Tag: Chronic Lymphocytic Leukemia

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

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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.

Chronic Lymphocytic Leukemia Therapy Guided by Minimal Residual Disease

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SUMMARY: 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) 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 CLL, Mantle Cell Lymphoma (MCL), and Waldenstrom Macroglobulinemia (WM). Four BTK inhibitors are presently approved by the FDA. They include first generation Ibrutinib (IMBRUVICA®) and second generation agents such as Acalabrutinib (CALQUENCE®), Zanubrutinib (BRUKINSA®) and Pirtobrutinib (JAYPIRCA®).

The pro-survival (anti-apoptotic) protein BCL2 is over expressed by CLL cells and regulates clonal selection and cell survival. Venetoclax (VENCLEXTA®) is a second generation, oral, selective, small molecule inhibitor of BCL2 and restores the apoptotic processes in tumor cells. The combination of Ibrutinib plus Venetoclax was noted to be synergistic.

The FLAIR trial initially compared Ibrutinib plus Rituximab with Fludarabine, Cyclophosphamide, and Rituximab (FCR) in previously untreated patients with CLL who were candidates for chemoimmunotherapy. This study in 2017 was adapted to include both Ibrutinib monotherapy, and Ibrutinib-Venetoclax, with therapy duration defined according to MRD (Minimal Residual Disease). An interim analysis of Ibrutinib monotherapy as compared with Ibrutinib-Venetoclax showed superiority of Ibrutinib-Venetoclax in achieving undetectable MRD. The researchers herein presented the results of a planned interim analysis, comparing MRD-guided Ibrutinib-Venetoclax with FCR.

The FLAIR study is a Phase III, multicenter, randomized, controlled, open-label platform trial, designed to evaluate the efficacy of the combination of Ibrutinib and Venetoclax compared to the standard of care regimen Fludarabine, Cyclophosphamide, and Rituximab (FCR), in previously untreated CLL patients. The study focused on individualizing the duration of treatment using high-sensitivity testing for Minimal Residual Disease (MRD) in the blood (less than 1 CLL cell in 10,000 by Flow cytometry). A total of 523 eligible patients were randomly assigned to receive either FCR (N=263) or Ibrutinib-Venetoclax (N=260). Patients in the FCR group received Rituximab 375 mg/m2 IV on day 1 of cycle 1, and at 500 mg/m2 on day 1 of cycles 2-6 of a 28-day cycle, Fludarabine 24 mg/m2 per day orally on day 1-5 and Cyclophosphamide 150 mg/m2 per day orally on days 1-5, for up to 6 cycles. Ibrutinib-Venetoclax group received 2 months of Ibrutinib lead-in at 420 mg orally daily followed by the addition of Venetoclax 400 mg orally daily, which could last from 2 to 6 years based on MRD. Venetoclax was escalated weekly starting from 20 mg. MRD assessment was conducted at 12 months and then every 6 months in the Ibrutinib-Venetoclax group. If MRD was negative, it was repeated at 3 months and 6 months in both peripheral blood and bone marrow. If all MRD tests were negative, the patient was treated for twice the duration from the start of Ibrutinib-Venetoclax treatment to the first MRD-negative test. Patients with more than 20% 17p deleted cells were excluded from the study. The median age was 62 years, and 41% had Binet Stage C disease. The Primary end point was Progression Free Survival (PFS) in the Ibrutinib-Venetoclax group, as compared with the FCR group. Key Secondary end points included Overall Survival, Response Rates, MRD, and Safety.

The median follow-up was 43.7 months. At 3 years, 97.2% of patients treated with Ibrutinib-Venetoclax remained progression-free compared to 76.8% with FCR (HR=0.13; P<0.0001). The 3 year Overall Survival was 98% in the Ibrutinib-Venetoclax group compared to 93% in the FCR group (HR=0.31; P<0.005). Patients with poor prognostic features, such as unmutated immunoglobulin genes (IGHV) or the 11q chromosome deletion, showed particularly favorable outcomes with Ibrutinib-Venetoclax. For example, patients with unmutated IGHV were about 14 times less likely to have disease progression with Ibrutinib-Venetoclax, than with FCR. At the latest follow-up, none of the patients with 11q chromosome deletion who were treated with Ibrutinib-Venetoclax had disease progression or had died, compared with 31.2% of patients with this deletion who were treated with FCR. At 3 years, 58% of the patients in the Ibrutinib-Venetoclax group had stopped therapy owing to undetectable MRD and after 5 years of Ibrutinib-Venetoclax therapy, 66% of the patients had undetectable MRD in the bone marrow and 93% had undetectable MRD in the peripheral blood.

The risk of infection was similar in the Ibrutinib-Venetoclax group and the FCR group. The incidence of serious cardiac adverse events was higher in the Ibrutinib-Venetoclax group, than in the FCR group (10.7% versus 0.4%).

This study concluded that MRD-directed treatment with Ibrutinib-Venetoclax improved Progression Free Survival and Overall Survival, as compared with FCR, among newly diagnosed CLL patients, establishing a new standard for CLL treatment.

Chronic Lymphocytic Leukemia Therapy Guided by Measurable Residual Disease. Munir T, Cairns DA, Bloor A, et al. for the National Cancer Research Institute Chronic Lymphocytic Leukemia Subgroup. December 10, 2023. DOI: 10.1056/NEJMoa2310063.

FDA Approves JAYPIRCA® for Chronic Lymphocytic Leukemia

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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.

First-Line Time Limited Venetoclax Combinations in Chronic Lymphocytic Leukemia

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SUMMARY: 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. Three BTK inhibitors are presently approved by the FDA. They include first generation Ibrutinib (IMBRUVICA®) and second generation agents such as Acalabrutinib (CALQUENCE®) and Zanubrutinib (BRUKINSA®).

The pro-survival (anti-apoptotic) protein BCL2 is over expressed by CLL cells and regulates clonal selection and cell survival. A new class of anticancer agents known as BH3-mimetic drugs mimic the activity of the physiologic antagonists of BCL2 and related proteins and promote apoptosis (programmed cell death). Venetoclax (VENCLEXTA®) is a second generation, oral, selective, small molecule inhibitor of BCL2 and restores the apoptotic processes in tumor cells.

In previously published studies, Venetoclax in combination with Obinutuzumab or Rituximab as first-line therapy led to a high incidence of undetectable Minimal Residual Disease (MRD) and long Progression-Free Survival, among patients who are not fit, and patients with relapsed disease. However, there is no data from prospective, randomized clinical trials evaluating the safety and efficacy of Venetoclax-Obinutuzumab combination in fit patients with CLL with normal renal function. Combining BCL2 inhibitors with BTK inhibitors have induced undetectable Minimal Residual Disease and improved disease control.

GAIA-CLL13 trial is a prospective, open-label, multicenter, four-group, Phase III trial, designed to evaluate the efficacy and safety of two fixed-duration regimens and one time-limited combination of Venetoclax plus anti-CD20 antibodies (Venetoclax-Rituximab, Venetoclax-Obinutuzumab, and Venetoclax-Obinutuzumab-Ibrutinib), as compared with chemoimmunotherapy, in the first-line treatment of young patients with CLL who are fit (low burden of coexisting conditions with no TP53 aberrations).

In this study, a total of 926 patients (N=926) were randomly assigned in a 1:1:1:1 ratio to receive six cycles of chemoimmunotherapy (N=229) or 12 cycles of treatment with either Venetoclax-Rituximab (N=237), Venetoclax-Obinutuzumab (N=229), or Venetoclax-Obinutuzumab-Ibrutinib (N=231). Chemoimmunotherapy consisted of Fludarabine 25 mg/m2 IV and Cyclophosphamide 250 mg/m2 IV, given on day 1-3 of each cycle, and patients older than 65 years of age received Bendamustine 90 mg/m2 IV on day 1 and 2 of each cycle. Rituximab 375 mg/m2 IV was added to chemotherapy on day 1 of cycle 1, and at a dose of 500 mg/m2 IV on day 1 of each of the next five cycles.

The three experimental regimens contained Venetoclax 400 mg orally daily for ten 28-day cycles after a 5-week ramp-up phase from day 22 in cycle 1 until the end of cycle 2. In the Venetoclax-Rituximab group, Rituximab was administered at a dose of 375 mg/m2 IV on day 1 of cycle 1 and at a dose of 500 mg/m2 on day 1 of each of the next five cycles. In the Obinutuzumab-containing regimens, Obinutuzumab was administered at a dose of 100 mg IV on day 1, 900 mg IV on day 2, and then 1000 mg IV on day 8 and 15 of cycle 1. On day 1 of the subsequent five cycles, Obinutuzumab was administered at a dose of 1000 mg IV. In the triple-combination regimen (Venetoclax-Obinutuzumab-Ibrutinib), Ibrutinib 420 mg orally daily was initiated along with the first Obinutuzumab infusion on day 1 of cycle 1 and was continued throughout the 12 treatment cycles, to which Venetoclax was added as described for the Venetoclax-Obinutuzumab regimen above. Ibrutinib was discontinued after two consecutive measurements of undetectable MRD or could be extended. The median patient age was 61 years and all the treatment groups were well balanced with respect to patient characteristics. The Primary end points were undetectable MRD ( less than 10−4, which meant less than 1 CLL cell in 10,000 leukocytes]) as assessed by flow cytometry in peripheral blood at month 15, and Progression Free Survival.

At 15 months, the percentage of patients with undetectable MRD, the Primary endpoint, was significantly higher in the Venetoclax-Obinutuzumab group (86.5%) and the Venetoclax-Obinutuzumab–Ibrutinib group (92.2%), compared to the chemoimmunotherapy group (52.0%), P<0.001 for both comparisons. However, the Primary endpoint of undetectable MRD was not significantly higher in the Venetoclax-Rituximab group compared to the chemoimmunotherapy group (57% versus 52%; P=0.32).

At a median follow up of 38.8 months, the interim analysis of 3-year Progression Free Survival (the second Primary end point) was superior in the Venetoclax-Obinutuzumab-Ibrutinib group (90.5%; HR=0.32; P<0.001) and the Venetoclax-Obinutuzumab group (87.7%; HR=0.42; P<0.001), compared to the chemoimmunotherapy group (75.5%). This PFS benefit was not seen in the in the Venetoclax-Rituximab group when compared to chemoimmunotherapy (80.8%; HR=0.79, P=0.18). Grade 3 and 4 infections were more common with chemoimmunotherapy (18.5%) and Venetoclax-Obinutuzumab–Ibrutinib (21.2%) than with Venetoclax-Obinutuzumab (13.2%) and Venetoclax-Rituximab (10.5%).

It was concluded that Venetoclax-Obinutuzumab combination with or without Ibrutinib was superior to chemoimmunotherapy as first-line treatment in fit patients with CLL, with higher rates of undetectable MRD and Progression Free Survival.

First-Line Venetoclax Combinations in Chronic Lymphocytic Leukemia. Eichhorst B, Niemann CU, Kater AP, et al., for the GCLLSG, the HOVON and Nordic CLL Study Groups, the SAKK, the Israeli CLL Association, and Cancer Trials Ireland. N Engl J Med 2023; 388:1739-1754

BRUKINSA® for First Line Treatment of Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

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SUMMARY: 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

BRUKINSA® Superior to IMBRUVICA® in Relapsed/Refractory CLL/SLL

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SUMMARY: The American Cancer Society estimates that for 2022, about 20,160 new cases of Chronic Lymphocytic Leukemia (CLL) will be diagnosed in the US and 4410 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. Ibrutinib (IMBRUVICA®) is an oral, irreversible inhibitor of BTK and inhibits cell proliferation and promotes programmed cell death (Apoptosis) by blocking B-cell activation and signaling. IMBRUVICA® demonstrated survival benefits, when compared to chemoimmunotherapy, both in previously untreated (RESONATE-2), as well as relapsed (RESONATE) CLL patients. However, toxicities leading to IMBRUVICA® discontinuation occurred in a significant number of patients, and Atrial Fibrillation was noted in 11-16% of patients and hypertension rates were between 20-26%.

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 IMBRUVICA®) and improve efficacy outcomes. BRUKINSA® demonstrated promising efficacy among patients with CLL/SLL (Small Lymphocytic Lymphoma), in early phase trials.

ALPINE study is a randomized, global, Phase III trial in which BRUKINSA® was compared with IMBRUVICA® in previously treated patients with relapsed or refractory CLL or SLL. In this trial, a total of 652 patients were randomly assigned 1:1 to receive either BRUKINSA® 160 mg orally twice daily or IMBRUVICA® 420 mg orally once daily, until disease progression or unacceptable toxicity. Enrolled patients had at least one prior systemic therapy and were required to have measurable lymphadenopathy by CT scan or MRI. Exclusion criteria included current or past Richter’s transformation and prior treatment with BTK inhibitors. The median age was 67 years, 45% of the patients had bulky disease with a tumor that was 5 cm or more in the greatest dimension, 73% had unmutated IGHV status, and 23% had a chromosome 17p deletion, TP53 mutation, or both and fewer than 15% of patients were on anticoagulants. The median number of previous lines of therapy was 1 and a total of 80% of the patients in the BRUKINSA® group and 76% of those in the IMBRUVICA® group had previously received chemoimmunotherapy. The Primary end point of the trial was Overall Response Rate (ORR) assessed by investigator and Independent Review Committee (IRC), and Secondary end points included Progression Free Survival (PFS), event rate of Atrial Fibrillation or Flutter, Duration of Response, Time to Treatment Failure, Overall Survival (OS), Patient-Reported Outcomes, and Safety.

A prespecified interim analysis showed that BRUKINSA® was superior to IMBRUVICA®, with respect to Overall Response Rate. The authors in this final analysis reported the clinical outcomes of Progression Free Survival, a key Secondary endpoint. Progression Free Survival was assessed with the use of a hierarchical testing strategy to determine whether BRUKINSA® was noninferior to IMBRUVICA®. If noninferiority was established, the superiority of BRUKINSA® was assessed and claimed if the two-sided P value was less than 0.05.

At a median follow up of 29.6 months, BRUKINSA® was found to be superior to IMBRUVICA® with respect to Progression Free Survival, as assessed by the investigators and Independent Review Committee (HR=0.65; P=0.002). The PFS at 24 months was 78.4% in the BRUKINSA® group and 65.9% in the IMBRUVICA® group. Median PFS was not reached in the BRUKINSA® group and was 34.2 months in the IMBRUVICA® group.

Among patients with a 17p deletion, a TP53 mutation, or both, those who received BRUKINSA® had longer PFS than those who received IMBRUVICA® (HR=0.53). The percentage of patients who were alive without disease progression at 24 months in this high-risk population was 72.6% in the BRUKINSA® group, and 54.6% in the IMBRUVICA® group. The PFS benefit was in favor of BRUKINSA® across major prespecified subgroups, including age, previous lines of therapy, disease stage, and IGHV mutational status.

Consistent with the findings at the interim analysis, the Overall Response Rate was higher in the BRUKINSA® group than in the IMBRUVICA® group, and were 86.2% and 75.7%, respectively, as assessed by the Independent Review Committee.

BRUKINSA® had a more favorable safety profile, with a lower incidence of cardiac disorders (21.3%), than in the IMBRUVICA® group (29.6%). Cardiac events leading to treatment discontinuation occurred in 0.3% of patients in the BRUKINSA® group and in 4.3% of patients in the IMBRUVICA® group. The incidence of Atrial fibrillation or flutter of any grade, a key Secondary endpoint, was lower in the BRUKINSA® group than in the IMBRUVICA® group (5.2% versus 13.3%).

It was concluded that in patients with Relapsed or Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma, treatment with BRUKINSA® resulted in a significantly longer Progression Free Survival, compared to those patients who received IMBRUVICA®, and BRUKINSA® was associated with fewer cardiac adverse events.

Zanubrutinib or Ibrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia. Brown JR, Eichhorst B, Hillmen P, et al. N Engl J Med 2023; 388:319-332.

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

BRUKINSA® Superior to IMBRUVICA® in Relapsed/Refractory CLL/SLL

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SUMMARY: The American Cancer Society estimates that for 2022, about 20,160 new cases of Chronic Lymphocytic Leukemia (CLL) will be diagnosed in the US and 4410 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. Ibrutinib (IMBRUVICA®) is an oral, irreversible inhibitor of BTK and inhibits cell proliferation and promotes programmed cell death (Apoptosis) by blocking B-cell activation and signaling. IMBRUVICA® demonstrated survival benefits when compared to chemoimmunotherapy both in previously untreated (RESONATE-2), as well as relapsed (RESONATE) CLL patients. However, toxicities leading to IMBRUVICA® discontinuation occurred in a significant number of patients, and Atrial Fibrillation was noted in 11-16% of patients and hypertension rates were between 20-26%.

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 IMBRUVICA®) and improve efficacy outcomes. BRUKINSA® demonstrated promising efficacy among patients with CLL/SLL (Small Lymphocytic Lymphoma), in early phase trials.

ALPINE study is a randomized, global, Phase III trial in which BRUKINSA® was compared with IMBRUVICA® in previously treated patients with relapsed or refractory CLL or SLL. In this trial, a total of 652 patients were randomly assigned 1:1 to receive either BRUKINSA® 160 mg orally twice daily or IMBRUVICA® 420 mg orally once daily, until disease progression or unacceptable toxicity. Enrolled patients had at least one prior systemic therapy and were required to have measurable lymphadenopathy by CT scan or MRI. Exclusion criteria included current or past Richter’s transformation and prior treatment with BTK inhibitors. Approximately 20% of patients had a del(17p) and/or TP53 mutation and fewer than 15% of patients were on anticoagulants. The Primary end point of the trial was Overall Response Rate (ORR) assessed by investigator and Independent Review Committee (IRC), and Secondary end points included Progression Free Survival (PFS), event rate of Atrial Fibrillation or Flutter, Duration of Response, Time to Treatment Failure, Overall Survival (OS), Patient-Reported Outcomes, and Safety.

BeiGene recently announced that BRUKINSA® achieved superior Progression Free Survival (PFS) when compared to IMBRUVICA® in the final analysis of this Phase III ALPINE trial, as assessed by an Independent Review Committee (IRC) and investigator. This data will be presented at future scientific meetings. The interim analysis conducted at a median follow-up was 15 months showed significantly higher Overall Response Rate with BRUKINSA®, compared with IMBRUVICA® (78.3% versus 62.5%; P =0.0006). The Overall Response Rate was higher in patients with del11q (83.6% versus 69.1%) and del17p (83.3% versus 53.8%) with BRUKINSA®, as well as the overall 12-month Progression Free Survival (94.9% versus 84.0%) and Overall Survival rates (97.0% versus 92.7%). Major bleeding rates as well as adverse events leading to treatment discontinuation, was lower with BRUKINSA®, compared to IMBRUVICA®. The rate of Atrial Fibrillation/Flutter, a pre-specified safety endpoint, was significantly lower with BRUKINSA®, compared to IMBRUVICA® (2.5% versus 10.1%; P=0.0014).

It was concluded from this randomized, Phase III study that, among patients with relapsed/refractory CLL/SLL, BRUKINSA® was superior to IMBRUVICA®, with a lower rate of Atrial Fibrillation/Flutter. The researchers added that BTK inhibition, with more complete and sustained BTK occupancy, results in improved efficacy and safety outcomes.

First interim analysis of ALPINE study: results of a phase 3 randomized study of zanubrutinib vs ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma. Brown JR, Hillmen P, Eichhorst B, et al. Presented at: 2022 SOHO Annual Meeting; September 28-October 1, 2022; Houston, TX. Poster CLL-115.