Fu, Tommy

Purpose Overall survival (OS) is the definitive and best-established primary efficacy end point to evaluate diffuse large B-cell lymphoma (DLBCL) therapies, but it requires prolonged follow-up. An earlier end point assessed post-treatment would expedite clinical trial conduct and accelerate patient access to effective new therapies. Our objective was to formally evaluate progression-free survival (PFS) and PFS at 24 months (PFS24) as surrogate end points for OS in first-line DLBCL. Patients and Methods Individual patient data were analyzed from 7,507 patients from 13 multicenter randomized controlled trials of active treatment in previously untreated DLBCL, published after 2002, with sufficient PFS data to predict treatment effects on OS. Trial-level surrogacy examining the correlation of treatment effect estimates of PFS/PFS24 and OS was evaluated using both linear regression ( R2WLS) and Copula bivariable ( R2Copula) models. Prespecified criteria for surrogacy required either R2WLS or R2Copula ≥ 0.80 and neither < 0.7, with lower-bound 95% CI > 0.60. Results Trial-level surrogacy for PFS was strong ( R2WLS = 0.83; R2Copula = 0.85) and met the predefined criteria for surrogacy. At the patient level, PFS strongly correlated with OS. The surrogate threshold effect had a hazard ratio of 0.89. Surrogacy was consistent across comparisons with or without rituximab and with rituximab maintenance trials. Trial-level surrogacy for PFS24 was relatively strong ( R2WLS = 0.77; R2Copula = 0.78) but did not meet prespecified criteria. At the patient level, PFS24 significantly correlated with OS. The surrogate threshold effect had an odds ratio of 1.51. Conclusion This large pooled analysis of individual patient data supports PFS as a surrogate end point for OS in future randomized controlled trials evaluating chemoimmunotherapy in DLBCL. Use of this end point may expedite therapeutic development with the intent of bringing novel therapies to this patient population years before OS results are mature.

This commentary describes the progress of the SEAL [Surrogate Endpoints for Aggressive Lymphoma] research group and invites collaboration in sharing data to continue building a large database of individual patient data from multiple clinical trials in DLBCL.

AbstractMantle cell lymphoma (MCL) is a type of non‐Hodgkin lymphoma (NHL) with aggressive disease characteristics resulting in multiple relapses after initial treatment. Lenalidomide is an immunomodulatory agent approved in the US for patients with relapsed/refractory MCL following bortezomib based on results from 3 multicenter phase II studies (2 including relapsed/refractory aggressive NHL and 1 focusing on MCL post‐bortezomib). The purpose of this report is to provide longer follow‐up on the MCL‐001 study (follow‐ups were 6.8 [NHL‐002], 7.6 [NHL‐003], and 52.2 [MCL‐001] months). The 206 relapsed MCL patients treated with single‐agent lenalidomide (25 mg/day PO, days 1 to 21 every 28‐days) had a median age of 67 years (63% ≥65 years), 91% with stage III/IV disease, and 50% with ≥4 previous treatment regimens. With a median follow‐up of X, the combined best overall response rate (ORR) was 33% (including 11% with complete remission [CR]/CR unconfirmed CRu). Lenalidomide produced rapid and durable responses with a median time to response of 2.2 months and median duration of response (DOR) of 16.6 months (95% CI: 11.1%‐29.8%). The safety profile was consistent and manageable; myelosuppression was the most common adverse event (AE). Overall, single‐agent lenalidomide showed consistent efficacy and safety in multiple phase II studies of heavily pretreated patients with relapsed/refractory MCL, including those previously treated with bortezomib.

Purpose Follicular lymphoma (FL) is an indolent cancer, with effective but rarely curative treatment options. As a standard study end point for first-line FL therapy, progression-free survival (PFS) requires extended follow-up (median PFS, > 7 years). To provide patients with earlier access to newer therapies, an earlier end point to expedite clinical trials is needed. Our objective was to formally assess the complete response rate at 30 months (CR30) after initiation of induction therapy as a potential surrogate end point for PFS in first-line FL therapy. Patients and Methods We analyzed individual patient data from 13 randomized multicenter trials of induction and maintenance regimens in first-line FL therapy published after 1990 and with sufficient data to evaluate whether CR30 could predict treatment effects on PFS. Correlation of the CR30 odds ratio with the PFS hazard ratio was evaluated by both linear regression (R2WLS) and bivariate copula (R2Copula) models. Prespecified criteria for surrogacy required either R2WLS or R2Copula ≥ 0.80, with a lower-bound 95% CI > 0.60. Results Data from eight induction and five maintenance randomized trials in 3,837 evaluable patients were analyzed. The prespecified surrogacy threshold was met, with an R2WLS of 0.88 (95% CI, 0.77 to 0.96) and an R2Copula of 0.86 (95% CI, 0.72 to 1.00). Multiple sensitivity and supplemental analyses supported the robustness of the findings. A minimum 11% absolute improvement in CR30 from a 50% control rate predicted a significant treatment effect on PFS (hazard ratio, 0.69). Conclusion This large, prospective, pooled analysis of randomized chemotherapy, immunotherapy, and chemoimmunotherapy trials demonstrates that CR30 is a surrogate end point for PFS in first-line FL treatment trials. Use of this end point may expedite therapeutic development with the intent of bringing novel therapies to this patient population years before PFS results are mature.

SummaryPatients with mantle cell lymphoma (MCL) generally respond to first‐line immunochemotherapy, but often show chemoresistance upon subsequent relapses, with poor outcome. Several studies of the immunomodulator, lenalidomide, have demonstrated its activity in MCL including the MCL‐001 study in relapsed/refractory patients who had failed defined prior therapies of anthracyclines or mitoxantrone, cyclophosphamide, rituximab and also bortezomib. We present here the long‐term efficacy follow‐up of the prospective phase II MCL‐001 study (N = 134), including new exploratory analyses with baseline Ki‐67 (MIB1), a biological marker of tumour proliferation. With longer follow‐up, lenalidomide showed a 28% overall response rate [ORR; 8% complete response (CR)/CR unconfirmed (CRu)]. Median duration of response (DOR), progression‐free survival and overall survival were 16·6, 4·0 and 20·9 months, respectively. Myelosuppression continued to be the most common grade 3/4 toxicity. Several studies of MCL patients treated with chemotherapy, rituximab and bortezomib have shown an inverse association between survival and Ki‐67. Ki‐67 data in 81/134 MCL‐001 patients showed similar ORRs in both low (<30% or <50%) versus high (≥30% or ≥50%) Ki‐67–expressing groups, yet lower Ki‐67 levels demonstrated superior CR/CRu, DOR and survival outcomes. Overall, lenalidomide showed durable efficacy with a consistent safety profile in heavily pretreated, relapsed/refractory MCL post‐bortezomib.