On December 7, 2019 AbbVie (NYSE: ABBV), a research-based global biopharmaceutical company, reported results from an extended follow-up analysis of the Phase 3 E1912 clinical study – designed and conducted by the ECOG-ACRIN Cancer Research Group (ECOG-ACRIN) and sponsored by the National Cancer Institute (NCI), which is part of the National Institutes of Health. Study results showed superior progression-free survival (PFS) and overall survival (OS) in patients with chronic lymphocytic leukemia (CLL) new to treatment (Press release, AbbVie, DEC 7, 2019, View Source [SID1234552036]).

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These results demonstrated the benefits of IMBRUVICA (ibrutinib) plus rituximab compared to a standard chemoimmunotherapy regimen of fludarabine, cyclophosphamide and rituximab (FCR) for previously untreated patients with CLL aged 70 years or younger. These results were featured today in the CLL Therapy Oral Presentation Session at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting, and served as the basis of the recent supplemental New Drug Application (sNDA) to the U.S. Food and Drug Administration (FDA) to expand further the IMBRUVICA prescribing label in CLL.

Additionally, a new integrated analysis of up to six years of long-term follow-up from the Phase 3 RESONATE and RESONATE-2 studies will be presented on December 8 at the ASH (Free ASH Whitepaper) Annual Meeting, evaluating the use of IMBRUVICA monotherapy in previously untreated patients. Results showed better PFS, OS and overall response rate (ORR), with good tolerability compared to use in the relapsed/refractory (R/R) setting.

"These latest findings add to the extensive clinical evidence supporting the use of IMBRUVICA, the most comprehensively studied BTK inhibitor in CLL, as both a single-agent and as a combination regimen to improve patient outcomes in early lines of treatment, which has previously been reserved for chemoimmunotherapy," said Danelle James, M.D., M.A.S., IMBRUVICA Clinical Development Lead, Pharmacyclics LLC, an AbbVie company. "We’re pleased to present extended follow-up results from the Phase 3 E1912 and RESONATE/RESONATE-2 studies at this year’s ASH (Free ASH Whitepaper) Annual Meeting – all of which are landmark clinical trials that have uniquely changed our understanding of CLL."

"Phase 3 RESONATE and RESONATE-2 trials have proven to be cornerstone studies that have significantly advanced the treatment of CLL among a variety of patients – and the latest data presented at this year’s ASH (Free ASH Whitepaper) Annual Meeting demonstrate using IMBRUVICA alone and earlier in CLL treatment results in improved patient outcomes," said Paul M. Barr, M.D., study investigator of the Phase 3 RESONATE and RESONATE-2 trials, and Associate Professor of Medicine, Hematology/Oncology at the Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York. "These results reaffirm the sustained disease control and safety profile of IMBRUVICA and further support its use as a chemotherapy-free option for previously untreated patients living with this common form of adult leukemia."

IMBRUVICA is a once-daily, first-in-class Bruton’s tyrosine kinase (BTK) inhibitor that is administered orally, and is jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and Janssen Biotech, Inc.

Abstract #33: E1912 extended follow-up of IMBRUVICA plus rituximab compared to FCR in patients with CLL/SLL aged 70 or younger

Oral Presentation: Saturday, December 7, 2019 at 7:30 a.m. EST

Longer-term outcomes data from the Phase 3 E1912 clinical trial – designed and conducted by ECOG-ACRIN and sponsored by the NCI – were presented today in an oral session. As previously reported in earlier data readouts, the study evaluated 354 previously untreated patients with CLL aged 70 years or younger who were randomly assigned to receive IMBRUVICA and rituximab or six courses of intravenous FCR chemoimmunotherapy every 28 days. The study met the primary endpoints of PFS and OS.

At a median follow-up of 48 months, 73 percent of patients in the IMBRUVICA plus rituximab treatment arm remained on IMBRUVICA with median time on treatment of 43 months (range of 0.2 to 61 months). The median time to progression or death after discontinuing IMBRUVICA was 23 months. Superior PFS benefits were sustained for the IMBRUVICA plus rituximab arm compared to the FCR treatment arm (hazard ratio [HR]: 0.39; 95 percent confidence interval [CI], 0.26-0.57; p<0.0001). OS also continued to favor the IMBRUVICA plus rituximab arm (HR=0.34, 95 percent CI, 0.15-0.79; p=0.009). Grade 3 and above treatment-related adverse events (AEs) were observed in 70 percent of patients in the IMBRUVICA plus rituximab arm versus 80 percent in the FCR arm (odds ratio [OR]: 0.56; 95 percent CI, 0.34 – 0.90; p=0.013).

The E1912 study served as the basis of the recent sNDA to the U.S. FDA to expand the IMBRUVICA label to include the combination with rituximab for the first-line treatment of patients with CLL or SLL. The submission is being reviewed by the FDA under the Real-Time Oncology Review pilot program.

Abstract #3054: New RESONATE/RESONATE-2 long-term analysis of ibrutinib monotherapy in earlier lines of CLL treatment

Poster Presentation: Sunday, December 8, 2019 at 6:00 p.m. EST

A new integrated analysis with up to six years of follow-up from the Phase 3 RESONATE (PCYC-1112) and RESONATE-2 (PCYC-1115/1116) studies evaluating IMBRUVICA monotherapy in previously untreated patients (n=136; median age of 73 years) and R/R patients (n=135; median age of 65 years for patients with 1-2 prior lines; median age of 67 years for patients with 3 or more lines) with CLL will be presented. Results reported IMBRUVICA monotherapy demonstrated improved PFS, OS and ORR, with sustained efficacy for the first-line patient group, including patients with high-risk prognostic features, compared to the R/R group.

At up to six years of follow-up (first-line group: median of 59.8 months; 1-2 prior lines: 66.2 months; 3 or more prior lines: 65.1 months), the median PFS was not reached for the first-line or the 1-2 prior lines groups, and median PFS was 40.1 months for the 3 or more prior lines group. A greater portion of patients treated with IMBRUVICA in earlier lines remained progression-free or alive at 60 months (first-line: 70 percent; 1-2 prior lines: 60 percent; 3 or more prior lines: 33 percent), and first-line treatment resulted in a 34 percent reduction in risk of disease progression or death compared to patients who had 1-2 prior lines of therapy (HR: 0.66; 95 percent CI, 0.40 – 1.09). PFS was significantly prolonged for patients receiving first-line treatment compared to those who have received 3 or more prior therapy (HR: 0.32; 95 percent CI, 0.21 – 0.49). Furthermore, median OS for the first-line or 1-2 prior lines group was not reached and was 67.4 months for the 3 or more prior lines group. At 60 months, the ORR was 92 percent (first-line), 96 percent (1-2 prior lines) and 88 percent (3 or more prior lines).

At the time of analysis, 58 percent of patients remain on IMBRUVICA in the first-line group. Overall, 6 percent of patients in the first-line group discontinued due to progressive disease, while it was the most common reason for discontinuation for patients who received 1-2 prior lines of therapy (22 percent) and for those who received 3 or more prior lines (37 percent). Across all three groups, 19 percent of patients discontinued due to AEs (first-line: 21 percent; 1-2 prior: 19 percent; 3 or more prior: 15 percent).

About IMBRUVICA

IMBRUVICA (ibrutinib) is an oral, once-daily medicine that works differently than chemotherapy as it blocks a protein called Bruton’s tyrosine kinase (BTK). 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.1,2 By blocking BTK, IMBRUVICA may help move abnormal B cells out of their nourishing environments in the lymph nodes, bone marrow, and other organs.3

Since its launch in 2013, IMBRUVICA has received 10 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’s macroglobulinemia (WM); 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.4

IMBRUVICA is now approved in 95 countries and has been used to treat more than 170,000 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.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for CLL recommends ibrutinib (IMBRUVICA) as a preferred regimen for the initial treatment of CLL/SLL and it is the only Category 1 single-agent regimen for treatment-naïve patients without deletion 17p.

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.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Hemorrhage: Fatal bleeding events have occurred in patients treated with IMBRUVICA. Major hemorrhage (≥ Grade 3, serious, or any central nervous system events; e.g., intracranial hemorrhage [including subdural hematoma], gastrointestinal bleeding, hematuria, and post procedural hemorrhage) have occurred in 4% of patients, with fatalities occurring in 0.4% of 2,838 patients exposed to IMBRUVICA in 27 clinical trials. Bleeding events of any grade, including bruising and petechiae, occurred in 39% of patients treated with IMBRUVICA.

The mechanism for the bleeding events is not well understood.

Use of either anticoagulant or antiplatelet agents concomitantly with IMBRUVICA increases the risk of major hemorrhage. In IMBRUVICA clinical trials, 3.1% of patients taking IMBRUVICA without antiplatelet or anticoagulant therapy experienced major hemorrhage. The addition of antiplatelet therapy with or without anticoagulant therapy increased this percentage to 4.4%, and the addition of anticoagulant therapy with or without antiplatelet therapy increased this percentage to 6.1%. Consider the risks and benefits of anticoagulant or antiplatelet therapy when co-administered with IMBRUVICA. Monitor for signs and symptoms of bleeding.

Consider the benefit-risk of withholding IMBRUVICA for at least 3 to 7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.

Infections: Fatal and non-fatal infections (including bacterial, viral, or fungal) have occurred with IMBRUVICA therapy. Grade 3 or greater infections occurred in 24% of 1,124 patients exposed to IMBRUVICA in clinical trials. Cases of progressive multifocal leukoencephalopathy (PML) and Pneumocystis jirovecii pneumonia (PJP) have occurred in patients treated with IMBRUVICA. Consider prophylaxis according to standard of care in patients who are at increased risk for opportunistic infections.

Monitor and evaluate patients for fever and infections and treat appropriately.

Cytopenias: Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (23%), thrombocytopenia (8%), and anemia (3%) based on laboratory measurements occurred in patients with B‑cell malignancies treated with single agent IMBRUVICA.

Monitor complete blood counts monthly.

Cardiac Arrhythmias: Fatal and serious cardiac arrhythmias have occurred with IMBRUVICA therapy. Grade 3 or greater ventricular tachyarrhythmias occurred in 0.2% of patients, and Grade 3 or greater atrial fibrillation and atrial flutter occurred in 4% of 1,124 patients exposed to IMBRUVICA in clinical trials. These events have occurred particularly in patients with cardiac risk factors, hypertension, acute infections, and a previous history of cardiac arrhythmias.

Periodically monitor patients clinically for cardiac arrhythmias. Obtain an ECG for patients who develop arrhythmic symptoms (e.g., palpitations, lightheadedness, syncope, chest pain) or new onset dyspnea. Manage cardiac arrhythmias appropriately, and if it persists, consider the risks and benefits of IMBRUVICA treatment and follow dose modification guidelines.

Hypertension: Hypertension of any grade occurred in 12% of 1,124 patients treated with IMBRUVICA in clinical trials. Grade 3 or greater hypertension occurred in 5% of patients with a median time to onset of 5.9 months (range, 0.03 to 24 months).

Monitor blood pressure in patients treated with IMBRUVICA and initiate or adjust anti-hypertensive medication throughout treatment with IMBRUVICA as appropriate.

Second Primary Malignancies: Other malignancies (10%) including non-skin carcinomas (4%) have occurred in 1,124 patients treated with IMBRUVICA in clinical trials. The most frequent second primary malignancy was non-melanoma skin cancer (6%).

Tumor Lysis Syndrome: Tumor lysis syndrome has been infrequently reported with IMBRUVICA therapy. Assess the baseline risk (e.g., high tumor burden) and take appropriate precautions.

Monitor patients closely and treat as appropriate.

Embryo-Fetal Toxicity: Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. Advise women to avoid becoming pregnant while taking IMBRUVICA and for 1 month after cessation of therapy. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Advise men to avoid fathering a child during the same time period.

ADVERSE REACTIONS

B-cell malignancies: The most common adverse reactions (≥20%) in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were thrombocytopenia (58%)*, diarrhea (41%), anemia (38%)*, neutropenia (35%)*, musculoskeletal pain (32%), rash (32%), bruising (31%), nausea (26%), fatigue (26%), hemorrhage (24%), and pyrexia (20%).

The most common Grade 3 or 4 adverse reactions (≥5%) in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were neutropenia (18%)*, thrombocytopenia (16%)*, and pneumonia (14%).

Approximately 7% (CLL/SLL), 14% (MCL), 14% (WM) and 10% (MZL) of patients had a dose reduction due to adverse reactions. Approximately 4-10% (CLL/SLL), 9% (MCL), and 7% (WM [5%] and MZL [13%]) of patients discontinued due to adverse reactions.

cGVHD: The most common adverse reactions (≥20%) in patients with cGVHD were fatigue (57%), bruising (40%), diarrhea (36%), thrombocytopenia (33%)*, muscle spasms (29%), stomatitis (29%), nausea (26%), hemorrhage (26%), anemia (24%)*, and pneumonia (21%).

The most common Grade 3 or higher adverse reactions (≥5%) reported in patients with cGVHD were pneumonia (14%), fatigue (12%), diarrhea (10%), neutropenia (10%)*, sepsis (10%), hypokalemia (7%), headache (5%), musculoskeletal pain (5%), and pyrexia (5%).

Twenty-four percent of patients receiving IMBRUVICA in the cGVHD trial discontinued treatment due to adverse reactions. Adverse reactions leading to dose reduction occurred in 26% of patients.

*Treatment-emergent decreases (all grades) were based on laboratory measurements.

DRUG INTERACTIONS

CYP3A Inhibitors: Co-administration of IMBRUVICA with strong or moderate CYP3A inhibitors may increase ibrutinib plasma concentrations. Dose modifications of IMBRUVICA may be recommended when used concomitantly with posaconazole, voriconazole, and moderate CYP3A inhibitors. Avoid concomitant use of other strong CYP3A inhibitors. Interrupt IMBRUVICA if strong inhibitors are used short-term (e.g., for ≤ 7 days). See dose modification guidelines in USPI sections 2.4 and 7.1.

CYP3A Inducers: Avoid coadministration with strong CYP3A inducers.

SPECIFIC POPULATIONS

Hepatic Impairment (based on Child-Pugh criteria): Avoid use of IMBRUVICA in patients with severe baseline hepatic impairment. In patients with mild or moderate impairment, reduce IMBRUVICA dose.

On December 7, 2019 Unum Therapeutics Inc. (NASDAQ: UMRX), a clinical-stage biopharmaceutical company focused on developing curative cell therapies for cancer, reported Phase 1 clinical updates for its Antibody-Coupled T cell Receptor (ACTR) engineered T-cell therapies, ACTR707 and ACTR087, in patients with relapsed or refractory CD20+ non-Hodgkin Lymphoma (r/r NHL) at the ASH (Free ASH Whitepaper) Annual Meeting, being held December 7-10, in Orlando, FL (Press release, Unum Therapeutics, DEC 7, 2019, View Source [SID1234552035]).

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"The clinical data presented at this year’s ASH (Free ASH Whitepaper) include updates from the ongoing Phase 1 trial of ACTR707 in combination with rituximab and the completed Phase 1 trial of ACTR087 in combination with rituximab, both conducted in patients with relapsed or refractory CD20+ NHL," said Jessica Sachs, M.D., Chief Medical Officer of Unum. "The data with ACTR707 at this year’s ASH (Free ASH Whitepaper) continue to support further dose-escalation in this Phase 1 trial and provide proof-of-mechanism for the ACTR platform that we are also applying in our lead program, a Phase 1 trial with ACTR707 in combination with trastuzumab in HER2+ solid tumor cancers. Safety data from the Phase 1 trial with ACTR087 presented at this year’s ASH (Free ASH Whitepaper) provide learnings that are being applied to ongoing clinical trials with ACTR T cell products.

Poster (#1587) Title: "Preliminary Clinical Results from a Phase 1 Study of ACTR707 in Combination With Rituximab in Subjects with Relapsed or Refractory CD20+ Non-Hodgkin Lymphoma"

ATTCK-20-03 is a Phase 1, multicenter, open-label, single-arm, dose-escalation trial evaluating ACTR707 in combination with rituximab in patients with r/r CD20+ NHL who, among other criteria, received adequate prior anti-lymphoma therapy, including anti-CD20 monoclonal antibody and chemotherapy. In this update from the first 20 patients treated, treatment with ACTR707 combined with rituximab generated clinical responses with no reports of cytokine-release syndrome (CRS) or severe neurotoxicity.
As reported today at ASH (Free ASH Whitepaper), a complete response was achieved in 40% (eight of 20) of patients in Cohorts 1 through 4. Of the eight complete responders, four remained in complete response at six months of follow-up, two remain in complete response but have not yet reached the six-month timepoint for evaluation, and two progressed before the six-month timepoint (Table 1).
Table 1: ACTR707 Preliminary Phase 1 trial clinical response results in r/r NHL (Cohorts 1-4)

Clinical Response (1) Cohort 1 (n=6) Cohort 2 (n=3) Cohort 3 (n=5) Cohort 4 (n=6) Cohorts 1-4 (n=20)
Complete Response 3 1 2 2 40% (8/20)
Partial Response 0 1 2 0 15% (3/20)
Stable Disease 0 0 0 1 5% (1/20)
Indeterminate Response 1 0 0 0 5% (1/20)
Progressive Disease 2 1 1 3 35% (7/20)
Overall Response Rate 50% (3/6) 67% (2/3) 80% (4/5) 33% (2/6) 55% (11/20)
ACTR707+T cells administered, target per patient (range) 25M (23-38M) 40M (30-50M) 55M (45-55M) 80M (65-100M)
(1) Data cutoff as of Nov 2019

In Cohorts 1 through 4, ACTR707 was reported to be well-tolerated in combination with rituximab. No dose-limiting toxicities (DLTs), no adverse events of CRS, and no severe neurological adverse events including neurotoxicity have been reported as of the November 2019 cutoff (Table 2).
Table 2: ACTR707 Preliminary Phase 1 trial safety results in r/r NHL (Cohorts 1-4)

Safety Event (1) Cohort 1 (n=6) Cohort 2 (n=3) Cohort 3 (n=5) Cohort 4 (n=6)
Dose-limiting toxicities 0 0 0 0
Severe neurologic events (> Grade 3) 0 0 0 0
CRS (any grade) 0 0 0 0
ACTR707-related SAEs 1 2 0 1
febrile neutropenia 1 1 0 1
cytopenia 0 1 0 0
(1) Data cutoff as of Nov 2019

Given favorable tolerability observed to date at relatively low doses, Unum announced in November plans to continue dose escalation in two additional cohorts (approximately four patients per cohort) in the trial, escalating the maximum dose up to 180M ACTR707+ T cells. Patient enrollment and planned dosing is underway, and Unum plans to report preliminary results from this dose escalation during 2020.
Additional details about the ATTCK-20-03 Phase 1 trial can be found here.

Oral Presentation Title (#244): "A Phase 1 Study of ACTR087 in Combination with Rituximab, in Subjects with Relapsed or Refractory CD20-Positive B-Cell Lymphoma"

Following the decision in 2018 to prioritize ACTR707 over ACTR087 for future development in r/r NHL and solid tumors, Unum completed enrollment in the ATTCK-20-2 trial, a Phase 1, multicenter, open-label, single-arm, dose-escalating trial evaluating ACTR087 in combination with rituximab in patients with r/r CD20+ NHL.

In this trial, ACTR087+ T cells, when combined with rituximab, expanded and persisted long-term (observed up to 1029 days in one patient) and generated complete responses lasting greater than six months in 20% (four of 20) of evaluable patients with aggressive CD20+ malignancies. In this trial, ACTR087 was administered across three cohorts (mean dose range of 19-67M cells).
Severe T cell-mediated toxicities (CRS and neurotoxicity) occurred in four of 26 patients who received ACTR087 in combination with rituximab, with different timing and symptomatology from those observed with currently available CD19 CAR T cell therapies. Baseline inflammation appeared to predispose patients to severe toxicity.

On December 7, 2019 Bristol-Myers Squibb Company (NYSE: BMY) reported the pivotal study of lisocabtagene maraleucel (liso-cel) an investigational CD19-directed CAR T-cell therapy with a defined composition of purified CD8+ and CD4+ CAR T cells in relapsed/refractory large B-cell lymphomas (TRANSCEND NHL 001) met its primary and secondary endpoints while demonstrating durable responses (Press release, Bristol-Myers Squibb, DEC 7, 2019, View Source [SID1234552034]). The data were presented during an oral session at the 2019 ASH (Free ASH Whitepaper) Annual Meeting in Orlando, Fla.

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"Longer-term follow-up from the TRANSCEND study shows that liso-cel resulted in a rapid, high rate of durable complete responses with low incidence of severe cytokine release syndrome and neurologic events in two and ten percent, respectively, among patients with relapsed/refractory large B-cell lymphomas," said Jeremy Abramson, M.D., Associate Professor of Medicine at Harvard Medical School and Director of the Lymphoma Center at Massachusetts General Hospital. "Additionally, responses with liso-cel were seen across patient groups including high-risk patients such as those with refractory disease, older patients and those with high tumor burden."

In the study, 344 patients were leukapheresed and 269 patients received liso-cel at one of three dose levels (50 x 106 n=51; 100 x 106 n=177; and 150 x 106 n=41). There were 25 patients that received nonconforming product and there were two instances where product could not be manufactured. Patients were heavily pretreated and had aggressive disease with a median of three prior therapies including 35% with prior autologous or allogeneic hematopoietic stem cell transplant (HSCT) and 67% with chemotherapy-refractory disease. Bridging therapy was administered to 59% of patients.

Among patients evaluable for efficacy (n=256), the overall response rate (ORR) was 73% (187/256, 95% CI: 67 – 78) with 53% of patients (136/256, 95% CI: 47 – 59) achieving a complete response (CR). Responses were similar across all patient subgroups. The median duration of response (DOR) for all patients was not reached (95% CI: 8.6 months – NR) at a median follow-up of 12 months (95% CI: 11.2 – 16.7). Median progression-free survival (PFS) was 6.8 months (95% CI: 3.3 – 14.1) and median overall survival (OS) was 21.1 months (95% CI: 13.3 – NR). The median PFS and OS for patients who achieved a CR was not reached with 65.1% of patients progression free and 85.5% of patients alive at 12 months, respectively.

Among all patients, 79% (213/269) had grade 3 or higher treatment-emergent adverse events (TEAE) including neutropenia (60%, 161/269), anemia (38%, 101/269) and thrombocytopenia (27%, 72/269). Instances of any grade cytokine release syndrome (CRS) occurred in 42% (113/269) of patients at a median onset of 5 days and grade 3 or higher CRS occurring in 2% (6/269) of patients. There were neurologic events (NEs) that occurred in 30% of patients (80/269) with grade 3 or higher NEs occurring in 10% (27/269) of patients at a median onset of 9 days. Nineteen and 21% of patients received tocilizumab and corticosteroids, respectively. There were four grade 5 TEAEs related to liso-cel in the study from diffuse alveolar damage, pulmonary hemorrhage, multiple organ dysfunction syndrome or cardiomyopathy. There were three grade 5 TEAEs considered unrelated to liso-cel from fludarabine leukoencephalopathy, septic shock and progressive multifocal leukoencephalopathy. Eight patients had ongoing CRS/NE at the time of death from other reasons. Prolonged grade 3 or higher cytopenias were reported in 37% (100/269) of patients.

"These pivotal longer-term results from TRANSCEND NHL 001 continue to give us confidence in the clinical profile of liso-cel. Importantly, these results were demonstrated in a study with more than 250 patients in a broad population reflective of clinical practice, including those with poor prognoses and a range of histologies," said Stanley Frankel, M.D., Senior Vice President, Cellular Therapy Development for Bristol-Myers Squibb. "We look forward to providing these data to support the regulatory approval for this treatment option for these patients with large B-cell lymphomas."

Based on results from TRANSCEND NHL 001, Bristol-Myers Squibb expects to complete the submission of a Biologics License Application to the U.S. FDA by the end of the year.

Liso-cel is not approved for any use in any country.

About Diffuse Large B-cell Lymphoma

Diffuse large B-cell lymphoma (DLBCL) is the most common and aggressive NHL, accounting for three out of every five cases. Approximately one-third of patients with DLBCL relapse after receiving first-line treatment, and about 10% have refractory disease. Historically, median life expectancy for patients who relapse or are refractory to current standard of care treatments following multiple lines of therapy is approximately six months.

Bristol-Myers Squibb: Advancing Cancer Research

At Bristol-Myers Squibb, patients are at the center of everything we do. The goal of our cancer research is to increase quality, long-term survival and make cure a possibility. We harness our deep scientific experience, cutting-edge technologies and discovery platforms to discover, develop and deliver novel treatments for patients.

Building upon our transformative work and legacy in hematology and Immuno-Oncology that has changed survival expectations for many cancers, our researchers are advancing a deep and diverse pipeline across multiple modalities. In the field of immune cell therapy, this includes registrational chimeric antigen receptor (CAR) T-cell agents for numerous diseases, and a growing early-stage pipeline that expands cell and gene therapy targets, and technologies. We are developing cancer treatments directed at key biological pathways using our protein homeostasis platform, a research capability that has been the basis of our approved therapies for multiple myeloma and several promising compounds in early to mid-stage development. Our scientists are targeting different immune system pathways to address interactions between tumors, the microenvironment and the immune system to further expand upon the progress we have made and help more patients respond to treatment. Combining these approaches is key to delivering new options for the treatment of cancer and addressing the growing issue of resistance to immunotherapy. We source innovation internally, and in collaboration with academia, government, advocacy groups and biotechnology companies, to help make the promise of transformational medicines a reality for patients.

About TRANSCEND NHL 001

TRANSCEND NHL 001 is an open-label, multicenter, pivotal phase 1 study to determine the safety, pharmacokinetics, and antitumor activity of liso-cel in patients with relapsed/refractory B-cell non-Hodgkin lymphoma, including diffuse large B-cell lymphoma, high-grade B-cell lymphoma, primary mediastinal B-cell lymphoma, follicular lymphoma Grade 3B and mantle cell lymphoma. The primary outcome measures were treatment-related adverse events, dose-limiting toxicities and objective response rate. Secondary outcome measures included complete response rate, duration of response and progression-free survival.

About Lisocabtagene Maraleucel (liso-cel)

Liso-cel is an investigational chimeric antigen receptor (CAR) T-cell therapy designed to target CD19, which is a surface glycoprotein expressed during normal B-cell development and maintained following malignant transformation of B cells. Liso-cel CAR T cells aim to target CD19 expressing cells through a CAR construct that includes an anti-CD19 single-chain variable fragment (scFv) targeting domain for antigen specificity, a transmembrane domain, a 4-1BB costimulatory domain hypothesized to increase T-cell proliferation and persistence, and a CD3-zeta T-cell activation domain. The defined composition of CD4+ and CD8+ CAR T cells in liso-cel may limit product variability; however, the clinical significance of defined composition is unknown.

On December 7, 2019 Bristol-Myers Squibb-Pfizer Alliance reported results from retrospective real-world data analyses reporting outcomes on the safety and effectiveness of Eliquis (apixaban) compared to low molecular weight heparin (LMWH) or warfarin for the treatment of venous thromboembolism (VTE) in patients with active cancer (n=14,086) (Press release, Pfizer, DEC 7, 2019, View Source [SID1234552033]). The real-world data analyses were highlighted during oral presentations at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in Orlando, Florida. Results from the primary analysis showed that Eliquis use was associated with lower rates of major bleeding (MB) (hazard ratio [HR]: 0.63, 95% confidence interval [CI]: 0.47-0.86, p=0.003), clinically-relevant non-major (CRNM) bleeding (HR: 0.81, 95% CI: 0.70-0.94, p=0.006) and recurrent VTE (HR: 0.61, 95% CI: 0.47-0.81, p=0.001) compared to LMWH. Eliquis was also associated with a lower rate of recurrent VTE (HR: 0.68, 95% CI: 0.52-0.90, p=0.007) and similar rates of major bleeding (HR: 0.73, 95% CI: 0.53-1.0, p=0.051) and CRNM bleeding (HR: 0.89, 95% CI: 0.77-1.04, p=0.145) compared to warfarin. Outcomes were defined based on diagnosis codes and setting of care.

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In a second oral presentation, results from a sub-group analysis of the primary study were highlighted based on different levels of risk for developing recurrent VTE, a blood clot most often found in the legs or lungs. Study findings were generally consistent with the primary analysis. It is important to note that, anticoagulants, including Eliquis, increase the risk of bleeding and can cause serious, potentially fatal bleeding. Please see important safety information below for Eliquis, including BOXED WARNINGS.

"Real-world evidence analyses such as this have the potential to provide additional insights into complex patient populations such as those with VTE and active cancer," said Alexander Cohen, M.D., Consultant Physician, Department of Hematology at Guy’s and St. Thomas’ NHS Foundation Trust. "Results from these analyses are a welcomed addition to the growing body of data around recurrent VTE in patients with active cancer."

VTE is the third most common cause of vascular death after heart attack and stroke.i VTE can be a major health problem among patients with cancer, with studies showing that patients with cancer are at a significantly increased risk for VTE compared to those without cancer.ii VTE is also a leading cause of death in cancer patients, and a significant predictor for all-cause mortality.iii,iv

In these real-world analyses, four U.S. commercial insurance claims databases were used to identify VTE patients with active cancer (defined as cancer diagnosis or cancer treatment [chemotherapy, radiation and/or cancer-related surgery] within six months before or 30 days after VTE diagnosis) who initiated apixaban, LMWH, or warfarin within 30 days following the first VTE event. The risk of events was evaluated using a Cox proportional hazard model. Inverse probability treatment weighting (IPTW) was used to balance patient characteristics between apixaban, LMWH, and warfarin cohorts. Patients were followed to the earliest of: health plan disenrollment, death, index therapy discontinuation, switch to another anticoagulant, study end, or a maximum of 6 months. This was done to evaluate the rates of MB, CRNMB, and recurrent VTE (fatal or non-fatal) among VTE patients with active cancer prescribed apixaban, LMWH, or warfarin in routine clinical practice.

"Cancer and VTE are closely linked. Patients with cancer have shown to be at increased risk of developing a blood clot," said Roland Chen, M.D., Vice President, Head of Clinical Development, Innovative Medicines, Bristol-Myers Squibb. "Given this risk and the medical complexities in patients with active cancers, it is important to increase awareness of symptoms related to VTE and bolster the visibility of this patient population to help improve health outcomes."

Real-world data have the potential to complement randomized, controlled clinical trial data by providing additional information about how a medicine performs in routine medical practice. Real-world data analyses also have several limitations. For example, the source and type of data used may limit the generalizability of the results and endpoints. Observational real-world studies can only evaluate association and not causality, and despite the use of methods to address measured confounding, residual confounding may still be present. Due to these limitations, real-world data analyses are not used as stand-alone evidence to validate the efficacy and/or safety of a treatment. Additionally, data regarding cancer stage, laboratory test results, biomarkers, and medications prescribed during hospitalization were not available. Mortality and fatal recurrent VTE could not be evaluated because commercial databases do not have complete death information.

"There is a growing opportunity to use real-world evidence to help inform the medical community, especially within complex patient populations, including those with active cancer and VTE," said Rory O’Connor, M.D., Chief Medical Officer, Pfizer Internal Medicine. "Data from real-world settings helps provide a more robust understanding of these patients and adds to the extensive body of real-world evidence evaluating the safety and effectiveness of Eliquis."

BMS-Pfizer Alliance Real-Word Data Program: These analyses are part of the Bristol-Myers Squibb-Pfizer Alliance global real-world data analysis program, ACROPOLIS (Apixaban ExperienCe Through Real-WOrld POpuLatIon Studies), designed to generate additional evidence from routine clinical practice settings to further inform healthcare decision makers, including healthcare providers and payers. These analyses allow for a broader understanding of patient outcomes associated with Eliquis outside of the clinical trial setting, as well as insight into other measures of healthcare delivery, such as hospitalization and costs. The ACROPOLIS program currently includes analyses of patients from more than 20 databases around the world, including anonymized medical records, medical and pharmacy health insurance claims data, and national health data systems. To date, the ACROPOLIS program includes a sample size of more than two million lives spanning more than 10 countries.

About Eliquis

Eliquis (apixaban) is an oral selective Factor Xa inhibitor. By inhibiting Factor Xa, a key blood clotting protein, Eliquis decreases thrombin generation and blood clot formation. Eliquis is approved for multiple indications in the U.S. based on efficacy and safety data from multiple Phase 3 clinical trials. The approval of Eliquis for stroke risk reduction in patients with NVAF is based on data from the Phase 3 ARISTOTLE and AVERROES studies of Eliquis in patients with NVAF. The approval of Eliquis for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and for the reduction in the risk of recurrent DVT and PE following initial therapy, is based on data from the global AMPLIFY and AMPLIFY-EXT studies.

U.S. FDA-Approved Indications for Eliquis: Eliquis is a prescription medicine indicated in the U.S. to reduce the risk of stroke and systemic embolism in patients with NVAF; for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE), in patients who have undergone hip or knee replacement surgery; for the treatment of DVT and PE; and to reduce the risk of recurrent DVT and PE, following initial therapy.

ELIQUIS Important Safety Information

WARNING: (A) PREMATURE DISCONTINUATION OF ELIQUIS INCREASES THE RISK OF THROMBOTIC EVENTS, (B) SPINAL/EPIDURAL HEMATOMA

(A) Premature discontinuation of any oral anticoagulant, including ELIQUIS, increases the risk of thrombotic events. If anticoagulation with ELIQUIS is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant.

(B) Epidural or spinal hematomas may occur in patients treated with ELIQUIS who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include:

• use of indwelling epidural catheters

• concomitant use of other drugs that affect hemostasis, such as nonsteroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants

• a history of traumatic or repeated epidural or spinal punctures

• a history of spinal deformity or spinal surgery

• optimal timing between the administration of ELIQUIS and neuraxial procedures is not known

Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary.

Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated.

CONTRAINDICATIONS

Active pathological bleeding
Severe hypersensitivity reaction to ELIQUIS (e.g., anaphylactic reactions)
WARNINGS AND PRECAUTIONS

Increased Risk of Thrombotic Events after Premature Discontinuation: Premature discontinuation of any oral anticoagulant, including ELIQUIS, in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. An increased rate of stroke was observed during the transition from ELIQUIS to warfarin in clinical trials in atrial fibrillation patients. If ELIQUIS is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant.
Bleeding Risk: ELIQUIS increases the risk of bleeding and can cause serious, potentially fatal, bleeding.
Concomitant use of drugs affecting hemostasis increases the risk of bleeding, including aspirin and other antiplatelet agents, other anticoagulants, heparin, thrombolytic agents, SSRIs, SNRIs, and NSAIDs.
Advise patients of signs and symptoms of blood loss and to report them immediately or go to an emergency room. Discontinue ELIQUIS in patients with active pathological hemorrhage.
The anticoagulant effect apixaban can be expected persist for at least 24 hours after the last dose (i.e., about two half-lives). An agent to reverse the anti-factor Xa activity of apixaban is available. Please visit www.andexxa.com for more information on availability of a reversal agent.
Spinal/Epidural Anesthesia or Puncture: Patients treated with ELIQUIS undergoing spinal/epidural anesthesia or puncture may develop an epidural or spinal hematoma which can result in long-term or permanent paralysis.
The risk of these events may be increased by the postoperative use of indwelling epidural catheters or the concomitant use of medicinal products affecting hemostasis. Indwelling epidural or intrathecal catheters should not be removed earlier than 24 hours after the last administration of ELIQUIS. The next dose of ELIQUIS should not be administered earlier than 5 hours after the removal of the catheter. The risk may also be increased by traumatic or repeated epidural or spinal puncture. If traumatic puncture occurs, delay the administration of ELIQUIS for 48 hours.

Monitor patients frequently and if neurological compromise is noted, urgent diagnosis and treatment is necessary. Physicians should consider the potential benefit versus the risk of neuraxial intervention in ELIQUIS patients.

Prosthetic Heart Valves: The safety and efficacy of ELIQUIS have not been studied in patients with prosthetic heart valves and is not recommended in these patients.
Acute PE in Hemodynamically Unstable Patients or Patients who Require Thrombolysis or Pulmonary Embolectomy: Initiation of ELIQUIS is not recommended as an alternative to unfractionated heparin for the initial treatment of patients with PE who present with hemodynamic instability or who may receive thrombolysis or pulmonary embolectomy.
Increased Risk of Thrombosis in Patients with Triple Positive Antiphospholipid Syndrome (APS): Direct- acting oral anticoagulants (DOACs), including ELIQUIS, are not recommended for use in patients with triple- positive APS. For patients with APS (especially those who are triple positive [positive for lupus anticoagulant, anticardiolipin, and anti–beta 2-glycoprotein I antibodies]), treatment with DOACs has been associated with increased rates of recurrent thrombotic events compared with vitamin K antagonist therapy.
ADVERSE REACTIONS

The most common and most serious adverse reactions reported with ELIQUIS were related to bleeding.
TEMPORARY INTERRUPTION FOR SURGERY AND OTHER INTERVENTIONS

ELIQUIS should be discontinued at least 48 hours prior to elective surgery or invasive procedures with a moderate or high risk of unacceptable or clinically significant bleeding. ELIQUIS should be discontinued at least 24 hours prior to elective surgery or invasive procedures with a low risk of bleeding or where the bleeding would be noncritical in location and easily controlled. Bridging anticoagulation during the 24 to 48 hours after stopping ELIQUIS and prior to the intervention is not generally required. ELIQUIS should be restarted after the surgical or other procedures as soon as adequate hemostasis has been established.
DRUG INTERACTIONS

Combined P-gp and Strong CYP3A4 Inhibitors: Inhibitors of P-glycoprotein (P-gp) and cytochrome P450 3A4 (CYP3A4) increase exposure to apixaban and increase the risk of bleeding. For patients receiving ELIQUIS doses of 5 mg or 10 mg twice daily, reduce the dose of ELIQUIS by 50% when ELIQUIS is coadministered with drugs that are combined P-gp and strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, or ritonavir). In patients already taking 2.5 mg twice daily, avoid coadministration of ELIQUIS with combined P-gp and strong CYP3A4 inhibitors.
Clarithromycin
Although clarithromycin is a combined P-gp and strong CYP3A4 inhibitor, pharmacokinetic data suggest that no dose adjustment is necessary with concomitant administration with ELIQUIS.

Combined P-gp and Strong CYP3A4 Inducers: Avoid concomitant use of ELIQUIS with combined P-gp and strong CYP3A4 inducers (e.g., rifampin, carbamazepine, phenytoin, St. John’s wort) because such drugs will decrease exposure to apixaban.
Anticoagulants and Antiplatelet Agents: Coadministration of antiplatelet agents, fibrinolytics, heparin, aspirin, and chronic NSAID use increases the risk of bleeding. APPRAISE-2, a placebo-controlled clinical trial of apixaban in high-risk post-acute coronary syndrome patients treated with aspirin or the combination of aspirin and clopidogrel, was terminated early due to a higher rate of bleeding with apixaban compared to placebo.
PREGNANCY

The limited available data on ELIQUIS use in pregnant women are insufficient to inform drug- associated risks of major birth defects, miscarriage, or adverse developmental outcomes. Treatment may increase the risk of bleeding during pregnancy and delivery, and in the fetus and neonate.
Labor or delivery: ELIQUIS use during labor or delivery in women who are receiving neuraxial anesthesia may result in epidural or spinal hematomas. Consider use of a shorter acting anticoagulant as delivery approaches.
LACTATION

Breastfeeding is not recommended during treatment with ELIQUIS.
Please see full Prescribing Information, including BOXED WARNINGS and Medication Guide, available at www.bms.com.

About the Bristol-Myers Squibb/Pfizer Collaboration

In 2007, Pfizer and Bristol-Myers Squibb entered into a worldwide collaboration to develop and commercialize apixaban, an oral anticoagulant discovered by Bristol-Myers Squibb. This global alliance combines Bristol-Myers Squibb’s long-standing strengths in cardiovascular drug development and commercialization with Pfizer’s global scale and expertise in this field.

On December 7, 2019 AbbVie (NYSE: ABBV), a research-based global biopharmaceutical company, reported results of a 7.5-year pooled analysis showing earlier treatment with IMBRUVICA (ibrutinib) monotherapy compared to later lines of therapy (LOT) extended progression-free survival (PFS) and increased the likelihood of a complete response (CR) in patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL) – demonstrating that some patients achieved a disappearance of any signs of disease (Press release, AbbVie, DEC 7, 2019, View Source [SID1234552032]).

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The updated pooled analysis includes three clinical trials: Phase 2 SPARK, Phase 3 RAY and Phase 2 PCYC-1104. Patients achieving a CR with IMBRUVICA had a strong response, with a median duration of therapy longer than 5.5 years. These results were presented today at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting.

"MCL is an aggressive B-cell malignancy in which most patients have poor prognosis and are likely to relapse after their initial line of therapy. For those treated with chemotherapy, progression-free survival generally declines with each successive line of treatment," said Simon Rule, M.D., Professor in Haematology, Peninsula Medical School, University of Plymouth, United Kingdom. "These extended follow-up results from the pooled analysis of ibrutinib compared to prior regimens are very encouraging for patients with relapsed or refractory MCL – as they showed treatment with ibrutinib at first relapse versus later lines of therapy resulted in a median progression-free survival of longer than two years."

"Building on the legacy of IMBRUVICA, these latest pooled data presented at ASH (Free ASH Whitepaper), which represent the longest follow-up to-date in mantle cell lymphoma, add to the unprecedented body of evidence supporting the use of IMBRUVICA monotherapy to treat this rare and aggressive form of non-Hodgkin’s lymphoma," said Danelle James, M.D., M.A.S., IMBRUVICA Clinical Development Lead, Pharmacyclics LLC, an AbbVie company. "We continue to be pleased by the proven efficacy and safety profile of this pioneering BTK inhibitor, which has shown to delay disease progression and improve durable responses when used at first relapse."

IMBRUVICA is a once-daily, first-in-class Bruton’s tyrosine kinase (BTK) inhibitor that is administered orally, and is jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and Janssen Biotech, Inc.

Abstract #1538: Long-term outcomes with IMBRUVICA versus the prior regimen: a pooled analysis in relapsed/refractory MCL with up to 7.5 years of extended follow-up

Poster Presentation: Saturday, December 7 at 5:30 p.m. EST

The pooled analysis evaluated 370 patients with R/R MCL (median 2 [range 1-9] prior LOTs) enrolled in the SPARK (MCL2001; NCT01599949), RAY (MCL3001; NCT01646021), and PCYC-1104 (NCT01236391) studies who received IMBRUVICA 560 mg orally once daily. For the regimen prior to IMBRUVICA, time to next treatment (TTNT) was used as a surrogate for PFS. Progression of disease (POD) on frontline treatment was categorized as early (TTNT less than 24 months) or late (TTNT of 24 months or longer). The median follow-up and exposure for IMBRUVICA-treated patients were 41 months (0.2 – 92.4) and 11.1 months (0.03 – 92.4), respectively. Treatment duration was three years or more in 22.4 percent of patients.

Results showed overall median PFS on IMBRUVICA was 12.5 months (9.8 – 16.6) compared to median TTNT on the prior regimen of 10.9 months (9.1-12.6). PFS for patients who received IMBRUVICA was longer than TTNT on the prior regimen for 50 percent of patients; for 27 percent of patients, PFS was longer than TTNT on the prior regimen by 12 months or more. At five years, PFS rate was 19 percent and overall survival (OS) rate was 41 percent. In patients with one prior LOT, median PFS was 25.4 months (17.5 – 51.8) and OS was 61.6 months (36.0 – not estimable [NE]). In patients with a CR, median PFS was 67.7 months (51.7 – NE) and OS was not reached (NE-NE).

Additionally, of the 99 patients who received IMBRUVICA in second-line, 43 percent had early frontline POD and 57 percent of them had late frontline POD. In patients with early frontline POD, median PFS with IMBRUVICA (13.8 months) was similar to median frontline TTNT (14.0 months); median duration of response (DOR) and OS on IMBRUVICA were 22.1 and 23.5 months, respectively. In patients with late frontline POD, median PFS with IMBRUVICA (57.5 months) was longer than median frontline TTNT (42.2 months); median DOR and OS on IMBRUVICA were not reached.

With up to 92 months of follow-up, 81.6 percent of patients had Grade 3 or higher treatment-emergent adverse events (TEAEs) and 64.9 percent had serious adverse events (SAEs). The most common Grade 3 or higher TEAEs were neutropenia (17 percent), pneumonia (13.5 percent) and thrombocytopenia (12.4 percent). The most common SAEs were pneumonia (13.2 percent), atrial fibrillation (5.7 percent), and dyspnea (4.3 percent).

About IMBRUVICA

IMBRUVICA (ibrutinib) is an oral, once-daily medicine that works differently than chemotherapy as it blocks a protein called Bruton’s tyrosine kinase (BTK). 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. By blocking BTK, IMBRUVICA may help move abnormal B cells out of their nourishing environments in the lymph nodes, bone marrow, and other organs.

Since its launch in 2013, IMBRUVICA has received 10 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’s macroglobulinemia (WM); 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.

IMBRUVICA is now approved in 95 countries and has been used to treat more than 170,000 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.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for CLL recommends ibrutinib (IMBRUVICA) as a preferred regimen for the initial treatment of CLL/SLL and it is the only Category 1 single-agent regimen for treatment-naïve patients without deletion 17p.

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.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Hemorrhage: Fatal bleeding events have occurred in patients treated with IMBRUVICA. Major hemorrhage (≥ Grade 3, serious, or any central nervous system events; e.g., intracranial hemorrhage [including subdural hematoma], gastrointestinal bleeding, hematuria, and post procedural hemorrhage) have occurred in 4% of patients, with fatalities occurring in 0.4% of 2,838 patients exposed to IMBRUVICA in 27 clinical trials. Bleeding events of any grade, including bruising and petechiae, occurred in 39% of patients treated with IMBRUVICA.

The mechanism for the bleeding events is not well understood.

Use of either anticoagulant or antiplatelet agents concomitantly with IMBRUVICA increases the risk of major hemorrhage. In IMBRUVICA clinical trials, 3.1% of patients taking IMBRUVICA without antiplatelet or anticoagulant therapy experienced major hemorrhage. The addition of antiplatelet therapy with or without anticoagulant therapy increased this percentage to 4.4%, and the addition of anticoagulant therapy with or without antiplatelet therapy increased this percentage to 6.1%. Consider the risks and benefits of anticoagulant or antiplatelet therapy when co-administered with IMBRUVICA. Monitor for signs and symptoms of bleeding.

Consider the benefit-risk of withholding IMBRUVICA for at least 3 to 7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.

Infections: Fatal and non-fatal infections (including bacterial, viral, or fungal) have occurred with IMBRUVICA therapy. Grade 3 or greater infections occurred in 24% of 1,124 patients exposed to IMBRUVICA in clinical trials. Cases of progressive multifocal leukoencephalopathy (PML) and Pneumocystis jirovecii pneumonia (PJP) have occurred in patients treated with IMBRUVICA. Consider prophylaxis according to standard of care in patients who are at increased risk for opportunistic infections.

Monitor and evaluate patients for fever and infections and treat appropriately.

Cytopenias: Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (23%), thrombocytopenia (8%), and anemia (3%) based on laboratory measurements occurred in patients with B‑cell malignancies treated with single agent IMBRUVICA.

Monitor complete blood counts monthly.

Cardiac Arrhythmias: Fatal and serious cardiac arrhythmias have occurred with IMBRUVICA therapy. Grade 3 or greater ventricular tachyarrhythmias occurred in 0.2% of patients, and Grade 3 or greater atrial fibrillation and atrial flutter occurred in 4% of 1,124 patients exposed to IMBRUVICA in clinical trials. These events have occurred particularly in patients with cardiac risk factors, hypertension, acute infections, and a previous history of cardiac arrhythmias.

Periodically monitor patients clinically for cardiac arrhythmias. Obtain an ECG for patients who develop arrhythmic symptoms (e.g., palpitations, lightheadedness, syncope, chest pain) or new onset dyspnea. Manage cardiac arrhythmias appropriately, and if it persists, consider the risks and benefits of IMBRUVICA treatment and follow dose modification guidelines.

Hypertension: Hypertension of any grade occurred in 12% of 1,124 patients treated with IMBRUVICA in clinical trials. Grade 3 or greater hypertension occurred in 5% of patients with a median time to onset of 5.9 months (range, 0.03 to 24 months).

Monitor blood pressure in patients treated with IMBRUVICA and initiate or adjust anti-hypertensive medication throughout treatment with IMBRUVICA as appropriate.

Second Primary Malignancies: Other malignancies (10%) including non-skin carcinomas (4%) have occurred in 1,124 patients treated with IMBRUVICA in clinical trials. The most frequent second primary malignancy was non-melanoma skin cancer (6%).

Tumor Lysis Syndrome: Tumor lysis syndrome has been infrequently reported with IMBRUVICA therapy. Assess the baseline risk (e.g., high tumor burden) and take appropriate precautions.

Monitor patients closely and treat as appropriate.

Embryo-Fetal Toxicity: Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. Advise women to avoid becoming pregnant while taking IMBRUVICA and for 1 month after cessation of therapy. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Advise men to avoid fathering a child during the same time period.

ADVERSE REACTIONS

B-cell malignancies: The most common adverse reactions (≥20%) in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were thrombocytopenia (58%)*, diarrhea (41%), anemia (38%)*, neutropenia (35%)*, musculoskeletal pain (32%), rash (32%), bruising (31%), nausea (26%), fatigue (26%), hemorrhage (24%), and pyrexia (20%).

The most common Grade 3 or 4 adverse reactions (≥5%) in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were neutropenia (18%)*, thrombocytopenia (16%)*, and pneumonia (14%).

Approximately 7% (CLL/SLL), 14% (MCL), 14% (WM) and 10% (MZL) of patients had a dose reduction due to adverse reactions. Approximately 4-10% (CLL/SLL), 9% (MCL), and 7% (WM [5%] and MZL [13%]) of patients discontinued due to adverse reactions.

cGVHD: The most common adverse reactions (≥20%) in patients with cGVHD were fatigue (57%), bruising (40%), diarrhea (36%), thrombocytopenia (33%)*, muscle spasms (29%), stomatitis (29%), nausea (26%), hemorrhage (26%), anemia (24%)*, and pneumonia (21%).

The most common Grade 3 or higher adverse reactions (≥5%) reported in patients with cGVHD were pneumonia (14%), fatigue (12%), diarrhea (10%), neutropenia (10%)*, sepsis (10%), hypokalemia (7%), headache (5%), musculoskeletal pain (5%), and pyrexia (5%).

Twenty-four percent of patients receiving IMBRUVICA in the cGVHD trial discontinued treatment due to adverse reactions. Adverse reactions leading to dose reduction occurred in 26% of patients.

*Treatment-emergent decreases (all grades) were based on laboratory measurements.

DRUG INTERACTIONS

CYP3A Inhibitors: Co-administration of IMBRUVICA with strong or moderate CYP3A inhibitors may increase ibrutinib plasma concentrations. Dose modifications of IMBRUVICA may be recommended when used concomitantly with posaconazole, voriconazole, and moderate CYP3A inhibitors. Avoid concomitant use of other strong CYP3A inhibitors. Interrupt IMBRUVICA if strong inhibitors are used short-term (e.g., for ≤ 7 days). See dose modification guidelines in USPI sections 2.4 and 7.1.

CYP3A Inducers: Avoid coadministration with strong CYP3A inducers.

SPECIFIC POPULATIONS

Hepatic Impairment (based on Child-Pugh criteria): Avoid use of IMBRUVICA in patients with severe baseline hepatic impairment. In patients with mild or moderate impairment, reduce IMBRUVICA dose.