Surrogate end points in lymphoma
Authors: C.L. Batlevi, A. Younes
Journal: Annals of Oncology (2018)

Overall survival is one of the most reliable end points to measure patients' benefit from a drug or intervention in the context of a clinical trial. However, to determine a survival benefit, trials require enrolling a large number of patients who are followed for several years. This process may delay the introduction of effective treatment to patients with unmet medical needs, such as cancer, in addition to increasing the cost of drug development. In 1992, the United States Food and Drug Administration (FDA) instituted the accelerated approval mechanism that allowed drugs for serious conditions to be approved based on a surrogate end point [1.Beaver J.A. Howie L.J. Pelosof L. et al.A 25-Year Experience of US Food and Drug Administration accelerated approval of malignant hematology and oncology drugs and biologics: a review.JAMA Oncol. 2018; 4: 849-856Crossref PubMed Scopus (160) Google Scholar]. Using a surrogate end point enabled the FDA to approve drugs by an average of 3.5 years faster. The most widely used surrogate end point in single-arm phase II clinical trials are overall response rate, while progression-free survival (PFS) or event-free survival (EFS) are typically used as surrogate end points in randomized trials. In the past 25 years, PFS was the primary end point in 27% of randomized trials that supported an accelerated approval for hematology and oncology indications [1.Beaver J.A. Howie L.J. Pelosof L. et al.A 25-Year Experience of US Food and Drug Administration accelerated approval of malignant hematology and oncology drugs and biologics: a review.JAMA Oncol. 2018; 4: 849-856Crossref PubMed Scopus (160) Google Scholar]. During the same period, overall survival was the most commonly used end point for regular approval, followed by PFS or TTP (35% and 34%, respectively). While using PFS and EFS as end points may allow faster drug approval compared with the standard OS end point, there is still a room for improvement. Typically, PFS and EFS are event-driven, which may also take several years to establish. In the past, the regulatory approval of rituximab in combination with chemotherapy for diffuse large B-cell lymphoma (DLBCL) was based on EFS or PFS [2.Pfreundschuh M. Trumper L. Osterborg A. et al.CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group.Lancet Oncol. 2006; 7: 379-391Abstract Full Text Full Text PDF PubMed Scopus (1706) Google Scholar, 3.Habermann T.M. Weller E.A. Morrison V.A. et al.Rituximab-CHOP versus CHOP alone or with maintenance rituximab in older patients with diffuse large B-cell lymphoma.J Clin Oncol. 2006; 24: 3121-3127Crossref PubMed Scopus (1145) Google Scholar, 4.Coiffier B. Lepage E. Briere J. et al.CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma.N Engl J Med. 2002; 346: 235-242Crossref PubMed Scopus (4480) Google Scholar]. The median duration between first enrollment and publication was 5 years. Recent randomized trials in newly diagnosed patients with DLBCL have taken a median of 4.5 years to complete enrollment, and median of 8.42 years (range 5.25–11.6 years) to be published. In the current study, Maurer et al. propose using a fixed time of 24 months to measure PFS (PFS24) as a surrogate end point in randomized clinical trials of immunochemotherapy for newly diagnosed patients with DLBCL. In a prior study that was also reported by Maurer et al., [5.Maurer M.J. Ghesquieres H. Jais J.P. et al.Event-free survival at 24 months is a robust end point for disease-related outcome in diffuse large B-cell lymphoma treated with immunochemotherapy.J Clin Oncol. 2014; 32: 1066-1073Crossref PubMed Scopus (245) Google Scholar] the authors proposed using EFS at 24 months (EFS24) as a surrogate end point. The study demonstrated that patients with DLBCL treated with standard immunochemotherapy who remain event-free 2 years after diagnosis have subsequent survival comparable to that of the age- and sex-matched general population. The study was based on data from prospectively enrolled patients treated with immunochemotherapy on to both registry and trial-based studies from the USA and Europe [5.Maurer M.J. Ghesquieres H. Jais J.P. et al.Event-free survival at 24 months is a robust end point for disease-related outcome in diffuse large B-cell lymphoma treated with immunochemotherapy.J Clin Oncol. 2014; 32: 1066-1073Crossref PubMed Scopus (245) Google Scholar]. The present study evaluated almost 6000 patients treated with immunochemotherapy who were enrolled on 14 randomized clinical trials. These trials did not collect complete data on EFS, so the authors used PFS24 instead. Similar to their prior conclusion, the authors reported that PFS24 was also a good predictor of overall survival. In DLBCL, failure to achieve complete remission at the end of therapy may require introducing a salvage regimen. In younger patients, salvage regimens are consolidated with stem-cell transplant, which may cure a fraction of patients. Thus, EFS, rather than PFS, may be the ideal end point for these patients. For the same reason, EFS is more ideal end point in clinical trials evaluating the efficacy of front-line regimens in patients with newly diagnosed Hodgkin lymphoma. In a recent randomized trial comparing standard ABVD with brentuximab vedotin plus AVD regimens in newly diagnosed patients with advanced stage Hodgkin lymphoma, a new primary end point termed modified PFS was used [6.Connors J.M. Jurczak W. Straus D.J. et al.Brentuximab vedotin with chemotherapy for stage III or IV Hodgkin's lymphoma.N Engl J Med. 2018; 378: 331-344Crossref PubMed Scopus (420) Google Scholar]. Modified PFS was defined as time to disease progression, death, or failure to achieve complete response after completion of frontline therapy according to review by an independent committee, followed by subsequent anticancer therapy. Thus, modified PFS is similar to EFS. The authors should be complimented for this outstanding work. However, since both studies suffered from a relatively short follow-up (<10 years), and did not include a representative proportion of elderly patients (older than 80 years), EFS24 and PFS24 can be considered exploratory or secondary end points. With longer follow-up, it is hoped that EFS24 may become a primary end point in clinical trials using immunochemotherapy in newly diagnosed patients with DLBCL. This work was supported in part by the MSK SPORE in lymphoma P50 CA192937-01A1 and the Memorial Sloan Kettering Cancer Center Core Grant P30 CA008748.