Roadmap for developing MRD as an early endpoint for drug approval in lymphoma

Advances in lymphoma therapy have extended survival, but exposed limitations of traditional trial endpoints efficacy assessments. We propose two MRD-informed endpoints to accelerate drug development and improve regulatory decision-making: modified PFS (mPFS) and undetectable MRD (uMRD) rate. mPFS is a specific variant of event free survival (EFS) defined as the time from study enrollment until positive end-of-treatment MRD, clinical progression, or death and has potential as a validated surrogate endpoint for traditional approval. uMRD rate at a prespecified timepoint measures depth of response and can be useful in early phase and later-line studies for accelerated approval. Here, we outline the potential that can be slow, reliant on inconsistent imaging studies, and insensitive to molecular disease burden. Novel surrogate trial endpoints can expand and accelerate innovative therapies reaching patients. Advances in technology have led to ultrasensitive methods for detection of measurable residual disease (MRD) in peripheral blood, including circulating tumor DNA (ctDNA) and immunoglobulin clonotype sequencing. MRD methods have been studied with clear biologic rationale and prognostic ability across lymphomas including large B-cell, mantle cell, Hodgkin, and follicular lymphoma. Incorporating MRD into trial endpoints can lead to shorter trial times and perhaps more accurate treatment endpoints incorporating MRD, detail the current MRD data in lymphomas, and provide a practical roadmap towards regulatory use of MRD-based surrogate endpoints to speed drug development.