Tag: Non-Hodgkin Lymphoma

FDA Approves JAYPIRCA® for Relapsed or Refractory Mantle Cell Lymphoma

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SUMMARY: The FDA on January 27, 2023, granted accelerated approval to JAYPIRCA® (Pirtobrutinib) for Relapsed or Refractory Mantle Cell Lymphoma (MCL) after at least two lines of systemic therapy, including a BTK inhibitor.

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. In the US, approximately 3,300 new cases of MCL are diagnosed 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.

Bruton’s 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 promotes 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 MCL include IMBRUVICA® (Ibrutinib) approved in 2013, CALQUENCE® (Acalabrutinib) approved in 2017, and BRUKINSA® (Zanubrutinib) approved in 2019. Covalent BTK inhibitors have transformed the treatment landscape of Mantle Cell Lymphoma. Despite the efficacy of covalent BTK inhibitors, treatment failure often occurs through development of resistance or intolerance.

JAYPIRCA® is a highly selective, reversible (non-covalent) Bruton’s Tyrosine Kinase (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. JAYPIRCA® is 300 times more selective in BTK inhibition versus 98% of other kinases tested in preclinical studies and inhibits both wildtype and C481-mutant BTK with equal low nM potency, and has favorable oral pharmacology. JAYPIRCA® 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 BRUIN Phase I/II clinical trial is the ongoing first-in-human, global, open-label, multicenter single armstudy, which evaluated the efficacy of JAYPIRCA® in previously treated patients with Mantle Cell Lymphoma (MCL), Chronic Lymphocytic Leukemia (CLL), Small Lymphocytic Lymphoma (SLL), or other Non-Hodgkin Lymphomas (NHL). The trial included a Phase I dose-escalation component in which the daily dosing of JAYPIRCA® between 25 mg and 300 mg was evaluated, a Phase Ib drug combination safety arm, and a Phase II dose-expansion component, in which JAYPIRCA® 200 mg daily, as a part of 28-day cycles, is being evaluated.

The present FDA approval is based on data from a subset of patients with Mantle Cell Lymphoma (N=120) in the BRUIN Phase I/II trial, treated with JAYPIRCA® 200 mg once daily until disease progression or unacceptable toxicity. Patients had received a median of three prior lines of therapy with 93% having two or more prior lines, and all patients received one or more prior lines of therapy containing a covalent BTK inhibitor. The most common prior BTK inhibitors received were Ibrutinib (67%), Acalabrutinib (30%), and Zanubrutinib (8%), and 83% had discontinued their last BTK inhibitor due to refractory or progressive disease. Patients with active Central Nervous System Lymphoma or allogeneic Hematopoietic Stem Cell Transplantation or CAR T-cell therapy within 60 days were excluded. The main efficacy measures were Overall Response Rate (ORR) and Duration of Response (DOR), as assessed by an Independent Review Committee, using 2014 Lugano criteria.

The ORR was 50%, with a Complete Response rate of 13%, and the Partial Response rate was 38%. The Time to Response was 1.8 months. The estimated median Duration of Response was 8.3 months, and the estimated Duration of Response rate at 6 months was 65.3%. The most common adverse reactions in 15% or more of MCL patients were fatigue, musculoskeletal pain, diarrhea, edema, dyspnea, pneumonia, and bruising. Grade 3 or 4 laboratory abnormalities in 10% or more of patients were cytopenias.

It was concluded that JAYPIRCA® offers a new approach to targeting the BTK pathway for Relapsed and Refractory Mantle Cell Lymphoma patients, previously treated with a covalent BTK inhibitor. The researchers added that this approval of JAYPIRCA® represents an important advance for this group of patients who currently have limited treatment options and have a poor prognosis.

Efficacy of Pirtobrutinib in Covalent BTK-Inhibitor Pre-Treated Relapsed / Refractory Mantle Cell Lymphoma: Additional Patients and Extended Follow-up from the Phase 1/2 BRUIN Study. Wang ML, Shah NN, Jurczak W. Presented at the 64th ASH Annual Meeting and Exposition, December 10-13, 2022, New Orleans, Louisiana. Abstract # 4218.

FDA Approves BRUKINSA® for Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

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SUMMARY: The FDA on January 19, 2023, approved BRUKINSA® (Zanubrutinib) for Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL). 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.

Bruton’s 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 promotes programmed cell death (Apoptosis) by blocking B-cell activation and signaling.

Zanubrutinib (BRUKINSA®) is an irreversible, potent, next-generation, small molecule inhibitor of Bruton’s Tyrosine Kinase, designed to deliver targeted and sustained inhibition of the BTK protein by optimizing bioavailability, half-life, and selectivity, while minimizing off-target inhibition of TEC- and EGFR-family kinases. It has been hypothesized that the increased selectivity of BRUKINSA® may minimize toxicities, (such as those often associated with Ibrutinib (IMBRUVICA®) and improve efficacy outcomes. BRUKINSA® demonstrated promising efficacy among patients with CLL/SLL (Small Lymphocytic Lymphoma), in early phase trials.

SEQUOIA is a randomized, multicenter, global Phase III trial, designed to evaluate the efficacy and safety of BRUKINSA® compared to Bendamustine plus Rituximab in patients with treatment naïve CLL or SLL. This trial consists of three cohorts:
Cohort 1 (N=479): Patients NOT harboring del(17p) were randomized 1:1 to receive BRUKINSA® (N=241) or Bendamustine plus Rituximab (N=238) until disease progression or unacceptable toxicity. Patients with del(17p) were not randomized to Bendamustine plus Rituximab, as they experience poor clinical outcomes and poor response to chemoimmunotherapy. Data from this group comprise the Primary endpoint
Cohort 2 (N=110): Patients WITH del(17p) received BRUKINSA® as a monotherapy.
Cohort 3 (enrollment ongoing): Patients WITH del(17p) or pathogenic TP53 variant receiving BRUKINSA® in combination with Venetoclax.

Treatment in Cohort 1 consisted of BRUKINSA® 160 mg orally twice daily as 28-day cycles or Bendamustine 90 mg/m2 IV on Days 1 and 2 for six cycles plus Rituximab 375 mg/m2 IV, the day before or on Day 1 of Cycle 1, and 500 mg/m2 IV on Day 1 of Cycles 2-6. Both treatment groups were well balanced, with more than 50% with unmutated IGHV gene and 18% with del(11q) in each group. Eligible patients had untreated CLL or SLL requiring treatment as per International Workshop on CLL criteria, were 65 years or older, or 18 years or older with comorbidities, WITHOUT del(17p), and had an ECOG PS of 0-2. The Primary endpoint of the SEQUOIA trial was Progression Free Survival (PFS) per Independent Review Committee (IRC) assessment in the randomized Cohort 1 group of patients. Secondary endpoints included Overall Response Rates (ORR), Overall Survival (OS) and Safety.

At the interim analysis, with a median follow-up of 26.2 months, BRUKINSA demonstrated superiority in PFS over Bendamustine plus Rituximab. The median PFS was Not Reached in the BRUKINSA® group and was 33.7 months in the Bendamustine plus Rituximab group. The 24-month PFS rate was 85.5% in the BRUKINSA® group, compared to 69.5% in in the Bendamustine plus Rituximab group (HR=0.42; P<0.0001). This PFS benefit was consistently observed across key patient subgroups, including patients with del(11q), unmutated IGHV status, Binet Stage C, and bulky disease.

In a separate non-randomized group of patients in Cohort 2 of SEQUOIA trial, BRUKINSA® monotherapy was evaluated in 110 patients with previously untreated CLL/SLL, WITH 17p deletion. The Overall Response Rate (ORR) per IRC was 88% and the median Duration of Response (DOR) was not reached after a median follow-up of 25.1 months. The 18-month PFS in this group was 90.6%. Across clinical trials of BRUKINSA® the most common adverse events were neutropenia, upper respiratory tract infection, thrombocytopenia, hemorrhage, and musculoskeletal pain. Atrial fibrillation or flutter were reported in 3.7% of patients.

The researchers from this study concluded that BRUKINSA® significantly improved Progression Free Survival compared to Bendamustine plus Rituximab, in patients with untreated CLL and SLL with an acceptable safety profile, like what has been reported in other BRUKINSA® clinical trials, with consistently low rates of atrial fibrillation. They added that BRUKINSA® as a highly selective BTK inhibitor, can potentially provide a chemo-free treatment option for CLL patients.

Zanubrutinib versus bendamustine and rituximab in untreated chronic lymphocytic leukaemia and small lymphocytic lymphoma (SEQUOIA): a randomised, controlled, phase 3 trial. Tam CS, Brown JR, Kahl BS, et al. The Lancet Oncology 2022;23:1031-1043

FDA Approves Bispecific Antibody LUNSUMIO® for Follicular Lymphoma

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SUMMARY: The FDA on December 22, 2022, granted accelerated approval to LUNSUMIO® (Mosunetuzumab-axgb), a bispecific CD20-directed CD3 T-cell engager for adult patients with Relapsed or Refractory Follicular Lymphoma (FL) after two or more lines of systemic therapy.

The American Cancer Society estimates that in 2022, about 80,470 people were diagnosed with Non Hodgkin Lymphoma (NHL) in the United States and about 20,250 individuals died 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 22% 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 Progression Free Survival of 6-8 years. However, approximately 30% of the patients will relapse in 3 years, and treatment options are limited for patients with relapses after multiple treatments. Patients with Follicular Lymphomas often experience a relapsing and remitting pattern of disease and may be exposed to multiple lines of therapy over the course of their disease. In spite of the availability of multiple systemic therapies for Follicular Lymphoma, the efficacy of these regimens drops off rapidly with later lines of therapy. Novel therapies are therefore being investigated to improve outcomes.

LUNSUMIO® is a first-in-class CD20 x CD3 T-cell engaging 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.

This FDA approval was based on the positive results from the Phase II GO29781 study, which is a multicenter, open-label, dose-escalation and dose-expansion trial evaluating the safety, efficacy, and pharmacokinetics of LUNSUMIO® in patients with heavily pretreated Follicular Lymphoma, including those who were at high risk of disease progression or whose disease was refractory to prior therapies. The efficacy population consisted of 90 enrolled patients with Relapsed or Refractory FL (Grade 1-3a) who had received at least two prior lines of systemic therapy, including an anti-CD20 monoclonal antibody and an alkylating agent.

LUNSUMIO® was administered IV in 21-day cycles with Cycle 1 step-up dosing of 1 mg on Cycle 1, Day 1, 2 mg on Cycle 1 Day 8, 60 mg on Cycle 1 Day 15, 60 mg on Cycle 2 Day 1, and 30 mg on Day 1 in subsequent cycles. Patients with a Complete Response discontinued therapy after 8 cycles. Patients with a Partial Response or Stable disease continued treatment for up to 17 cycles unless they experienced progressive disease or unacceptable toxicity. The Primary endpoint was Objective Response Rate (ORR) assessed by an Independent Review Committee according to standard criteria for Non-Hodgkins Lymphoma.

The ORR was seen in 80% of patients treated with LUNSUMIO® with 60% achieving Complete Responses. A majority of patients (57%) maintained responses for at least 18 months. With a median follow up of 14.9 months among responders, the estimated median Duration of Response was 22.8 months and the estimated Duration of Response at 12 months and 18 months was 62% and 57%, respectively. Among 218 patients with hematologic malignancies who received LUNSUMIO® at the recommended dose, the most common Adverse Event was Cytokine Release Syndrome (CRS) seen in 39% of patients, which can be severe and life-threatening. The median duration of CRS events was 3 days. Other common Adverse Events included fatigue, rash, fever and headache.

It was concluded from this study that in patients with heavily pretreated Follicular Lymphoma, chemotherapy-free, fixed-duration treatment with LUNSUMIO® induced high rates of Complete Remissions with favorable safety profile, allowing potential administration as an outpatient regimen.

Safety and efficacy of mosunetuzumab, a bispecific antibody, in patients with relapsed or refractory follicular lymphoma: a single-arm, multicentre, phase 2 study. Budde LE, Sehn LH, Matasar M, et al. The Lancet Oncology 2022; 23:1055-1065.

BREYANZI® (Lisocabtagene maraleucel)

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The FDA on June 24, 2022, approved BREYANZI® (Lisocabtagene maraleucel) for adult patients with Large B-Cell Lymphoma (LBCL) who have refractory disease to first-line chemoimmunotherapy, or relapse within 12 months of first-line chemoimmunotherapy; or refractory disease to first-line chemoimmunotherapy or relapse after first-line chemoimmunotherapy and are not eligible for Hematopoietic Stem Cell Transplantation (HSCT) due to comorbidities or age. It is not indicated for the treatment of patients with primary Central Nervous System lymphoma. BREYANZI® is a product of Juno Therapeutics, Inc.

Late Breaking Abstract – ASCO 2022: IMBRUVICA® plus Bendamustine and Rituximab for Older Patients with Untreated Mantle Cell Lymphoma

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SUMMARY: The American Cancer Society estimates that in 2022, about 80,470 people will be diagnosed with Non Hodgkin Lymphoma (NHL) in the United States and about 20,250 individuals will die of this disease. In the US, approximately 3,300 new cases of MCL are diagnosed 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. These patients often receive less aggressive first line therapy such as Bendamustine plus Rituximab, and this regimen has demonstrated superior Progression Free Survival compared to R-CHOP, with a better safety profile. Further, the addition of Rituximab maintenance therapy after induction therapy with Bendamustine and Rituximab has shown significantly prolonged Progression Free Survival or Overall Survival in two independent observational studies.

Bruton’s 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. Following binding of antigen to the B-Cell Receptor, kinases such as Syk (Spleen Tyrosine Kinase), Lyn (member of the Src family of protein tyrosine kinases) and BTK (Bruton’s Tyrosine Kinase) are activated, with subsequent propagation through PI3K/Akt, MAPK, and NF-κB pathways. This results in B-cell activation and proliferation. The 3 BTK inhibitors presently approved by the FDA for MCL include, IMBRUVICA® (Ibrutinib) approved in 2013, CALQUENCE® (Acalabrutinib) approved in 2017, and BRUKINSA® (Zanubrutinib) approved in 2019.

Single agent IMBRUVICA® is presently approved by the FDA for the treatment of MCL patients who have received at least one prior therapy. In a Phase Ib study, the addition of IMBRUVICA® to Bendamustine and Rituximab therapy was safe and effective with a Complete Response Rate of 76%, among patients with untreated, relapsed, or refractory MCL.

SHINE study is an international, randomized, double-blind, Phase III trial , in which a combination of IMBRUVICA® with Bendamustine plus Rituximab and Rituximab maintenance therapy was compared with placebo with Bendamustine plus Rrituximab and Rituximab maintenance therapy, in elderly patients with untreated Mantle Cell Lymphoma (MCL). A total of 523 previously untreated patients, 65 years of age or older, who had a centrally confirmed diagnosis of Mantle Cell Lymphoma with Cyclin D1 overexpression or translocation breakpoints at t(11;14) were randomly assigned in a 1:1 ratio to receive either to six cycles of IMBRUVICA® along with Bendamustine and Rituximab (N=261) or six cycles of placebo along with Bendamustine and Rituximab (N=262). IMBRUVICA® 560 mg or placebo was administered orally once daily. Bendamustine was administered at 90 mg/m2 IV on days 1 and 2 of each 28 day cycle along with Rituximab 375 mg/m2 IV on day 1 of each 28 day cycle. Patients in either arm who achieved a Complete or Partial Response continued to receive IMBRUVICA® or placebo daily along with Rituximab maintenance therapy at a dose of 375 mg/m2 IV every 8 weeks for up to 12 additional doses. Patients with stable disease after induction treatment could continue to receive IMBRUVICA® or placebo until disease progression or unacceptable toxicities. Both treatment groups were well balanced. The median age of the patients was 71 years and eligible patients had documented Stage II to IV disease with at least one measurable site of disease that was at least 1.5 cm in the longest diameter. Patients were excluded if stem-cell transplantation was planned or if they had known CNS involvement. The Primary endpoint was Progression Free Survival (PFS). Secondary endpoints included Objective Response Rate, Complete Response Rate, Overall Survival and Safety.

The study met its Primary endpoint and at a median follow up of 84.7 months, the median PFS was 80.6 months in the IMBRUVICA® group and 52.9 months in the placebo group (HR for disease progression or death=0.75; P=0.01). The Complete Response Rate was 65.5% in the IMBRUVICA® group and 57.6% in the placebo group (P=0.06). The Overall Survival was similar in the two treatment groups. Grade 3 or 4 adverse events during treatment were 81.5% in the IMBRUVICA® group and 77.3% in the placebo group and the most common Grade 3 and 4 adverse events were rash, pneumonia, and atrial fibrillation.

The authors concluded that treatment with IMBRUVICA® in combination with standard chemoimmunotherapy significantly prolonged Progression Free Survival, and may be a new treatment option for elderly patients with newly diagnosed Mantle Cell Lymphoma, who may not be candidates for intensive chemotherapy or Autologous Stem Cell Transplantation.

Ibrutinib plus Bendamustine and Rituximab in Untreated Mantle-Cell Lymphoma. Wang ML, Jurczak W, Jerkeman M, et al. June 3, 2022. DOI: 10.1056/NEJMoa2201817.
DOI: 10.1200/JCO.2022.40.17_suppl.LBA7502 Journal of Clinical Oncology 40, no. 17_suppl (June 10, 2022)