Real-world impact of matched targeted therapy on survival in advanced biliary tract cancer: An international collaborative study.
Authors: Zheng-Lin Binbin , Hoyek Celine , Kosiorek Heidi E. , Abidoye Oluseyi , Eslinger Cody , Sonbol Mohamad Bassam , Wu Christina , Tran Nguyen H. , Babiker Hani M. , Roberts Lewis R. , Yoshino Takayuki , Ikeda Masafumi , Morizane Chigusa , Bando Hideaki , Nakamura Yoshiaki , Fujisawa Takao , Ahn Daniel H. , Borad Mitesh J. , Shibuki Taro , Bekaii-Saab Tanios S. 
Published: January 2025

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Background:
The prognosis of advanced BTC remains poor. Although targeted agents have expanded late-line options, many patients (pts) become ineligible for these therapies after progressing on first-line treatment. Herein, we examined the real-world impact of targeted therapy on survival in advanced BTC.
Methods:
In this international collaborative study between the Mayo Clinic (US) and the National Cancer Center East (Japan), we included pts with advanced BTC with comprehensive tumor molecular profiling who had received at least 30 days of systemic therapy. Pts were categorized into 3 groups: 1) non-actionable, 2) pts with alterations who received matched targeted therapy at any point during their treatment (matched group), and 3) those with mutations who did not receive matched therapy (unmatched group). OS was calculated from the start date of first-line therapy until death and compared among three subgroups using Cox regression models.
Results:
Of 932 pts, 366 (39.3%) had an actionable alteration, and 135 of these received matched therapy. 566 (61.7%) did not have an actionable alteration (Table). The most common alterations were somatic
BRCA1/2
(N=106, 11.4%),
HER2
amplification (N=65, 7%),
FGFR2
fusion (N=61, 6.5%),
KRAS G12C/D
(N=46, 4.9%), and
IDH1
(N=38, 4.1%). 78.7% of
FGFR2
fusions were found in Caucasian pts, whereas
BRCA1/2
(97.5%),
HER2
(78.5%), and
KRAS G12C/D
(67.4%) alterations were more prevalent in Asian pts. The median OS was significantly longer in the matched group (21.4 months; 95% CI 18.4-27.9) compared to the unmatched group (14.6 months; 95% CI 12.8-17.6) and the non-actionable group (17.2 months; 95% CI 15.5-19.0). The 36-month OS rate was 33% in the matched group vs. 7% in the unmatched group (p < 0.0001). After adjusting for age, gender, prior surgical resection, primary tumor location, and country of origin, matched targeted therapy remained a strong independent predictor for improved OS (HR 0.61; 95% CI 0.48-0.79).
Conclusions:
These real-world findings suggest that matched targeted therapies significantly improve survival in advanced BTC, underscoring the need to incorporate them earlier in the treatment course and address barriers to treatment access. The regional prevalence of actionable alterations should also be considered when developing new targeted therapies.

Patient baseline characteristics stratified by actionable alterations and targeted therapy.

Non-actionable(N=566)
Unmatched group(N=231)
Matched group(N=135)

Site, n (%)

Japan
409 (72%)
166 (72%)
50 (37%)

US
157 (28%)
65 (28%)
85 (63%)

Age at Dx > 65, n (%)
324 (57%)
122 (53%)
54 (40%)

Female, n (%)
235 (42%)
92 (40%)
77 (57%)

Primary tumor location (category), n (%)

Intrahepatic
217 (43%)
115 (55%)
99 (76%)

Extrahepatic
150 (30%)
39 (19%)
17 (13%)

Gallbladder
142 (28%)
54 (26%)
14 (11%)

Prior surgical resection, n (%)
220 (42%)
74 (34%)
48 (37%)