ABSTRACT
Introduction Tafasitamab is a humanized, Fc-modified, anti-CD19 monoclonal antibody (mAb) shown to enhance antibody-dependent cellular cytotoxicity and phagocytosis. It is approved by the FDA under accelerated approval (July 2020) in combination with lenalidomide (LEN) for treatment of relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) in adult patients ineligible for autologous stem cell transplantation. To evaluate if newly diagnosed DLBCL patients would also benefit from this regimen, this Phase Ib study (First-MIND;NCT04134936) was designed to first assess the safety and tolerability of tafasitamab ± LEN in addition to rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) in newly diagnosed DLBCL patients. Methods Eligible patients were ≥18 years old, with treatment-naïve DLBCL, international prognostic index (IPI) 2-5 and Eastern Cooperative Oncology Group performance status (ECOG PS) 0-2. Patients with known double- or triple-hit and transformed lymphoma were excluded. Patients were randomized 1:1 to either six 21-day [D] cycles of R-CHOP (R-CHO, D1;P, D1-5) + tafasitamab (12 mg/kg IV, D1, 8, 15) (Arm A) or R-CHOP + tafasitamab + LEN (25 mg orally, D1-10) (Arm B). Granulocyte colony-stimulating factor and venous thromboembolism prophylaxis was mandatory. The primary safety endpoint was incidence of treatment-emergent adverse events (TEAEs);secondary endpoints included overall response rate (ORR), positron emission tomography (PET)-complete response (CR) rate, and partial response (PR) rate at end of treatment (EOT). Tumor measurements by PET/CT or PET/MRI at EOT were performed according to Lugano 2014 criteria within 6±2 weeks after Day 21 of the last treatment cycle the patient started. Results From December 2019 to August 2020, 83 patients were screened in nine countries across 34 sites in Europe and the US;66 were randomized (Arm A, n=33;Arm B, n=33). Data cut-off for this analysis: 13 March 2021. Median age was 64.5 years (range 20-86). Many patients had high-risk disease: IPI 2: 24/66 (36.4%), IPI 3: 29/66 (43.9%), IPI 4: 11/66 (16.7%), IPI 5: 2/66 (3.0%);ECOG PS ≥2: 6/66 (9.1%). Most patients had Stage III/IV disease 62/66 (93.9%);29/66 (43.9%) had bulky disease. All patients experienced at least one TEAE. The most frequent Grade ≥3 TEAEs by system organ class were blood and lymphatic disorders (81.8% patients overall), experienced by 24 patients (72.7%) in Arm A and 30 patients (90.9%) in Arm B. Grade ≥3 neutropenia and thrombocytopenia occurred in 19/33 (57.6%) and 4/33 (12.1%) (Arm A), and 28/33 (84.8%) and 12/33 (36.4%) (Arm B) patients, respectively;Grade ≥3 febrile neutropenia was experienced by 6/33 (18.2%) patients in each arm. Grade ≥3 infusion-related reactions to both rituximab and tafasitamab occurred in no patients in Arm A and one patient (3.0%) in Arm B, and 7/33 (21.2%) (Arm A) and 9/33 (27.3%) (Arm B) patients had a Grade ≥3 infection and/or infestation (Figure 1). Serious TEAEs occurred in 14/33 (42.4%) patients in Arm A and 17/33 (51.5%) patients in Arm B. Two out of 33 (6.1%) and one out of 33 (3.0%) patients discontinued study treatment due to TEAEs in Arms A and B, respectively. There were four deaths unrelated to tafasitamab and/or LEN (COVID-19 pneumonia, sepsis, and urosepsis). The average relative dose intensity of R-CHOP in each cycle was maintained in both arms. ORR at EOT was observed in 25/33 patients (75.8%;95% confidence interval [CI]: 57.7-88.9) in Arm A and 27/33 patients (81.8%;95% CI: 64.5-93.0) in Arm B. Conclusion These data suggest that both regimens are tolerable and do not impair dosing and scheduling of R-CHOP. Toxicities were similar to those expected with R-CHOP with or without LEN. With tumor follow-up still ongoing, the ORR at EOT suggests that patients with treatment-naïve DLBCL may achieve clinically meaningful efficacy tafasitamab and LEN in addition to standard treatment. A Phase III, multicenter, randomized, double-blind, placebo-controlled trial will assess efficacy and safety of R-CHOP + t fasitamab + LEN vs R-CHOP in newly diagnosed patients with high intermediate and high risk DLBCL, and is currently recruiting (frontMIND study;NCT04824092). Funding: MorphoSys AG. [Formula presented] Disclosures: Belada: Roche: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding;Gilead Sciences: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding;Janssen-Cilag: Consultancy, Research Funding;Takeda: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding;MorphoSys AG: Consultancy, Research Funding;Debiopharm Group: Consultancy;Pharmacyclics: Research Funding;Archigen Biotech: Research Funding;Reddys: Research Funding. André: Johnson & Johnson: Research Funding;Roche: Other: Travel/accomodation/expenses, Research Funding;Incyte: Consultancy;Gilead: Consultancy, Other: Travel/Accommodations/Expenses;Karyopharm: Consultancy;Bristol-Myers-Squibb: Consultancy, Other: Travel/Accommodations/Expenses;Takeda: Consultancy, Research Funding;Celgene: Other: Travel/accomodation/expenses;AbbVie: Other: Travel/accomodation/expenses. Pérez Persona: Amgen: Consultancy, Other: Support for attending meetings and/or travel, Speakers Bureau;BMS/Celgene: Consultancy, Other: Support for attending meetings and/or travel, Speakers Bureau;AbbVie: Other: Support for attending meetings and/or travel, Speakers Bureau;Takeda: Speakers Bureau;Sanofi: Consultancy, Speakers Bureau;AstraZeneca: Speakers Bureau;GSK: Consultancy;Incyte: Consultancy. Staber: Roche: Consultancy, Honoraria, Research Funding;AbbVie: Consultancy, Honoraria;Gilead: Consultancy, Honoraria;Janssen: Consultancy, Honoraria;Astra Zeneca: Consultancy, Honoraria;Takeda: Consultancy, Research Funding;MSD: Consultancy, Honoraria;BMS: Consultancy, Honoraria;Incyte: Consultancy, Honoraria, Research Funding;Beigene: Consultancy, Honoraria. Trneny: AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses;Amgen: Consultancy, Honoraria;Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses;Gilead Sciences: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses;Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses;MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses;Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses;Celgene: Consultancy;1st Faculty of Medicine, Charles University, General Hospital in Prague: Current Employment;Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Portola: Honoraria, Membership on an entity's Board of Directors or advisory committees;AstraZeneca: Honoraria. Brackertz: MorphoSys AG: Current Employment. Shah: MorphoSys AG: Current Employment. Sporchia: MorphoSys AG: Current Employment. Burke: MorphoSys: Consultancy;Adaptive Biotechnologies: Consultancy;Verastem: Consultancy;AstraZeneca: Consultancy;Bristol Myers Squibb: Consultancy;Kymera: Consultancy;X4 Pharmaceuticals: Consultancy;AbbVie: Consultancy;SeaGen: Consultancy, Speakers Bureau;Kura: Consultancy;Roche/Genentech: Consultancy;Epizyme: Consultancy;Beigene: Consultancy, Speakers Bureau. Nowakowski: Celgene, NanoString Technologies, MorphoSys: Research Funding;Celgene, MorphoSys, Genentech, Selvita, Debiopharm Group, Kite/Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Tafasitamab is a humanized Fc-modified cytolytic CD19 targeting monoclon l antibody. In combination with lenalidomide (LEN), it received accelerated approval in July 2020 for adult patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) not otherwise specified (NOS), including arising from lowâ€'grade lymphoma, who are ineligible for autologous stem cell transplant (ASCT). Following FDA approval, we are now evaluating the safety and efficacy of tafasitamab in combination with LEN as an add-on to first-line therapy with R-CHOP in newly diagnosed patients with DLBCL.
ABSTRACT
Background: Tafasitamab is a humanized, Fc-modified anti-CD19 monoclonal antibody that enhances antibody-dependent cellular cytotoxicity and phagocytosis. It is FDA-approved in combination with lenalidomide for adult patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) not otherwise specified (NOS), including arising from low-grade lymphoma, who are ineligible for autologous stem cell transplant (ASCT). Aims: First-MIND (NCT04134936) is a Phase Ib, open-label, randomized study to assess the safety and preliminary efficacy of tafasitamab + R-CHOP or tafasitamab + lenalidomide + R-CHOP in patients with newly diagnosed DLBCL. Methods: Eligible patients were aged ≥18 years, treatment-na.ve, with DLBCL, international prognostic index (IPI) 2-5 and Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2. Patients with known double- or triple-hit and transformed lymphoma were excluded. Treatment comprised six 21-day cycles of R-CHOP + tafasitamab (12 mg/kg IV, Day [D] 1, 8 and 15) (arm A) or R-CHOP + tafasitamab (12 mg/kg IV, D1, 8 and 15) + lenalidomide (25 mg orally, D1-10) (arm B). G-CSF and VTE prophylaxis was mandatory. Primary objective is safety;secondary objectives include overall response rate (ORR) and PET-CR rate at end of treatment, progression-free survival, long-term safety, pharmacokinetics and immunogenicity. Results: From Dec 2019 to Aug 2020, 83 patients were screened in nine countries across Europe and the US;66 were randomized (arm A: n=33;arm B, n=33). Data cut-off: 9 Dec 2020;the study is ongoing. Median age was 64.5 years (range 20-86 years). Overall, 30% of patients (20/66) were ≥70 years and many had high-risk disease: IPI 2 28.8%, IPI 3 45.5%, IPI 4 25.8%. ECOG PS: 47.0% of patients were ECOG PS 0, 43.9% PS 1, 9.1% PS 2. Most patients had stage III/IV disease (92%);45.5% had bulky disease. All patients experienced a treatment-emergent adverse event (TEAE);555 events occurred in arm A and 570 in arm B. Grade ≥3 neutropenia was observed in 54.5% (arm A) and 66.7% (arm B) of patients. Grade ≥3 thrombocytopenia was observed in 12.1% (arm A) and 30.3% (arm B) of patients. Six patients in each arm experienced febrile neutropenia. Diarrhea, fatigue and vomiting were comparable between the two arms. Grade ≥3 nervous system disorders were experienced by 6.1% of patients in arm A and 12.1% in arm B (the majority of events were polyneuropathies related to vincristine). Infusion-related reactions to both rituximab and tafasitamab occurred in 12.1% (arm A) and 18.2% (arm B) of patients, and 21.2% (arm A) and 27.3% (arm B) of patients had a grade ≥3 infection and/or infestation (TEAEs by system organ class [SOC] shown in Figure 1). Serious TEAEs occurred in 42.4% (arm A) and 51.5% (arm B) of patients. There were three deaths unrelated to tafasitamab and/or lenalidomide (sepsis, urosepsis and COVID-19 pneumonia). Dose intensity of R-CHOP was maintained in both treatment arms. Among 60 patients who completed tumor assessments after cycle 3, ORR was 89.7% (arm A) and 93.5% (arm B). Summary/Conclusion: These data suggest that R-CHOP + tafasitamab or tafasitamab + lenalidomide is tolerable in patients with treatment- na.ve DLBCL. Dosing and scheduling of R-CHOP is not affected by the addition of tafasitamab. Toxicities are similar to those expected with R-CHOP alone or R-CHOP + lenalidomide. Updated safety and early efficacy data will be presented at the conference.
ABSTRACT
Background: Tafasitamab is a humanized, Fcmodified anti-CD19 monoclonal antibody that enhances antibody-dependent cellular cytotoxicity and phagocytosis. It is FDAapproved with LEN for adult patients (pts) with relapsed/refractory (R/R) DLBCL ineligible for autologous stem cell transplantation. FirstMIND (NCT04134936) is a Phase Ib, open-label, randomized study of tafa + R-CHOP or tafa + LEN + R-CHOP in newly diagnosed DLBCL. Methods: Eligible pts were ≥18 years, treatmentnaïve, with histologically confirmed DLBCL not otherwise specified, international prognostic index (IPI) 2-5 and ECOG performance status (PS) 0-2. Pts with known double-or triple-hit and transformed lymphoma were excluded. Treatment (Tx) comprised six 21-day cycles of tafa (12 mg/kg IV, Day [D] 1, 8, 15) + R-CHOP (arm A) or tafa (12 mg/kg IV, D1, 8, 15) + LEN (25 mg orally, D1-10) + R-CHOP (arm B). G-CSF and VTE prophylaxis was mandatory. Primary objective is safety;secondary objectives are ORR, PET-CR rate at end of Tx, PFS, long-term safety, pharmacokinetics, immunogenicity. Results: From Dec 2019 to Aug 2020, 83 pts were screened in Europe and the US;66 were randomized (33 per arm). Data cut-off for this analysis: 9 Dec 2020;study is ongoing. Median age was 64.5 years (range 20-86). Overall, 30% (20/66) of pts were ≥70 years and many had high-risk disease: IPI 2 29%, IPI 3 46%, IPI 4 26%. ECOG PS: 47% of pts were ECOG PS 0, 44% PS 1, 9% PS 2. Most pts had stage III/IV disease (92%);46% had bulky disease. All pts experienced a treatment-emergent adverse event (TEAE). Grade ≥3 neutropenia and thrombocytopenia occurred in 54.5% and 12.1% (arm A) and 66.7% and 30.3% (arm B) of pts, respectively (Table). Serious TEAEs occurred in 42.4% (arm A) and 51.5% (arm B) of pts. There were three deaths, unrelated to tafa and/or LEN (sepsis, urosepsis, and COVID-19 pneumonia). R-CHOP dose intensity was maintained in both arms. Among 60 pts who completed tumor assessments after cycle 3, ORR was 89.7% (arm A) and 93.5% (arm B). Conclusions: These data suggest R-CHOP + tafa or tafa + LEN is tolerable in pts with Tx-naïve DLBCL and that R-CHOP dosing is not affected. Toxicities are similar to those expected with R-CHOP or R-CHOP + LEN. Updated safety and early efficacy data will be presented at the conference.