Purpose
Quantitative benefit‐risk (B‐R) assessments are used to characterize treatment by combining key benefits and risks into a single metric but have historically been done for the “average” patient. Our aim was to conduct an individualized assessment for the oral antiplatelet vorapaxar by combining trial and real‐world data to further personalize the treatment profiles.
Methods
Using linked UK health care databases, we developed risk prediction equations for key ischemic and bleeding events using Cox proportional hazards models. Trial hazard ratios, relative to placebo, were applied to baseline risk estimates to compute expected attributable risks, summed to derive a per‐patient net clinical benefit (NCB). High risk subgroups were defined a priori, and Gaussian mixture models (GMM) were fit to characterize the NCB distribution and identify subgroups with similar NCBs.
Results
NCB was consistently positive for all subgroups, likely due to the outcome correlation, and would remain positive with a 12‐fold increase in bleeding risk. GMMs identified three distinct NCB subgroups. Compared with the middle/lower NCB subgroups, those with a higher NCB tended to be older, female, and have higher CV disease burden.
Conclusions
Personalized B‐R assessments are feasible and clinically valuable and can be used to better predict who would benefit most from therapy.
Introduction
Tafasitamab plus lenalidomide (TAFA + LEN) received accelerated US Food and Drug Administration approval and conditional European Medicines Agency approval for treatment of adults with relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) not eligible for autologous stem cell transplant. This study investigates the relative efficacy of TAFA + LEN versus comparator treatments.
Methods
Matching-adjusted indirect comparisons (MAICs) of TAFA + LEN were performed using data from L-MIND, and comparator studies assessing rituximab-based combination therapies, including polatuzumab vedotin + bendamustine + rituximab (POLA + BR) bendamustine + rituximab (BR), and gemcitabine + oxaliplatin + rituximab (R-GEMOX) to provide relative efficacy estimates for overall survival (OS), progression-free survival (PFS), duration of response (DOR), objective response rate (ORR), and complete response rate (CRR). Patient-level data from L-MIND were weighted to match reported distributions of clinically validated prognostic factors and effect modifiers in comparator trials. MAIC results versus multiple BR studies were pooled using meta-analysis.
Results
MAICs were feasible versus POLA + BR and BR. Compared to POLA + BR, TAFA + LEN was associated with significantly longer DOR [hazard ratio (HR) 0.34 (95% CI 0.12, 0.98);
p
= 0.045]. Due to concerns about the proportional hazard assumption for OS and PFS, separate HRs were estimated before and after 4 months of follow-up. OS after 4 months, was significantly greater for TAFA + LEN versus POLA + BR [HR 0.41 (95% CI 0.19, 0.90);
p
= 0.026]. Compared with BR, TAFA + LEN was associated with significantly improved OS [GO29365 comparator trial: HR 0.39 (95% CI 0.18, 0.82);
p
= 0.014], PFS (pooled data: HR 0.39 (95% CI 0.29, 0.53);
p
< 0.001], DOR [pooled data: HR 0.35 (95% CI 0.25, 0.50);
p
< 0.001], and CRR [pooled data: odds ratio 2.43 (95% CI 1.33, 4.41);
p
= 0.004].
Conclusion
In MAIC analyses, treatment with TAFA + LEN for R/R DLBCL provided better OS and PFS outcomes than standard treatment regimens. Validation from large, randomized, phase 3 clinical trials is required to confirm these results.
Supplementary Information
The online version contains supplementary material available at 10.1007/s12325-022-02094-5.
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