote in a new tab)
“With each additional tumour marker that was elevated at baseline, median OS was numerically shorter: unadjusted median OS was 8.9 months if all tumour markers at baseline were not elevated and 7.0 months, 4.0 months, and 3.2 months in the event of having 1, 2, or 3 elevated baseline tumour markers, respectively (Figure 1).” (opens the source at this quote in a new tab)

Survival: real-world United States outcomes across lines of therapy

“All-cause mortality was 53% with a median survival of 11.5 months.” (opens the source at this quote in a new tab)
“The median OS from the index date was 11.5 months (Figure 3A & B). In total, 70.1% (n = 289), 47.8% (n = 197), 34.9% (n = 144) and 29.6% (n = 122) of patients survived 6, 12, 18 and 24 months, respectively, from the index date.” (opens the source at this quote in a new tab)
“The median OS time from first presumed BTC diagnosis was 13.3 months.” (opens the source at this quote in a new tab)
“The median time on 2LOT was 3.6 months and was longer for patients with stage III disease (4.6 months) than for patients with stage IV and stage I/II disease (3.6 months).” (opens the source at this quote in a new tab)

Mortality: United States and global mortality burden

“Liver and intrahepatic bile duct cancer is the sixth leading cause of cancer death in the United States. The death rate was 6.6 per 100,000 men and women per year based on 2020–2024 deaths, age-adjusted.” (opens the source at this quote in a new tab)

Mortality: gallbladder cancer survival has not improved over three decades

“Among the 55 studies included, more than 320,000 people, suggest that survival improvements for gallbladder cancer have stagnated over the past three decades. No significant improvements in 5-year relative survival rates were observed worldwide. After age standardization, the highest 5-year relative survival rate is 30.6 % (Changzhou, China, 2011–2013 and Korea, 2013–2019), while the lowest is 6.0 % (Austria, 1990).” (opens the source at this quote in a new tab)

Tovecimig (CTX-009)

Natural history, survival, and mortality