Clinical Advances in Hematology & Oncology

February 2025 - Volume 23, Issue 1, Supplement 3

Highlights in Large B-Cell Lymphoma and Follicular Lymphoma From the 66th ASH Annual Meeting and Exposition

Expert Commentary by:
Grzegorz S. Nowakowski, MD
Professor of Medicine and Oncology
Enterprise Chair, Lymphoid Malignancy Group
Enterprise Deputy Director, Mayo Clinic Comprehensive Cancer Center for Clinical Research
Mayo Clinic
Rochester, Minnesota

A Review of Selected Presentations From ASH 2024
December 7-10, 2024   •   San Diego, California

Golcadomide + R-CHOP Has High MRD Negativity Across High-Risk, Untreated a-BCL

Golcadomide is an investigational cereblon E3 ligase modulator (CELMoD) that binds to cereblon to induce targeted degradation of Ikaros/Aiolos, 2 transcription factors involved in the development of B-cell malignancy.1,2 Degradation of Ikaros and Ailos by golcadomide induces direct antitumor activity and exerts immunomodulatory activity.

The open-label, phase 1b, dose escalation and expansion trial CC-220-DLBCL-001 is evaluating the safety and activity of golcadomide added to first-line rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with aggressive B-cell lymphoma (a-BCL). As reported previously, golcadomide plus R-CHOP demonstrated preliminary activity in patients with high-risk disease, with a 1-year progression-free survival (PFS) rate of 86% and high rates of minimal residual disease (MRD) negativity.3 At ASH 2024, Jason R. Westin, MD, and colleagues presented an updated analysis from the CC-220-DLBCL-001 trial evaluating the circulating tumor DNA (ctDNA) kinetics of golcadomide plus R-CHOP in different patient subgroups and the association between MRD and clinical outcomes (Figure 1).4

The study enrolled patients with previously untreated a-BCL with a measurable lesion of 1.5 cm or greater. Patients had an International Prognostic Index (IPI) score of 0 to 5 in part 1 (dose escalation) or 2 to 5 in part 2 (dose expansion). Patients in the dose escalation group received golcadomide at increasing dose levels on days 1 through 7 or days 1 through 10 plus R-CHOP-21 (R-CHOP in 21-day cycles). Patients in the dose expansion group were randomly assigned to golcadomide at 0.2 mg (n=35) or 0.4 mg (n=37) on days 1 through 7 plus R-CHOP-21. Treatment was continued for 6 cycles. Most patients (83%) had high-risk disease, defined as an IPI score of 3 to 5 or IPI score of 1 or 2 with at least 1 lesion with a maximum diameter of 7 cm or greater and/or a screening lactate dehydrogenase of at least 13 × upper limit of normal. Molecular high risk was defined as a high baseline ctDNA (≥102.5 hGE/mL) or genomically defined patient populations with poor outcomes. 

After a median follow-up of 14.3 months, golcadomide 0.4 mg plus R-CHOP was associated with complete metabolic responses regardless of the cell of origin that were detected early in treatment. The median duration of response (DOR) was not reached overall (n=37) or in high-risk patients (n=31). The 12-month PFS rate was 85% overall and 86% in high-risk patients, and the 12-month overall survival (OS) rate was 91% and 93%, respectively. 

MRD negativity was observed starting at day 1 of cycle 2. At the end of treatment with golcadomide 0.4 mg plus R-CHOP, the rate of MRD negativity was 90% overall (26/29), 91% in patients with an IPI score of 3 to 5 (20/22), 93% in all high-risk patients (26/28), 87% in patients with high ctDNA at baseline (13/15), and 80% in patients at high genomic risk (4/5). Rates of MRD negativity in some high-risk subgroups were higher with golcadomide 0.4 mg than with golcadomide 0.2 mg, supporting use of the higher dose in ongoing trials. The randomized, phase 3 GOLSEEK-1 trial is comparing golcadomide 0.4 mg plus R-CHOP vs placebo plus R-CHOP in patients with previously untreated LBCL with an IPI score of 1 or 2 and high risk or IPI score of 3 to 5 (NCT06356129). 

References

1. Matyskiela ME, Zhang W, Man HW, et al. A cereblon modulator (CC-220) with improved degradation of Ikaros and Aiolos. J Med Chem. 2018;61(2):535-542.

2. Chavez JC, Nastoupil LJ, Morschhauser F, et al. Efficacy and safety of golcadomide, a novel cereblon E3 ligase modulator (CELMoD) agent, combined with rituximab in a phase 1/2 open-label study of patients with relapsed/refractory non-Hodgkin lymphoma. Blood. 2023;142(suppl 1):4496. 

3. Hoffmann M, Vassilakopoulos T, Munoz J, et al. Golcadomide (golca [CC-99282]), a potential first-in-class oral CELMoD™ agent, plus R-CHOP in patients (pts) with untreated aggressive B-cell lymphoma (a-BCL): safety and 12-month efficacy results. Presented at: European Hematology Association 2024 Congress; June 13-16, 2024; Madrid, Spain. Abstract S235.

4. Amzallag A, Basavanhally T, Westin JR, et al. Golcadomide + R-CHOP has high minimal residual disease (MRD) negativity across high-risk, untreated aggressive B-cell lymphoma (a-BCL). Presented at: 66th ASH Annual Meeting and Exposition; December 7-10, 2024; San Diego, California, USA. Abstract 579.

Tafasitamab + Lenalidomide and Rituximab for R/R FL: Results From a Phase 3 Study (inMIND)

Tafasitamab is a CD19-targeted monoclonal antibody that has direct cytotoxic effects and immune-modifying effects. In the single-arm, phase 2 L-MIND trial, tafasitamab demonstrated activity in combination with lenalidomide in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), with a complete response (CR) rate of 43% (34/80) in patients ineligible for autologous stem cell transplant.1 These findings led to the 2020 US Food and Drug Administration (FDA) approval of tafasitamab plus lenalidomide in patients with R/R DLBCL not eligible for autologous stem cell transplant.2

The double-blind, placebo-controlled, international, multicenter, phase 3 inMIND trial is evaluating tafasitamab plus lenalidomide and rituximab (R2) in patients with R/R follicular lymphoma (FL) or marginal zone lymphoma.3 The trial was open to patients with grade 1 to 3A FL or marginal zone lymphoma who had received at least 1 prior line of therapy including an anti-CD20 monoclonal antibody but had not received R2. Patients were randomly assigned to receive tafasitamab 12 mg/kg or placebo intravenously (IV) for 12 cycles (weekly in cycles 1-3 then every 2 weeks in cycles 4-12) plus lenalidomide 20 mg/day on days 1 through 21 for 12 cycles and rituximab 375 mg/m2 IV for 5 cycles (weekly in cycle 1 then every 4 weeks in cycles 2-5). Patients with FL were stratified based on whether they had disease progression within 24 months of their initial diagnosis (POD24), refractoriness to prior anti-CD20 therapy, and the number of prior lines of therapy (1 vs ≥2). 

At ASH 2024, Laurie H. Sehn, MD, MPH, presented results from the 548 enrolled patients with FL assigned to tafasitamab plus R2 (n=273) or placebo plus R2 (n=275) (Figure 2). The median age overall was 64.0 years (range, 31-88 years); the median time since initial FL diagnosis was 5.3 years (range, 0-34 years), 25.2% of patients had grade 3A FL, and 52.4% had a Follicular Lymphoma International Prognostic Index (FLIPI) score of 3 to 5. Patients had received a median of 1 prior line of therapy (range, 1-10), 31.6% had POD24, and 42.5% were refractory to a prior anti-CD20 therapy.

The primary endpoint, PFS by investigator assessment, was significantly longer with tafasitamab plus R2 vs placebo plus R2 (median PFS, 22.4 vs 13.9 months; hazard ratio [HR], 0.43; P<.0001); this PFS benefit was maintained in the independent review committee analysis, in which the median PFS was not reached vs 16.0 months (HR, 0.41; P<.0001). The PFS benefit with the addition of tafasitamab was maintained whether patients had POD24, whether they were refractory to a prior anti-CD20 therapy, and whether they had received 1 or multiple lines of prior therapy.

Tafasitamab plus R2 was also associated with significant improvements over placebo plus R2 in the positron emission tomography–complete response (PET-CR) rate (49.4% vs 39.8%; odds ratio [OR], 1.5; nominal P=.0286), overall response rate (ORR) (83.5% vs 72.4%; OR, 2.0; nominal P=.0014), median DOR (21.2 vs 13.6 months; HR, 0.47; P<.0001), and median time to next treatment (not reached vs 28.8 months; HR, 0.45; P<.0001). After a median follow-up of 15.3 months, there was no significant difference in OS between arms but the futility threshold was not reached and a positive trend in the tafasitamab-containing arm was observed (HR, 0.59; 95% CI, 0.31-1.13).

The most frequent grade 3 or 4 treatment-emergent adverse events (TEAEs) in the tafasitamab plus R2 and placebo plus R2 arms, respectively, were neutropenia (39.8% vs 37.5%), pneumonia (8.4% vs 5.1%), thrombocytopenia (6.2% vs 7.4%), neutrophil count reduction (5.8% vs 6.6%), and anemia (4.4% vs 5.9%). Rates of dose interruptions or delays were similar between groups at 74% and 70%, respectively, as were rates of study treatment discontinuation, at 11% and 7%, respectively. Rates of lenalidomide discontinuation owing to TEAEs were similar with tafasitamab and placebo (14% vs 11%) as were rates of lenalidomide dose reduction, with median relative dose intensity of 86% and 87%, respectively. Fatal adverse events (AEs) included COVID-19 (n=2), COVID-19 pneumonia (n=2), sepsis (n=2), gastric adenocarcinoma (n=1), large intestine carcinoid tumor (n=1), bronchopulmonary aspergillosis (n=1), cardiac failure (n=1), pneumonia (n=1), and an unexplained death (n=1). 

Investigators concluded that the study validated the approach of combining an anti-CD19 antibody with an anti-CD20 antibody in the treatment of FL. They noted that tafasitamab plus R2 can be administered in academic or community settings and could be a potential new standard of care for patients with R/R FL. 

References

1. Salles G, Duell J, González Barca E, et al. Tafasitamab plus lenalidomide in relapsed or refractory diffuse large B-cell lymphoma (L-MIND): a multicentre, prospective, single-arm, phase 2 study. Lancet Oncol. 2020;21(7):978-988.

2. U.S. Food & Drug Administration. FDA grants accelerated approval to tafasitamab-cxix for diffuse large B-cell lymphoma. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-tafasitamab-cxix-diffuse-large-b-cell-lymphoma. Accessed January 21, 2025.

3. Sehn LH, Luminari S, Scholz CS, et al. Tafasitamab plus lenalidomide and rituximab for relapsed or refractory follicular lymphoma: results from a phase 3 study (inMIND). Presented at: 66th ASH Annual Meeting and Exposition; December 7-10, 2024; San Diego, California, USA. Abstract LBA-1.

Longer Follow-up of Golcadomide, a Cereblon E3 Ligase Modulator (CELMoD™) Agent, ± Rituximab in Patients With R/R DLBCL

The first clinical trial of golcadomide was a multicenter, open-label, phase 1/2 dose-escalation and expansion study (CC-99282-NHL-001) in which golcadomide was administered as monotherapy or with rituximab in patients with R/R DLBCL or FL. This 2-part multicenter study enrolled patients with R/R DLBCL or FL after at least 2 lines of therapy or with DLBCL after at least 1 line of therapy who were unfit for transplant. Following the dose-escalation phase, patients in the dose-expansion phase received golcadomide at 0.2 mg or 0.4 mg alone or with rituximab in intermittent schedules. The total duration of golcadomide treatment was up to 2 years. 

At ASH 2024, Jean-Marie Michot, MD, presented a study update that focused on Cohort C, which enrolled 77 patients with R/R DLBCL who were randomly assigned to golcadomide 0.2 mg plus rituximab (n=39) or golcadomide 0.4 mg plus rituximab (n=38) (Figure 3).1 Patients had received a median of 4 prior lines of therapy (range, 1-11); 55% had received prior chimeric antigen receptor (CAR) T-cell therapy and 27% had received a bispecific antibody. 

After a median follow-up of 10.2 months, 20% of patients remained on treatment and 78% had discontinued treatment, primarily owing to progressive disease (56%). The most frequent treatment-related AE was neutropenia, with an incidence of 49% (46% grade 3/4) with golcadomide 0.2 mg plus rituximab and 76% (74% grade 3/4) with golcadomide 0.4 mg plus rituximab. Neutropenia was considered by investigators to be as expected and related to Ikaros degradation and was managed with granulocyte colony-stimulating factor (G-CSF) and/or dose interruptions. Nonhematologic treatment-related AEs were infrequent.

Golcadomide plus rituximab was associated with an ORR of 48% (30% CR) overall, 35% (18% CR) with golcadomide 0.2 mg plus rituximab, and 60% (43% CR) with golcadomide 0.4 mg plus rituximab. In subgroup analyses, golcadomide 0.4 mg plus rituximab was associated with an ORR of 50% (33% CR) in patients previously treated with CAR T-cell therapy and 71% (53% CR) in CAR T-cell therapy–naive patients. Responses were also observed regardless of cell of origin and use of prior therapies. 

The median DOR was 8.34 months (range, 1.5-26.7 months); responses exceeding 12 months occurred in 8 patients. Reductions in ctDNA were observed starting at day 15 of cycle 1 and included cases of MRD negativity. Reductions in ctDNA during cycles 1 and 2 correlated with responses to treatment. 

Investigators concluded that golcadomide plus rituximab was associated with predictable and manageable safety consistent with prior reports with golcadomide monotherapy, and that the combination of golcadomide and rituximab showed promising efficacy in patients with heavily pretreated R/R DLBCL, supporting the ongoing development of the regimen.

Reference 

1. Michot JM, Morschhauser F, Ferrari S, et al. Longer follow-up of golcadomide, a cereblon E3 ligase modulator (CELMoD™) agent, ± rituximab in patients with R/R DLBCL. Presented at: 66th ASH Annual Meeting and Exposition; December 7-10, 2024; San Diego, California, USA. Abstract 869.

Three-Year Update From the EPCORE NHL-1 Trial: Epcoritamab Leads to Deep and Durable Responses in R/R LBCL

Epcoritamab is a CD3 × CD20 bispecific antibody that received FDA approval in 2023 for use in adults with R/R DLBCL and high-grade B-cell lymphoma after 2 or more lines of systemic therapy.1 The approval followed results of the open-label, multicenter, single-arm EPCORE NHL-1 trial, in which epcoritamab demonstrated an ORR of 63.1% (40.1% CR), a 2-year PFS rate of 27.8%, and a 2-year OS rate of 44.6% in this population.2 At ASH 2024, Julie M. Vose, MD, MBA, presented a 3-year update from the EPCORE NHL-1 trial in patients with R/R LBCL (Table 1).3

The trial enrolled patients with R/R CD20-positive LBCL who had received at least 2 prior lines of systemic therapy, including an anti-CD20 monoclonal antibody. Patients received epcoritamab subcutaneously at 48 mg until progressive disease or unacceptable toxicity. Of the 157 enrolled patients (median age, 64 years [range, 20-83 years]; median of 3 prior lines of therapy [range, 2-11]), 61% had primary refractory disease, 75% were refractory to at least 2 consecutive prior lines of therapy, and 39% had received prior CAR T-cell therapy. 

After a median follow-up of 37.1 months, 12% of patients were still on treatment. The ORR was 59% overall (92/157), with a CR rate of 41%, and 50% in patients with DLBCL transformed from FL (16/32), with a CR rate of 44%. The median DOR was 20.8 months overall and not reached in patients with DLBCL transformed from FL (3-year DOR rate, 39% and 55%, respectively). The median duration of complete response (DOCR) was 36.1 months overall.

The median PFS was 4.2 months overall. Among patients with a CR, the median PFS was 37.3 months and the 3-year PFS rate was 53%. The median OS was 18.5 months overall and not reached among patients with a CR. At 3 years, 75% of patients with a CR had not started a new antilymphoma therapy. Fifteen patients with a CR paused epcoritamab for more than 6 weeks, primarily owing to AEs (8/10 owing to COVID-19); all patients maintained a CR at their next imaging assessment. Among 119 patients evaluable for MRD, 45% attained MRD negativity at any point and 98% of evaluable patients (40/41) were MRD-negative at day 1 of cycle 13.

The most common TEAEs were cytokine release syndrome (CRS) (51%; 3% grade 3), fatigue (25%), and pyrexia (25%). Investigators noted that the incidence and severity of CRS, immune effector cell–associated neurotoxicity syndrome (ICANS), and serious infections were similar to prior reports. Of the patients receiving epcoritamab for at least 2 years, 73% did not develop a grade 3 or higher infection after 2 years.

Investigators concluded that the efficacy and safety findings support treatment until progression and suggest long-term disease-free survival in these patients.

References

1. U.S. Food & Drug Administration. FDA grants accelerated approval to epcoritamab-bysp for relapsed or refractory diffuse large B-cell lymphoma and high-grade B-cell lymphoma. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-grants-accelerated-approval-epcoritamab-bysp-relapsed-or-refractory-diffuse-large-b-cell. Accessed January 21, 2025.

2. Thieblemont C, Karimi YH, Ghesquieres H, et al. Epcoritamab in relapsed/refractory large B-cell lymphoma: 2-year follow-up from the pivotal EPCORE NHL-1 trial. Leukemia. 2024;38(12):2653-2662. 

3. Vose JM, Cheah CY, Clausen MR, et al. 3-year update from the EPCORE NHL-1 trial: epcoritamab leads to deep and durable responses in relapsed or refractory large B-cell lymphoma. Presented at: 66th ASH Annual Meeting and Exposition; December 7-10, 2024; San Diego, California, USA. Abstract 4480.

Fixed-Duration Epcoritamab + R-CHOP Induces High Complete Response Rates in Patients With Previously Untreated DLBCL With High-Risk Features: Long-Term Results From the EPCORE NHL-2 Trial

There is a need for more effective therapies for patients with DLBCL, particularly for those with high-risk features, as no new regimens have demonstrated an OS improvement over first-line R-CHOP. The combination of epcoritamab plus R-CHOP in patients with newly diagnosed DLBCL was evaluated in Arm 1 of the EPCORE NHL-2 trial. At ASH 2024, Lorenzo Falchi, MD, presented long-term results from this cohort, with a median follow-up of 27.4 months (Figure 4).1

EPCORE NHL-2 Arm 1 enrolled 47 patients with newly diagnosed CD20-positive DLBCL considered high risk, with an IPI score of 3 or greater, to receive epcoritamab 48 mg subcutaneously weekly in cycles 1 through 4, every 3 weeks in cycles 5 through 6, and every 4 weeks thereafter for up to 1 year, plus R-CHOP. The median age of enrolled patients was 64 years (range, 19-82 years); 53% had an IPI score of 4 or 5 at screening, 21% had double-hit or triple-hit lymphoma, and 34% had bulky disease (>10 cm). 

The CR rate with epcoritamab plus R-CHOP in the efficacy-evaluable population (n=46) was 87% overall, 91% in patients who completed 6 cycles of R-CHOP with epcoritamab (n=44), 83% in patients with double-hit or triple-hit lymphoma (n=6), 82% in patients with an IPI score of 3 (n=22), 88% in patients with an IPI score of 4 or 5 (n=25), and 88% in patients with bulky disease (n=16). CRs were durable, as they were sustained in 94% of patients (30/32) who completed treatment. 

MRD negativity was attained in 91% of evaluable patients (30/33); MRD negativity was attained by day 1 of cycle 3 in 83% of patients (25/30), including 5 of 6 patients with double-hit or triple-hit lymphoma. 

After a median follow-up of 21.1 months, the median DOCR had not been reached; at 21 months, 83% of CRs were sustained. After 21 months, the PFS rate was 82%. After a median follow-up of 27.4 months, most patients were alive; the 24-month OS rate was 87% overall and 83% in the patients with double-hit or triple-hit lymphoma. 

The most frequent grade 3 or 4 TEAEs were neutropenia (66%) and anemia (32%). Febrile neutropenia occurred in 5 patients. G-CSF was administered to 36% of patients. There were 2 grade 5 TEAEs of COVID-19 and septic shock. CRS developed in 60% of patients overall but was primarily grade 1 or 2, with 4% developing grade 3 events. ICANS developed in 2 patients (4%) and was grade 1 or 2. All cases of CRS and ICANS resolved after a median time of 2 days and 2.5 days, respectively.

Investigators concluded that epcoritamab plus R-CHOP demonstrated high rates of durable CRs in patients with high-risk DLBCL, including in patients with double-hit or triple-hit lymphoma, and demonstrated a manageable safety profile. The regimen is being evaluated in an ongoing phase 3 trial in patients with previously untreated DLBCL (NCT05578976). 

Reference

1. Falchi L, Offner F, de Vos S, et al. Fixed-duration epcoritamab + R-CHOP induces high complete response rates in patients with previously untreated diffuse large B-cell lymphoma with high-risk features: long-term results from the EPCORE NHL-2 trial. Presented at: 66th ASH Annual Meeting and Exposition; December 7-10, 2024; San Diego, California, USA. Abstract 581.

Five-Year Analysis of the POLARIX Study: Prolonged Follow-up Confirms Positive Impact of Polatuzumab Vedotin + Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone (Pola-R-CHP) on Outcomes

The antibody-drug conjugate polatuzumab vedotin received approval for use in patients with previously untreated DLBCL, not otherwise specified (NOS), or high-grade B-cell lymphoma who have an IPI score of 2 or greater, in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) based on the POLARIX trial, in which polatuzumab vedotin plus R-CHP (Pola-R-CHP) was associated with a significant improvement in PFS over R-CHOP in patients with previously treated intermediate-risk or high-risk DLBCL.1,2 

At ASH 2024, Gilles Salles, MD, PhD, presented 5-year outcomes from the POLARIX study, which enrolled 879 patients with previously untreated DLBCL and randomly assigned them to Pola-R-CHP (n=440) or R-CHOP (n=439) for 6 cycles, followed by rituximab for 2 cycles (Figure 5).3

After a median follow-up of 54.9 months, Pola-R-CHP demonstrated a sustained improvement in PFS over R-CHOP, with 5-year PFS rates of 64.9% and 59.1%, respectively (HR, 0.77; 95% CI, 0.62-0.97). The 5-year disease-free survival rates were 71.8% and 66.5%, respectively (HR, 0.75; 95% CI, 0.57-1.00). Subsequent therapies were required by 38.3% of patients on the Pola-R-CHP arm vs 61.7% of patients on the R-CHOP arm, reflecting a 23.4% reduction in the need for subsequent therapies. 

The 5-year OS rate was 82.3% with Pola-R-CHP and 79.5% with R-CHOP (HR, 0.85; 95% CI, 0.63-1.15). There were fewer deaths overall in the Pola-R-CHP arm than the R-CHOP arm (80 vs 92). However, most deaths (50% in the Pola-R-CHP arm and 55% in the R-CHOP arm) were owing to progressive disease. Lymphoma-unrelated deaths occurred at a similar rate between arms. Subset analyses suggested similar treatment effect with Pola-R-CHP across subgroups, including high-risk subgroups, although investigators cautioned that these analyses are exploratory and underpowered.

An expanded population cohort that added 121 patients from a Chinese extension study showed similar outcomes as the initial global population. A competing risk analysis in the expanded population found a lower cumulative incidence of lymphoma-related deaths with Pola-R-CHP vs R-CHOP at 5 years (9.02% vs 12.05%). 

Safety profiles were comparable between arms, as previously reported. The incidence of new serious AEs in long-term follow-up was 1.8% with Pola-R-CHP and 2.2% with R-CHOP. The expanded population showed less than a 5% difference between Pola-R-CHP and R-CHOP in rates of hematologic toxicities and infections. The most frequent grade 3 or higher AEs reported with Pola-R-CHP and R-CHOP were neutropenia (43.6% vs 41.2%), infection (15.2% vs 13.3%), and anemia (11.3% vs 9.8%). Secondary malignancies occurred in 1.0% and 2.4% of patients, respectively.

Investigators concluded that the 5-year data confirm Pola-R-CHP as a standard of care for patients with previously untreated intermediate- or high-risk DLBCL. 

References

1. U.S. Food & Drug Administration. FDA approves polatuzumab vedotin-piiq for previously untreated diffuse large B-cell lymphoma, not otherwise specified, and high-grade B-cell lymphoma. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-polatuzumab-vedotin-piiq-previously-untreated-diffuse-large-b-cell-lymphoma-not. Accessed January 27, 2025.

2. Tilly H, Morschhauser F, Sehn LH, et al. Polatuzumab vedotin in previously untreated diffuse large B-cell lymphoma. N Engl J Med. 2022;386(4):351-363.

3. Salles G, Morschhauser F, Sehn LH, et al. Five-year analysis of the POLARIX study: prolonged follow-up confirms positive impact of polatuzumab vedotin + rituximab, cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP) on outcomes. Presented at: 66th ASH Annual Meeting and Exposition; December 7-10, 2024; San Diego, California, USA. Abstract 469.

Fixed-Duration Epcoritamab + R2 Drives Deep and Durable Responses in Patients With R/R FL: 2-Year Follow-up From Arm 2 of the EPCORE NHL-2 Trial

Lenalidomide plus rituximab (R2) is a commonly used regimen in patients with R/R FL based on results from the phase 3 AUGMENT trial, which demonstrated an improvement in PFS with the addition of lenalidomide to rituximab in patients with recurrent indolent lymphoma.1 Epcoritamab is a CD3 × CD20 bispecific antibody that received FDA approval in 2024 for adults with R/R FL after 2 or more lines of systemic therapy following results of the open-label, multicenter, single-arm EPCORE NHL-1 trial, in which epcoritamab demonstrated an ORR of 82.0% (62.5% CR) and a manageable safety profile.2,3

At ASH 2024, Lorenzo Falchi, MD, presented a 2-year follow-up from Arm 2 of the EPCORE NHL-2 trial evaluating fixed-duration epcoritamab plus R2 in patients with R/R FL (Table 2).4 The trial enrolled 111 patients with R/R CD20-positive FL (grade 1-3A, stage II-IV) who had previously received treatment including an anti-CD20 antibody. Patients received subcutaneous epcoritamab via a 2-step (0.16 and 0.8 mg) step-up dosing regimen in cycle 1 and at 48 mg doses either once weekly in cycles 1 through 3, every 2 weeks in cycles 4 through 9, and every 4 weeks starting in cycle 10 (Arm 2a) or weekly in cycles 1 through 2 and every 4 weeks starting in cycle 3 (Arm 2b) for up to 2 years, plus rituximab 375 mg/m2 IV weekly for 1 cycle then every 2 weeks in subsequent cycles and lenalidomide at 20 mg/day on days 1 through 21 of each cycle. 

The trial enrolled 111 patients (median age, 65 years; range, 30-80 years), including 61% with stage IV disease, 59% with a FLIPI score of 3 to 5, and 50% with POD24 after any first-line treatment. Patients had received a median of 1 prior line of therapy (range, 1-7). After a median follow-up of 25.3 months, 48% of patients had discontinued treatment, 37% had completed treatment per protocol, and 15% were still on treatment.

The ORR with epcoritamab plus R2 was 96% (87% CR) and 88% of patients attained MRD negativity at any point. The CR rate was 92% in patients receiving second-line therapy, 79% in patients with POD24 after first-line chemoimmunotherapy, 90% in primary refractory patients, and 82% in double-refractory patients.

Rates of MRD negativity in high-risk subgroups included 87% in patients with POD24 to first-line chemoimmunotherapy (26/30), 89% in patients with primary refractory disease (25/28), and 85% in double-refractory patients (23/27). Responses were durable, with the median DOR and DOCR not reached after a median follow-up of 21 months. At 21 months, 86% of CRs and 78% of all responses were maintained. Responses were durable across high-risk subgroups.

After a median follow-up of 22.3 months, median PFS was not reached overall (21-month PFS rate, 80%), 27.6 months in patients with POD24 after first-line chemoimmunotherapy (21-month PFS rate, 75%), 27.6 months in primary refractory patients (21-month PFS rate, 78%), 23.7 months in double-refractory patients (21-month PFS rate, 71%), and not reached in patients with 1 prior line of therapy (21-month PFS rate, 83%). MRD negativity was associated with higher PFS. After a median follow-up of 24.7 months, 85% of patients had not initiated a next line of therapy.

After a median follow-up of 25.3 months, median OS was not reached overall or in key subgroups reported; 24-month OS rates were 90% overall, 88% in primary refractory patients, 86% in double-refractory patients, and 84% in patients with POD24 after first-line chemoimmunotherapy.

The most frequent grade 3 or higher TEAE was neutropenia (53%). Investigators noted that rates of neutropenia were consistent with prior reports of R2.1 G-CSF was administered to 51% of patients, including as prophylaxis to 26%. Febrile neutropenia occurred in 3 patients. The trial was conducted during the COVID-19 pandemic; as a result, there were 5 fatal cases of COVID-19; no other fatal TEAEs occurred. 

CRS occurred in 51% of patients but was primarily grade 1 or 2; 2% of patients developed grade 3 CRS. No clinical CRS occurred, and CRS did not lead to any discontinuations of epcoritamab. One patient developed a grade 1 ICANS event that resolved in 7 days without treatment. 

Investigators concluded that the results support the ongoing phase 3 EPCORE FL-1 trial comparing epcoritamab plus R2 vs R2 in patients with R/R FL (NCT05409066).

References

1. Leonard JP, Trneny M, Izutsu K, et al. AUGMENT: a phase III study of lenalidomide plus rituximab versus placebo plus rituximab in relapsed or refractory indolent lymphoma. J Clin Oncol. 2019;37(14):1188-1199. 

2. U.S. Food & Drug Administration. FDA grants accelerated approval to epcoritamab-bysp for relapsed or refractory follicular lymphoma. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-epcoritamab-bysp-relapsed-or-refractory-follicular-lymphoma. Accessed January 21, 2025.

3. Linton KM, Vitolo U, Jurczak W, et al. Epcoritamab monotherapy in patients with relapsed or refractory follicular lymphoma (EPCORE NHL-1): a phase 2 cohort of a single-arm, multicentre study. Lancet Haematol. 2024;11(8):e593-e605. 

4. Falchi L, Balari AS, Leppä S, et al. Fixed-duration epcoritamab + R2 drives deep and durable responses in patients with R/R FL: 2-year follow-up from arm 2 of the EPCORE NHL-2 trial. Presented at: 66th ASH Annual Meeting and Exposition; December 7-10, 2024; San Diego, California, USA. Abstract 342.

Golcadomide ± Rituximab Demonstrates Durable Efficacy and Is Well Tolerated in Patients With R/R FL: Updated Results From the Phase 1/2 CC-99282-NHL-001 Study>

The phase 1/2 CC-99282-NHL-001 study is evaluating golcadomide as a single agent and in combination with rituximab in patients with R/R DLBCL or FL.1 The study included patients with R/R DLBCL or FL after at least 2 lines of therapy or with DLBCL after at least 1 line of therapy and unfit for transplant. Patients received golcadomide monotherapy at a range of doses in the dose-escalation phase and received golcadomide with or without rituximab at 0.2 mg or 0.4 mg on days 1 through 14 every 28 days in the dose-expansion phase. 

At ASH 2024, Julio C. Chavez presented results from 58 patients with stage III or IV FL who received golcadomide monotherapy in the dose-escalation phase (n=12) or who received golcadomide 0.2 mg plus rituximab (n=22) or golcadomide 0.4 mg plus rituximab (n=36) in the dose-expansion phase (Figure 6).1 Patients had received a median of 3 prior lines of therapy (range, 1-12), including 21% with prior T-cell–directed therapy and 32% with prior lenalidomide. 

After a median follow-up of 30 months, the best ORR was 67% (42% CR) with single-agent golcadomide, 72% (36% CR) with golcadomide 0.2 mg plus rituximab, and 92% (68% CR) with golcadomide 0.4 mg plus rituximab. In subset analyses, responses were observed in patients previously treated with lenalidomide (ORR 100%; 63% CR) and in patients previously treated with CAR T-cell therapies (ORR 87%; 50% CR); no patients with a response had developed progressive disease at the time of data analysis. 

The most frequent grade 3 or 4 toxicity was neutropenia, reported in 83% of patients receiving golcadomide monotherapy, 55% of patients receiving golcadomide 0.2 mg plus rituximab, and 44% of patients receiving golcadomide 0.4 mg plus rituximab. Rates of febrile neutropenia were 17%, 5%, and 9%, respectively. Investigators noted that neutropenia was managed using G-CSF and/or dose interruptions. Nonhematologic AEs were primarily low grade and manageable. 

Investigators concluded that golcadomide plus rituximab was an effective, safe, and well-tolerated combination in patients with R/R FL. The trial is ongoing and continues to enroll patients with R/R DLBCL and FL to receive golcadomide as monotherapy or in combination with rituximab.

Reference

1. Chavez JC, Fleury Perini G, et al. Golcadomide (GOLCA) ± rituximab demonstrates durable efficacy and is well tolerated in patients with relapsed/refractory follicular lymphoma (R/R FL): updated results from the phase 1/2 CC-99282-NHL-001 study. Presented at: 66th ASH Annual Meeting and Exposition; December 7-10, 2024; San Diego, California, USA. Abstract 3018.