FDA Approves BREYANZI®, First CAR-T Cell Therapy for Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma

SUMMARY: The FDA on March 14, 2024 granted accelerated approval to BREYANZI® (Lisocabtagene maraleucel, Liso-cel), a CD19-directed Chimeric Antigen Receptor (CAR) T-cell therapy, for the treatment of adults with relapsed or refractory Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL) who have received at least two prior lines of therapy (including a Brutons Tyrosine Kinase-BTK inhibitor and a B-Cell Lymphoma 2-BCL2 inhibitor).

The American Cancer Society estimates that for 2024, about 20,700 new cases of Chronic Lymphocytic Leukemia (CLL) will be diagnosed in the US and 4440 patients will die of the disease. CLL accounts for about one-quarter of the new cases of leukemia. The average age of patients diagnosed with CLL is around 70 years, and CLL is rarely seen in people under age 40, and is extremely rare in children. Patients with CLL often receive continuous therapy with either Brutons Tyrosine Kinase (BTK) inhibitors such as Ibrutinib (IMBRUVICA®) Acalabrutinib (CALQUENCE®) and Zanubrutinib (BRUKINSA®), time limited therapy with BCL2 inhibitor Venetoclax, given along with anti-CD20 antibody Obinutuzumab, or under certain circumstances, chemoimmunotherapy. Patients have few options and poor outcomes upon progression on these therapies, and there is an unmet need for novel therapies.

Chimeric Antigen Receptor (CAR) T-cell therapy is a type of immunotherapy and consists of T cells collected from the patient’s blood in a leukapheresis procedure, and genetically engineered to produce special receptors on their surface called Chimeric Antigen Receptors (CAR). These reprogrammed cytotoxic T cells with the Chimeric Antigen Receptors on their surface are now able to recognize a specific antigen on tumor cells. These genetically engineered and reprogrammed CAR T-cells are grown in the lab and are then infused into the patient. These cells in turn proliferate in the patients body and the engineered receptor on the cell surface help recognize and kill cancer cells that expresses that specific antigen.

BREYANZI® is a CD19-directed genetically modified autologous T cell immunotherapy, that seeks out cancer cells expressing the antigen CD19, which is found uniquely on B cells and destroy them. BREYANZI® was previously approved by the FDA for treatment of adults with relapsed or refractory Large B-cell lymphoma, who received at least one prior therapy. Patients, following treatment with CAR T-cells, develop B-cell aplasia (absence of CD19 positive cells) due to B-cell destruction and may need immunoglobin replacement. Hence, B-cell aplasia can be a useful therapeutic marker, as continued B-cell aplasia has been seen in all patients who had sustained remission, following CAR T-cell therapy. Cytokine Release Syndrome, an inflammatory process, is the most common and serious side effect of CAR T-cell therapy and is associated with marked elevation of Interleukin-6. Cytokine release is important for T-cell activation and can result in high fevers and myalgias. This is usually self limiting although if severe can be associated with hypotension and respiratory insufficiency. Tocilizumab (ACTEMRA®), an Interleukin-6 receptor blocking antibody, produces a rapid improvement in symptoms. This is however not recommended unless the symptoms are severe and life threatening, as blunting the cytokine response can in turn negate T-cell proliferation. Elevated serum ferritin and C-reactive protein levels are surrogate markers for severe Cytokine Release Syndrome. The CAR T-cells have been shown to also access sanctuary sites such as the CNS and eradicate cancer cells. CD19 antigen is expressed by majority of the B-cell malignancies and therefore most studies using CAR T-cell therapy have focused on the treatment of advanced B-cell malignancies.

TRANSCEND CLL 004 is an open-label, single-arm, multicenter Phase1/2 study, conducted in the United States, to evaluate the efficacy and safety of BREYANZI® in adult patients with relapsed or refractory CLL/SLL. This study included 117 eligible patients who underwent leukapheresis between January 2018 and June 2022, at 27 sites in the United States. Patients received a single intravenous infusion of BREYANZI® at one of two target dose levels: 50×10⁶ (Dose Level 1) or 100×10⁶ (Dose Level 2) Chimeric Antigen Receptor-positive T cells. The median age was 65 years, 68% were men, 44% had bulky lymphadenopathy, and 83% had high-risk cytogenetics. All patients had previously received and failed treatment with a BTK inhibitor and 80% had received prior Venetoclax. Among these patients, 60% had progressed on BTK inhibitors and had Venetoclax failure. Patients had a median of five prior lines of therapy. The Primary endpoint was Complete Response or Remission (including with incomplete marrow recovery), assessed by Independent Review in efficacy-evaluable patients with previous BTK inhibitor progression and Venetoclax failure at Dose Level 2 (100×10⁶). The total efficacy analysis included 89 patients treated at a dose level of 100×10⁶ CAR-positive T cells, with 49 patients evaluable.

In the Primary efficacy analysis set treated at a dose level of 100×10⁶ (N=49), the Complete Response or Remission rate (including with incomplete marrow recovery) was statistically significant at 18% (P=0.0006). The Overall Response Rate was 45%, and the median Duration of Response was 35.3 months. The median Duration of Response in the Complete Responders was Not Reached at the time of data cutoff and Minimal Residual Disease negativity rates were 100% in blood and 92.3% in bone marrow among Complete Responders. The median time to first response was 1.2 months, and for Complete Response or Remission was 3.0 months, respectively.

Among 89 patients in the study treated with BREYANZI®, Cytokine Release Syndrome (CRS) and neurologic events were mostly low-grade. CRS of any grade occurred in 83% of patients, with grade 3 CRS reported in 9% of patients, and with no grade 4 or 5 events reported. Any-grade neurologic events were reported in 46% of patients, with grade 3 neurologic events reported in 20% of patients, and one grade 4 neurologic event reported. No deaths due to either toxicity were reported.

It was concluded that a single infusion of BREYANZI® induced Complete Response or Remission in patients with relapsed or refractory CLL/SLL, including those with previous treatment failure on both BTK inhibitors and Venetoclax. It is the first CAR T-cell therapy approved in this setting and the safety profile was deemed manageable, offering a potential breakthrough in the treatment paradigm for these challenging diseases. Further confirmatory trials will be required to validate these findings and support continued approval of BREYANZI® for this indication.

Lisocabtagene maraleucel in chronic lymphocytic leukaemia and small lymphocytic lymphoma (TRANSCEND CLL 004): a multicentre, open-label, single-arm, phase 1-2 study. Siddiqi T, Maloney DG, Kenderian SS, et al. The Lancet. 2023;402:641-654.

Late Breaking Abstract – ASH 2023: Oral Ibrutinib-Venetoclax Combination Improved Outcomes in Mantle Cell Lymphoma

SUMMARY: It is estimated that approximately 3,300 new cases of Mantle Cell Lymphoma (MCL) are diagnosed in the US each year. Mantle Cell Lymphoma is an aggressive B-cell lymphoma and accounts for approximately 6% of all Non Hodgkin Lymphomas in adults, and is associated with a high relapse rate following dose-intensive therapies. Early and late relapses in patients with MCL have been attributed to persistence of residual disease.

Majority of patients with MCL are elderly and are not candidates for aggressive treatment or Autologous Stem Cell Transplantation. The four BTK inhibitors presently approved by the FDA for MCL include IMBRUVICA® (Ibrutinib) approved in 2013, CALQUENCE® (Acalabrutinib) approved in 2017, BRUKINSA® (Zanubrutinib) approved in 2019 and JAYPIRCA® (Pirtobrutinib) approved in 2023.

Brutons Tyrosine Kinase (BTK) is a member of the Tec family of kinases, downstream of the B-cell receptor, and is predominantly expressed in B-cells. It is a mediator of B-cell receptor signaling in normal and transformed B-cells. BTK inhibitors inhibit cell proliferation, and promote programmed cell death (Apoptosis) by blocking B-cell activation and signaling. Single agent Ibrutinib is presently approved by the FDA for the treatment of MCL patients who have received at least one prior therapy. Venetoclax (VENCLEXTA®) is a second generation, oral, selective, small molecule inhibitor of BCL2 and restores the apoptotic processes in tumor cells. By virtue of their unique and complementary mechanism of action, Ibrutinib in combination with Venetoclax demonstrated promising clinical activity in early phase MCL studies (N Engl J Med 2018; 378:1211-1223).

The Sympatico trial, is a multinational, randomized, double-blind, phase III study conducted to compare the combination of Ibrutinib and Venetoclax with Ibrutinib plus placebo, in patients with relapsed or refractory Mantle Cell Lymphoma (MCL). In this study, a total of 267 adult patients (N=267) with relapsed or refractory MCL who had previously received at least one prior line of therapy were randomly assigned in a 1:1 ratio to receive Ibrutinib 560 mg orally once daily concurrently with, either oral Venetoclax given at a standard 5-week ramp-up dose to a target dose of 400 mg once daily (N=134), or Placebo (N=133) for 2 years, followed by single-agent Ibrutinib until progressive disease (PD) or unacceptable toxicity. The median age was 68 years, 96% of patients had an ECOG PS of 0-1, 17% had 3 or more prior lines of therapy, and 22% were at increased risk for Tumor Lysis Syndrome (TLS). Both treatment groups were well balanced, and randomization was stratified based on ECOG PS, prior lines of therapy, and TLS risk based on tumor burden and Creatinine Clearance. The study evaluated the efficacy of the combination therapy across various subgroups, including those with high-risk features such as blastoid variant or TP53-mutated MCL. The Primary endpoint was investigator assessed Progression Free Survival (PFS) using Lugano criteria, and key Secondary endpoints included Complete Response (CR) rate, Time To Next Treatment (TTNT), Overall Survival (OS), and Overall Response Rate (ORR) by investigator assessment.

With a median follow up of 51.2 months, the median PFS was significantly longer with the Ibrutinib-Venetoclax combination, compared with the Placebo group (31.9 months versus 22.1 months; HR=0.65; P=0.0052). These PFS benefits were consistent across patient subgroups, including those with blastoid-variant or TP53-mutated MCL. In the combination group, 54% of patients achieved a Complete Remission, compared to 32% in the Placebo group (P=0.0004). The Time to Next Treatment in the combination group was median Not Reached (NR) versus 35.4 months in the Placebo group. At the time of this primary analysis, the median OS was 44.9 months with the Ibrutinib-Venetoclax combination versus 38.6 months with Ibrutinib plus Placebo, but the difference was not statistically significant. Adverse events were more common among patients who received the combination therapy, and included cytopenias and pneumonia.

It was concluded that a combination of Ibrutinib and Venetoclax was synergistic and demonstrated efficacy and safety, for the treatment of relapsed or refractory Mantle Cell Lymphoma, providing a potential new standard of care for this patient population. This chemo-free treatment option represents a milestone achievement in Mantle Cell Lymphoma treatment.

Ibrutinib Combined with Venetoclax in Patients with Relapsed/Refractory Mantle Cell Lymphoma: Primary Analysis Results from the Randomized Phase 3 Sympatico Study. Wang M, Jurczak W, Trněný M, et al. Presented at the 2023 ASH Annual Meeting & Exposition December 9-12, 2023. LBA-2.

FDA Approves JAYPIRCA® for Chronic Lymphocytic Leukemia

SUMMARY: The FDA on December 1, 2023, granted accelerated approval to Pirtobrutinib (JAYPIRCA®) for adults with Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma (CLL/SLL), who have received at least two prior lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor. The American Cancer Society estimates that for 2023, about 18,740 new cases of Chronic Lymphocytic Leukemia (CLL) will be diagnosed in the US and 4490 patients will die of the disease. CLL accounts for about one-quarter of the new cases of leukemia. The average age of patients diagnosed with CLL is around 70 years, and is rarely seen in people under age 40, and is extremely rare in children. Patients with CLL often receive continuous therapy with either Brutons Tyrosine Kinase (BTK) inhibitor, time limited therapy with BCL2 inhibitor Venetoclax given along with anti-CD20 antibody Obinutuzumab, or under certain circumstances, chemoimmunotherapy.

Brutons Tyrosine Kinase (BTK) is a member of the Tec family of kinases, downstream of the B-cell receptor, and is predominantly expressed in B-cells. It is a mediator of B-cell receptor signaling in normal and transformed B-cells. BTK inhibitors inhibit cell proliferation and promote programmed cell death (Apoptosis) by blocking B-cell activation and signaling. BTK is a validated molecular target found across numerous B-cell leukemias and lymphomas including Chronic Lymphocytic Leukemia (CLL), Mantle Cell Lymphoma (MCL), and Waldenstrom Macroglobulinemia (WM).

The 3 covalent BTK inhibitors presently approved by the FDA for CLL/SLL include IMBRUVICA® (Ibrutinib), CALQUENCE® (Acalabrutinib), and BRUKINSA® (Zanubrutinib). Although covalent BTK inhibitors have dramatically improved outcomes for patients with CLL or SLL, they are not curative. Despite the efficacy of covalent BTK inhibitors, treatment failure often occurs through development of resistance or intolerance.

Pirtobrutinib (JAYPIRCA®) is a highly selective, reversible (non-covalent) BTK inhibitor, developed to reversibly bind BTK, deliver consistently high target coverage regardless of BTK turnover rate, and preserve activity in the presence of the C481 acquired resistance mutations. Pirtobrutinib is 300 times more selective in BTK inhibition versus 98% of other kinases tested in preclinical studies, and inhibits both wild type and C481-mutant BTK with equal low nM potency, and has favorable oral pharmacology. Pirtobrutinib is well tolerated and demonstrated promising efficacy in patients with poor-prognosis B-cell malignancies following prior therapy, including prior covalent BTK inhibitors (Mato et al. Lancet, 2021).

The present FDA approval was based on BRUIN trial, which is an open-label, international, single-arm, multicohort, Phase I-II trial, conducted to evaluate the efficacy of Pirtobrutinib in patients with Relapsed or Refractory B-cell cancers. The trial involved patients receiving Pirtobrutinib monotherapy in either the Phase I or Phase II portion. In the Phase I portion, patients received Pirtobrutinib at doses ranging from 25 to 300 mg once daily in 28-day cycles. In the Phase II portion, patients received the recommended dose of 200 mg once daily. Majority of patients (85%) received the recommended dose of 200 mg once daily. Treatment was continued until disease progression or unacceptable toxicities. This analysis included 247 patients (N=247) with CLL or SLL, who had previously received a BTK inhibitor, among who the median number of previous lines of therapy was 3, and 100 patients (40.5%) had also received a B-Cell Lymphoma 2 (BCL2) inhibitor such as Venetoclax. This efficacy cohort (N=247) consisted of 86 patients from the Phase I portion and 161 patients from the Phase II portion. The median age was 69 years and in addition to previous BTK inhibitor therapy and BCL2 inhibitors, patients had also received anti-CD20 antibody (87.9%), chemotherapy (78.9%), PI3K inhibitors (18.2%), Chimeric Antigen Receptor (CAR) T-cell therapy (5.7%), and Allogeneic Stem-Cell Transplantation (2.4%). In those who received previous BTK inhibitor therapy, treatment was discontinued due to disease progression in 77% of patients and 23% discontinued due to toxicities or other reasons. High-risk molecular features were common in this patient group, and when present included the presence of a del(17p) or TP53 mutation or both (46.6%), complex karyotype (42%), and unmutated IGHV (84.8%). The Primary endpoint was Overall Response Rate (ORR), and Secondary endpoints included Progression Free Survival and Safety.

Among the patients who had previously received a BTK inhibitor, the ORR with Pirtobrutinib was 73.3% which were mostly Partial Responses. In the subset of patients who had previously received both a BTK inhibitor and a BCL2 inhibitor, the ORR was 70%. In the overall efficacy cohort, the median Progression Free Survival (PFS) at a median follow up of 19.4 months was 19.6 months. The median PFS was 22.1 months among patients who had received a BTK inhibitor but not a BCL2 inhibitor, and the median PFS was 16.8 months in the subset of patients who had previously received both a BTK inhibitor and a BCL2 inhibitor. The most common adverse events were infections, bleeding and neutropenia, and some adverse events that are typically associated with BTK inhibitors such as hypertension, atrial fibrillation or flutter and major hemorrhage occurred less frequently, and only 2.8% discontinued Pirtobrutinib due to a treatment-related adverse event.

It was concluded that Pirtobrutinib showed efficacy in patients with heavily pretreated CLL or SLL and these data continue to reinforce the ability of Pirtobrutinib to extend the benefit of BTK inhibition for patients with CLL or SLL, following treatment with a covalent BTK inhibitor.

Pirtobrutinib after a Covalent BTK Inhibitor in Chronic Lymphocytic Leukemia. Mato AR, Woyach JA, Brown JR, et al. N Engl J Med 2023;389:33-44.

FDA Approves Glofitamab for Relapsed or Refractory Large B-Cell Lymphomas

SUMMARY: The FDA on June 15, 2023, granted accelerated approval to Glofitamab-gxbm (COLUMVI®) for Relapsed or Refractory Diffuse Large B-Cell Lymphoma, Not Otherwise Specified (DLBCL, NOS) or Large B-Cell Lymphoma (LBCL) arising from Follicular Lymphoma, after two or more lines of systemic therapy.

The American Cancer Society estimates that in 2023, about 80,550 people will be diagnosed with Non Hodgkin Lymphoma (NHL) in the United States and about 20,180 individuals will die of this disease. Diffuse Large B-Cell Lymphoma (DLBCL) is the most common of the aggressive Non-Hodgkin lymphomas in the United States, and the incidence has steadily increased 3-4% each year. More than half of patients are 65 or older at the time of diagnosis and the incidence is likely to increase with aging of the American population. The etiology of Diffuse Large B-Cell Lymphoma is unknown. Contributing risk factors include immunosuppression (AIDS, transplantation setting, autoimmune diseases), UltraViolet radiation, pesticides, hair dyes, and diet.

DLBCL is a neoplasm of large B cells and the most common chromosome abnormality involves alterations of the BCL-6 gene at the 3q27 locus, which is critical for germinal center formation. Two major molecular subtypes of DLBCL arising from different genetic mechanisms have been identified, using Gene Expression Profiling: Germinal Center B-cell-like (GCB) and Activated B-Cell-like (ABC). Patients in the GCB subgroup have a higher 5-year survival rate, independent of clinical IPI (International Prognostic Index) risk score, whereas patients in the ABC subgroup have a significantly worse outcome. Regardless, R-CHOP regimen (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone), given every 21 days, for 6 cycles, delivered with curative intent, is the current standard of care for patients of all ages, with newly diagnosed DLBCL, regardless of molecular subtype. Approximately 30-40% of patients experience disease progression or relapse, during the first 2 years and attempts to improve on R-CHOP regimen have not been successful. Maintenance treatment strategy following R-CHOP, to better control the disease, delay disease progression and improve long term survival, have included Autologous Stem Cell Transplantation, CAR T-cell therapy, maintenance treatment with agents such as oral protein kinase inhibitor Enzastaurin and Everolimus. Outcomes for transplant-ineligible patients with Relapsed/Refractory DLBCL patients remain poor. There is a critical unmet need for this patient group.

Glofitamab is a CD20-directed CD3 T-cell engager bispecific antibody, designed to target CD20 on the surface of B cells and CD3 on the surface of T cells. This dual targeting activates and redirects a patient’s existing T cells to engage and eliminate target B cells by releasing cytotoxic proteins into the B cells. Glofitamab differs from other CD20-directed CD3 T-cell engager bispecific antibodies in that it has two anti-CD20 binding domains. It is therefore bivalent for the tumor antigen and monovalent for the T-cell CD3 protein. Further, it is a time-limited therapy.

The present FDA approval was based on positive data from the NP30179 study, which is a Phase I/II, multicenter, open-label, dose-escalation and expansion study, evaluating the safety, efficacy and pharmacokinetics of Glofitamab in patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma (DLBCL). Once the recommended Phase II dose of Glofitamab was established, patients with DLBCL who had previously received at least two lines of therapy were enrolled in the expansion cohorts. This expansion cohort included 154 patients (N=154), who had Relapsed or Refractory disease, and had received at least two previous lines of therapy including at least one anti-CD20 antibody-containing regimen and at least one anthracycline-containing regimen.

Eighty percent of patients had Relapsed or Refractory DLBCL, and 20% had LBCL arising from Follicular Lymphoma. Approximately 85% of patients were refractory to their most recent therapy and 33% had received prior CAR T-cell therapy. This study excluded patients with active or previous Central Nervous System lymphoma or disease. Treatment consisted of a single dose of Obinutuzumab 1,000 mg IV on Cycle 1 Day 1, to deplete circulating and lymphoid tissue B cells and to mitigate Cytokine Release Syndrome, followed by fixed-duration Glofitamab monotherapy administered by IV infusion according to a step-up dosing schedule (2.5 mg on Day 8 of Cycle 1 and 10 mg on Day 15 of Cycle 1), then 30 mg on Day 1 of each subsequent cycle for a maximum of 12 cycles. The cycle length was 21 days. Patients were hospitalized for the first dose of Glofitamab and subsequent doses were administered in the outpatient setting unless Cytokine Release Syndrome of Grade 2 or higher was reported after the first dose. The Primary end point was Complete Response (CR) rate according to assessment by an Independent Review Committee. Key Secondary end points included Duration of Response, Progression Free Survival, and Safety. The efficacy analysis included 132 patients.

The Overall Response Rate (ORR) was 56% with a Complete Response rate of 43%. With an estimated median follow up of 11.6 months among responders, the estimated median Duration of Response was 18.4 months. Further, 68.5% of patients who achieved a response continued to respond for 9 months or longer. The median Time to Response was 42 days. The most common adverse reactions, excluding laboratory abnormalities were Cytokine Release Syndrome (CRS), musculoskeletal pain, rash, and fatigue. CRS occurred in 70% (with 4.1% Grade 3 or higher CRS), Immune Effector Cell-Associated Neurotoxicity (ICANS) in 4.8%, serious infections in 16%, and tumor flare in 12%. The most common Grade 3 to 4 laboratory abnormalities were lymphopenia and neutropenia, decrease in serum phosphate and fibrinogen levels, and increase in serum uric acid.

It was concluded that a fixed duration treatment of off-the-shelf therapy with Glofitamab induced durable Complete Responses, among patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma.

Glofitamab for Relapsed or Refractory Diffuse Large B-Cell Lymphoma. Dickinson MJ, Carlo-Stella C, Morschauser F, et al. N Eng J Med. 2022;387:2220-2231.

FDA Approves BiSpecific Antibody EPKINLY® for Aggressive Non Hodgkin Lymphomas

SUMMARY: The FDA on May 19, 2023, granted accelerated approval to Epcoritamab-bysp (EPKINLY®) for relapsed or refractory Diffuse Large B-Cell Lymphoma (DLBCL) not otherwise specified, including DLBCL arising from indolent lymphoma, and High-Grade B-Cell Lymphoma after two or more lines of systemic therapy. The American Cancer Society estimates that in 2023, about 80,550 people will be diagnosed with Non Hodgkin Lymphoma (NHL) in the United States and about 20,180 individuals will die of this disease. Diffuse Large B-Cell Lymphoma (DLBCL) is the most common of the aggressive Non-Hodgkin lymphomas in the United States, and the incidence has steadily increased 3-4% each year. More than half of patients are 65 or older at the time of diagnosis and the incidence is likely to increase with aging of the American population. The etiology of Diffuse Large B-Cell Lymphoma is unknown. Contributing risk factors include immunosuppression (AIDS, transplantation setting, autoimmune diseases), UltraViolet radiation, pesticides, hair dyes, and diet.

DLBCL is a neoplasm of large B cells and the most common chromosome abnormality involves alterations of the BCL-6 gene at the 3q27 locus, which is critical for germinal center formation. Two major molecular subtypes of DLBCL arising from different genetic mechanisms have been identified, using Gene Expression Profiling: Germinal Center B-cell-like (GCB) and Activated B-Cell-like (ABC). Patients in the GCB subgroup have a higher 5-year survival rate, independent of clinical IPI (International Prognostic Index) risk score, whereas patients in the ABC subgroup have a significantly worse outcome. Regardless, R-CHOP regimen (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone), given every 21 days, for 6 cycles, delivered with curative intent, is the current standard of care for patients of all ages, with newly diagnosed DLBCL, regardless of molecular subtype. Approximately 30-40% of patients experience disease progression or relapse, during the first 2 years and attempts to improve on R-CHOP regimen have not been successful. Maintenance treatment strategy following R-CHOP, to better control the disease, delay disease progression and improve long term survival, have included Autologous Stem Cell Transplantation, CAR T-cell therapy, maintenance treatment with agents such as oral protein kinase inhibitor Enzastaurin and Everolimus. Outcomes for transplant-ineligible patients with Relapsed/Refractory DLBCL patients remain poor.

Epcoritamab is a CD20-directed CD3 T-cell engager bispecific antibody, designed to target CD20 on the surface of B cells and CD3 on the surface of T cells. This dual targeting activates and redirects a patient’s existing T cells to engage and eliminate target B cells by releasing cytotoxic proteins into the B cells.

EPCORE NHL-1 is an ongoing, open-label, multi-cohort, multicenter, Phase 1/2b, single-arm trial in which the safety, tolerability, pharmacokinetics and preliminary efficacy of Epcoritamab in combination with standard-of-care (SOC) agents are being examined in patients with relapsed, progressive or refractory CD20+ mature B-cell Non-Hodgkin Lymphoma (NHL), including Diffuse Large B-Cell Lymphoma. Phase 1 of the trial consists of a first-in-human, dose-escalation portion, and Phase 2 is the expansion and optimization part.

The Phase 2 expansion cohort included 157 patients with relapsed/refractory Large B-Cell Lymphoma who were previously treated with a median of 3 lines of prior therapy. The median age was 64 years and median time from initial diagnosis was 1.6 yrs. Approximately 39% of patients had received prior CAR T-cell therapy, 20% had prior Autologous Stem Cell Transplantation, 61% had Primary refractory disease and 14% of patients with Diffuse Large B-Cell Lymphoma were confirmed Double Hit/Triple Hit by central FISH. Epcoritamab was administered subcutaneously in 28-day cycles until disease progression or unacceptable toxicity. Mitigation of Cytokine Release Syndrome included step-up dosing and corticosteroid prophylaxis in the first cycle alone. Step-up dosing was 0.16 mg on Day 1, 0.8 mg on Day 8, and 48 mg on Day 15 and Day 22 in Cycle 1, followed by fixed dosing of 48 mg weekly dosing during Cycles 2-3, every other week during Cycle 4-9, and then every four weeks on Day 1 of subsequent cycles. Per protocol, 24-hour hospitalization was required only for the first full dose (48 mg) to ensure close observation of patients. The Primary endpoint was Overall Response Rate (ORR) by Independent Review Committee. Key Secondary endpoints included the Duration of Response (DOR), time to response, Progression Free Survival (PFS), Overall Survival (OS), Complete Response (CR) rate, Safety, and tolerability.

At a median follow-up of 10.7 months, the Overall Response Rate for the total population was 63%, with a Complete Response Rate of 39%. The median Duration of Response was 12.0 months and was Not Reached among complete responders. Overall and Complete Response rates were similar across key prespecified subgroups. The median time to response was 1.4 months. MRD negativity was assessed by a ctDNA NGS assay and 46.4% were MRD negative at any time point on treatment. MRD negativity was reached at a median of 8 weeks for complete responders, and high MRD negativity rates were observed across all prespecified subgroups. MRD-negative responses were durable and correlated with PFS. The most common adverse events were Cytokine Release Syndrome (majority were Grade 1 or 2, with most events occurring after the first full dose), fever and fatigue. Immune effector Cell-Associated Neurotoxicity Syndrome occurred in 6.4% of patients.

It was concluded that subcutaneous single agent Epcoritamab is a convenient, off-the-shelf therapy that resulted in deep and durable responses, including high MRD negativity rates, with manageable safety, in highly refractory patients with Large B-cell lymphoma, including those with prior CAR T-cell exposure.

Epcoritamab, a Novel, Subcutaneous CD3xCD20 Bispecific T-Cell-Engaging Antibody, in Relapsed or Refractory Large B-Cell Lymphoma: Dose Expansion in a Phase I/II Trial. Thieblemont C, Phillips T, Ghesquieres H, et al. J Clin Oncol. 2023;;41:2238-2247.