Huang, Dan

Purpose: In RE-MIND2 (NCT04697160), patient-level outcomes from the L-MIND study (NCT02399085) of tafasitamab plus lenalidomide were retrospectively compared with patient-level matched observational cohorts treated with National Cancer Care Network (NCCN)/European Society for Medical Oncology (ESMO)-listed systemic therapies for relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Patients and Methods: Data were collected from health records of eligible patients aged ≥18 years with histologically confirmed DLBCL who had received ≥2 systemic therapies for DLBCL (including ≥1 anti-CD20 therapy). Patients from L-MIND were matched with patients from the RE-MIND2 observational cohort using estimated propensity score-based 1:1 nearest-neighbor matching, balanced for nine covariates. The primary analysis compared tafasitamab plus lenalidomide with patients who received any systemic therapy for R/R DLBCL (pooled in one cohort) or bendamustine plus rituximab (BR) or rituximab plus gemcitabine and oxaliplatin (R-GemOx; as two distinct cohorts). The primary endpoint was overall survival (OS). Secondary endpoints included treatment response and time-to-event outcomes. Results: In RE-MIND2, 3,454 patients were enrolled from 200 sites in North America, Europe, and Asia-Pacific. Strictly matched pairs of patients consisted of tafasitamab plus lenalidomide versus systemic therapies pooled (n = 76 pairs), versus BR (n = 75 pairs), and versus R­GemOx (n = 74 pairs). Significantly prolonged OS was reported with tafasitamab plus lenalidomide versus systemic pooled therapies [hazard ratios (HR): 0.55; P = 0.0068], BR (HR: 0.42; P < 0.0001), and R-GemOx (HR: 0.47; P = 0.0003). Conclusions: RE-MIND2, a retrospective observational study, met its primary endpoint, demonstrating prolonged OS with tafasitamab plus lenalidomide versus BR and R-GemOx. See related commentary by Cherng and Westin, p. 3908

Abstract Background Several therapies are recommended by NCCN/ESMO guidelines for autologous stem cell transplant (ASCT)-ineligible patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). In the single-arm, Phase II L-MIND study (NCT02399085), the chemotherapy-free regimen tafasitamab + lenalidomide (LEN) demonstrated efficacy for this patient population. In the absence of randomized clinical trial data, RE-MIND2 (NCT04697160), an observational, retrospective cohort study, compared patient outcomes from L-MIND with matched patient populations treated with NCCN/ESMO recommended therapies for ASCT-ineligible patients with R/R DLBCL. Methods Data were retrospectively collected between 1 April and 13 November 2020 from academic and public hospitals, as well as private practices in North America, Europe and Asia Pacific. To ensure consistency with L-MIND I/E criteria, patients aged ≥18 years with histologically confirmed DLBCL and who had received ≥2 systemic therapies for DLBCL (including ≥1 anti-CD20 therapy) were enrolled. For the main analysis, patients from the L-MIND tafasitamab + LEN cohort were matched with patients from the RE-MIND2 observational cohort using estimated propensity score-based 1:1 nearest neighbor matching, balanced for six baseline characteristics: age (<70 vs ≥70 years), refractoriness to last line of therapy (yes vs no), number of prior lines of therapy (1 vs 2/3), history of primary refractoriness (yes vs no), prior ASCT (yes vs no), and Eastern Cooperative Oncology Group performance status (0-1 vs ≥2). A sensitivity analysis was performed using an inverse probability of treatment weighting method calculating the average effect of the treatment on the treated, to generate balanced cohorts based on nine baseline characteristics: age, refractoriness to last line of therapy, number of previous lines of therapy, history of primary refractoriness, prior ASCT, Ann Arbor Stage (I/II vs III/IV), elevated LDH (yes vs no), neutropenia (yes vs no), and anemia (yes vs no). Additional sensitivity analyses accounting for missing baseline characteristics using multiple imputation technique were performed. Data are presented for tafasitamab + LEN versus polatuzumab vedotin + bendamustine + rituximab (pola-BR), rituximab + LEN (R2), and CD19 CAR-T therapies (CAR-T). The primary endpoint was overall survival (OS). Secondary endpoints included objective response rate (ORR), complete response rate, progression-free survival and duration of response. Results Of 3,454 patients enrolled from 200 sites, 106, 106, and 149 patients were treated with pola-BR, R2, and CAR-T, respectively. For the comparative analysis, matched patient pairs were created using 1:1 nearest neighbor matching with a caliper. Matched pairs consisted of: tafasitamab + LEN vs pola-BR, n=24 pairs; vs R2, n=33 pairs; and vs CAR-T, n=37 pairs. A significant OS benefit was associated with tafasitamab + LEN compared to pola-BR (HR: 0.44, 95% confidence interval [CI]: 0.20-0.96; p=0.038) and R2 (HR=0.44, 95% CI: 0.22-0.84; p=0.014) (Figure 1A-B). There was no significant difference in OS benefit between tafasitamab + LEN and CAR-T (HR=0.95, 95% CI: 0.47-1.91; p=0.891) (Figure 1C). ORR was 62.5% (15/24) for tafasitamab + LEN vs 58.3% (14/24) for pola-BR (p=1.000), 63.6% (21/33) vs 30.3% (10/33) for R2 (p=0.013), and 59.5% (22/37) vs 75.7% (28/37) for CAR-T (p=0.214). Improved outcomes were also observed with tafasitamab + LEN for other secondary endpoints (Table 1). Results are consistent with those obtained in the sensitivity analyses. Conclusions The results of this retrospective cohort analysis suggest that the novel tafasitamab + LEN combination may significantly improve health outcomes, with a prolonged survival benefit for ASCT-ineligible R/R DLBCL patients, relative to NCCN/ESMO recommended therapies. Tafasitamab + LEN improved survival outcomes compared with pola-BR and R2 in closely matched patient populations. Comparable outcomes were observed for tafasitamab + LEN vs CAR-T. Although based on limited patient numbers, these data may be clinically relevant in the context of emerging therapies for R/R DLBCL. While this study design does not replace randomized data, it remains more rigorous than inter-trial comparison. The limitations of comparing clinical trial and matched retrospective real-world data will be discussed. Funding: MorphoSys AG. Figure 1 Figure 1. Disclosures Nowakowski: Celgene, MorphoSys, Genentech, Selvita, Debiopharm Group, Kite/Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene, NanoString Technologies, MorphoSys: Research Funding. Joffe: AstraZeneca. Epizyme: Consultancy. Fleury: Abbvie, Astrazeneca, BMS, Celgene, Janssen, Kite-Gilead, Merck, Novartis, Roche, Seattle Genetics: Other: conference and advisory role. Peters: AbbVie, Incyte: Consultancy, Honoraria. Greil: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Daiichi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Sandoz: Honoraria, Research Funding. Ku: Roche: Consultancy; Antegene: Consultancy; Genor Biopharma: Consultancy. Marks: Kite/Gilead: Membership on an entity's Board of Directors or advisory committees; AbbVie: Other: Meeting attendance; Kite/Gilead: Honoraria; Merck: Consultancy. Kim: AstraZeneca: Research Funding. Zinzani: BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck Sharp & Dohme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ImmuneDesign: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Trotman: Beigene: Research Funding; Celgene: Research Funding; Bristol Myers Squibb: Research Funding; Roche: Research Funding; Janssen: Research Funding; PCYC Pharmacyclics: Research Funding. Sabatelli: Incyte: Current Employment, Current equity holder in publicly-traded company. Huang: MorphoSys: Current Employment. Waltl: MorphoSys: Current Employment. Winderlich: MorphoSys: Current Employment, Current equity holder in publicly-traded company. Ambarkhane: MorphoSys: Current Employment, Other: Support for attending meetings/travel. Kurukulasuriya: MorphoSys: Current Employment, Current equity holder in publicly-traded company, Other: Support for attending meetings/travel. Cordoba: Pfizer: Research Funding; Kyowa-Kirin: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADCTherapeutics: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hess: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead/Kite: Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genmab: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; EUSA: Honoraria, Membership on an entity's Board of Directors or advisory committees. Salles: Miltneiy: Consultancy; Novartis: Consultancy; Morphosys: Consultancy, Honoraria; Janssen: Consultancy; Genentech/Roche: Consultancy; Kite/Gilead: Consultancy; Regeneron: Consultancy, Honoraria; Velosbio: Consultancy; Takeda: Consultancy; Allogene: Consultancy; Ipsen: Consultancy; Loxo: Consultancy; Rapt: Consultancy; Genmab: Consultancy; Incyte: Consultancy; Epizyme: Consultancy, Honoraria; Debiopharm: Consultancy; BMS/Celgene: Consultancy; Beigene: Consultancy; Abbvie: Consultancy, Honoraria; Bayer: Honoraria.

Background L-MIND (NCT02399085) is an ongoing, open-label, single-arm, Phase II study of tafasitamab + lenalidomide (LEN) in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) who are ineligible for autologous stem cell transplant. Progression-free survival (PFS) estimates the treatment effect of the study drug only, while overall survival (OS) also includes effects of potential subsequent cancer treatments or palliative care. Given that not all OS and PFS events have occurred after a long follow-up duration, traditional survival analyses may underestimate survival benefit for tafasitamab + LEN by assuming the same mortality rate for the whole population. We used mixture cure models to estimate the proportion of long-term survivors (LTS) and survival benefit associated with tafasitamab + LEN treatment. Methods In the L-MIND study (data cut-off: Nov 30, 2019), 80/81 enrolled patients with R/R DLBCL received tafasitamab + LEN, with a median and maximum follow-up duration of 31.8 months (95% CI: 27.2-35.9) and 43.5 months, respectively. The Kaplan-Meier (KM) plots of PFS and OS were observed to plateau after 30 months, with the majority of events reported up to that time-point and very few events beyond this time-point. Patients without a PFS event or patients who did not decease after the observed plateau exhibit a high survival benefit from tafasitamab + LEN treatment and are considered LTS. Thus, the patient population can be considered to consist of two sub-populations - LTS and non-LTS. A "mixture cure model" was fitted on the PFS and OS data to estimate the proportion of LTS and associated mean survival for the two sub-populations (Lambert PC, et al. 2007). To incorporate background mortality (Bansal, et al. 2019), age- and sex-specific US mortality rates (US CDC 2017) were factored in for the entire study population (enrolled in Europe and US). The weighted average of the mean survival for the two sub-populations provided an estimate of the mean survival for the whole population. For comparative purposes, standard parametric models without considering an LTS proportion were fitted on PFS and OS data additionally. Sensitivity analyses were performed considering different survival distributions (exponential distribution, Weibull distribution and log-logistic distribution). Results By using a mixture cure model fitted to PFS and OS data separately, the estimated proportion of LTS for the tafasitamab + LEN combination was 42% (95% CI: 30-55) and 47% (95% CI: 29-66), respectively. The predicted mean survival when mixture cure model was fitted on PFS data was 16.7 years for LTS patients vs 0.5 years for non-LTS patients, yielding 7.3 years for the overall population. Under this mixture cure model, the survival rates of patients with tafasitamab + LEN treatment were 40.2% and 36.0% at 2 and 5 years. Similar results were obtained when the mixture cure model was fitted on OS data. Using a standard parametric model (Weibull distribution), the predicted mean survival in the overall population was 2.8 years fitting PFS data (Figure 1) and 4.5 years fitting OS data (Figure 2). Conclusions PFS and OS KM curves for the L-MIND study reaching a long plateau and not following a Weibull distribution suggest the presence of an LTS subgroup. Standard parametric models may lead to a biased estimation of the OS benefit in such situations. The mixture cure model suggests that the treatment of R/R DLBCL patients with tafasitamab + LEN is associated with a high LTS proportion. The survival rates of patients with tafasitamab + LEN treatment were 40.2% and 36.0% at 2 and 5 years. Disclosures Salles: Takeda:Honoraria;BMS/Celgene:Honoraria, Other: consultancy or advisory role;Debiopharm:Consultancy, Honoraria, Other: consultancy or advisory role;Genmab:Honoraria, Other;Karyopharm:Honoraria;Kite, a Gilead Company:Honoraria, Other: consultancy or advisory role ;Epizyme:Honoraria, Other: consultancy or advisory role;Janssen:Honoraria, Other: consultancy or advisory role;Abbvie:Other: consultancy or advisory role;Roche:Honoraria, Other: consultancy or advisory role;Novartis:Honoraria, Other: consultancy or advisory role;MorphoSys:Honoraria, Other: consultancy or advisory role;Autolos:Other: consultancy or advisory role.Goswami:MorphoSys AG:Ended employment in the past 24 months.Bagnardi:MorphoSys AG:Consultancy.Dey:MorphoSys AG:Current Employment.Winderlich:MorphoSys AG:Current Employment.Ambarkhane:MorphoSys AG:Current Employment.Huang:MorphoSys AG:Current Employment.Nowakowski:Curis:Consultancy;Kymera:Consultancy;Kite:Consultancy;Ryvu:Consultancy, Membership on an entity's Board of Directors or advisory committees;Celgene/BMS:Consultancy, Research Funding;Seattle Genetics:Consultancy;MorphoSys:Consultancy, Research Funding;NanoString:Research Funding.