Lancet (London, England) · 2026
Tafasitamab plus lenalidomide and R-CHOP versus R-CHOP for first-line treatment of patients with high-risk diffuse large B-cell lymphoma (frontMIND): a global, phase 3, randomised, double-blind, placebo-controlled trial.
СтатьяРандомизированное исследованиеКлиническое исследование III фазыМногоцентровое исследованиеНазвание и аннотация: Перевод в очереди
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Lenz Georg, Trněný Marek, Burke John M, Nowakowski Grzegorz S, Fox Christopher P, Chiappella Annalisa, Duell Johannes, Jeon Young Woo, Cheah Chan Y, Westin Jason, Ye Joseph Z, Caguioa Priscilla B, Belada David, Shin Ho-Jin, Oh Sung Yong, Amorim Sandy, Ku Matthew, Mocikova Heidi, Jiménez Javier López, Gaidano Gianluca, Rosenwald Andreas, Chiarle Roberto, Colucci Philomena, Ioannidis Sonia, Cheng Lulu, Vitolo Umberto, frontMIND Study Investigators
Аннотация
BACKGROUND: Approximately 40% of patients with high-risk diffuse large B-cell lymphoma (DLBCL) are not cured with first-line R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone or prednisolone). We aimed to investigate the addition of tafasitamab (an Fc-enhanced anti-CD19 monoclonal antibody) and lenalidomide to R-CHOP (tafa-len-R-CHOP) in patients with high-risk aggressive B-cell lymphomas.
METHODS: frontMIND is a phase 3, randomised, double-blind, placebo-controlled study conducted at 298 centres in North America, South America, Europe, and the Asia-Pacific region. Patients aged 18-80 years with previously untreated, high-intermediate-risk or high-risk DLBCL or high-grade B-cell lymphoma (HGBL) were randomly allocated (1:1), stratified by International Prognostic Index (IPI) or age-adjusted IPI and geographical region, to receive six 21-day cycles of standard R-CHOP (rituximab 375 mg/m2 intravenous on day 1, cyclophosphamide 750 mg/m2 intravenous on day 1, doxorubicin 50 mg/m2 intravenous on day 1, vincristine 1·4 mg/m2 [maximum 2 mg] intravenous on day 1, and prednisone or prednisolone 100 mg/day orally on days 1-5); patients in the tafa-len-R-CHOP group additionally received tafasitamab (12 mg/kg intravenous on days 1, 8, and 15) plus lenalidomide (25 mg/day orally on days 1-10), while those in the R-CHOP group received matching placebos. The primary endpoint was investigator-assessed progression-free survival (defined as time from randomisation to disease progression or death from any cause), analysed in the intention-to-treat population; safety was included as a secondary endpoint among all patients who received at least one dose of study treatment. The trial is registered with ClinicalTrials.gov (NCT04824092) and EUDRA-CT (2020-002990-84) and is active but no longer enrolling.
FINDINGS: Between May 11, 2021, and March 2, 2023, 1229 patients were screened, among whom 899 were randomly allocated: 448 (50%) to the tafa-len-R-CHOP group and 451 (50%) to the R-CHOP group. At the time of primary analysis (median follow-up 35·2 months [95% CI 35·0-35·4]), progression-free survival was improved in the tafa-len-R-CHOP group versus the R-CHOP group (hazard ratio [HR] 0·75 [95% CI 0·59-0·96]; p=0·0194), with 2-year progression-free survival rates of 71·1% (66·3-75·4) with tafa-len-R-CHOP versus 62·9% (57·9-67·5) with R-CHOP. Interim HR for overall survival was 0·85 (0·63-1·14). The overall rate of grade 3 or higher treatment-emergent adverse events was higher with tafa-len-R-CHOP (384 [87%] of 443) than with R-CHOP (340 [76%] of 447). Additionally, a higher rate of fatal treatment-emergent adverse events was observed with tafa-len-R-CHOP (26 [6%]) than with R-CHOP (17 [4%]). However, the number of overall deaths in the study was lower with tafa-len-R-CHOP than with R-CHOP (82 [19%] vs 97 [22%]). Based on disposition data, rates of premature discontinuation of all study drugs were similar in the tafa-len-R-CHOP group (71 [16%] of 443) and R-CHOP group (66 [15%] of 447).
INTERPRETATION: Progression-free survival was significantly improved with tafa-len-R-CHOP versus R-CHOP; however, the safety profile indicated increases in adverse events, including treatment-emergent adverse events leading to death, with the addition of tafasitamab and lenalidomide. Overall survival data are immature; follow-up is ongoing. Further analyses, including of circulating tumor DNA, will help to assess whether deeper molecular responses are contributing to the progression-free survival benefit observed with tafa-len-R-CHOP. Tafa-len-R-CHOP might represent a potential new first-line treatment for patients with high-risk DLBCL or HGBL.
FUNDING: Incyte Corporation.
METHODS: frontMIND is a phase 3, randomised, double-blind, placebo-controlled study conducted at 298 centres in North America, South America, Europe, and the Asia-Pacific region. Patients aged 18-80 years with previously untreated, high-intermediate-risk or high-risk DLBCL or high-grade B-cell lymphoma (HGBL) were randomly allocated (1:1), stratified by International Prognostic Index (IPI) or age-adjusted IPI and geographical region, to receive six 21-day cycles of standard R-CHOP (rituximab 375 mg/m2 intravenous on day 1, cyclophosphamide 750 mg/m2 intravenous on day 1, doxorubicin 50 mg/m2 intravenous on day 1, vincristine 1·4 mg/m2 [maximum 2 mg] intravenous on day 1, and prednisone or prednisolone 100 mg/day orally on days 1-5); patients in the tafa-len-R-CHOP group additionally received tafasitamab (12 mg/kg intravenous on days 1, 8, and 15) plus lenalidomide (25 mg/day orally on days 1-10), while those in the R-CHOP group received matching placebos. The primary endpoint was investigator-assessed progression-free survival (defined as time from randomisation to disease progression or death from any cause), analysed in the intention-to-treat population; safety was included as a secondary endpoint among all patients who received at least one dose of study treatment. The trial is registered with ClinicalTrials.gov (NCT04824092) and EUDRA-CT (2020-002990-84) and is active but no longer enrolling.
FINDINGS: Between May 11, 2021, and March 2, 2023, 1229 patients were screened, among whom 899 were randomly allocated: 448 (50%) to the tafa-len-R-CHOP group and 451 (50%) to the R-CHOP group. At the time of primary analysis (median follow-up 35·2 months [95% CI 35·0-35·4]), progression-free survival was improved in the tafa-len-R-CHOP group versus the R-CHOP group (hazard ratio [HR] 0·75 [95% CI 0·59-0·96]; p=0·0194), with 2-year progression-free survival rates of 71·1% (66·3-75·4) with tafa-len-R-CHOP versus 62·9% (57·9-67·5) with R-CHOP. Interim HR for overall survival was 0·85 (0·63-1·14). The overall rate of grade 3 or higher treatment-emergent adverse events was higher with tafa-len-R-CHOP (384 [87%] of 443) than with R-CHOP (340 [76%] of 447). Additionally, a higher rate of fatal treatment-emergent adverse events was observed with tafa-len-R-CHOP (26 [6%]) than with R-CHOP (17 [4%]). However, the number of overall deaths in the study was lower with tafa-len-R-CHOP than with R-CHOP (82 [19%] vs 97 [22%]). Based on disposition data, rates of premature discontinuation of all study drugs were similar in the tafa-len-R-CHOP group (71 [16%] of 443) and R-CHOP group (66 [15%] of 447).
INTERPRETATION: Progression-free survival was significantly improved with tafa-len-R-CHOP versus R-CHOP; however, the safety profile indicated increases in adverse events, including treatment-emergent adverse events leading to death, with the addition of tafasitamab and lenalidomide. Overall survival data are immature; follow-up is ongoing. Further analyses, including of circulating tumor DNA, will help to assess whether deeper molecular responses are contributing to the progression-free survival benefit observed with tafa-len-R-CHOP. Tafa-len-R-CHOP might represent a potential new first-line treatment for patients with high-risk DLBCL or HGBL.
FUNDING: Incyte Corporation.