Surrogate endpoints in clinical trials: when is good...good enough?

The successful completion of practice-changing clinical trials is hampered by multiple potential challenges including regulatory procedures, patient recruitment, safety concerns, and cost (1). Study duration is a primary factor in clinical trial feasibility and several approaches have been employed to mitigate its impact. Overall survival (OS) has long been the predominant primary endpoint in cancer clinical trials due to its objectivity, clarity, patient benefit, and role in regulatory approval for new therapies. However, its large sample size requirements, cost, and long follow-up times make OS a challenging endpoint to utilize and impractical in many situations. Recently, surrogate measures of efficacy have been proposed to expedite cancer therapy development and overcome the broadly understood limitations of OS (2). Recurrence-free survival (RFS) has successfully been implemented as a surrogate clinical trial endpoint with similar recognized value as OS, and has been evaluated in colon, gastrointestinal, lung, and renal cancers, however less work has been performed in hepato-biliary-pancreatic (HBP) malignancies (3-6).

In their recent work, “Surrogacy of recurrence-free survival for overall survival as an endpoint of clinical trials of perioperative adjuvant therapy in hepatobiliary-pancreatic cancers: A retrospective study and meta-analysis”, Imamura and colleagues assessed the correlation between RFS and OS for multiple malignancies, including HBP (7). They performed a retrospective analysis of patients undergoing curative-intent resections (R0 or R1) for HBP malignancies between September 2002 and June 2022 at a single center, including over 4,200 patients with either pancreatic ductal adenocarcinoma (PDAC), biliary tract cancer (BTC), hepatocellular carcinoma (HCC), or colorectal liver metastases (CRLM). The authors reported low correlation coefficients between RFS and OS for HCC (ρ=0.67) and CRLM (ρ=0.53), but strong for PDAC (ρ=0.80) and BTC (ρ=0.75). The authors attribute the poorer correlation between DFS and OS for HCC and CRLM to prolonged survival after recurrence (SAR) with these pathologies, owing to the wide variety of therapies available after recurrence occurs, including salvage therapies (7). In their landmark analysis, concordance rates between death and recurrence at 5 years postoperatively was >73% for PDAC and BTC, both increasing over time and plateauing at 3 years. They also performed a meta-analysis of all randomised controlled trials (RCTs) focusing on neoadjuvant or adjuvant therapies, where strong correlation coefficients were observed for the RFS hazard ratio and OS hazard ratio in PDAC (ρ=0.88) and BTC (ρ=0.87), further bolstering their single-center results.

The US Food and Drug Administration (FDA) currently mandates that surrogate endpoints for clinical approval “must be reasonably likely to predict clinical benefit”. Presently, disease-free survival (DFS) is defined as a clinical endpoint as well as a surrogate endpoint for both “traditional approval” and “accelerated approval” for gastric, colorectal, renal and breast cancers (8). DFS (or RFS) as a clinical endpoint has been utilized for over two decades and the FDA Oncologic Drugs Advisory Committee (ODAC) currently recommends that RCTs utilize DFS as the primary endpoint for RCTs evaluating adjuvant treatment in colon cancer due to its well-studied correlation with OS (3). Validating surrogate endpoints in cancer clinical trials is critically important as they likely increase study feasibility, decrease cost, and hasten development of novel therapies. Implementation of RFS as a primary endpoint is thought to decrease study sample size and follow-up duration required and subsequently reduce overall cost of studies. Several recent and ongoing clinical trials evaluating adjuvant chemotherapy strategies for pancreatic cancer use RFS as a primary endpoint including NEONAX and APACT (9,10). The use of DFS in APACT allowed for earlier assessment of treatment efficacy which in this case showed no significant difference in DFS with the use of nab-paclitaxel plus gemcitabine versus gemcitabine alone. Interestingly, this trial utilized independent assessment of DFS which had not previously been used before to improve trial rigor and reduce unintentional investigator bias (9).

Imamura and colleagues also performed a meta-analysis of available trials to evaluate the correlation of RFS and OS in HBP malignancies. This “modern era” analysis is important, as two previous meta-analyses assessing the use of RFS as a surrogate for OS in patients with PDAC drew conflicting results (11,12). These previous studies were performed only in patients undergoing upfront resection, while the present study included a larger proportion of trials with patients receiving neoadjuvant systemic therapy, better reflecting modern treatment paradigms. RFS may be a more appropriate surrogate endpoint in this population, as a significant proportion of patients may not receive adjuvant treatment after their index HBP surgery, confounding RFS (9).

The results from the BTC cohort should be interpreted with caution as the authors included patients with five distinct subtypes of biliary tract cancers including: intrahepatic and extrahepatic cholangiocarcinoma, gallbladder adenocarcinoma, and ampulla of Vater carcinoma in their analysis. BTC are rare diseases, accounting for just 3% of all gastrointestinal cancers, and can have highly variable biologies and treatment options, affecting both RFS and OS (13). Additionally, more than 80% of cases are classified as unresectable at the time of diagnosis, limiting the population of post-resection patients who can be analyzed (14). Recurrence rates for BTC following resection range from 50–70% and second-line treatment recommendations have changed over time. The introduction of immunotherapy into standard treatment pathways (e.g., cholangiocarcinoma) could have a significant effect on OS after recurrence, lengthening SAR and diminishing the prognostic value of RFS. It is also important to note that this study’s results showing a poor correlation between RFS and OS in patients with CRLM, are inconsistent with other large studies in this population (15). And while statistically significant, the correlation coefficients reported by Imamura (PDAC, ρ=0.88; BTC, ρ=0.87) are lower than large meta-analyses of other GI malignancies (ρ=0.97) (15) , further suggesting heterogeneity in these patient cohorts and available treatments.

In the current era of resource limitation in clinical research and the rapid development of new therapies, the importance of validated and efficient surrogate endpoints in clinical trials cannot be understated. In this important work, Imamura and colleagues attempt to address the critical question of when RFS may appropriately substitute OS, in the interest of both researchers and patients in future trials. The actual impact of using surrogate endpoints in clinical trials is not well understood. Given their current utilization in ongoing studies, more rigorous analyses of their supposed benefits and actual costs are desperately needed. The movement towards improving clinical trial feasibility and cost-effectiveness through surrogate endpoints is a noble one, however researchers must ensure they are implemented in a manner that primarily benefits patients, rather than the researchers themselves.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, HepatoBiliary Surgery and Nutrition. The article did not undergo external peer review.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-24-607/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Fogel DB. Factors associated with clinical trials that fail and opportunities for improving the likelihood of success: A review. Contemp Clin Trials Commun 2018;11:156-64. [Crossref] [PubMed]
2. Fiteni F, Westeel V, Pivot X, et al. Endpoints in cancer clinical trials. J Visc Surg 2014;151:17-22. [Crossref] [PubMed]
3. Sargent DJ, Wieand HS, Haller DG, et al. Disease-free survival versus overall survival as a primary end point for adjuvant colon cancer studies: individual patient data from 20,898 patients on 18 randomized trials. J Clin Oncol 2005;23:8664-70. [Crossref] [PubMed]
4. Oba K, Paoletti X, Alberts S, et al. Disease-free survival as a surrogate for overall survival in adjuvant trials of gastric cancer: a meta-analysis. J Natl Cancer Inst 2013;105:1600-7. [Crossref] [PubMed]
5. Harshman LC, Xie W, Moreira RB, et al. Evaluation of disease-free survival as an intermediate metric of overall survival in patients with localized renal cell carcinoma: A trial-level meta-analysis. Cancer 2018;124:925-33. [Crossref] [PubMed]
6. Mauguen A, Pignon JP, Burdett S, et al. Surrogate endpoints for overall survival in chemotherapy and radiotherapy trials in operable and locally advanced lung cancer: a re-analysis of meta-analyses of individual patients' data. Lancet Oncol 2013;14:619-26. [Crossref] [PubMed]
7. Imamura T, Ohgi K, Mori K, et al. Surrogacy of Recurrence-free Survival for Overall Survival as an Endpoint of Clinical Trials of Perioperative Adjuvant Therapy in Hepatobiliary-pancreatic Cancers: A Retrospective Study and Meta-analysis. Ann Surg 2024;279:1025-35. [Crossref] [PubMed]
8. U.S. Food and Drug Administration. Guidance for Industry: Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims. [Internet]. 2009 [cited 2024 Oct 24]. Available online: https://www.fda.gov/media/71195/download
9. Tempero MA, Pelzer U, O'Reilly EM, et al. Adjuvant nab-Paclitaxel + Gemcitabine in Resected Pancreatic Ductal Adenocarcinoma: Results From a Randomized, Open-Label, Phase III Trial. J Clin Oncol 2023;41:2007-19. [Crossref] [PubMed]
10. Ettrich TJ, Berger AW, Perkhofer L, et al. Neoadjuvant plus adjuvant or only adjuvant nab-paclitaxel plus gemcitabine for resectable pancreatic cancer - the NEONAX trial (AIO-PAK-0313), a prospective, randomized, controlled, phase II study of the AIO pancreatic cancer group. BMC Cancer 2018;18:1298. [Crossref] [PubMed]
11. Petrelli F, Tomasello G, Ghidini M, et al. Disease-free survival is not a surrogate endpoint for overall survival in adjuvant trials of pancreatic cancer: a systematic review of randomized trials. HPB (Oxford) 2017;19:944-50. [Crossref] [PubMed]
12. Nie RC, Zou XB, Yuan SQ, et al. Disease-free survival as a surrogate endpoint for overall survival in adjuvant trials of pancreatic cancer: a meta-analysis of 20 randomized controlled trials. BMC Cancer 2020;20:421. [Crossref] [PubMed]
13. Ellis H, Raghavan S, Wolpin BM, et al. How we treat advanced biliary tract cancers in the second-line setting. Clin Adv Hematol Oncol 2023;21:35-42.
14. Amonkar MM, Abderhalden LA, Fox GE, et al. Clinical outcomes for previously treated patients with advanced biliary tract cancer: a meta-analysis. Future Oncol 2024;20:863-76. [Crossref] [PubMed]
15. Kataoka K, Mori K, Nakamura Y, et al. Survival benefit of adjuvant chemotherapy based on molecular residual disease detection in resected colorectal liver metastases: subgroup analysis from CIRCULATE-Japan GALAXY. Ann Oncol 2024;35:1015-25. [Crossref] [PubMed]