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J. Duell et al.
were no unexpected toxicities. Subgroup analyses revealed consistent long-term efficacy results across most subgroups of patients. This extended follow-up of L-MIND confirms the long duration of response, meaningful overall survival, and well-defined safety profile of tafasitamab plus lenalidomide followed by tafasitamab monotherapy in patients with relapsed/refractory diffuse large B-cell lymphoma ineligible for autologous stem cell transplantation. ClinicalTrials.gov identifier: NCT02399085.
Introduction
Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma, account- ing for 25-45% of new cases of lymphoma each year.1 The introduction of rituximab treatment, an anti-CD20 antibody, alongside cyclophosphamide, doxorubicin, prednisone, and vincristine (R-CHOP) as an initial stan- dard-of-care immunotherapy has improved patients’ out- comes; however, 30–40% of patients continue to experi- ence relapse or are refractory to this first-line therapy.2 For these relapsed or refractory (R/R) patients, alternative effective and tolerable treatment options are limited and, thus, their prognosis is poor.2
Current treatment options for R/R DLBCL include sal- vage chemotherapy followed by high-dose chemothera- py and autologous stem-cell transplantation (ASCT).3,4 However, the majority of patients with R/R DLBCL who undergo ASCT subsequently relapse.2 More recently- developed therapies, such as chimeric antigen receptor (CAR) T-cell therapy and the antibody-drug conjugate polatuzumab vedotin in combination with bendamustine and rituximab, have shown improved patients’ outcomes.5-7 However, CAR T-cell therapies have been associated with severe adverse events, including grade ≥3 cytokine release syndrome and neurotoxicity, and some can be difficult to administer safely and successfully.5,6 Thus, there remains an urgent need for novel, tolerable, and easy-to-administer treatment options for patients with R/R DLBCL, particularly those ineligible for ASCT.
The combination of tafasitamab (MOR208, previously XmAb5574), an Fc-modified, humanized anti-CD19 monoclonal antibody, with lenalidomide has been shown to be effective and well-tolerated in patients with R/R DLBCL who are ineligible for ASCT.8 The phase II study, L-MIND, demonstrated an objective response rate of 60%, with 43% of patients achieving a complete response (CR).8 Moreover, the responses were durable, with a median duration of response (DoR) of 21.7 months.8 To further determine the long-term clinical effi- cacy and safety of tafasitamab plus lenalidomide treat- ment in patients with R/R DLBCL, we provide updated data based on a minimum follow-up of 35 months. Additionally, to understand the effectiveness of this novel treatment regimen in clinically relevant subgroups of patients, we present long-term efficacy analyses stratified according to important baseline covariates of prognostic significance.
Methods
Study conduct
L-MIND was an open-label, single-arm, multicenter, phase II study (NCT02399085).8 The study was approved by the institu- tional review boards at each study site, and conducted in accor- dance with International Council for Harmonization Good
Clinical Practice guidelines and the Declaration of Helsinki; all patients provided written informed consent. We present data after 35 months of follow-up from the last patient enrolled.
Study design and patients
Details of the L-MIND study have been published elsewhere; eligibility criteria are further described in the Online Supplementary Methods.8 Patients with primary refractory disease were excluded, although until a protocol amendment in June 2016, primary refractoriness was defined as no response or pro- gressive disease (PD) within <3 months of frontline therapy, rather than 6 months. Therefore, prior to this amendment patients with relapse or PD 3-6 months from frontline therapy were included, and form a subgroup of ‘primary refractory patients’ as per B-cell lymphoma National Comprehensive Cancer Network guidelines.3 Patients with rituximab-refractory disease had no response to or PD following a rituximab-contain- ing regimen within <6 months of completion of therapy.
Patients received up to 12 cycles (28 days each) of tafasitamab and lenalidomide, followed by tafasitamab monotherapy in patients with stable disease or better, until PD. Tafasitamab (12 mg/kg intravenously) was administered on days 1, 8, 15, and 22 during cycles 1-3, with a loading dose on day 4 of cycle 1, and on days 1 and 15 from cycle 4 onwards. Lenalidomide (25 mg orally) was self-administered on days 1-21 of each 28-day cycle. For further details see the Online Supplementary Methods.
Study outcomes
The primary endpoint was the objective response rate (CR plus partial response [PR]), assessed by an independent review committee (IRC), according to the 2007 International Working Group response criteria for malignant lymphoma.9 Secondary endpoints included DoR (time from initial CR or PR to first observation of PD), progression-free survival (PFS; time from first dosing to lymphoma progression or death), overall survival (OS; time from first dosing to date of death), and incidence and severity of adverse events. Exploratory subgroup analyses were performed to evaluate DoR, PFS, and OS by refractoriness to prior treatment, as well as age, gender, International Prognostic Index (IPI) score, prior ASCT, and number of prior treatment lines. Rituximab refractoriness was defined as a response less than PR to any rituximab-containing regimen during the course of treatment or PD within ≤6 months of treatment completion. Refractoriness to last prior treatment and primary refractoriness were defined as a best response less than PR to the most recent therapy or to first-line treatment, respectively, or PD before or ≤6 months after completion of that treatment.
Statistical analyses
The previously published primary analysis for the L-MIND study (data cut-off: November 30, 2018)8 was carried out when all patients had completed a minimum of 12 months’ follow-up. The data cut-off date for the present analyses was October 30, 2020. The full analysis set comprised patients who received both tafasitamab and lenalidomide and was used to analyze efficacy outcomes. The safety analysis set comprised patients who received any study medication.
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haematologica | 2021; 106(9)