Tafasitamab/Lenalidomide Plus R-CHOP Found to be Tolerable, Active in Untreated DLBCL

Pipeline Report | <b>Pipeline Report: December 2021</b>

The addition of tafasitamab and lenalidomide to rituximab, cyclophosphamide, doxorubicin, and prednisone demonstrated increased but generally comparable adverse effects and higher, prolonged, and deeper responses vs the combination of tafasitamab and R-CHOP alone in patients with previously untreated diffuse large B-cell lymphoma.

The addition of tafasitamab-cxix (Monjuvi) and lenalidomide (Revlimid) to rituximab (Rituxan), cyclophosphamide, doxorubicin, and prednisone (R-CHOP) demonstrated increased but generally comparable adverse effects (AEs) and higher, prolonged, and deeper responses vs the combination of tafasitamab and R-CHOP alone in patients with previously untreated diffuse large B-cell lymphoma (DLBCL), according to findings from the primary analysis of the phase 1b First-MIND trial (NCT04134936) that were presented at the 2021 ASH Annual Meeting and Exposition.

Regarding safety, all patients experienced at least 1 treatment-emergent AE (TEAE), the most common of which included blood and lymphatic system disorders in the tafasitamab/R-CHOP (84.8%) and tafasitamab/lenalidomide/R-CHOP (93.9%) arms. Additionally, grade 3 or greater events were higher in the tafasitamab/lenalidomide/R-CHOP arm.

Regarding efficacy, the objective response rate (ORR) at the end of treatment was 76% (n = 25) with tafasitamab/R-CHOP vs 82% (n = 27) with tafasitamab/lenalidomide/R-CHOP. The best ORR was 90.9% (complete response [CR], n = 29; partial response [PR], n = 1) vs 93.9% (CR, n = 25; PR, n = 6), respectively.

“These data suggest that R-CHOP plus tafasitamab plus lenalidomide is tolerable, and that the addition of tafasitamab plus lenalidomide does not impair dosing and scheduling of R-CHOP, as indicated by the consistent median average relative dose intensity of R-CHOP in both arms,” lead study author David Belada, PhD, medical faculty in the Department of Haematology at Charles University in Hradec Kralove, Czech Republic, and coauthors wrote in the poster.

The frontline standard of care for patients with previously untreated DLBCL has been 6 cycles of R-CHOP. However, 15% to 20% of patients with untreated DLBCL have low CD20 expression, which has been associated with poor response to rituximab-based treatments.

CD19 is another widely expressed target across B-cell malignancies and approximately 90% of DLBCL, making tafasitamab, a humanized Fc-modified, CD19-directed monoclonal antibody, an attractive treatment strategy.

In July 2020, the combination of tafasitamab and lenalidomide received accelerated approval from the FDA for the treatment of patients with relapsed/refractory DLBCL who are ineligible for autologous stem cell transplant.

The open-label, randomized First-MIND trial enrolled patients at least 18 years of age with newly diagnosed, histologically confirmed DLBCL not otherwise specified with an International Prognostic Index (IPI) between 2 and 5, an ECOG performance status between 0 and 2, and R-CHOP eligible disease.

Patients were excluded if they had known double- or triple-hit lymphoma, transformed non-Hodgkin lymphoma, evidence of composite lymphoma, history of radiation therapy to at least 25% of the bone marrow for other diseases, history of anthracycline therapy, known central nervous system involvement, or active hepatitis B or C infection.

Patients were randomized to 12 mg/kg of intravenous (IV) tafasitamab on days 1, 8, and 15 plus R-CHOP on days 1 through 5 for 6, 21-day cycles (n = 33; Arm A), or 12 mg/kg of IV tafasitamab on days 1, 8, 15 plus 25 mg of oral lenalidomide on days 1 through 10 and R-CHOP on days 1 through 5 for 6, 21-day cycles (n = 33).

Granulocyte-colony stimulating factor prophylaxis was mandated in both arms, and venous thromboembolism prophylaxis was mandated only in Arm B.

The primary end point was the incidence and severity of TEAEs; key secondary end points included the ORR at the end of treatment. Additional end points included duration of response (DOR) and duration of CR.

From December 2019 to August 2020, 83 patients across 54 sites in Europe and the United States were enrolled. A total of 17 patients were excluded and 66 were randomized, all of whom were included in the efficacy analysis.

In the tafasitamab/R-CHOP and tafasitamab/lenalidomide/R-CHOP arms, respectively, 28 vs 29 patients completed treatment and are in continued follow-up.

Baseline characteristics were balanced between the treatment arms, and the median age was 64.5 years (range, 20-86).

Overall, 65% (n = 43/66) of patients were over the age of 60 years, and many patients had high-risk disease; 36% of patients had an IPI of 2 and 64% had an IPI of at least 3. Moreover, 47% of patients had an ECOG performance status of 0, 44% had an ECOG performance status of 1, and 9% had an ECOG performance status of 2.

Ninety-four percent of patients had stage III/IV disease and 44% had bulky disease.

Additional findings showed that the time course of median absolute platelet count and median neutrophil count were similar in both treatment arms.

Although a higher incidence of grade 3 or greater neutropenia and thrombocytopenia was reported in the tafasitamab/lenalidomide/R-CHOP arm, the frequency of febrile neutropenia was similar in both arms at 18.2%.

The most common non-hematologic TEAEs across arms were diarrhea (all-grade, 30.3%; grade ≥3, 4.5%), nausea (all-grade, 28.8%; all grade ≤2), and vomiting (all-grade, 22.7%; grade ≥3, 1.5%).

Serious TEAEs occurred in 42.4% of patients on tafasitamab/R- CHOP vs 51.5% of patients on tafasitamab/lenalidomide/R-CHOP.

“Toxicities were similar to those expected with R-CHOP, with or without lenalidomide,” wrote Belada and coauthors.

Four deaths were reported, none of which were related to tafasitamab and/or lenalidomide; 2 deaths were reported in Arm A from sepsis and urosepsis, and 2 deaths were reported in Arm B from COVID-19 and pneumonia.

Double the number of patients in Arm A discontinued treatment vs those in Arm B because of TEAEs, at 6.1% vs 3%, respectively.

Regarding dosing, 84.8% (n = 28/330) of patients in Arm A and 90.9% (n = 30/33) of patients in Arm B completed 6 cycles of R-CHOP. The average relative dose intensity of R-CHOP was unaffected during all 6 cycles of treatment, with a median average relative dose intensity of 100% in both arms.

A total of 45.5% (n = 15) of patients skipped at least 1 dose of lenalidomide in Arm B, and some patients in each cycle experienced treatment delays; the most common reason for delay was a neutrophil count under 1000/mm3.

Additional efficacy data showed that the 6-month DOR rate was 82.6% in Arm A vs 86.2% in Arm B. The 6-month duration of CR rates were 83.6% vs 95.2%, respectively.

“With tumor follow-up still ongoing, the ORR at the end of treatment suggests that patients with treatment-naïve DLBCL may achieve clinically meaningful efficacy with tafasitamab and lenalidomide, in addition to standard treatment,” concluded Belada.

The ongoing phase 3, multicenter, randomized, double-blind, placebo-controlled frontMIND trial (NCT04824092) is evaluating the efficacy and safety of R-CHOP plus tafasitamab and lenalidomide vs R-CHOP alone in patients with newly diagnosed, high-intermediate and high-risk DLBCL.

Reference

Belada D, Kopeckova K, Burgues JMB, et al. First-MIND: primary analysis from a phase Ib, open-label, randomized study to assess safety of tafasitamab or tafasitamab + lenalidomide in addition to R‑CHOP in patients with newly diagnosed diffuse large B-cell lymphoma. Presented at: 2021 ASH Annual Meeting; December 9-14, 2021; Atlanta, GA. Abstract 3556.