Background: Up to 40% of patients relapse or are refractory (R/R) to R-CHOP, the current standard of care for diffuse large B-cell lymphoma (DLBCL), indicating an unmet need, particularly in patients with high-intermediate and high-risk disease (International Prognostic Index [IPI] 3–5). POLARIX (NCT03274492) evaluated a modified regimen substituting polatuzumab vedotin for vincristine (pola-R-CHP), demonstrating modest improvement in progression-free survival (PFS) with no overall survival (OS) benefit between treatment arms. The addition of lenalidomide (LEN) to R-CHOP improved both PFS and OS in the Eastern Cooperative Oncology Group (ECOG)-ACRIN E1412 trial but not in the Phase III ROBUST study, in which a lower dose of LEN was used, despite a positive trend toward 2-year PFS in a subgroup analysis.
The chemo-free immunotherapy tafasitamab + LEN, has received accelerated approval in the United States (2020) and conditional marketing authorization in Europe and Canada (2021) in adult patients with R/R DLBCL ineligible for ASCT based on the pivotal L-MIND trial (NCT02399085). The primary analysis of First-MIND (NCT04134936), a Phase Ib randomized safety study of R-CHOP + tafasitamab ± LEN in patients with previously untreated and newly diagnosed DLBCL, demonstrated that adding tafasitamab + LEN does not impair dosing and scheduling of R-CHOP, with toxicities similar to those expected with R-CHOP alone (ASH 2021; #3556).
Aims: frontMIND (NCT04824092) will investigate the efficacy and safety of R-CHOP + tafasitamab + LEN vs R-CHOP alone in previously untreated patients with high-intermediate and high-risk DLBCL.
Methods: frontMIND is a Phase III, multicenter, randomized, double-blind, placebo-controlled study (Figure). Approximately 880 patients are planned to be randomized at approximately 350 centers in North and South America, Europe, and Asia-Pacific. Eligible patients aged 18‒80 years with previously untreated local biopsy-proven, CD20-positive DLBCL with IPI score 3–5 (age-adjusted IPI 2–3 if ≤60 years) and ECOG performance score 0–2 will be enrolled. Patients with transformed lymphoma (except double or triple hit lymphoma) are excluded. Patients will be randomized 1:1 to receive six 21-day (D) cycles of either R-CHOP + tafasitamab (12 mg/kg intravenously, D 1, 8, and 15) + LEN (25 mg orally, D1–10) or R-CHOP plus tafasitamab + LEN placebos. Patients will be followed for up to 5 years after the end of treatment. The primary endpoint is investigator-assessed PFS. Secondary endpoints include investigator-assessed event-free survival, OS, safety, and tafasitamab serum concentration (trough and Cmax levels). Sensitivity and specificity of minimal residual disease for early detection of disease progression is an exploratory endpoint; further minimal residual disease parameters may also be investigated.
Results: Results for this study are not yet available: outcome data as described above will be presented in due course.
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Summary/Conclusion: There remains a high unmet need to improve treatment options for newly diagnosed patients, especially with high-intermediate and high-risk DLBCL (IPI 3–5). The combination of tafasitamab, LEN and R-CHOP may have synergistic potential. Preliminary data from the First-MIND study suggest that tafasitamab ± LEN + R-CHOP may be tolerable in patients with treatment-naïve DLBCL. The Phase III frontMIND study will provide further evaluation of clinical benefits and safety in patients with newly diagnosed high-intermediate and high-risk DLBCL.