Background & Aims: Surrogate endpoints are increasingly used in biliary tract cancer (BTC) trials. While this may expedite drug approval and decrease costs, surrogate endpoints may not always correlate with an overall survival (OS) advantage. We aimed to explore the association of progression-free survival (PFS), objective response rate (ORR) and disease control rate (DCR) with OS at the trial-and patient-level. Methods: For the trial-level analysis, we performed a systematic review of Pubmed/MEDLINE, Embase, Cochrane, clinicaltrials. gov and conference proceedings for phase II-III trials in advanced BTC. We used a weighted linear regression to measure the correlation of OS with PFS, ORR and DCR. For the patient-level analysis, we analyzed patients included in five randomized trials and three real-world datasets. The protocol is registered with PROSPERO, CRD42023398279. Results: For the trial-level analysis, we included 41 studies, involving 88 treatment arms and 7,817 patients. The coefficient of determination (R2) of the model was 0.71 (95% CI 0.56-0.86) for PFS, 0.01 (0-0.08) for ORR and 0.39 (0.14-0.64) for DCR. Predefined subgroup analysis showed consistent results. For the patient-level analysis, we included a total of 2,506 patients, 783 in randomized trials (first-line 512, second-line 271) and 1,723 in routine clinical care (first-line chemotherapy 773, first-line chemotherapy-durvalumab 628, second-line chemotherapy 322). Across the distinct datasets, the correlation coefficient ranged from 0.73 to 0.86 for PFS. A responder analysis found no association between response and survival. Conclusion: PFS shows a moderate correlation with OS both at the trial-and patient-level, while ORR and DCR show a low correlation. Whilst PFS is currently the best candidate surrogate marker for OS, our results highlight the need for novel endpoints in this field. (c) 2025 Published by Elsevier B.V. on behalf of European Association for the Study of the Liver.
Association of candidate surrogate endpoints with overall survival in advanced biliary tract cancer
Salani, Francesca;Fornaro, Lorenzo;Vivaldi, Caterina;Parisi, Alessandro;Diana, Anna;Scartozzi, Mario;Schirripa, Marta;Salani, Francesca;Tonini, Giuseppe;Boccaccino, Alessandra;Masi, Gianluca;Lonardi, Sara;
2025-01-01
Abstract
Background & Aims: Surrogate endpoints are increasingly used in biliary tract cancer (BTC) trials. While this may expedite drug approval and decrease costs, surrogate endpoints may not always correlate with an overall survival (OS) advantage. We aimed to explore the association of progression-free survival (PFS), objective response rate (ORR) and disease control rate (DCR) with OS at the trial-and patient-level. Methods: For the trial-level analysis, we performed a systematic review of Pubmed/MEDLINE, Embase, Cochrane, clinicaltrials. gov and conference proceedings for phase II-III trials in advanced BTC. We used a weighted linear regression to measure the correlation of OS with PFS, ORR and DCR. For the patient-level analysis, we analyzed patients included in five randomized trials and three real-world datasets. The protocol is registered with PROSPERO, CRD42023398279. Results: For the trial-level analysis, we included 41 studies, involving 88 treatment arms and 7,817 patients. The coefficient of determination (R2) of the model was 0.71 (95% CI 0.56-0.86) for PFS, 0.01 (0-0.08) for ORR and 0.39 (0.14-0.64) for DCR. Predefined subgroup analysis showed consistent results. For the patient-level analysis, we included a total of 2,506 patients, 783 in randomized trials (first-line 512, second-line 271) and 1,723 in routine clinical care (first-line chemotherapy 773, first-line chemotherapy-durvalumab 628, second-line chemotherapy 322). Across the distinct datasets, the correlation coefficient ranged from 0.73 to 0.86 for PFS. A responder analysis found no association between response and survival. Conclusion: PFS shows a moderate correlation with OS both at the trial-and patient-level, while ORR and DCR show a low correlation. Whilst PFS is currently the best candidate surrogate marker for OS, our results highlight the need for novel endpoints in this field. (c) 2025 Published by Elsevier B.V. on behalf of European Association for the Study of the Liver.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
