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Novel treatment strategies have shifted the treatment landscape for patients with diffuse large B-cell lymphoma, particularly for those with relapsed/refractory disease. However, uncertainty remains regarding the therapeutic value of these novel agents compared to existing salvage chemotherapy regimens. In addition, the high cost associated with these agents puts both patients and health systems at risk of financial toxicity, further complicating their use. The development of clinical pathways incorporating oncology stewardship principles are necessary in order to maximize value-based care. This comprehensive review assesses the efficacy and safety data available for novel treatment options in relapsed/refractory diffuse large B-cell lymphoma and applies stewardship principles to evaluate their optimal place in therapy, with the aim of optimizing safe, effective, and financially responsible patient care.

Summary Background Activating mutations of EZH2, an epigenetic regulator, are present in approximately 20% of patients with follicular lymphoma. We investigated the activity and safety of tazemetostat, a first-in-class, oral EZH2 inhibitor, in patients with follicular lymphoma. Methods This study was an open-label, single-arm, phase 2 trial done at 38 clinics or hospitals in France, the UK, Australia, Canada, Poland, Italy, Ukraine, Germany, and the USA. Eligible patients were adults (≥18 years) with histologically confirmed follicular lymphoma (grade 1, 2, 3a, or 3b) that had relapsed or was refractory to two or more systemic therapies, had an Eastern Cooperative Oncology Group performance status of 0–2, and had sufficient tumour tissue for central testing of EZH2 mutation status. Patients were categorised by EZH2 status: mutant (EZH2mut) or wild-type (EZH2WT). Patients received 800 mg of tazemetostat orally twice per day in continuous 28-day cycles. The primary endpoint was objective response rate based on the 2007 International Working Group criteria for non-Hodgkin lymphoma, assessed by an independent radiology committee. Activity and safety analyses were done in patients who received one dose or more of tazemetostat. This study is registered with ClinicalTrials.gov , NCT01897571 , and follow-up is ongoing. Findings Between July 9, 2015, and May 24, 2019, 99 patients (45 in the EZH2mut cohort and 54 in the EZH2WT cohort) were enrolled in the study. At data cutoff for the analysis (Aug 9, 2019), the median follow-up was 22·0 months (IQR 12·0–26·7) for the EZH2mut cohort and 35·9 months (24·9–40·5) for the EZH2WT cohort. The objective response rate was 69% (95% CI 53–82; 31 of 45 patients) in the EZH2mut cohort and 35% (23–49; 19 of 54 patients) in the EZH2WT cohort. Median duration of response was 10·9 months (95% CI 7·2–not estimable [NE]) in the EZH2mut cohort and 13·0 months (5·6–NE) in the EZH2WT cohort; median progression-free survival was 13·8 months (10·7–22·0) and 11·1 months (3·7–14·6). Among all 99 patients, treatment-related grade 3 or worse adverse events included thrombocytopenia (three [3%]), neutropenia (three [3%]), and anaemia (two [2%]). Serious treatment-related adverse events were reported in four (4%) of 99 patients. There were no treatment-related deaths. Interpretation Tazemetostat monotherapy showed clinically meaningful, durable responses and was generally well tolerated in heavily pretreated patients with relapsed or refractory follicular lymphoma. Tazemetostat is a novel treatment for patients with follicular lymphoma. Funding Epizyme.

Context: Treatment options that are more tolerable, readily available, and capable of inducing deep and durable responses are needed in patients with relapsed or refractory (R/R) large B-cell lymphoma (LBCL). Epcoritamab is a novel, subcutaneous (SC) CD3xCD20 bispecific antibody with preliminary potent antitumor activity. Objective: Report primary results from the LBCL expansion cohort in the phase 2 study of SC epcoritamab in patients with R/R B-cell NHL (EPCORE NHL-1; NCT03625037). Patients: Adults with R/R CD20+ LBCL were included. Patients had DLBCL (including double/triple-hit and transformed), high-grade B-cell lymphoma (HGBCL), primary mediastinal LBCL (PMBCL), or follicular lymphoma (FL) grade (G) 3B. As of January 31, 2022, 157 patients were treated. Interventions: Patients received epcoritamab (priming and intermediate doses followed by 48 mg) as 1-mL SC injections (QW, cycle [C] 1–3; Q2W, C4–9; Q4W, C≥10) until disease progression or unacceptable toxicity. Results: The 157 patients had a median of 3 (range, 2–11) prior lines of therapy (LOT), 61 (38.9%) received prior CAR T, 61% had primary refractory disease, and 83% were refractory to the last LOT. With a median follow-up of 10.7 mo, the overall response rate (ORR) by IRC (Lugano/PET-CT) was 63% with 39% complete response (CR). ORR/CR rates were 69%/42% for CAR T–naive patients and 54%/34% for CAR T–exposed patients. Median duration of response was 12 mo overall and not reached among complete responders. ORR was similar across prespecified subgroups of age, prior LOT, and de novo or transformed disease. The most common treatment-emergent AEs were CRS (49.7%; 31.8% G1, 15.3% G2, 2.5% G3), pyrexia (23.6%), fatigue (22.9%), neutropenia (21.7%), and diarrhea (20.4%). Ten patients (6.4%) experienced ICANS; all but one event was G1–2, and the G5 ICANS was the only treatment-related death. Conclusions: Epcoritamab is a convenient, SC, off-the-shelf therapy that demonstrated clinically meaningful, compelling efficacy including deep and durable responses in a challenging-to-treat, highly refractory LBCL population. Efficacy was observed in both CAR T–exposed and CAR T–naive patients. The safety profile was manageable and consistent with previous findings. Funding: This study was funded by Genmab A/S and AbbVie.

Background: Single-agent polatuzumab vedotin (pola) and obinutuzumab (G) demonstrated safety/clinical activity in separate B-cell non-Hodgkin lymphoma (B-NHL) trials. Methods: Open-label, non-randomised, phase 1b/2 study (ROMULUS) of patients with relapsed/refractory (R/R) B-NHL evaluating safety/efficacy of pola 1·8 mg/kg + G 1000 mg in 21-day cycles, up to eight cycles. Primary objectives were safety/tolerability and anti-tumour response. Findings: Eighty-eight patients were enrolled and received ≥1 dose of any study drug; 43 patients with R/R follicular lymphoma (FL) and 45 with R/R diffuse large B-cell lymphoma (DLBCL). Grade 3–4 AEs occurred in 48·5% (n=48/88) of patients, most commonly, neutropenia (18·6%; n=18). In R/R FL, the most frequent any-grade adverse event (AE) was fatigue (n=23/43; 53·5%) and in R/R DLBCL diarrhoea (n=16/45; 35·6%). In R/R FL, the complete response (CR) rate (by independent review committee) was 36·1% (n=13/36; 90% confidence interval [CI]: 22·9–51·2) with an objective response rate (ORR) of 66·7% (n=24/36; 90% CI: 51·7–79·5). The ORR in R/R DLBCL was 19·4% (n=6/31; 90% CI: 8·8–34·7; no CRs). In R/R FL, investigator-assessed median duration of response was 8·5 months (interquartile range [IQR]: 6×3–9×7) and in R/R DLBCL was 3·7 months (IQR: 3×3–not estimable [NE]); median progression-free survival was 11·5 months (IQR: 7×8-12×4) and 2·8 months (IQR: 1×5-6×3); and median overall survival was not reached and 10·7 months, respectively. Interpretation: While the anti-tumour activity of pola (1.8 mg/kg)-G in R/R DLBCL was modest, pola-G warrants further investigation as a treatment for R/R FL. Trial Registration: www.clinicaltrials.gov (NCT01691898). Funding Statement: F. Hoffmann-La Roche. Declaration of Interests: T.P. has received research support from AbbVie and Pharmacyclics, and reports advisory board participation for Genentech, Inc., Bayer, Gilead, Pharmacyclics, Incyte, and Seattle Genetics. M.B. has no disclosures; the clinical and intellectual work on this paper was performed prior to employment with the Cigna Corporation and does not reflect the opinions or support of the Cigna Corporation. A.I.C. has acted as a consultant and has received research funding from Genentech, Inc. J.E. has nothing to disclose. A.C. reports advisory board participation for Celgene, Janssen, and iQone, and has received lecture fees from Celgene, Janssen, F. Hoffman-La Roche Ltd, and Servier. C.D. has served as a consultant/advisory board participant for Bristol-Myers Squibb, Celgene, Merck, Genentech, Inc./F. Hoffman-La Roche Ltd, and Seattle Genetics, and has received research support from Seattle Genetics, Bristol-Myers Squibb, Merck, Genentech, Inc., Incyte, LAM Therapeutics, Millennium/Takeda, MEI Pharma, and Trillium. J.C. is an employee of F. Hoffmann-La Roche Ltd. D.R. was a consultant to Genentech, Inc. at the time the study was carried out. J.H. is an employee of Genentech, Inc. F.M. has participated in advisory boards for Celgene, F. Hoffman-La Roche Ltd, Gilead, Bristol-Myers Squibb, Epizyme, and Bayer, and reports receiving lecture fees from Celgene, Janssen, F. Hoffman-La Roche Ltd, and Novartis, and research support from AbbVie, Pharmacyclics, and advisory board fees from Genentech, Inc., Bayer, Gilead, Pharmacyclics, Incyte, and Seattle Genetics. I.W.F. has acted as a consultant for AbbVie, Seattle Genetics, TG Therapeutics, and Verastem Oncology, and has received research funding from Acerta Pharma, Agios, Calithera Biosciences, Celgene, Constellation Pharmaceuticals, Genentech, Inc., Gilead Sciences, Incyte, Infinity Pharmaceuticals, Janssen, Karo Pharma, Kite Pharma, Novartis, Pharmacyclics, Portola Pharmaceuticals, F. Hoffman-La Roche Ltd, TG Therapeutics, Trillium Therapeutics, AbbVie, ArQule, BeiGene, Curis Inc., FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem Oncology, Gilead Sciences, Astra Zeneca, Juno Therapeutics, Unum Therapeutics, and MorphoSys AG. Ethics Approval Statement: Institutional review boards/ethics committees approved the protocol. The study was conducted in accordance with the principles of the Declaration of Helsinki, the International Council for Harmonisation guidelines for Good Clinical Practice, and country-specific laws and regulations. All patients provided written informed consent.

Context The treatment of relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) remains an area of unmet need. Combination therapies may improve treatment outcomes. Objectives Primary objective of a Phase 1/2 study (NCT03684694; Phase 1 part): Characterize the safety and tolerability of Lonca (an antibody-drug conjugate comprising a humanized anti-CD19 monoclonal antibody conjugated to a pyrrolobenzodiazepine dimer toxin) plus ibrutinib (a Bruton’s tyrosine kinase inhibitor) and identify the maximum tolerated dose (MTD) or the recommended Phase 2 dose and schedule. Secondary objective: Evaluate antitumor effects. Design Dose escalation and dose expansion, open-label, single-arm, combination study in patients (≥18 years) with R/R DLBCL or R/R MCL. Interventions MTD was determined during dose escalation as Lonca 60 µg/kg IV every 3 weeks (Q3W) for 2 cycles and oral ibrutinib 560 mg/day PO for up to 1 year. After disease assessment at Week 14, patients with partial response/stable disease may receive 2 additional Lonca cycles Q4W at Cycles 5–6. Results At data cut-off (January 4, 2021), 30 patients with DLBCL (non-germinal center B-cell [non-GCB] DLBCL 24; GCB DLBCL 6) and 7 with MCL received the MTD during Phase 1. Median patient age: 72 years (range 40–91); 28 (75.7%) had Stage 4 disease. Patients received a median of 2 (range 1–6) prior therapies. Patients received a median of 2 Lonca cycles (range 1–4) and 4 (range 1–14) ibrutinib cycles. Median treatment duration: 105 days (range 18–379). Treatment-emergent adverse events (TEAEs) occurred in 37/37 (100%) patients. Grade ≥3 TEAEs occurred in 24/37 (64.9%) patients; the most common (≥5%) were anemia (4 [10.8%]), neutropenia (4 [10.8%]), thrombocytopenia (2 [5.4%]), and fatigue (2 [5.4%]). TEAEs leading to treatment discontinuation occurred in 3 (8.1%) patients. Overall response rate (ORR; 36 evaluable patients) was 63.9% (complete response 36.1%; partial response 27.8%). ORR for non-GCB DLBCL, GCB DLBCL, all DLBCL, and MCL patients was 66.7%, 20.0%, 58.6%, and 85.7%, respectively. Conclusions Results indicate that Lonca 60 µg/kg plus ibrutinib 560 mg has encouraging antitumor activity with manageable toxicity in R/R DLBCL and R/R MCL. Research Funding ADC Therapeutics SA

Background Umbralisib is an oral, once-daily inhibitor of PI3Kδ and CK1e that is highly selective for the delta isoform. The UNITY-NHL trial (NCT02793583) is a multicenter, open-label, Phase 2b study evaluating umbralisib in previously treated NHL patients. Herein, we present results from the UNITY-NHL study. Methods 208 patients with R/R marginal zone, follicular, or small lymphocytic lymphoma (MZL, FL, SLL) unresponsive to prior treatments (≥1 MZL; ≥2 FL/SLL), including ≥1 anti-CD20–based therapy, were administered umbralisib 800mg orally once-daily until disease progression, unacceptable toxicity, or study withdrawal. The primary endpoint of the study was overall response rate (ORR) as assessed by an independent review committee, according to the revised IWG criteria. Results At a median follow up of 27.8 months, MZL patients (n=69) had an ORR of 49.3% (95% CI 37.0% - 61.6%) with 15.9% achieving a complete response (CR), and a Disease Control Rate (DCR: CR+PR+SD) of 82.6%. Median time-to-response (TTR): 2.8 months (95% CI 2.7 - 2.9). No patient who achieved CR has progressed to date. At a median follow up of 27.5 months, FL patients (n=117) had an ORR of 45.3% (95% CI 36.1% - 54.8%) with 5.1% achieving a CR, and a DCR of 79.5%. Median TTR: 4.6 months (95% CI 3.0 - 5.6). At a median follow up of 29.3 months, SLL patients (n=22) had an ORR of 50.0% (95% CI 28.2 - 71.8) with 4.5% achieving a CR, and a DCR of 86.4%. Median TTR: 2.7 months (95% CI 2.4 - 2.8). At least one grade ≥3 treatment-emergent adverse event (TEAE) was reported in 53.4% of patients. TEAEs led to umbralisib discontinuation in 32 patients (15.4%). Grade ≥3 TEAEs reported in ≥10% of patients: neutropenia (11.5%) and diarrhea (10.1%). Increased ALT/AST (grade ≥3) occurred in 6.7%/7.2% of patients. Conclusions Umbralisib achieved meaningful clinical activity in a heavily pretreated iNHL population. The safety profile was manageable, with a relatively low incidence of immune-mediated toxicities and AE-related discontinuations. These results suggest umbralisib has a favorable benefit-risk profile in this patient population and have supported the Accelerated Approval of umbralisib in previously treated MZL and FL patients.

Although outcomes after first-line therapy for patients with indolent or aggressive non-Hodgkin lymphoma (NHL) are continually improving, relapse is still common. Current treatment options for patients with relapsed or refractory disease have limited efficacy, and various targeted therapies are under investigation to help improve outcomes in this patient population. The phosphatidylinositol 3-kinase (PI3K) pathway was identified as being involved in hematologic malignancies, leading to significant research for potential therapeutic agents. This has led to 3 PI3K inhibitors (idelalisib, copanlisib, and duvelisib) being approved for the treatment of patients with relapsed or refractory follicular lymphoma who have received at least 2 prior systemic therapies, with reported response rates of 40% to 59%. With potential class-specific and PI3K isoform-related toxicities that may limit clinical utility, the safety of the approved PI3K inhibitors has been carefully evaluated to weigh the risk/benefit ratio of therapy. Currently, there are no approved PI3K inhibitors for patients with aggressive NHL. A number of newer PI3K inhibitors are in clinical development for the treatment of relapsed or refractory NHL, aiming to improve treatment benefit for patients. We discuss a number of attributes that are important to increase the therapeutic potential of newer PI3K inhibitors. More promising results may come from combination trials with these newer PI3K inhibitors, developed to limit toxicities (including long-term adverse events), and other antitumor agents.

Successful treatment of relapsed/refractory and rare subtypes of lymphomas remains a therapeutic challenge. Though the use of tumor profiling is increasing, little is described about how providers ...