On June 12, 2021 The Janssen Pharmaceutical Companies of Johnson & Johnson reported overall survival (OS) results from the Phase 3 MAIA (NCT02252172) study showing the addition of DARZALEX ▼(daratumumab) to lenalidomide and dexamethasone (D-Rd) resulted in a statistically significant survival benefit over lenalidomide and dexamethasone (Rd) alone in patients with newly diagnosed multiple myeloma (NDMM) who were ineligible for autologous stem cell transplant (ASCT) and were treated to progression (Press release, Johnson & Johnson, JUN 12, 2021, View Source [SID1234583933]).1 These data were featured in the European Hematology Association (EHA) (Free EHA Whitepaper) 2021 Virtual Press Briefing and will be presented as a late-breaking abstract during the EHA (Free EHA Whitepaper) Virtual Congress (Abstract #LB1901).

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The prespecified interim analysis for OS found that after a median follow-up of nearly five years (56.2 months), a 32 percent reduction in the risk of death was observed in the D-Rd treatment arm vs. Rd arm.1 Median OS was not reached in either arm [hazard ratio (HR): 0.68, 95 percent confidence interval (CI), 0.53-0.86; p=0.0013].1 Median progression-free survival (PFS) was not reached after nearly five years and the PFS benefit observed with D-Rd was maintained, with a 47 percent reduction in risk of disease progression or death [HR: 0.53; 95 percent CI, 0.43-0.66; p<0.0001].1 These data are expected to form the basis of future regulatory submissions.

"The treatment of multiple myeloma becomes more complex with each relapse. Therefore, it is critical to achieve deep treatment responses and improved survival with frontline therapy," said Thierry Facon*, M.D., Professor of Haematology at Lille University Hospital, Lille, France and study investigator. "These results strongly support the use of daratumumab, lenalidomide and dexamethasone as a new standard of care to extend survival and improve clinical outcomes in transplant ineligible patients with newly diagnosed multiple myeloma."

All patients enrolled in the MAIA study (n=737) were diagnosed with NDMM, were ineligible for high-dose chemotherapy and ASCT, and received 28-day cycles of D-Rd (n=368) or Rd (n=369). Patients were treated until disease progression or unacceptable toxicity.1 The median age of patients was 73 years (range, 45-90 years). Median PFS was not reached with D-Rd vs. 34.4 months with Rd [HR, 0.53; 95 percent CI, 0.43-0.66; p<0.0001]. Of the 186 patients in the Rd arm who received subsequent therapy, 46 percent received daratumumab.1

Additional New Findings from the MAIA Longer-Term Follow-Up Analysis:

Estimated five-year OS rate of 66 percent with D-Rd vs. 53 percent with Rd (HR: 0.68; 95 percent CI, 0.53-0.86; p=0.0013).1
Estimated five-year PFS rate of 53 percent with D-Rd vs. 29 percent with Rd [HR: 0.53; 95 percent CI, 0.43-0.66; p<0.0001].1
Median time to next treatment was not reached with D-Rd vs. 42.4 months with Rd [HR, 0.47; 95 percent CI, 0.37-0.59 p<0.0001].1
Updated overall response rate (ORR) of 93 percent with D-Rd vs. 82 percent with Rd.1
No new safety concerns were identified in the D-Rd arm. The most common Grade 3 or 4 treatment-emergent adverse events were neutropenia (D-Rd: 54 percent; Rd: 37 percent); pneumonia (D-Rd: 19 percent; Rd: 11 percent); anaemia (D-Rd: 17 percent; Rd: 22 percent); and lymphopenia (D-Rd: 16 percent; Rd: 11 percent).1

"These latest findings from the MAIA study demonstrate the impact of this daratumumab combination regimen on long-term survival in the frontline setting, further establishing the importance of daratumumab as a backbone therapy in the treatment of multiple myeloma," said Craig Tendler, M.D., Vice President, Late Development and Global Medical Affairs, Oncology, Janssen Research & Development, LLC. "These results provide hope and confidence for newly diagnosed patients with multiple myeloma seeking effective treatment regimens that improve long term outcomes and reflect our commitment to continuing to explore the full potential of daratumumab in multiple myeloma."

"Despite multiple myeloma being a difficult to treat, incurable blood cancer, we are pleased to see this daratumumab-based regimen in combination with lenalidomide and dexamethasone continue to deliver positive overall survival and progression-free results to patients with newly diagnosed multiple myeloma within this extended follow-up" said Edmond Chan, EMEA Therapeutic Area Lead Haematology, Janssen-Cilag Ltd. "The new findings from the MAIA study reinforce the transformative role of daratumumab in multiple myeloma and highlight our ongoing commitment to changing what a multiple myeloma diagnosis means to patients".

#ENDS#

About the MAIA Trial2

The randomised, open-label, multicentre Phase 3 study included 737 newly diagnosed patients with multiple myeloma ineligible for high-dose chemotherapy and ASCT, aged 45-90 years (median age of 73).1 Patients were randomised to receive either daratumumab-Rd (D-Rd) or Rd alone in 28-day cycles. In the D-Rd arm, patients received daratumumab 16 milligrams per kilogram (mg/kg) IV weekly for Cycles 1 – 2, every two weeks for Cycles 3 – 6 and every 4 weeks for Cycle 7 and thereafter.1 Patients in the D-Rd and Rd treatment arms received 25 mg of lenalidomide on Days 1 – 21 of each 28-day cycle, and dexamethasone at 40 mg once a week for each cycle. Patients in both treatment arms continued until disease progression or unacceptable toxicity.1

Earlier results from the MAIA study supported the European Commission (EC) approval of daratumumab in combination with Rd, marking the first approval of a CD-38 monoclonal antibody for patients with transplant ineligible NDMM. These data were also published in The New England Journal of Medicine in 2019.

About daratumumab

In August 2012, Janssen Biotech, Inc. and Genmab A/S entered a worldwide agreement, which granted Janssen an exclusive license to develop, manufacture and commercialise daratumumab. Since launch, it is estimated that nearly 190,000 patients have been treated with daratumumab worldwide.3 Daratumumab is also the only CD38-directed antibody approved to be given subcutaneously to treat patients with multiple myeloma (MM). Daratumumab SC is co-formulated with recombinant human hyaluronidase PH20 (rHuPH20), Halozyme’s ENHANZE drug delivery technology.4

CD38 is a surface protein that is highly expressed across MM cells, regardless of the stage of disease. Daratumumab binds to CD38 and induces myeloma cell death through multiple immune-mediated mechanisms of action, including complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP), as well as through apoptosis, in which a series of molecular steps in a cell lead to its death.5

Data across nine Phase 3 clinical trials in the frontline and relapsed settings for MM and newly diagnosed light chain (AL) amyloidosis, have shown that daratumumab-based regimens resulted in significant improvement in progression-free survival and/or overall survival.6,7,8,9,10,11,12,13,14 Additional studies have been designed to assess the efficacy and safety of daratumumab in the treatment of other malignant and pre-malignant haematologic diseases in which CD38 is expressed.15

For further information on daratumumab, please see the Summary of Product Characteristics at View Source

About Multiple Myeloma

Multiple myeloma (MM) is an incurable blood cancer that starts in the bone marrow and is characterised by an excessive proliferation of plasma cells.16 In Europe, more than 50,900 people were diagnosed with MM in 2020, and more than 32,500 patients died.17 Around 50 percent of newly diagnosed patients do not reach five-year survival,18,19 and almost 29 percent of patients with MM will die within one year of diagnosis.20

Although treatment may result in remission, unfortunately, patients will most likely relapse as there is currently no cure.21 Relapsed and refractory MM is defined as disease that is nonresponsive while on salvage therapy, or progresses within 60 days of last therapy in patients who have achieved minimal response (MR) or better at some point previously before then progressing in their disease course.22 While some patients with MM have no symptoms at all, others are diagnosed due to symptoms that can include bone problems, low blood counts, calcium elevation, kidney problems or infections.23 Patients who relapse after treatment with standard therapies, including proteasome inhibitors and immunomodulatory agents, have poor prognoses and require new therapies for continued disease control.24

On June 12, 2021 The Janssen Pharmaceutical Companies of Johnson & Johnson reported primary results from the pivotal Phase 3 GLOW study (NCT03462719) evaluating fixed-duration IMBRUVICA (ibrutinib) plus venetoclax (I+V) compared to chlorambucil plus obinutuzumab (Clb+O) for first-line treatment of elderly or unfit patients with chronic lymphocytic leukaemia (CLL) (Press release, Johnson & Johnson, JUN 12, 2021, View Source;Based-Combination-Regimen-as-an-All-Oral-Fixed-Duration-Treatment-Demonstrated-Superior-Progression-Free-Survival-in-Adult-Patients-with-Previously-Untreated-Chronic-Lymphocytic-Leukaemia [SID1234583932]).

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The study demonstrated superior progression-free survival (PFS) of a once-daily, all-oral, fixed-duration regimen of I+V versus Clb+O as first-line treatment of CLL; the study also showed improved duration of remission and significantly improved depth of remission.1 With I+V, undetectable minimal residual disease (uMRD) in peripheral blood (PB) was sustained by 85 percent of patients one year after end of treatment.1 The safety and tolerability profile of I+V was consistent with CLL treatment in an older population with comorbidities.1 These data were featured in the European Hematology Association (EHA) (Free EHA Whitepaper) 2021 Virtual Press Briefing and will be presented as a late-breaking abstract during the EHA (Free EHA Whitepaper) Virtual Congress (Abstract #LB1902).

"In the GLOW study, two very active blood cancer treatments are combined to create a complementary therapeutic regimen with the hope that deep responses might enable treatment-free remission for patients," said Arnon Kater*, M.D., Ph.D., deputy head of haematology, University of Amsterdam Faculty of Medicine, the Netherlands and principal study investigator. "The data from GLOW showed that ibrutinib in an oral, once-daily fixed-duration combination with venetoclax outperformed a standard chemoimmunotherapy regimen for older or unfit patients, providing the first comparative evidence that this approach has the potential to improve depth of response and, therefore, extends time to progression versus standard therapy."

The GLOW study evaluated the efficacy and safety of first-line fixed-duration I+V versus Clb+O in elderly patients with CLL, or patients aged 18-64 with a cumulative illness rating scale (CIRS) score of greater than six or creatinine clearance less than 70 mL/min.1 The CIRS score measures comorbidity, or concurrent non-CLL illness, in patients across multiple body systems.2 GLOW excluded patients with del(17p) or known TP53 mutations. Randomisation to fixed-duration I+V or a standard six 28-day cycle of Clb+O was stratified by immunoglobulin heavy chain variable region gene (IgHV) mutational status and del(11q) status.1 Patients in the I+V arm received three cycles of ibrutinib lead-in therapy followed by 12 cycles of combination I+V therapy, and all patients stopped therapy regardless of MRD status.1 In the study, 106 patients received I+V and 105 received Clb+O (n=211; median age, 71 years).1

At a median follow-up of 27.7 months, independent review committee (IRC)-assessed PFS for fixed-duration I+V was superior to Clb+O (Hazard Ratio [HR] 0.216, 95 percent confidence interval [CI], 0.131-0.357; p < 0.0001) and the improvement in PFS favouring I+V was consistent across predefined subgroups, including older patients and patients with higher comorbidity scores.1 Median PFS was not reached for I+V and was 21 months for Clb+O (95 percent CI, 16.6-24.7).1 At three months after the end of treatment (EOT+3), the rate of uMRD was significantly higher for I+V versus Clb+O in bone marrow (51.9 percent versus 17.1 percent, respectively; p < 0.0001) and peripheral blood (54.7 percent versus 39.0 percent, respectively; p < 0.0001). Complete response (CR) rates (including complete response with incomplete haematologic recovery) by IRC assessment were also significantly higher for fixed-duration I+V versus Clb+O (38.7 percent vs. 11.4 percent; p < 0.0001).1

Responses to fixed-duration I+V were sustained after EOT; 84.5 percent (49/58) of patients maintained peripheral blood uMRD from EOT+3 to the assessment 12 months after EOT (EOT+12).1 Thereby, with a median follow-up of 27.7 months, time to next anti-cancer therapy was extended with I+V vs Clb+O (HR 0.143 [95 percent CI, 0.05-0.41]).1

The most common Grade 3 or higher treatment-emergent adverse events (AEs) for fixed-duration I+V were neutropaenia/neutrophil count decrease (34.9 percent), infections (17 percent), diarrhoea (10.4 percent); and neutropenia/neutrophil count decrease (49.5 percent), thrombocytopaenia (20 percent), and infections (11.4 percent) for Clb+O.1 Deaths during treatment occurred in seven patients on fixed-duration I+V and two patients on Clb+O.1 At time of analysis, overall survival was immature; there were eleven deaths in the fixed-duration I+V arm and twelve in the Clb+O arm.1

Data from the Fixed-Duration Cohort of the Phase 2 CAPTIVATE (PCYC-1142) Study of Ibrutinib-Based Combination Regimen in Previously Untreated Patients with CLL (Abstract #S147)

GLOW is part of a comprehensive development programme exploring the potential of ibrutinib-based fixed-duration therapy in previously untreated CLL. This includes the fixed-duration cohort from the Phase 2 CAPTIVATE study in young, fit patients that was recently presented at the 2021 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting and will also be presented at EHA (Free EHA Whitepaper) (Abstract #S147). The CAPTIVATE study evaluated previously untreated CLL patients 70 years or younger, including patients with high-risk disease.3 In the fixed-duration cohort (N=159; median age, 60 years), all patients received three cycles of ibrutinib lead-in therapy followed by 12 cycles of combination I+V therapy and then stopped therapy regardless of MRD status.3 More than 90 percent of patients completed 12 cycles of I+V treatment.3 At a median follow-up of 27.9 months, the CR rate in the overall population was 56 percent (n=88; 95 percent CI, 48–64) and was consistent across high-risk subgroups.3 Results also showed that 95 percent of patients treated with fixed-duration I+V were alive and progression-free at two years and deep remissions were seen across all subgroups, including patients with high-risk CLL.3

The safety profile of the I+V regimen in CAPTIVATE was consistent with known safety profiles of ibrutinib and venetoclax.3 Of note, 21 percent of patients were at risk for tumour lysis syndrome (TLS) based on high tumour burden at baseline, and this was reduced to one percent after three cycles of ibrutinib lead-in therapy.3 Adverse events (AEs) were primarily Grade 1/2.3 The most common Grade 3/4 AEs were neutropaenia (33 percent), infections (eight percent), hypertension (six percent), and neutrophil count decrease (five percent).3 Discontinuations due to AEs were infrequent (three percent for ibrutinib).3

"Ibrutinib and venetoclax have complementary mechanisms of action, and the promising results from the CAPTIVATE and GLOW studies show that this all-oral regimen that many patients can take at home may provide an effective, flexible treatment option for patients with CLL seeking a fixed-duration therapy," said Craig Tendler, M.D., Vice President, Late Development and Global Medical Affairs, Oncology, Janssen Research & Development, LLC. "Between these two studies, more than 400 patients across the age and fitness spectrum of CLL patients requiring frontline therapy have been treated with ibrutinib in combination with venetoclax, further demonstrating the potential of ibrutinib in this regimen across multiple patient groups."

"Ibrutinib has been used to treat more than 230,000 patients worldwide and continues to be a mainstay in the treatment of CLL," said Edmond Chan, EMEA Therapeutic Area Lead Haematology, Janssen-Cilag Ltd. "Our goal has always been to lead in innovation, address unmet needs and improve quality of life for patients. This latest data is an encouraging step forward, meaning ibrutinib could be an option both for patients who require continuous treatment as well as those for whom a fixed-duration treatment is most appropriate."

#ENDS#

About Ibrutinib
Ibrutinib is a once-daily, first-in-class Bruton’s tyrosine kinase (BTK) inhibitor that is administered orally, and is jointly developed and commercialised by Janssen Biotech, Inc. and Pharmacyclics LLC, an AbbVie company.4 Ibrutinib blocks the BTK protein; the BTK protein sends important signals that tell B cells to mature and produce antibodies. BTK signalling is needed by specific cancer cells to multiply and spread.5 By blocking BTK, ibrutinib may help move abnormal B cells out of their nourishing environments in the lymph nodes, bone marrow, and other organs.6

Ibrutinib was first approved by the European Commission (EC) in 2014, and approved indications to date include:4

Chronic lymphocytic leukaemia (CLL): As a single agent or in combination with rituximab or obinutuzumab for the treatment of adult patients with previously untreated CLL, and as a single agent or in combination with bendamustine and rituximab (BR) for the treatment of adult patients with CLL who have received at least one prior therapy.
Mantle cell lymphoma (MCL): As a single agent for the treatment of adult patients with relapsed or refractory MCL.
Waldenström’s macroglobulinemia (WM): As a single agent for the treatment of adult patients who have received at least one prior therapy or in first-line treatment for patients unsuitable for chemo-immunotherapy, and in combination with rituximab for the treatment of adult patients.
Ibrutinib is approved in more than 100 countries, and, to date, has been used to treat more than 230,000 patients worldwide.7 Ibrutinib is the only BTKi that has demonstrated overall survival benefits in three CLL clinical trials, with response durability persisting up to 8 years,8,9,10 and more than seven out of ten patients alive and without disease progression after six and a half years.9 Ibrutinib has also been shown to mediate short- and long-term immune restoration.11

Ibrutinib has been comprehensively studied, with more than 150 active clinical trials in several blood cancers and other serious diseases. For a full list of side effects and information on dosage and administration, contraindications and other precautions when using ibrutinib please refer to the Summary of Product Characteristics for further information.

About Chronic Lymphocytic Leukaemia
Chronic lymphocytic leukaemia (CLL) is typically a slow-growing blood cancer of the white blood cells.12 The overall incidence of CLL in Europe is approximately 4.92 cases per 100,000 persons per year and is about 1.5 times more common in men than in women.13 CLL is predominantly a disease of the elderly, with a median age of 72 years at diagnosis.14

The disease eventually progresses in the majority of patients, and they are faced with fewer treatment options with each relapse. Patients are often prescribed multiple lines of therapy as they relapse or become resistant to treatments.

On June 12, 2021 Kite, a Gilead Company (Nasdaq: GILD), reported follow-up results from the pivotal ZUMA-5 trial of Yescarta (axicabtagene ciloleucel) – the first and only CAR T-cell therapy approved in patients with relapsed or refractory indolent follicular lymphoma (FL) (Press release, Kite Pharma, JUN 12, 2021, View Source [SID1234583931]). At a minimum follow-up of 18 months, 94% of patients had achieved a response, and secondary endpoints of median progression-free survival (PFS) and overall survival (OS) were not yet reached. In a weighted analysis comparing ZUMA-5 patients with a minimum of 18 months follow-up with those observed in SCHOLAR-5, an external control cohort, Yescarta demonstrated superior OS and PFS over currently available treatments. These data were presented today as a part of a late-breaking session at the 26th Annual Meeting of the European Hematology Association (EHA) (Free EHA Whitepaper) (EHA2021) taking place virtually this year from June 9-17 (Abstract #LB1904).

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"Follicular lymphoma is one of the most common non-Hodgkin lymphomas, and patients can experience frequent relapses, which quickly leaves us short of treatment options," said Professor John Gribben, Professor of Medical Oncology at the Cancer Research UK Barts Centre, London, UK and study author. "We are very encouraged by these data that suggest a significant and sustained survival benefit with Yescarta even after multiple rounds of prior treatment."

The propensity score analysis compared follow-up data (median follow-up of 23.3 months; in at least 80 patients with FL) from the pivotal Phase 2 ZUMA-5 study (n=86) to a weighted sample from the SCHOLAR-5 external control cohort of current therapies (n=85), balanced for patient characteristics through propensity scoring. Ninety-four percent of patients in the ZUMA-5 cohort achieved a response compared to 50% of patients in the control cohort (median follow-up of 26.2 months), with an odds ratio of 16.2 (95% confidence interval [CI]: 5.6-46.9). Yescarta demonstrated a 58% reduction in the risk of death (HR: 0.42; 95% CI: 0.21-0.83, p=0.01) and 70% reduction in the risk of disease progression, relapse or death (HR: 0.30; 95% CI: 0.18-0.49, p<0.001) versus current therapies in the control cohort. While median OS and PFS were both not reached in ZUMA-5, median PFS and OS were 12.7 months and 59.8 months, respectively, in the control cohort.

In the ZUMA-5 safety analysis set (n=146), Grade 3 or higher cytokine release syndrome (CRS) and neurologic toxicities occurred in 8% and 21% of patients, respectively.

"In an indolent disease like follicular lymphoma, longer-term data that demonstrate durable responses are critical. After a patient with follicular lymphoma relapses, the duration of response shortens with each new therapy," said Caron A. Jacobson, MD, MMSc, Medical Director, Immune Effector Cell Therapy Program, Dana-Farber Cancer Institute and Assistant Professor of Medicine, Harvard Medical School. "The continued durable benefit demonstrated by axicabtagene ciloleucel at nearly two years is exciting, and the substantial survival benefit over current therapies that we’re seeing in the SCHOLAR-5 analysis is encouraging. These follow-up data reinforce axicabtagene ciloleucel as an important advance for a group of patients who have historically had few options."

Yescarta received accelerated approval from the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with relapsed or refractory follicular lymphoma after two or more lines of systemic therapy in March 2021. The Yescarta U.S. Prescribing Information has a BOXED WARNING for the risks of CRS and neurologic toxicities, and Yescarta is approved with a risk evaluation and mitigation strategy (REMS) due to these risks; see below for Important Safety Information.

About ZUMA-5

ZUMA-5 is an ongoing, single-arm, open-label, multicenter trial evaluating 146 patients (≥18 years old) with relapsed or refractory iNHL including FL, who received at least two prior lines of systemic therapy, including the combination of an anti-CD20 monoclonal antibody and an alkylating agent. Efficacy was established on the basis of objective response rate (ORR) and duration of response (DoR) as assessed by an independent review committee per the 2014 Lugano Classification.

About SCHOLAR-5

SCHOLAR-5 is an international, multicenter, retrospective external control cohort of patients with relapsed or refractory FL. Data were sourced from seven institutions across five countries from patients who initiated a third-line or higher therapy after July 2014. In these later lines of treatment, therapeutic regimens are highly heterogenous and without any clear standard of care. Data from the pivotal idelalisib DELTA trial were also included. ZUMA-5 eligibility criteria were applied to the cohort, with patients excluded or censored upon transformation. Single agent anti-CD20 antibody was not counted as line of therapy for eligibility, similar to ZUMA-5 eligibility requirements.

About Indolent Follicular Lymphoma

Follicular lymphoma (FL) is a form of indolent non-Hodgkin lymphoma (iNHL) in which malignant tumors slowly grow but can become more aggressive over time. FL is the most common form of indolent lymphoma and the second most common type of lymphoma globally. It accounts for approximately 22% of all lymphomas diagnosed worldwide. Currently, there are limited options for the treatment of relapsed or refractory indolent FL after two or more lines of therapy.

About Yescarta

Yescarta is a CD19-directed genetically modified autologous T cell immunotherapy indicated for the treatment of:

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, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.
Limitations of Use: Yescarta is not indicated for the treatment of patients with primary central nervous system lymphoma.
Adult patients with relapsed or refractory follicular lymphoma (FL) after two or more lines of systemic therapy. This indication is approved under accelerated approval based on response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).
U.S. IMPORTANT SAFETY INFORMATION

BOXED WARNING: CYTOKINE RELEASE SYNDROME AND NEUROLOGIC TOXICITIES

Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients receiving Yescarta. Do not administer Yescarta to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids.
Neurologic toxicities, including fatal or life-threatening reactions, occurred in patients receiving Yescarta, including concurrently with CRS or after CRS resolution. Monitor for neurologic toxicities after treatment with Yescarta. Provide supportive care and/or corticosteroids as needed.
Yescarta is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Yescarta and Tecartus REMS Program.
CYTOKINE RELEASE SYNDROME (CRS), including fatal or life-threatening reactions, occurred. CRS occurred in 88% (224/254) of all patients with non-Hodgkin lymphoma (NHL), including Grade ≥3 in 10%. CRS occurred in 94% (101/108) of patients with large B-cell lymphoma (LBCL), including Grade ≥3 in 13%. Among patients with LBCL who died after receiving Yescarta, 4 had ongoing CRS events at the time of death. The median time to onset of CRS was 2 days (range: 1-12 days) and the median duration was 7 days (range: 2-58 days) for patients with LBCL. CRS occurred in 84% (123/146) of patients with indolent non-Hodgkin lymphoma (iNHL), including Grade ≥3 in 8% (11/146). Among patients with iNHL who died after receiving Yescarta, 1 patient had an ongoing CRS event at the time of death. The median time to onset of CRS was 4 days (range: 1-20 days) and median duration was 6 days (range: 1-27 days) for patients with iNHL. Key manifestations of CRS (≥10%) in all patients combined included fever (80%), hypotension (38%), tachycardia (29%), hypoxia (21%), chills (21%), and headache (13%). Serious events that may be associated with CRS include cardiac arrhythmias (including atrial fibrillation and ventricular tachycardia), cardiac arrest, cardiac failure, renal insufficiency, capillary leak syndrome, hypotension, hypoxia, multi-organ failure and hemophagocytic lymphohistiocytosis/macrophage activation syndrome. In a subsequent cohort of LBCL patients, tocilizumab and/or corticosteroids were administered for ongoing Grade 1 events. CRS occurred in 93% (38/41) of these patients and 2% (1/41) had Grade 3 CRS, with no patients experiencing a Grade 4 or 5 event. The median time to onset of CRS was 2 days (range: 1 to 8 days) and the median duration of CRS was 7 days (range: 2 to 16 days). Key manifestations of CRS (>5%) included pyrexia, hypotension, chills, headache, nausea, tachycardia, C-reactive protein increased, fatigue, hypoxia, and vomiting. Ensure that 2 doses of tocilizumab are available prior to Yescarta infusion. Following infusion, monitor patients for signs and symptoms of CRS at least daily for 7 days at the certified healthcare facility, and for 4 weeks thereafter. Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time. At the first sign of CRS, institute treatment with supportive care, tocilizumab, or tocilizumab and corticosteroids as indicated.

NEUROLOGIC TOXICITIES that were fatal or life-threatening occurred. Neurologic toxicities occurred in 81% (206/254) of all patients with NHL receiving Yescarta, including Grade ≥3 in 26%. Neurologic toxicities occurred in 87% (94/108) of patients with LBCL, including Grade ≥3 in 31%. The median time to onset was 4 days (range: 1-43 days) and the median duration was 17 days for patients with LBCL. Neurologic toxicities occurred in 77% (112/146) of patients with iNHL, including Grade ≥3 in 21%. The median time to onset was 6 days (range: 1-79 days) and the median duration was 16 days for patients with iNHL. 98% of all neurologic toxicities in patients with LBCL and 99% of all neurologic toxicities in patients with iNHL occurred within the first 8 weeks of Yescarta infusion. Neurologic toxicities occurred within the first 7 days of infusion for 89% of affected patients with LBCL and 74% of affected patients with iNHL. The most common neurologic toxicities (≥10%) in all patients combined included encephalopathy (53%), headache (45%), tremor (31%), dizziness (20%), delirium (16%), aphasia (15%), and insomnia (11%). Prolonged encephalopathy lasting up to 173 days was noted. Serious events, including leukoencephalopathy and seizures, as well as fatal and serious cases of cerebral edema, have occurred. In a subsequent cohort of LBCL patients who received corticosteroids at the onset of Grade 1 toxicities, neurologic toxicities occurred in 78% (32/41) of these patients and 20% (8/41) had Grade 3 neurologic toxicities with no patients experiencing a Grade 4 or 5 event. The median time to onset of neurologic toxicities was 6 days (range: 1-93 days) with a median duration of 8 days (range: 1-144 days). The most common neurologic toxicities were consistent with the overall LBCL population treated with Yescarta. Following Yescarta infusion, monitor patients for signs and symptoms of neurologic toxicities at least daily for 7 days at the certified healthcare facility, and for 4 weeks thereafter, and treat promptly.

REMS: Because of the risk of CRS and neurologic toxicities, Yescarta is available only through a restricted program called the Yescarta and Tecartus REMS Program which requires that: Healthcare facilities that dispense and administer Yescarta must be enrolled and comply with the REMS requirements and must have on-site, immediate access to a minimum of 2 doses of tocilizumab for each patient for infusion within 2 hours after Yescarta infusion, if needed for treatment of CRS. Certified healthcare facilities must ensure that healthcare providers who prescribe, dispense, or administer Yescarta are trained about the management of CRS and neurologic toxicities. Further information is available at www.YescartaTecartusREMS.com or 1-844-454-KITE (5483).

HYPERSENSITIVITY REACTIONS: Allergic reactions, including serious hypersensitivity reactions or anaphylaxis, may occur with the infusion of Yescarta.

SERIOUS INFECTIONS: Severe or life-threatening infections occurred. Infections (all grades) occurred in 47% (119/254) of all patients with NHL. Grade ≥3 infections occurred in 19% of patients, Grade ≥3 infections with an unspecified pathogen occurred in 15%, bacterial infections in 5%, viral infections in 2%, and fungal infections in 1%. Yescarta should not be administered to patients with clinically significant active systemic infections. Monitor patients for signs and symptoms of infection before and after infusion and treat appropriately. Administer prophylactic anti-microbials according to local guidelines. Febrile neutropenia was observed in 40% of all patients with NHL and may be concurrent with CRS. In the event of febrile neutropenia, evaluate for infection and manage with broad-spectrum antibiotics, fluids, and other supportive care as medically indicated. In immunosuppressed patients, including those who have received Yescarta, life-threatening and fatal opportunistic infections including disseminated fungal infections (e.g., candida sepsis and aspergillus infections) and viral reactivation (e.g., human herpes virus-6 [HHV-6] encephalitis and JC virus progressive multifocal leukoencephalopathy [PML]) have been reported. The possibility of HHV-6 encephalitis and PML should be considered in immunosuppressed patients with neurologic events and appropriate diagnostic evaluations should be performed. Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients treated with drugs directed against B cells. Perform screening for HBV, HCV, and HIV in accordance with clinical guidelines before collection of cells for manufacturing.

PROLONGED CYTOPENIAS: Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and Yescarta infusion. Grade ≥3 cytopenias not resolved by Day 30 following Yescarta infusion occurred in 30% of all patients with NHL and included neutropenia (22%), thrombocytopenia (13%), and anemia (5%). Monitor blood counts after infusion.

HYPOGAMMAGLOBULINEMIA and B-cell aplasia can occur. Hypogammaglobulinemia occurred in 17% of all patients with NHL. Monitor immunoglobulin levels after treatment and manage using infection precautions, antibiotic prophylaxis, and immunoglobulin replacement. The safety of immunization with live viral vaccines during or following Yescarta treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during Yescarta treatment, and until immune recovery following treatment.

SECONDARY MALIGNANCIES may develop. Monitor life-long for secondary malignancies. In the event that one occurs, contact Kite at 1-844-454-KITE (5483) to obtain instructions on patient samples to collect for testing.

EFFECTS ON ABILITY TO DRIVE AND USE MACHINES: Due to the potential for neurologic events, including altered mental status or seizures, patients are at risk for altered or decreased consciousness or coordination in the 8 weeks following Yescarta infusion. Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, during this initial period.

ADVERSE REACTIONS: The most common adverse reactions (incidence ≥20%) in patients with LBCL included CRS, fever, hypotension, encephalopathy, tachycardia, fatigue, headache, decreased appetite, chills, diarrhea, febrile neutropenia, infections with pathogen unspecified, nausea, hypoxia, tremor, cough, vomiting, dizziness, constipation, and cardiac arrhythmias. The most common non-laboratory adverse reactions (incidence ≥20%) in patients with iNHL included fever, CRS, hypotension, encephalopathy, fatigue, headache, infections with pathogen unspecified, tachycardia, febrile neutropenia, musculoskeletal pain, nausea, tremor, chills, diarrhea, constipation, decreased appetite, cough, vomiting, hypoxia, arrhythmia, and dizziness.

On June 12, 2021 AbbVie (NYSE: ABBV) reported new data from the Phase 3 GLOW study comparing the efficacy and safety of the combination of IMBRUVICA (ibrutinib) plus VENCLEXTA/VENCLYXTO (venetoclax) (I+V) versus chlorambucil plus obinutuzumab (C+O) for first-line treatment in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who had active disease requiring treatment per the International Workshop on CLL (iwCLL) criteria (Press release, AbbVie, JUN 12, 2021, View Source [SID1234583922]). The study met its primary endpoint of superior progression-free survival (PFS) as assessed by an independent review committee (IRC) with a HR 0.216 (95% CI, 0.131-0.357; p < 0.0001), demonstrating a reduction in the risk of disease progression or death for I+V of approximately 78% compared to C+O. I+V is the first all-oral, once-daily, chemotherapy-free, fixed-duration investigational combination. Results of the study will be presented at the European Hematology Association (EHA) (Free EHA Whitepaper) 2021 Virtual Congress (Abstract #LB1902) during late-breaking abstract session on June 12 from 4:00-5:30 p.m. CEST.

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The PFS benefit with I+V was consistent across pre-specified subgroups, including patients 65 years and older and those with comorbidities (CIRS >6). The median PFS for C+O was 21 months while the median PFS for I+V had not been reached at the time of analysis. The safety profile of I+V was generally consistent with the safety profile of the single agents and tolerability profiles were consistent with CLL treatment in the enrolled patient population.

"With CLL being one of the most common types of blood cancer, the expansion of research into additional treatment options for patients is an important clinical undertaking," said Arnon Kater, M.D., Ph.D., deputy head of hematology, University of Amsterdam Faculty of Medicine. "The progression-free survival findings of ibrutinib and venetoclax in the GLOW study are promising and show the potential to become an additional treatment option for people living with CLL."

Secondary endpoints included rates of undetectable minimal residual disease (uMRD), complete response rate (CR) and overall response rate (ORR). The rate of uMRD in the bone marrow as assessed by next generation sequencing was significantly higher for patients treated with I+V compared to those treated with C+O (p<0.0001). Three months after the completion of treatment uMRD was observed in 51.9% and 17.1%, respectively. Peripheral blood (PB) uMRD persisted 12 months after end of treatment in 49% with I+V and 12% with C+O. The CR rate was also significantly higher with I+V vs. C+O (38.7% vs. 11.4%) (p < 0.0001). The ORR was not significantly different between I+V and C+O treated groups. Time to subsequent therapy was longer for I+V (HR 0.143, 95% CI 0.05-0.41).

"We are encouraged by these results, which further support the efficacy of these two well-established therapies," said Mohamed Zaki, M.D., Ph.D., vice president and head, global oncology development, AbbVie. "We remain steadfast in our commitment to continue the research and development of this combination as a potential treatment for CLL with the ultimate goal to put patients into remission with a fixed-duration, oral therapy."

The safety profile of I+V was generally consistent with the safety profile of the single agents and tolerability profiles were consistent with CLL treatment in the enrolled patient population. Most common grade ≥3 treatment-emergent adverse events (AEs) were neutropenia (34.9%), infections (17%), and diarrhea (10.4%) for I+V; neutropenia (49.5%), infections (11.4%), and thrombocytopenia (20%) for C+O. At time of analysis, overall survival was immature; there were eleven deaths in the fixed-duration I+V arm and twelve in the C+O arm. Deaths during treatment occurred in seven patients on I+V and two patients on C+O.

Results from the ongoing Phase 2 CAPTIVATE study, assessing the I+V combination for first-line treatment of patients with CLL or SLL (PCYC-1142), were presented at the 2021 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (Abstract #7501) and the EHA (Free EHA Whitepaper) 2021 Virtual Congress.

About CLL
CLL is one of the two most common forms of leukemia in adults and is a type of cancer that can develop from cells in the bone marrow that later mature into certain white blood cells (called lymphocytes). While these cancer cells start in the bone marrow, they later spread into the blood. There are approximately 195,129 people with CLL living in the United States with more than 21,000 newly diagnosed patients in 2021.1,2 CLL is predominately a disease of the elderly, with a median age at diagnosis of 70 years and is more common among men than women.3

About the GLOW Study
The GLOW study is a randomized, open label Phase 3 trial comparing progression-free survival in patients treated with either I+V or C+O as assessed by an Independent Review Committee. It enrolled patients (pts) aged ≥65 years or 18-64 years with cumulative illness rating scale score >6 or creatinine clearance <70 mL/min who had active disease requiring treatment per the International Workshop on CLL (iwCLL) criteria. Patients with del(17p) or known TP53 mutations were excluded. There were 211 patients randomly assigned in a 1:1 ratio to receive either I+V (106) and or C+O (105) and the median age was 71 years. Patients assigned to I+V received treatment for 15 cycles (1 cycle is 28 days), starting with three cycles of ibrutinib monotherapy lead-in followed by the combination of I+V for 12 cycles. Patients assigned to C+O were treated for six cycles.

About IMBRUVICA (Ibrutinib)
IMBRUVICA (ibrutinib) is a once-daily, first-in-class BTK inhibitor that is administered orally, and is jointly developed and commercialized by Pharmacyclics, LLC, an AbbVie Company, and Janssen Biotech, Inc. (Janssen). The BTK protein sends important signals that tell B cells to mature and produce antibodies. BTK signaling is needed by specific cancer cells to multiply and spread.4,5 By blocking BTK, IMBRUVICA may help move abnormal B cells out of their nourishing environments in the lymph nodes, bone marrow, and other organs.6

Since its launch in 2013, IMBRUVICA has received 11 FDA approvals across six disease areas: chronic lymphocytic leukemia (CLL) with or without 17p deletion (del17p); small lymphocytic lymphoma (SLL) with or without del17p; Waldenström macroglobulinemia; previously-treated patients with mantle cell lymphoma (MCL)*; previously-treated patients with marginal zone lymphoma (MZL) who require systemic therapy and have received at least one prior anti-CD20-based therapy* – and previously-treated patients with chronic graft-versus-host disease (cGVHD) after failure of one or more lines of systemic therapy.7

IMBRUVICA is now approved in more than 100 countries and has been used to treat more than 230,000 patients worldwide across its approved indications. IMBRUVICA is the only FDA-approved medicine in WM and cGVHD. IMBRUVICA has been granted four Breakthrough Therapy Designations from the U.S. FDA. This designation is intended to expedite the development and review of a potential new drug for serious or life-threatening diseases. IMBRUVICA was one of the first medicines to receive FDA approval via the Breakthrough Therapy Designation pathway.

Since 2019, the National Comprehensive Cancer Network (NCCN), a not-for-profit alliance of 28 leading cancer centers devoted to patient care, research, and education, recommends ibrutinib (IMBRUVICA) as a preferred regimen for the initial treatment of CLL/SLL and has Category 1 treatment status for treatment-naïve patients without deletion 17p. Since January 2020, the NCCN Guidelines have categorized IMBRUVICA with or without rituximab as a preferred regimen for the treatment of relapsed/refractory MCL. As of September 2020, the NCCN guidelines were updated to reflect IMBRUVICA with or without rituximab as the only Category 1 preferred regimen for both untreated and previously treated WM patients.

IMBRUVICA is being studied alone and in combination with other treatments in several blood and solid tumor cancers and other serious illnesses. IMBRUVICA is the most comprehensively studied BTK inhibitor, with more than 150 ongoing clinical trials. There are approximately 30 ongoing company-sponsored trials, 14 of which are in Phase 3, and more than 100 investigator-sponsored trials and external collaborations that are active around the world. For more information, visit www.IMBRUVICA.com

*Accelerated approval was granted for the MCL and MZL indications based on overall response rate. Continued approval for MCL and MZL may be contingent upon verification and description of clinical benefit in confirmatory trials.

About VENCLEXTA/VENCLYXTO (venetoclax)
VENCLEXTA/VENCLYXTO (venetoclax) is a first-in-class medicine that selectively binds and inhibits the B-cell lymphoma-2 (BCL-2) protein. In some blood cancers, BCL-2 prevents cancer cells from undergoing their natural death or self-destruction process, called apoptosis. VENCLXEXTA/VENCLYXTO targets the BCL-2 protein and works to help restore the process of apoptosis.

VENCLEXTA/VENCLYXTO is being developed by AbbVie and Roche. It is jointly commercialized by AbbVie and Genentech, a member of the Roche Group, in the U.S. and by AbbVie outside of the U.S. Together, the companies are committed to BCL-2 research and to studying venetoclax in clinical trials across several blood cancers. Venetoclax is approved in more than 80 countries, including the U.S.

IMPORTANT SAFETY INFORMATION

US IMBRUVICA Important Side Effect Information7
Before taking IMBRUVICA, tell your healthcare provider about all of your medical conditions, including if you:

have had recent surgery or plan to have surgery. Your healthcare provider may stop IMBRUVICA for any planned medical, surgical, or dental procedure.
have bleeding problems.
have or had heart rhythm problems, smoke, or have a medical condition that increases your risk of heart disease, such as high blood pressure, high cholesterol, or diabetes.
have an infection.
have liver problems.
are pregnant or plan to become pregnant. IMBRUVICA can harm your unborn baby. If you are able to become pregnant, your healthcare provider will do a pregnancy test before starting treatment with IMBRUVICA. Tell your healthcare provider if you are pregnant or think you may be pregnant during treatment with IMBRUVICA.
Females who are able to become pregnant should use effective birth control (contraception) during treatment with IMBRUVICA and for 1 month after the last dose.
Males with female partners who are able to become pregnant should use effective birth control, such as condoms, during treatment with IMBRUVICA and for 1 month after the last dose.
are breastfeeding or plan to breastfeed. Do not breastfeed during treatment with IMBRUVICA and for 1 week after the last dose.
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking IMBRUVICA with certain other medicines may affect how IMBRUVICA works and can cause side effects.
How should I take IMBRUVICA?

Take IMBRUVICA exactly as your healthcare provider tells you to take it.
Take IMBRUVICA 1 time a day.
Swallow IMBRUVICA capsules or tablets whole with a glass of water.
Do not open, break or chew IMBRUVICA capsules.
Do not cut, crush or chew IMBRUVICA tablets.
Take IMBRUVICA at about the same time each day.
If you miss a dose of IMBRUVICA take it as soon as you remember on the same day. Take your next dose of IMBRUVICA at your regular time on the next day. Do not take extra doses of IMBRUVICA to make up for a missed dose.
If you take too much IMBRUVICA call your healthcare provider or go to the nearest hospital emergency room right away.
What should I avoid while taking IMBRUVICA?

You should not drink grapefruit juice, eat grapefruit, or eat Seville oranges (often used in marmalades) during treatment with IMBRUVICA. These products may increase the amount of IMBRUVICA in your blood.
What are the possible side effects of IMBRUVICA?
IMBRUVICA may cause serious side effects, including:

Bleeding problems (hemorrhage) are common during treatment with IMBRUVICA, and can also be serious and may lead to death. Your risk of bleeding may increase if you are also taking a blood thinner medicine. Tell your healthcare provider if you have any signs of bleeding, including: blood in your stools or black stools (looks like tar), pink or brown urine, unexpected bleeding, or bleeding that is severe or that you cannot control, vomit blood or vomit looks like coffee grounds, cough up blood or blood clots, increased bruising, dizziness, weakness, confusion, change in your speech, or a headache that lasts a long time or severe headache. 
Infections can happen during treatment with IMBRUVICA. These infections can be serious and may lead to death. Tell your healthcare provider right away if you have fever, chills, weakness, confusion, or other signs or symptoms of an infection during treatment with IMBRUVICA.
Decrease in blood cell counts. Decreased blood counts (white blood cells, platelets, and red blood cells) are common with IMBRUVICA, but can also be severe. Your healthcare provider should do monthly blood tests to check your blood counts.
Heart problems. Serious heart rhythm problems (ventricular arrhythmias, atrial fibrillation, and atrial flutter), heart failure, and death have happened in people treated with IMBRUVICA, especially in people who have an increased risk for heart disease, have an infection, or who have had heart rhythm problems in the past. Tell your healthcare provider if you get any symptoms of heart problems, such as feeling as if your heart is beating fast and irregular, lightheadedness, dizziness, shortness of breath, swelling of the feet, ankles, or legs, chest discomfort, or you faint. If you develop any of these symptoms, your healthcare provider may do a test to check your heart (ECG) and may change your IMBRUVICA dose.
High blood pressure (hypertension). New or worsening high blood pressure has happened in people treated with IMBRUVICA. Your healthcare provider may start you on blood pressure medicine or change current medicines to treat your blood pressure.
Second primary cancers. New cancers have happened during treatment with IMBRUVICA, including cancers of the skin or other organs.
Tumor lysis syndrome (TLS). TLS is caused by the fast breakdown of cancer cells. TLS can cause kidney failure and the need for dialysis treatment, abnormal heart rhythm, seizure, and sometimes death. Your healthcare provider may do blood tests to check you for TLS.
The most common side effects of IMBRUVICA in adults with B-cell malignancies (MCL, CLL/SLL, WM and MZL) include:

diarrhea
tiredness
muscle and bone pain
rash
bruising
The most common side effects of IMBRUVICA in adults with cGVHD include:

tiredness
bruising
diarrhea
mouth sores (stomatitis)
muscle spasms
nausea
pneumonia
Diarrhea is a common side effect in people who take IMBRUVICA. Drink plenty of fluids during treatment with IMBRUVICA to help reduce your risk of losing too much fluid (dehydration) due to diarrhea. Tell your healthcare provider if you have diarrhea that does not go away.
These are not all the possible side effects of IMBRUVICA. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

General information about the safe and effective use of IMBRUVICA 
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use IMBRUVICA for a condition for which it was not prescribed. Do not give IMBRUVICA to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about IMBRUVICA that is written for health professionals.

Please click here for full Prescribing Information.

Uses of VENCLEXTA (venetoclax) in US

VENCLEXTA is a prescription medicine used:

to treat adults with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).
in combination with azacitidine, or decitabine, or low-dose cytarabine to treat adults with newly diagnosed acute myeloid leukemia (AML) who:
are 75 years of age or older, or
have other medical conditions that prevent the use of standard chemotherapy.
It is not known if VENCLEXTA is safe and effective in children.

Important VENCLEXTA (venetoclax) US Safety Information

US VENCLEXTA Important Safety Information8
What is the most important information I should know about VENCLEXTA?
VENCLEXTA can cause serious side effects, including:
Tumor lysis syndrome (TLS). TLS is caused by the fast breakdown of cancer cells. TLS can cause kidney failure, the need for dialysis treatment, and may lead to death. Your healthcare provider will do tests to check your risk of getting TLS before you start taking VENCLEXTA. You will receive other medicines before starting and during treatment with VENCLEXTA to help reduce your risk of TLS. You may also need to receive intravenous (IV) fluids into your vein. Your healthcare provider will do blood tests to check for TLS when you first start treatment and during treatment with VENCLEXTA. It is important to keep your appointments for blood tests. Tell your healthcare provider right away if you have any symptoms of TLS during treatment with VENCLEXTA, including fever, chills, nausea, vomiting, confusion, shortness of breath, seizures, irregular heartbeat, dark or cloudy urine, unusual tiredness, or muscle or joint pain.

Drink plenty of water during treatment with VENCLEXTA to help reduce your risk of getting TLS.
Drink 6 to 8 glasses (about 56 ounces total) of water each day, starting 2 days before your first dose, on the day of your first dose of VENCLEXTA, and each time your dose is increased.

Your healthcare provider may delay, decrease your dose, or stop treatment with VENCLEXTA if you have side effects. When restarting VENCLEXTA after stopping for 1 week or longer, your healthcare provider may again check for your risk of TLS and change your dose.

Who should not take VENCLEXTA?
Certain medicines must not be taken when you first start taking VENCLEXTA and while your dose is being slowly increased because of the risk of increased TLS.

Tell your healthcare provider about all the medicines you take, including prescription and over-the counter medicines, vitamins, and herbal supplements. VENCLEXTA and other medicines may affect each other causing serious side effects.
Do not start new medicines during treatment with VENCLEXTA without first talking with your healthcare provider.
Before taking VENCLEXTA, tell your healthcare provider about all of your medical conditions, including if you:

have kidney or liver problems.
have problems with your body salts or electrolytes, such as potassium, phosphorus, or calcium.
have a history of high uric acid levels in your blood or gout.
are scheduled to receive a vaccine. You should not receive a "live vaccine" before, during, or after treatment with VENCLEXTA, until your healthcare provider tells you it is okay. If you are not sure about the type of immunization or vaccine, ask your healthcare provider. These vaccines may not be safe or may not work as well during treatment with VENCLEXTA.
are pregnant or plan to become pregnant. VENCLEXTA may harm your unborn baby. If you are able to become pregnant, your healthcare provider should do a pregnancy test before you start treatment with VENCLEXTA, and you should use effective birth control during treatment and for at least 30 days after the last dose of VENCLEXTA. If you become pregnant or think you are pregnant, tell your healthcare provider right away.
are breastfeeding or plan to breastfeed. It is not known if VENCLEXTA passes into your breast milk. Do not breastfeed during treatment with VENCLEXTA and for 1 week after the last dose.
What should I avoid while taking VENCLEXTA?
You should not drink grapefruit juice or eat grapefruit, Seville oranges (often used in marmalades), or starfruit while you are taking VENCLEXTA. These products may increase the amount of VENCLEXTA in your blood.

What are the possible side effects of VENCLEXTA?
VENCLEXTA can cause serious side effects, including:

Low white blood cell counts (neutropenia). Low white blood cell counts are common with VENCLEXTA, but can also be severe. Your healthcare provider will do blood tests to check your blood counts during treatment with VENCLEXTA and may pause dosing.
Infections. Death and serious infections such as pneumonia and blood infection (sepsis) have happened during treatment with VENCLEXTA. Your healthcare provider will closely monitor and treat you right away if you have a fever or any signs of infection during treatment with VENCLEXTA.
Tell your healthcare provider right away if you have a fever or any signs of an infection during treatment with VENCLEXTA.

The most common side effects of VENCLEXTA when used in combination with obinutuzumab or rituximab or alone in people with CLL or SLL include low white blood cell counts; low platelet counts; low red blood cell counts; diarrhea; nausea; upper respiratory tract infection; cough; muscle and joint pain; tiredness; and swelling of your arms, legs, hands, and feet.

The most common side effects of VENCLEXTA in combination with azacitidine or decitabine or low-dose cytarabine in people with AML include nausea; diarrhea; low platelet count; constipation; low white blood cell count; fever with low white blood cell count; tiredness; vomiting; swelling of arms, legs, hands, or feet; fever; infection in lungs; shortness of breath; bleeding; low red blood cell count; rash; stomach (abdominal) pain; infection in your blood; muscle and joint pain; dizziness; cough; sore throat; and low blood pressure.

VENCLEXTA may cause fertility problems in males. This may affect your ability to father a child. Talk to your healthcare provider if you have concerns about fertility.

These are not all the possible side effects of VENCLEXTA. Call your doctor for medical advice about side effects.

You are encouraged to report side effects of prescription drug to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088.

If you cannot afford your medication, contact genentech-access.com/patient/brands/venclexta for assistance.

The full U.S. prescribing information, including Medication Guide, for VENCLEXTA can be found here. 

Indications and Important VENCLYXTO (venetoclax) EU Safety Information9
Indication
Venclyxto in combination with obinutuzumab is indicated for the treatment of adult patients with previously untreated chronic lymphocytic leukaemia (CLL).

Venclyxto in combination with rituximab is indicated for the treatment of adult patients with CLL who have received at least one prior therapy.

Venclyxto monotherapy is indicated for the treatment of CLL:

In the presence of 17p deletion or TP53 mutation in adult patients who are unsuitable for or have failed a B-cell receptor pathway inhibitor, or
In the absence of 17p deletion or TP53 mutation in adult patients who have failed both chemoimmunotherapy and a B-cell receptor pathway inhibitor.
Venclyxto in combination with a hypomethylating agent is indicated for the treatment of adult patients with newly diagnosed acute myeloid leukaemia (AML) who are ineligible for intensive chemotherapy.

Contraindications

Hypersensitivity to the active substance or to any of the excipients is contraindicated. Concomitant use of strong CYP3A inhibitors at initiation and during the dose-titration phase due to increased risk for tumour lysis syndrome (TLS). Concomitant use of preparations containing St. John’s wort as Venclyxto efficacy may be reduced.

Special Warnings & Precautions for Use

Tumour Lysis syndrome, including fatal events, has occurred in patients when treated with Venclyxto. For CLL and AML, please refer to the indication-specific recommendations for prevention of TLS in the Venclyxto summary of product characteristic (SmPC).

Patients should be assessed for risk and should receive appropriate prophylaxis, monitoring, and management for TLS. The risk of TLS is a continuum based on multiple factors, including comorbidities. Venclyxto poses a risk for TLS at initiation and during the dose-titration phase. Changes in electrolytes consistent with TLS that require prompt management can occur as early as 6 to 8 hours following the first dose of Venclyxto and at each dose increase.

Neutropenia (grade 3 or 4) has been reported. Complete blood counts should be monitored throughout the treatment period.

In patients with AML, neutropenia (grade 3 or 4) is common before starting treatment. The neutrophil counts can worsen with Venetoclax in combination with a hypomethylating agent. Neutropenia can recur with subsequent cycles of therapy. Dose modification and interruptions for cytopenias are dependent on remission status.

For CLL and AML, please refer to the indication-specific recommendations for dose modifications for toxicities in the Venclyxto SmPC.

Serious infections including sepsis with fatal outcome have been reported. Monitoring of any signs and symptoms of infection is required. Suspected infections should receive prompt treatment including antimicrobials and dose interruption or reduction as appropriate.

Live vaccines should not be administered during treatment or thereafter until B-cell recovery.

Drug Interactions

In CLL and AML CYP3A inhibitors may increase Venclyxto plasma concentrations.

In CLL, at initiation and dose-titration phase, strong CYP3A inhibitors are contraindicated due to increased risk for TLS and moderate CYP3A inhibitors should be avoided. If moderate CYP3A inhibitors must be used, please refer to the recommendations for dose modifications in the Venclyxto SmPC.

In AML, please refer to the AML-specific recommendation for dose modifications for potential interactions with CYP3A inhibitors, in the Venclyxto SmPC.

Avoid concomitant use of P-gp and BCRP inhibitors at initiation and during the dose titration phase.

CYP3A4 inducers may decrease Venclyxto plasma concentrations. Avoid coadministration with strong or moderate CYP3A inducers. These agents may decrease venetoclax plasma concentrations.

Co-administration of bile acid sequestrants with VENCLYXTO is not recommended as this may reduce the absorption of VENCLYXTO.

Adverse Reactions

CLL

The most commonly occurring adverse reactions (>=20%) of any grade in patients receiving venetoclax in the combination studies with obinutuzumab or rituximab were neutropenia, diarrhoea, and upper respiratory tract infection. In the monotherapy studies, the most common adverse reactions were neutropenia/neutrophil count decreased, diarrhoea, nausea, anaemia, fatigue, and upper respiratory tract infection.

The most frequently occurring serious adverse reactions (>=2%) in patients receiving venetoclax in combination with obinutuzumab or rituximab were pneumonia, sepsis, febrile neutropenia, and TLS. In the monotherapy studies, the most frequently reported serious adverse reactions (>=2%) were pneumonia and febrile neutropenia.

Discontinuations due to adverse reactions occurred in 16% of patients treated with venetoclax in combination with obinutuzumab or rituximab in the CLL14 and Murano studies, respectively. In the monotherapy studies with venetoclax, 11% of patients discontinued due to adverse reactions.

Dosage reductions due to adverse reactions occurred in 21% of patients treated with the combination of venetoclax and obinutuzumab in CLL14, in 15% of patients treated with the combination of venetoclax and rituximab in Murano, and in 14% of patients treated with venetoclax in the monotherapy studies. The most common adverse reaction that led to dose interruptions was neutropenia.

AML

The most commonly occurring adverse reactions (>=20%) of any grade in patients receiving venetoclax in combination with azacitidine or decitabine in the VIALE-A and M14-358, respectively, were thrombocytopenia, neutropenia, febrile neutropenia, nausea, diarrhoea, vomiting, anaemia, fatigue, pneumonia, hypokalaemia, and decreased appetite, haemorrhage, dizziness/syncope, hypotension, headache, abdominal pain, and anaemia.

The most frequently reported serious adverse reactions (≥5%) in patients receiving venetoclax in combination with azacitidine were febrile neutropenia, pneumonia, sepsis and haemorrhage. In M14-358, the most frequently reported serious adverse reactions (≥5%) were febrile neutropenia, pneumonia, bacteraemia and sepsis.

Discontinuations due to adverse reactions occurred in 24% of patients treated with venetoclax in combination with azacitidine in the VIALE-A study, and 26% of patients treated with venetoclax in combination with decitabine in the M14-358 study, respectively.

Dosage reductions due to adverse reactions occurred in 2% of patients in VIALE-A, and in 6 % of patients in M14-358. Venetoclax dose interruptions due to adverse reactions occurred in 72% and 65 % of patients, respectively. The most common adverse reaction that led to dose interruption (>10%) of Venetoclax in VIALE-A, were febrile neutropenia, neutropenia, pneumonia, and thrombocytopenia. The most common adverse reactions that led to dose interruption (≥5%) of venetoclax in M14-358 were febrile neutropenia, neutropenia/neutrophil count decreased, pneumonia, platelet count decreased, and white blood cell count decreased.

Special Populations

Patients with reduced renal function (CrCl <80 mL/min) may require more intensive prophylaxis and monitoring to reduce the risk of TLS at initiation and during the dose-titration phase. Safety in patients with severe renal impairment (CrCl <30 mL/min) or on dialysis has not been established, and a recommended dose for these patients has not been determined.

For patients with severe (Child-Pugh C) hepatic impairment, a dose reduction of at least 50% throughout treatment is recommended.

Venclyxto may cause embryo-fetal harm when administered to a pregnant woman. Advise nursing women to discontinue breastfeeding during treatment.

This is not a complete summary of all safety information. See VENCLYXTO full summary of product characteristics (SmPC) at View Source Globally, prescribing information varies; refer to the individual country product label for complete information.

About AbbVie in Oncology
At AbbVie, we are committed to transforming standards of care for multiple blood cancers while advancing a dynamic pipeline of investigational therapies across a range of cancer types. Our dedicated and experienced team joins forces with innovative partners to accelerate the delivery of potentially breakthrough medicines. We are evaluating more than 20 investigational medicines in over 300 clinical trials across some of the world’s most widespread and debilitating cancers. As we work to have a remarkable impact on people’s lives, we are committed to exploring solutions to help patients obtain access to our cancer medicines. For more information, please visit View Source

On June 11, 2021 Shanghai Yingli Pharmaceuticals Ltd (Yingli Pharma), a clinical stage pharmaceutical company providing new therapies for cancer and metabolic diseases, reported the topline data from a clinical trial sponsored by the company at the annual meeting of the European Hematology Association (EHA) (Free EHA Whitepaper) being held June 9-17, 2021 (Press release, Yingli Pharmaceutical, JUN 11, 2021, View Source [SID1234598445]).

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The study entitled ‘A Phase 2 study of an oral PI3Kδ inhibitor YY-20394 in patients with relapsed or refractory follicular lymphoma’ will be presented at EHA (Free EHA Whitepaper) by Dr. Lugui Qiu, a lead investigator from Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences, Tianjin, China. This is a registration study that enrolled 93 relapsed or refractory Follicular Lymphoma (FL) patients having received 2 or more prior systemic therapies and was conducted at 32 clinical sites in China. Linperlisib was evaluated as a monotherapy for safety, tolerability and efficacy at recommended phase 2 dose of 80 mg once daily. Following a data cutoff on March 15, 2021, the fully enrolled study was analyzed for 89 evaluable patients. The Overall Response Rate (ORR) was 79.5%, with 12.4% Complete Response, 67.4% Partial Response, and 16.1% Stable Disease, combining to achieve a Disease Control Rate of 96.6%. Previously, the Phase 1 study of linperlisib had shown similar preliminary efficacy of 90% ORR in 10 patients with r/r FL. As of the data cutoff for the Phase 2, the median Progression Free Survival was 11.8 months, and the Duration of Response was 12.3 months. Forty seven patients were continuing to receive linperlisib treatment.

Follicular Lymphoma is increasingly harder to treat if patients progress on previous therapies, usually immuno-chemotherapy is a mainstay as a prior treatment. On this study, 65% of the patients had received 3 or more prior systemic treatments, and all patients had previously received rituximab-based therapies.

The safety data from the FL Phase 2 study indicated that linperlisib was generally safe and tolerable with manageable adverse events. Most of the adverse events were Grade 1 and Grade 2. The most common (>5%) treatment related hematologic adverse events of ≥ Grade 3 were neutropenia (15.1%), leukocytopenia (5.4%), lymphocytopenia (5.4%). The most common (>5%) treatment related non-hematologic adverse events of ≥ Grade 3 were pneumonia (15.1%).

Dr. Lugui Qiu, a prinicipal investigator on the study, stated "FL is complicated as the relapsed and refractory patients tend to progress rapidly, requiring aggressive therapies. From the clinical findings with linperlisib treatment of FL patients, we are seeing durable responses for most patients. Patients are in desperate need of effective therapies that target these lymphoma key signaling pathways and therapies that are oral medications, easy for patients to use outside of a clinic."

Dr. Zusheng Xu, General Manager of Yingli Pharma commented "We are excited to be developing Linperlisib for the treatment of lymphomas and solid tumors. Linperlisib is a next-generation PI3Kδ-selective inhibitor. The clinical data suggest that Linperlisib might be a potentially advantageous treatment option for patients. We have applied a linperlisib marketing approval in China in relapsed or refractory FL, based on the data from this phase II registration study. We hope to broaden the use of linperlisib and are exploring its anti-tumor activities in different indications in additional clinical trials."

Dr. Qiu also indicated "It is a major step that Linperlisib has been accepted by the NMPA for the NDA application, and we are very optimistic about the outcome."

About Linperlisib

Linperlisib (YY-20394) is a highly selective and potent PI3Kδ inhibitor that has shown a favorable safety profile, exciting anti-tumor activities, and good PK and pharmaceutical properties as an oral once-a-day agent in late-stage clinical development. A phase 1 clinical trial was completed in 2020 demonstrating linperlisib to be a safe and tolerable agent, and a recommended phase 2 dose of 80 mg QD was established. Linperlisib was awarded NMPA Breakthrough Therapy status in China, leading to the current trial. In addition, linperlisib received FDA Orphan Drug Designations for FL, CLL/SLL, and T cell lymphoma. A clinical trial in r/r FL is launching in the US. Multiple linperlisib clinical trials being conducted in other lymphomas, solid tumors, and in combination with gemcitabine/oxaliplatin in r/r DLBCL. Preliminary results from a PTCL Phase1b study were reported at ASCO (Free ASCO Whitepaper) 2021, indicating an overall response rate of 70% with 33% CRs in 30 evaluable patients with r/r PTCL, a difficult to treat and aggressive form of lymphoma.