Health-related quality of life in participants with advanced biliary tract cancer from the randomized phase III KEYNOTE-966 study

Changhoon Yoo; Makoto Ueno; Heinz-Josef Klümpen; Robin Kate Kelley; Arndt Vogel; Junji Furuse; Zhenggang Ren; Thomas Yau; Stephen Lam Chan; Masato Ozaka; Sang Cheul Oh; Shanzhi Gu; Joon Oh Park; Juan W Valle; Julien Edeline; Jong Gwang Kim; Shital Kamble; Josephine M Norquist; Li Yu; Usha Malhotra; Richard S Finn

doi:10.1016/j.jhep.2025.03.019

Health-related quality of life in participants with advanced biliary tract cancer from the randomized phase III KEYNOTE-966 study

J Hepatol. 2025 Mar 26:S0168-8278(25)00207-7. doi: 10.1016/j.jhep.2025.03.019. Online ahead of print.

Authors

Changhoon Yoo¹, Makoto Ueno², Heinz-Josef Klümpen³, Robin Kate Kelley⁴, Arndt Vogel⁵, Junji Furuse⁶, Zhenggang Ren⁷, Thomas Yau⁸, Stephen Lam Chan⁹, Masato Ozaka¹⁰, Sang Cheul Oh¹¹, Shanzhi Gu¹², Joon Oh Park¹³, Juan W Valle¹⁴, Julien Edeline¹⁵, Jong Gwang Kim¹⁶, Shital Kamble¹⁷, Josephine M Norquist¹⁷, Li Yu¹⁷, Usha Malhotra¹⁷, Richard S Finn¹⁸

Affiliations

¹ Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea. Electronic address: yooc@amc.seoul.kr.
² Kanagawa Medical Center, Yokohama, Japan.
³ Amsterdam University Medical Center, Amsterdam, Netherlands.
⁴ University of California San Francisco, San Francisco, CA, USA.
⁵ Hannover Medical School, Hannover, Germany; Toronto General Hospital, University Health Network and Princess Margaret Cancer Center, Toronto, ON, Canada.
⁶ Kyorin University Hospital, Tokyo, Japan (currently at Kanagawa Cancer Center, Yokohama, Japan.
⁷ Zhongshan Hospital Fudan University, Shanghai, China.
⁸ The University of Hong Kong, Hong Kong, China.
⁹ State Key Laboratory of Translational Oncology, Department of Clinical Oncology, Sir Y.K. Pao Centre for Cancer, The Chinese University of Hong Kong, Hong Kong, China.
¹⁰ The Cancer Institute Hospital of the Japanese Foundation for Cancer Research (JFCR), Tokyo, Japan.
¹¹ Korea University Goru Hospital, Seoul, Republic of Korea.
¹² Hunan Cancer Hospital, Changsha, China.
¹³ Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
¹⁴ Cholangiocarcinoma Foundation, Salt Lake City, UT, USA; Division of Cancer Sciences, University of Manchester, Manchester, UK.
¹⁵ Centre Eugène Marquis, Rennes, France.
¹⁶ Department of Hematology/Oncology, Kyungpook National University Chilgok Hospital, Daegu, Republic of Korea.
¹⁷ Merck & Co., Inc., Rahway, NJ, USA.
¹⁸ University of California, Los Angeles, Los Angeles, CA, USA.

PMID: 40154623
DOI: 10.1016/j.jhep.2025.03.019

Abstract

Background & aims: In the randomized, double-blind, phase 3 KEYNOTE-966 trial, pembrolizumab plus gemcitabine and cisplatin demonstrated a significant improvement in overall survival as first-line therapy for advanced biliary tract cancer (BTC). We present the prespecified health-related quality of life (HRQoL) outcomes from KEYNOTE-966.

Methods: HRQoL was assessed using the European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30), EORTC QLQ-BIL21, and EuroQoL 5 Dimensions 5 Levels (EQ-5D-5L) questionnaires. Data from the latest time point with ≥60% completion and ≥80% compliance (week 18) were compared to baseline. Least squares means (LSM) for change from baseline to week 18 were compared using a constrained longitudinal analysis model in six prespecified domains: QLQ-C30 global health status/quality of life (GHS/QoL), physical functioning, and role functioning; QLQ-BIL21 pain and jaundice scores, and EQ-5D-5L visual analog score. The analysis population was all treated participants with ≥1 completed HRQoL assessment. Between-arm difference in time to confirmed deterioration (TTD) was assessed using a stratified Cox proportional hazards model with randomization stratification factors.

Results: KEYNOTE-966 randomized 1,069 participants into the study (n=533 pembrolizumab arm; n=536 placebo arm). Questionnaire compliance was >87% from baseline to week 18 in both arms. LSM changes from baseline to week 18 were similar between arms for all prespecified domains. TTD estimates were also similar between arms, including GHS/QoL (median not reached [NR] in the pembrolizumab arm versus 21.2 months in the placebo arm; HR=0.86, 95% CI=0.70-1.07); jaundice (NR versus NR; HR=1.20, 95% CI=0.94-1.54), and pain (NR versus NR; HR=0.79, 95% CI=0.59-1.05).

Conclusion: HRQoL was maintained after adding pembrolizumab to gemcitabine and cisplatin, further supporting this regimen as first-line treatment for advanced BTC.

Impact and implications: Biliary tract cancer (BTC) is often diagnosed at late stages because most patients do not present with disease-specific symptoms. Compared with the general population, patients with advanced BTC report worse physical, emotional, and functional well-being. In KEYNOTE-966, adding the programmed cell death protein 1 (PD-1) inhibitor pembrolizumab to gemcitabine and cisplatin as first-line therapy for participants with advanced BTC produced a statistically significant and clinically meaningful improvement in overall survival. The prespecified patient-reported outcomes results from KEYNOTE-966 presented herein demonstrated that health-related quality of life was maintained after adding pembrolizumab to gemcitabine and cisplatin, further supporting this regimen as first-line treatment for advanced BTC.

Clinical trial registration: Clinicaltrials.gov, NCT04924062.

Keywords: biliary tract neoplasms; cisplatin; gemcitabine; immune checkpoint inhibitors; patient reported outcome measures; pembrolizumab; quality of life.

Associated data

ClinicalTrials.gov/NCT04924062