POLIVY® in Previously Untreated Diffuse Large B-Cell Lymphoma

SUMMARY: The American Cancer Society estimates that in 2021, about 81,560 people will be diagnosed with Non Hodgkin Lymphoma (NHL) in the United States and about 20,720 individuals will die of this disease. Diffuse Large B-Cell Lymphoma (DLBCL) is the most common of the aggressive Non-Hodgkin lymphoma’s 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 five 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, 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.

CD79b is a B-cell specific surface protein, which is a component of the B-cell receptor and is ubiquitously expressed on the surface of malignant B cells. POLIVY® (Polatuzumab vedotin) is a CD79b-directed Antibody-Drug Conjugate (ADC) with activity against dividing B cells. It consists of three components: 1) the humanized ImmunoGlobulin G1 (IgG1) monoclonal antibody specific for human CD79b; 2) the small molecule anti-mitotic agent MMAE (monomethyl auristatin E) and 3) a protease-cleavable linker that covalently attaches MMAE to the Polatuzumab antibody. Upon binding to CD79b, POLIVY® is internalized, and the linker is cleaved by lysosomal proteases thus enabling intracellular delivery of MMAE. MMAE then binds to microtubules and kills dividing cells by inhibiting cell division and inducing apoptosis. POLIVY® demonstrated efficacy in patients with Relapsed or Refractory DLBCL, resulting in significantly longer Overall Survival when combined with Bendamustine and Rituximab, compared to Bendamustine and Rituximab alone. Based on these finding, the FDA granted accelerated approval to POLIVY® in June 2019.

In a Phase Ib-II study POLIVY® in combination with Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone (pola-R-CHP) resulted in a 89% Overall Response rate and 77% Complete Responses when given as first line therapy, in patients with DLBCL. In this study, Vincristine was excluded from the regimen owing to the risk of overlapping neurotoxicities with POLIVY®. The present POLARIX trial was conducted to evaluate the efficacy and safety of pola-R-CHP as compared with R-CHOP, in patients with previously untreated DLBCL.

The POLARIX is a randomized, double-blind, placebo-controlled, International Phase III trial in which a total of 879 treatment naïve, CD20-positive, intermediate or high-risk DLBCL patients were randomly assigned in a 1:1 ratio to receive 6 cycles of either pola-R-CHP (N=440) or R-CHOP (N=439). Patients on Day 1 of each 21 day cycle, received POLIVY® 1.8 mg/kg IV and a placebo matching Vincristine IV (pola-R-CHP group) or a placebo matching POLIVY® and intravenous Vincristine at a dose of 1.4 mg/m2 (maximum of 2 mg) (R-CHOP group), along with Rituximab 375 mg/m2 IV, Cyclophosphamide 750 mg/m2 IV and Doxorubicin 50 mg/m2 IV. All the patients also received Prednisone 100 mg orally once daily on Days 1-5 of each of the first six cycles. During cycles 7 and 8, patients in both treatment groups received Rituximab monotherapy at 375 mg/m2 IV. The median patient age was 65 years and stratification was based on IPI score and presence or absence of bulky disease, Subtypes of DLBCL were centrally evaluated and were balanced between the two treatment groups. Patients were eligible regardless of the Cell of Origin or the presence of rearrangements in MYC, BCL2, BCL6, or a combination of these. Patients with known CNS involvement were excluded but CNS prophylaxis with intrathecal chemotherapy was permitted, in accordance with institutional practice guidelines. The use of Granulocyte Colony-Stimulating Factor (G-CSF) was required during the first six cycles of treatment for primary prophylaxis against neutropenia and consolidative radiotherapy to initial sites of bulky disease or extranodal sites was allowed at the discretion of the investigator. The Primary end point was Progression Free Survival (PFS). Secondary end points included Overall Survival (OS) and Safety.

At a median follow up of 28.2 months, the PFS was significantly higher in the pola-R-CHP group compared to the R-CHOP group. The PFS at 2 years was 76.7% in the pola-R-CHP group versus 70.2% in the R-CHOP group (stratified HR=0.73; P=0.02). Treatment with pola-R-CHP resulted in a risk of disease progression, relapse, or death that was 27% lower, compared to R-CHOP. Patient subgroups that did not show a clear benefit with pola-R-CHP included patients 60 years of age or younger, patients with the Germinal Center B-cell-like subtype of DLBCL, patients who had bulky disease, and patients who had lower IPI scores. Overall Survival at 2 years did not differ significantly between the treatment groups and the researchers attributed the lack of a significant difference between the two groups in Overall Survival, to the availability of new, effective treatments for relapsed or refractory DLBCL, as well as short duration of follow up at the time of this reporting. The safety profile was similar in the two treatment groups.

The authors concluded that among patients with previously untreated intermediate-risk or high-risk DLBCL, the risk of disease progression, relapse, or death was lower among those who received pola-R-CHP than among those who received R-CHOP.

Polatuzumab Vedotin in Previously Untreated Diffuse Large B-Cell Lymphoma. Tilly H, Morschhauser F, Sehn LH, et al. December 14, 2021. DOI: 10.1056/NEJMoa2115304

Non Hodgkin Lymphoma Treated with B-Cell Depleting Immunotherapy May Result in Prolonged Hospital Stay and Higher Morbidity after Covid-19 Infection

SUMMARY: The SARS-CoV-2 Coronavirus (COVID-19) induced pandemic first identified in December 2019 in Wuhan, China, has contributed to significant mortality and morbidity in the US, and the number of infections, continue to exponentially increase worldwide. Majority of the patients present with treatment-resistant pyrexia and respiratory insufficiency, with some of these patients progressing to a more severe systemic disease and multiple organ dysfunction.

Patients with lymphoproliferative disorders may be immune deficient due to their underlying disease or due to the therapies they receive, which in turn can increase the incidence and severity of infections. Patients with Non Hodgkin Lymphoma are often treated with CD20 targeted, B-cell depleting monoclonal antibodies such as RITUXAN® (Rituximab) or GAZYVA® (Obinutuzumab), as they were shown to improve survival among patients with B-cell Non-Hodgkin Lymphoma. Depleting B cells dampens the body’s ability to generate antibody responses to new pathogens, which may impact the clinical course of COVID-19. The authors in this study analyzed the clinical course of COVID-19 infection in hospitalized lymphoma patients, and characterized the determinants of worse outcomes.

It has been shown in several studies and registries that patients with hematologic malignancies including lymphomas have a higher incidence of death from COVID-19 compared with other types of cancer. Additional risk factors for COVID-19-related mortality include older age and relapsed or refractory disease. To better understand the risk factors associated with worse outcomes from COVID-19 in this patient population, the authors conducted a retrospective study of 111 patients with lymphoma, hospitalized for COVID-19, at any of the 16 French hospitals, during March and April 2020. The researchers specifically focused on identifying factors associated with prolonged hospital stay (longer than 30 days), or hospitalization for recurrent symptoms for more than 30 days and death, and used length of hospital stay as a proxy for persistent COVID-19 infection. Study patients included those formerly treated for lymphoma, those currently undergoing treatment, or had no treatment.

Of the 111 patients included in this study, 57% (N=63) had previously received B-cell-depleting therapy. The most common type of lymphoma was Diffuse Large B-Cell Lymphoma. Twenty nine percent (29%) of all patients required a prolonged hospital stay (longer than 30 days) due to severe COVID-19 symptoms and persistent disease. The median age of patients with persistent COVID-19 was 64 years and 63% were male. More than two-thirds (69%) had at least one significant comorbidity. None of the patients with T-cell lymphoma included in the study (N=8) experienced persistent COVID-19 infection.

At a median follow-up of 191 days, the 6-month Overall Survival for the entire cohort was 69%. Older age (70 years and over) as well as relapsed/refractory disease were both associated with worse survival and prolonged hospital stays. After adjusting for age, comorbidities, and the presence of relapsed/refractory disease, the researchers noted that receipt of B-cell-depleting treatment within the previous 12 months nearly doubled the likelihood of a prolonged hospital stay and more than doubled the risk of death. After 1 month, 41% of patients who received anti-CD20 monoclonal antibodies were still hospitalized for COVID-19 versus 13% not treated with those antibodies.

The authors concluded that standardized guidelines on the use of anti-CD20 therapies are needed to help us make decisions during the COVID-19 pandemic, and convalescent plasma may be a treatment consideration for B-cell-depleted patients with persistent COVID-19. Patients who recently received B-cell depleting therapies and have COVID-19 should be closely monitored. Additionally, the efficacy and timing of vaccination in this particular population needs further study.

Prolonged in-hospital stay and higher mortality after Covid-19 among patients with non-Hodgkin lymphoma treated with B-cell depleting immunotherapy. Dulery R, Lamure S, Delord M, et al. Am J Hematol. 2021;96:934-944.

No Difference in Overall Survival between R-CHOP and R-EPOCH in Advanced MYC-Rearranged, Double Hit, or Triple Hit DLBCL

SUMMARY: The American Cancer Society estimates that in 2021, about 81,560 people will be diagnosed with Non Hodgkin Lymphoma (NHL) in the United States and about 20,720 individuals will die of this disease. Diffuse Large B-Cell Lymphoma (DLBCL) is the most common of the aggressive Non-Hodgkin lymphoma’s 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 the 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 five 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 (RITUXAN®-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.

MYC is a proto-oncogene and transcription factor and is rearranged in up to 15% of patients with DLBCL. MYC activation is an important adverse prognostic feature and results in aggressive cellular proliferation associated with DNA replication and transcription, protein synthesis, and altered cellular metabolism. BCL2 is a potent anti-apoptotic factor and dual rearrangement of MYC with BCL2 and less commonly, BCL6, occurs in 5% to 7% of cases of DLBCL. Further, both MYC and BCL2 proteins can be overexpressed, either with or without the underlying respective chromosomal rearrangements, in about 30% of patients with DLBCL.

The combination of MYC activation and anti-apoptosis (BCL2) results in a clinically aggressive phenotype called Double-Hit Lymphoma (DHL), which is associated with poor long-term survival after standard chemoimmunotherapy. Similar poor outcomes have been noted in patients with MYC activation along with BCL2, and BCL6 rearrangement, known as Triple Hit Lymphoma (THL).

The long term survival for patients with DHL or THL treated with R-CHOP is less than 20%. Patients are therefore often treated with more intensive regimens such as R-EPOCH (Rituximab, Etoposide, Prednisone, Vincristine, Cyclophosphamide, and Doxorubicin), although prospective data supporting the use of one regimen over another are limited.

The present study was conducted to compare Overall Survival of patients with advanced stage MYC-rearranged DLBCL and DHL/THL who were treated with R-CHOP versus R-EPOCH. The researchers analyzed de-identified data from a nationwide Flatiron Health Electronic Health Record database on patients diagnosed with DLBCL at 280 cancer clinics in the U.S. between January 2011, and June 2020. Among 6,809 total DLBCL patients, 443 (6.5%) were found to have MYC-rearranged DLBCL. Among these, 218 patients had advanced Stage (III/IV) disease at diagnosis, 64 patients had MYC-rearranged DLBCL only, and 117 and 37 had DHL or THL, respectively. Among those patients with DHL/THL, 43 patients (median age 73 years) were treated with R-CHOP and 111 patients (median age 67 years) received R-EPOCH. Among those with MYC-rearranged DLBCL only, 36 received R-CHOP (median age 70 years), and 28 received R-EPOCH (median age 61 years).

The investigators found no difference in the 4-year Overall Survival rates between the R-CHOP and R-EPOCH treatment arms in different patient groups. Among the MYC-rearranged DLBCL cohort, the 4-year Overall Survival rates were 32.8% with R-CHOP versus 30.4% with R-EPOCH regimens. In the DHL/THL group of patients, the 4-year Overall Survival rates were 54.5% with R-CHOP versus 49.6% with R-EPOCH. Among DHL/THL patient group, 89% of deaths occurred within 2 years of diagnosis, and among MYC- rearranged DLBCL, 78% of deaths occurred in the first 2 years. ECOG Performance Status score of 2 or more and elevated LDH were independently associated with worse mortality for these patients, by multivariate analysis.

It was concluded from this analysis that Overall Survival outcomes were similar between patients with MYC-rearranged Diffuse Large B-Cell Lymphoma and Double-Hit lymphoma/Triple-Hit Lymphoma (THL) who were treated with R-CHOP versus R-EPOCH. The authors suggested that further studies are needed to better risk stratify patients with DLBCL, for optimizing outcomes.

No difference in overall survival between R-CHOP and R-EPOCH among patients with advanced stage MYC-rearranged, double hit, or triple hit diffuse large B-cell lymphoma. Magnusson T, Narkhede M, Mehta A, et al. Abstract #S224. Presented at the EHA2021 Virtual Congress, June 9-17, 2021.

ZYNLONTA® (Loncastuximab tesirine-lpyl)

The FDA on April 23, 2021 granted accelerated approval to ZYNLONTA®, a CD19-directed antibody and alkylating agent conjugate, for adult patients with Relapsed or Refractory Large B-Cell Lymphoma after two or more lines of systemic therapy, including Diffuse Large B-Cell Lymphoma (DLBCL) not otherwise specified, DLBCL arising from Low Grade Lymphoma, and High-Grade B-cell Lymphoma. ZYNLONTA® is a product of ADC Therapeutics SA.

FDA Approves Antibody Drug Conjugate ZYNLONTA® for Large B-Cell Lymphoma

SUMMARY: The FDA on April 23, 2021 granted accelerated approval to ZYNLONTA® (Loncastuximab tesirine-lpyl ), a CD19-directed antibody and alkylating agent conjugate, for adult patients with Relapsed or Refractory Large B-Cell Lymphoma after two or more lines of systemic therapy, including Diffuse Large B-Cell Lymphoma (DLBCL) not otherwise specified, DLBCL arising from Low Grade Lymphoma, and High Grade B-Cell Lymphoma.

The American Cancer Society estimates that in 2021, about 81,560 people will be diagnosed with Non Hodgkin Lymphoma (NHL) in the United States and about 20,720 individuals will die of this disease. Diffuse Large B-Cell Lymphoma (DLBCL) is the most common of the aggressive Non-Hodgkin lymphoma’s 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 the 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 five 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 (RITUXAN®-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. For patients who fail first line therapy, outcomes are poor, worsening with each line of therapy, and the chance for cure or long term disease-free survival diminishes. There is a significant unmet need for patients with Relapsed/Refractory DLBCL.

ZYNLONTA® is a CD19-directed Antibody Drug Conjugate comprised of a humanized anti-CD19 antibody, conjugated through a linker to a potent pyrrolobenzodiazepine (PBD) dimer toxin. Once bound to a CD19-expressing cell, ZYNLONTA® is internalized by the cell following which the toxic payload is released. The potent toxin then binds irreversibly to DNA to create highly potent interstrand cross-links that block DNA strand separation, thereby disrupting essential DNA metabolic processes such as replication and ultimately resulting in cell death. CD19 is a clinically validated target for the treatment of B-cell malignancies.

The present FDA approval of ZYNLONTA® was based on LOTIS-2, which is an open-label, single arm trial in which 145 adult patients who had Relapsed or Refractory DLBCL or High Grade B-Cell Lymphoma were included. This study included transplant eligible and ineligible patients, patients with double or triplet-hit lymphoma, and patients who previously received stem cell transplant or CD 19-targeted CAR-T cell therapy. Patients received ZYNLONTA® 0.15 mg/kg every 3 weeks for 2 cycles, then 0.075 mg/kg every 3 weeks for subsequent cycles. Treatment was continued until progressive disease or unacceptable toxicity. Enrolled patients had at least two prior systemic regimens. The main efficacy outcome measure was Overall Response Rate (ORR). Pre-specified analyses of ORR and Duration of Response (DoR) by demographic and clinical characteristics were performed, and ORR was assessed by independent reviewer according to the Lugano response criteria.

The ORR was 48.3% with a Complete Response Rate of 24.1%. The Partial Response (PR) rate was 24.1%. Patients had a median time to response of 1.3 months and the median Duration of Response for the 70 responders was 10.3 months (inclusive of patients who were censored). The most common Grade 3 or higher treatment-related adverse events included neutropenia with a low incidence of febrile neutropenia, thrombocytopenia, Gamma-Glutamyl Transferase increase, and anemia.

The authors concluded that ZYNLONTA® had substantial single-agent antitumor activity in patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma, with encouraging and durable responses noted in patients with high-risk characteristics.

Efficacy and Safety of Loncastuximab Tesirine (ADCT-402) in Relapsed/Refractory Diffuse Large B-Cell Lymphoma. Caimi PF, Ai WZ, Alderuccio JP, et al. Presented at the 62nd ASH Annual Meeting and Exposition, December 5-8,2020. Abstract#1183

Worse Outcomes from COVID-19 Infection in Lymphoma Patients Treated with Anti-CD20 Monoclonal Antibodies

SUMMARY: The SARS-CoV-2 Coronavirus (COVID-19) induced pandemic first identified in December 2019 in Wuhan, China, has contributed to significant mortality and morbidity in the US, and the number of infections, continue to exponentially increase worldwide. Majority of the patients present with treatment-resistant pyrexia and respiratory insufficiency, with some of these patients progressing to a more severe systemic disease and multiple organ dysfunction.

Patients with lymphoproliferative disorders may be immune deficient due to their underlying disease or due to the therapies they receive, which in turn can increase the incidence and severity of infections. Patients with Non Hodgkin Lymphoma are often treated with CD20 targeted, B-cell depleting monoclonal antibodies such as RITUXAN® (Rituximab) or GAZYVA® (Obinutuzumab), as they were shown to improve survival among patients with B-cell Non-Hodgkin Lymphoma. Depleting B cells dampens the body’s ability to generate antibody responses to new pathogens, which may impact the clinical course of COVID-19. The authors in this study analyzed the clinical course of COVID-19 infection in lymphoma patients, and characterized the determinants of worse outcomes.

It has been shown in several studies and registries that patients with hematologic malignancies including lymphomas have a higher incidence of death from COVID-19 compared with other types of cancer. Additional risk factors for COVID-19-related mortality include older age and relapsed or refractory disease. To better understand the risk factors associated with worse outcomes from COVID-19 in this patient population, the authors conducted a retrospective study of 111 patients with lymphoma hospitalized for COVID-19 at any of the 16 French hospitals during March and April 2020. The researchers specifically focused on identifying factors associated with prolonged hospital stay (longer than 30 days), or hospitalization for recurrent symptoms for more than 30 days and death, and used length of hospital stay as a proxy for persistent COVID-19 infection. Study patients included those formerly treated for lymphoma, those currently undergoing treatment, or had no treatment.

Of the 111 patients included in this study, 57% (N=63) had previously received B-cell-depleting therapy. The most common type of lymphoma was Diffuse Large B-Cell Lymphoma. Twenty nine percent (29%) of all patients required a prolonged hospital stay (longer than 30 days) due to severe COVID-19 symptoms and persistent disease. The median age of patients with persistent COVID-19 was 64 years and 63% were male. More than two-thirds (69%) had at least one significant comorbidity. None of the patients with T-cell lymphoma included in the study (N=8) experienced persistent COVID-19 infection.

At a median follow-up of 191 days, the 6-month Overall Survival for the entire cohort was 69%. Older age (70 years and over) as well as relapsed/refractory disease were both associated with worse survival and prolonged hospital stays. After adjusting for age, comorbidities, and the presence of relapsed/refractory disease, the researchers noted that receipt of B-cell-depleting treatment within the previous 12 months nearly doubled the likelihood of a prolonged hospital stay and more than doubled the risk of death. After 1 month, 41% of patients who received anti-CD20 monoclonal antibodies were still hospitalized for COVID-19 versus 13% not treated with those antibodies.

The authors concluded that standardized guidelines on the use of anti-CD20 therapies are needed to help us make decisions during the COVID-19 pandemic, and convalescent plasma may be a treatment consideration for B-cell-depleted patients with persistent COVID-19. Patients who recently received B-cell depleting therapies and have COVID-19 should be closely monitored. Additionally, the efficacy and timing of vaccination in this particular population needs further study.

High incidence of persistent COVID-19 among patients with lymphoma treated with B-cell depleting immunotherapy. Lamure S, Dulery R, Delord M, et al. AACR Virtual Meeting: COVID-19 and Cancer. Abstract S09-02. Presented on February 5, 2021.

BREYANZI® (Lisocabtagene maraleucel)

The FDA on February 5, 2021 approved BREYANZI® for the treatment of adult patients with Relapsed or Refractory (R/R) Large B-Cell Lymphoma after two or more lines of systemic therapy, including Diffuse Large B-Cell Lymphoma (DLBCL) not otherwise specified (including DLBCL arising from indolent lymphoma), High-Grade B-Cell Lymphoma, Primary Mediastinal Large B-Cell Lymphoma, and Follicular Lymphoma Grade 3B. BREYANZI® is a product of Juno Therapeutics, Inc.

UKONIQ® (Umbralisib)

The FDA on February 5, 2021 granted accelerated approval to UKONIQ®, a kinase inhibitor including PI3K-delta and casein kinase CK1-epsilon, for the following indications:
• Adult patients with Relapsed or Refractory Marginal Zone Lymphoma (MZL) who have received at least one prior anti-CD20-based regimen;
• Adult patients with Relapsed or Refractory Follicular Lymphoma (FL) who have received at least three prior lines of systemic therapy.

UKONIQ® is a product of TG Therapeutics Inc.

FDA Approves UKONIQ® for Relapsed or Refractory Marginal Zone and Follicular Lymphomas

SUMMARY: The FDA on February 5, 2021 granted accelerated approval to UKONIQ® (Umbralisib), a kinase inhibitor including PI3K-delta and Casein Kinase CK1-epsilon, for adult patients with Relapsed or Refractory Marginal Zone Lymphoma (MZL) who have received at least one prior anti-CD20-based regimen and adult patients with Relapsed or Refractory Follicular Lymphoma (FL) who have received at least three prior lines of systemic therapy. The American Cancer Society estimates that in 2021, about 81,560 people will be diagnosed with Non Hodgkin Lymphoma (NHL) in the United States and about 20,720 individuals will die of this disease. Indolent Non Hodgkin Lymphomas are mature B cell lymphoproliferative disorders and include Follicular Lymphoma, Nodal Marginal Zone Lymphoma (NMZL), Extranodal Marginal Zone Lymphoma (ENMZL) of Mucosa-Associated Lymphoid Tissue (MALT), Splenic Marginal Zone Lymphoma (SMZL), LymphoPlasmacytic Lymphoma (LPL) and Small Lymphocytic Lymphoma (SLL). Follicular Lymphoma is the most indolent form and second most common form of all NHLs and they are a heterogeneous group of lymphoproliferative malignancies. Approximately 20% of all NHLs are Follicular Lymphomas (FL).

Advanced stage indolent NHL is not curable and as such, prolonging Progression Free Survival (PFS) and Overall Survival (OS), while maintaining Quality of Life, have been the goals of treatment intervention. Asymptomatic patients with indolent NHL are generally considered candidates for “watch and wait” approach. Patients with advanced stage symptomatic Follicular Lymphoma are often treated with induction chemoimmunotherapy followed by maintenance RITUXAN® (Rituximab). This can result in a median PFS of 6-8 yrs and a median OS of 12-15 yrs. However, approximately 30% of the patients will relapse in 3 years and treatment options are limited for patients with relapses, after multiple treatments.

UKONIQ® is an oral, once-daily, dual inhibitor of Phosphatidylinositol-3-Kinase-delta (PI3Kδ) and Casein Kinase 1-epsilon (CK1-epsilon) that exhibits improved selectivity for the delta isoform of PI3K. In contrast with other PI3K inhibitors, there was a low incidence of immune-mediated toxicities with UKONIQ® possibly attributable to enhanced selectivity for the PI3Kδ isoform as well as inhibition of CK1-epsilon.

The present FDA approval was based on the UNITY-NHL trial (NCT02793583), which is global, multicenter, open-label, multicohort, Phase IIb registration study, designed to evaluate the safety and efficacy of UKONIQ® in previously treated NHL patients. This study had a total 208 patients with indolent NHL and included 69 patients with MZL (splenic, nodal, extranodal), 117 patients with FL (grade 1, 2, 3a), and 22 patients with Small Lymphocytic Lymphoma (SLL). MZL patients were Relapsed/Refractory to 1 or more prior lines of treatment, which included an anti-CD20, while FL and SLL patients were Relapsed/Refractory to 2 or more prior lines of therapy, which included an anti-CD20 and an alkylating agent. UKONIQ® was administered at 800 mg orally once daily in 28-day treatment cycles until disease progression or unacceptable tolerability. The median age was 66 years and the median duration of treatment exposure was 8.4 months. Pneumocystis jiroveci Pneumonia (PCP) and anti-viral prophylaxis were mandated for all patients. The Primary endpoint of the study was Overall Response Rate (ORR) as assessed by an Independent Review Committee (IRC) and Secondary endpoints included Duration of Response (DoR), Progression Free Survival (PFS), Time To Response (TTR), and Safety.

With a median follow up of 27.8 months, the ORR for patients with MZL was 49%, with a 16% Complete Response (CR) rate and a Disease Control Rate (CR+PR+SD) of 82.6%. The ORR was consistent amongst MZL subtypes and no patients who achieved CR had experienced disease progression to date. Additionally, the median DoR and median PFS was not reached for this patient population.

Among patients with FL, with a median follow up of 27.5 months, the ORR was 45%, with 5% achieving a CR, and a DCR of 79.5%. The median TTR was 4.6 months and the median DoR was 11.1 months. The median PFS was 10.6 months.

Among SLL patients, with a median follow up of 29.3 months, the ORR was 50%, with 4.5% achieving a CR, and a DCR of 86.4%. The median TTR was 2.7 months and the median DoR was 18.3 months. The median PFS was 20.9 months.

The most common toxicities included increased creatinine, diarrhea/colitis, fatigue, transaminase elevation, musculoskeletal pain, neutropenia, anemia, thrombocytopenia, upper respiratory tract infection, nausea, vomiting, abdominal pain, reduced appetite, and cutaneous reactions.

It was concluded from this study that UKONIQ® has a favorable benefit-risk profile and achieved meaningful clinical activity in a heavily pretreated population of patients with indolent NHL. The authors added that the safety profile was manageable, with a relatively low incidence of immune-mediated toxicities and treatment discontinuations.

Umbralisib, the Once Daily Dual Inhibitor of PI3Kδ and Casein Kinase-1ε Demonstrates Clinical Activity in Patients with Relapsed or Refractory Indolent Non-Hodgkin Lymphoma: Results from the Phase 2 Global Unity-NHL Trial. Zinzani PL, Samaniego F, Jurczak W, et al. Presented at the 62nd ASH Annual Meeting and Exposition, December 5-8, 2020. Abstract # 2934.