On December 2, 2018 Kura Oncology, Inc. (Nasdaq: KURA), a clinical-stage biopharmaceutical company focused on the development of precision medicines for oncology, reported preliminary data in angioimmunoblastic T-cell lymphoma (AITL) and CXCL12+ peripheral T-cell lymphoma (PTCL), the two expansion cohorts in its Phase 2 clinical trial of its lead drug candidate tipifarnib in patients with relapsed or refractory PTCL (Press release, Kura Oncology, DEC 2, 2018, View Source [SID1234531800]).

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The data, presented today at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in San Diego, showed encouraging activity with tipifarnib in late-stage PTCL patients, including a significant association between CXCL12 expression and clinical benefit, and proof of concept in AITL, an aggressive form of T-cell lymphoma often characterized by high levels of CXCL12 expression. A copy of the poster is available on the Company’s website at www.kuraoncology.com.

"The mechanism of action of farnesyl transferase inhibitors has remained elusive for several decades," said Antonio Gualberto, M.D., Ph.D., Head of Development and Chief Medical Officer of Kura Oncology. "Our initial data in HRAS mutant head and neck cancer provided strong evidence of activity in tumors driven by this oncogene. However, many other tumors such as T- and B-cell lymphomas, myeloid leukemias, pancreatic or breast cancers, in which anecdotal evidence of tipifarnib activity has been reported, do not usually carry HRAS mutations. We believe the preliminary results reported at ASH (Free ASH Whitepaper) validate our observation that the CXCL12 pathway is a therapeutic target of tipifarnib and provide a potential path to expand the development of tipifarnib well beyond HRAS mutant solid tumors by using CXCL12-related biomarkers to enrich for patients most likely to benefit from treatment. We will continue our efforts to identify these patient subsets and to bring this important drug candidate to patients in need."

As of November 21, 2018, a total of 39 patients were enrolled in the ongoing Phase 2 trial, including 19 patients with AITL (16 patients in the AITL extension cohort and 3 patients in the previous portion of the study). Six of the 16 AITL patients were not evaluable as of the data cutoff date, including two who were pending initial efficacy assessments. Of the 13 evaluable AITL patients, two achieved a complete response (CR) and four achieved a partial response (PR), for an objective response rate (ORR) of 46% (six of 13). According to the study protocol, the AITL cohort is considered positive when four or more responses are observed.

The study also identified a particularly responsive subset within AITL and non-AITL patients. Specifically, patients with a high ratio of expression of CXCL12 to its receptor CXCR4 experienced a 50% ORR (five of 10) and a 90% clinical benefit rate (nine of 10 with either complete response, partial response or stable disease) with tipifarnib. Patients in this Phase 2 trial had a median of three prior lines of therapy (range 1-7). The high CXCL12/CXCR4 expression ratio had 90% sensitivity and 93% specificity to identify PTCL patients likely to benefit from tipifarnib.

In addition to the Phase 2 clinical data, the results from two ancillary, non-clinical studies were also reported at ASH (Free ASH Whitepaper). In the first, the expression of CXCL12 and CXCR4 was investigated using tumor bank samples of PTCL patients treated with standard-of-care agents. Worse prognosis was observed in PTCL patients with high CXCL12/CXCR4 expression ratio, indicating that CXCL12 is a negative prognostic factor for standard PTCL therapy. In the second study, the effect of the incubation of stroma cells with tipifarnib on CXCL12 secretion was investigated in a mouse model of bone marrow culture. Tipifarnib reduced secretion of the CXCL12 chemokine from the stromal cells, providing a potential mechanism of action for the observed clinical activity.

"To our knowledge, these results position tipifarnib as the first CXCL12 inhibitor with reported proof-of-concept data, marking a significant advancement in our development strategy," said Troy Wilson, Ph.D., President and CEO of Kura Oncology. "Our data suggest that as many as 40% of PTCL patients express high CXCL12. In addition, the discovery of CXCL12-related biomarkers offers the potential to increase the opportunity for tipifarnib into other hematological and solid tumor indications. We intend to explore those indications while continuing to gather additional data from our ongoing Phase 2 study and expect to provide an update at a medical meeting next year."

The Phase 2 study was designed to investigate the anti-tumor activity of tipifarnib in patients with relapsed or refractory PTCL. After preliminary data suggested that CXCL12 expression was associated with tipifarnib’s clinical activity, two expansion cohorts were added to enroll patients with tumors expected to overexpress CXCL12: AITL tumors, and those non-AITL tumors that lack a single nucleotide variation in the 3’-untranslated region (3′-UTR) of the CXCL12 gene (CXCL12+ PTCL). CXCL12 is a stroma-derived chemokine that promotes the progression of lymphoma and other hematological and solid tumors carrying the CXCR4 receptor, and our previous results had suggested an association between CXCL12 expression and the most common form of the 3’-UTR CXCL12 variant. In the expansion cohorts, both the presence or absence of this variant and the expression levels of CXCL12 and CXCR4 were assessed.

In the expansion cohorts in the Phase 2 trial tipifarnib was dosed at 300 mg twice daily on days 1-21 of a 28-day cycle. The reported data indicated that tipifarnib was generally well-tolerated, with adverse events consistent with its known safety profile. The most common treatment-related adverse events (grade ≥ 3) were hematology-related, including neutropenia, thrombocytopenia, leukopenia, febrile neutropenia and anemia.

Last week, the U.S. Patent and Trademark Office (USPTO) issued a new patent for tipifarnib as a method of treating patients with AITL. In May 2018, the USPTO issued a patent for tipifarnib as a method of treating patients with certain CXCL12-expressing cancers, including PTCL. Both patents expand protection for tipifarnib, providing exclusivity in the U.S. to 2037.

Webcast Information

Kura’s management will host a webcast at 11:30 p.m. ET / 8:30 p.m. PT today, December 2, 2018, following the conclusion of the poster presentation at the ASH (Free ASH Whitepaper) 2018 Annual Meeting. The live audio webcast and slides of the presentation will be available from the Investors and Media section of the company website at www.kuraoncology.com, and will be archived there for 30 days.

About Tipifarnib

Kura Oncology’s lead drug candidate, tipifarnib, is a potent and highly selective inhibitor of farnesylation, a key cell signaling process implicated in cancer initiation and development. Tipifarnib was previously studied in more than 5,000 cancer patients and showed compelling and durable anti-cancer activity in certain patient subsets, however no molecular mechanism of action had previously been determined that could explain its activity across a range of diverse clinical indications, including squamous tumors that carry mutant HRAS, as well as in lymphoid, myeloid and solid tumors that do not carry HRAS mutations. Leveraging advances in next-generation sequencing as well as emerging information about cancer genetics and tumor biology, Kura is seeking to identify those patients most likely to benefit from tipifarnib. In November 2018, Kura initiated its first global, registration-directed trial of tipifarnib in patients with recurrent or metastatic HRAS mutant HNSCC

On December 2, 2018 Immune Design (Nasdaq: IMDZ), an immunotherapy company focused on next-generation therapies in oncology, reported long-term follow up results from a randomized Phase 2 clinical trial of 10 ug intratumoral G100, a TLR4 agonist, with or without pembrolizumab, in follicular lymphoma patients (Press release, Immune Design, DEC 2, 2018, View Source [SID1234531785]).

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In the 26 naïve and relapsed/refractory patients in the randomized trial, the data continue to support the clinical activity of G100, with overall response rates of 46% and 23% in patients receiving a G100 regimen that includes low-dose radiation, with or without pembrolizumab, respectively. Also, disease control was shown in 92% and 85% of patients treated with the G100 regimen with or without pembrolizumab, respectively. In addition, responses appeared to be durable, with overall progression free survival at 11.1 or 7.4 months in patients treated with the G100 regimen with or without pembrolizumab, respectively. The data were presented today at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting being held in San Diego.

"Follicular lymphoma continues to be a difficult-to-treat malignancy, particularly in the relapsed setting, and to date immunotherapy has not been successful and the current standard of care is associated with a number of serious adverse events," said Carlos Paya, M.D., chief executive officer of Immune Design. "We are encouraged by the potential for lymphoma patients with G100, a first in class immuno-modulatory agent that leads to systemic anti-lymphoma benefit when injected intratumorally. The high response rates, favorable durability and excellent safety profile we’re seeing for G100 has prompted us to embark on a potentially pivotal clinical trial in the relapsed refractory setting, as well as pursue additional trials in earlier lines of therapy in follicular lymphoma and other malignancies."

Additional data presented in the poster:

Increases in immunogenicity markers of CD8+ T-cells and CD8/CD4 ratio in the tumor microenvironment correlated with clinical response (p= .0858 and .0357 respectively). Similarly, a decrease in C20-expressing tumor cells correlated with improved clinical outcomes (p=.0221).

G100 was well tolerated and the combination with pembrolizumab did not cause unexpected or worsening toxicity.
About G100

G100 is Immune Design’s lead product candidate and contains a potent synthetic small molecule toll-like receptor-4 (TLR-4) agonist called Glucopyranosyl Lipid A (GLA). G100 activates innate and adaptive immunity in the tumor microenvironment to generate an immune response against the tumor’s pre-existing diverse set of antigens. A growing set of clinical and preclinical data have demonstrated the ability of G100 to activate tumor-infiltrating lymphocytes, macrophages and dendritic cells, and promote antigen-presentation and the recruitment of T cells to the tumor. The induction of local and systemic immune responses has been shown to result in local and abscopal (shrinking of tumors outside the scope of the localized treatment) tumor control. G100 is currently in development to treat patients with relapsed follicular lymphoma (FL), a sub-type of Non-Hodgkin lymphoma. Immune Design intends to start a study in earlier-stage lymphoma patients in combination with rituximab, a standard treatment for lymphomas, and is evaluating studies in other B-cell malignancies beyond FL, as well as potential solid tumor indications.

On December 2, 2018 Celgene Corporation (NASDAQ: CELG) and Acceleron Pharma Inc. (NASDAQ: XLRN) reported results from the pivotal, phase 3 MEDALIST trial evaluating the efficacy and safety of investigational luspatercept to treat patients with ring sideroblast (RS+) myelodysplastic syndromes (MDS)-associated anemia who require red blood cell transfusions and who had failed, were intolerant to, or ineligible for erythropoietin therapy (Press release, Celgene, DEC 2, 2018, View Source [SID1234531801]). Results were presented by Alan F. List, M.D. during the Plenary Scientific Session at the 60th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition in San Diego, C.A. (Abstract #1).

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"Severe anemia resulting in red blood cell transfusion dependence is a significant challenge for patients with low- and intermediate-risk MDS. Those who become resistant or refractory to currently available treatments have limited alternatives," said Dr. List, President and CEO of Moffitt Cancer Center. "The findings from MEDALIST are very exciting as they support the hypothesis that targeting red blood cell precursor maturation could help to address patients’ anemia and allow them to achieve transfusion independence."

MEDALIST met the primary endpoint of red blood cell transfusion independence (RBC-TI) for 8 or more weeks during the first 24 weeks of the study. Treatment with luspatercept resulted in a statistically significantly greater proportion of patients achieving RBC-TI ≥ 8 weeks compared to placebo. The study also found in secondary endpoints that treatment with luspatercept resulted in a statistically significant higher percentage of patients achieving RBC-TI of 12 or more weeks in the first 24 or 48 weeks of the study, as well as hematologic improvement-erythroid (HI-E) of 8 or more weeks.

Endpoints Luspatercept Placebo P-Value
RBC-TI ≥8 weeks (weeks 1-24) 37.9 % (58/153) 13.2 % (10/76) < 0.0001
RBC-TI ≥12 weeks (weeks 1-24) 28.1 % (43/153) 7.9 % (6/76) 0.0002
RBC-TI ≥12 weeks (weeks 1-48) 33.3 % (51/153) 11.8 % (9/76) 0.0003
HI-E ≥ 8 weeks (IWG 2006, weeks 1-24) 52.9 % (81/153) 11.8 % (9/76) < 0.0001

MEDALIST Safety Summary

Treatment-emergent adverse events (TEAEs) of Grade 3 or 4 were reported in 42.5% (65/153) of patients receiving luspatercept and 44.7% (34/76) of patients receiving placebo. Progression to acute myeloid leukemia (AML) occurred in four patients, three patients (2.0%) receiving luspatercept and one patient (1.3%) receiving placebo. Five patients receiving luspatercept (3.3%) and four patients receiving placebo (5.3%) experienced one or more TEAE that resulted in death.

Most common TEAEs of any Grade in Greater than 10% of Patients in Either Arm

Luspatercept
N=153

Placebo
N=76

Fatigue 26.8 % 13.2 %
Diarrhea 22.2 % 9.2 %
Asthenia 20.3 % 11.8 %
Nausea 20.3 % 7.9 %
Dizziness 19.6 % 5.3 %
Back pain 19.0 % 6.6 %

"The MEDALIST results demonstrate the potential clinical benefit of luspatercept in achieving red blood cell transfusion independence in patients with low-to-intermediate risk RS+ MDS, an area in need of new treatments," said Alise Reicin, MD, President, Global Clinical Development for Celgene. "Based on these results, we are encouraged that this first-in-class erythroid maturation agent may help these patients address the underlying cause of their disease-related chronic anemia."

"It’s truly an honor to showcase the results from the MEDALIST trial as the first presentation of the ASH (Free ASH Whitepaper) Plenary Session," said Habib Dable, President and Chief Executive Officer of Acceleron. "The results from the MEDALIST trial increase our confidence in the potential of luspatercept to provide a meaningful treatment option for patients suffering from lower-risk RS+ MDS worldwide. We’re excited to continue our clinical development program in MDS, beta-thalassemia, and myelofibrosis, while also exploring additional applications for luspatercept in a range of diseases associated with anemia."

Luspatercept is not approved in any region for any indication. The companies are planning regulatory application submissions of luspatercept in the United States and Europe in the first half of 2019.

About MEDALIST

MEDALIST is a phase 3, randomized, double blind, placebo-controlled, multi-center study evaluating the safety and efficacy of luspatercept in patients with very low-, low-, or intermediate-risk non-del(5q) myelodysplastic syndromes (MDS). All patients were RBC transfusion dependent and were either refractory or intolerant to prior erythropoiesis-stimulating agent (ESA) therapy, or were ESA naïve with endogenous serum erythropoietin ≥ 200 U/L, and had no prior treatment with disease modifying agents. The median age of the patients enrolled in the trial was 71 years in the luspatercept treatment group and 72 years in the placebo group. Median transfusion burden in both treatment arms was 5 RBC units/8 weeks. 229 patients were randomized to receive either luspatercept 1.0 mg/kg (153 patients) or placebo (76 patients) via subcutaneous injection once every 21 days. The study was conducted at 65 sites in 11 countries.

About Luspatercept

Luspatercept is a first-in-class erythroid maturation agent (EMA) that is believed to regulate late-stage red blood cell maturation. Acceleron and Celgene are jointly developing luspatercept as part of a global collaboration. Phase 3 clinical trials continue to evaluate the safety and efficacy of luspatercept in patients with MDS (the MEDALIST trial) and in patients with beta-thalassemia (the BELIEVE trial). The COMMANDS phase 3 trial in first-line, lower-risk, MDS patients, the BEYOND phase 2 trial in non-transfusion-dependent beta-thalassemia, and a phase 2 trial in myelofibrosis are ongoing. For more information, please visit www.clinicaltrials.gov.

On December 2, 2018 AbbVie (NYSE: ABBV), a research-based global biopharmaceutical company, reported the results of up to seven years of clinical trial follow-up for IMBRUVICA (ibrutinib) monotherapy in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), the longest follow-up for a Bruton’s tyrosine kinase (BTK) inhibitor to date (Press release, AbbVie, DEC 2, 2018, View Source [SID1234531819]). The updated Phase 1b/2 data demonstrated durable responses in CLL/SLL patients with an overall response rate (ORR) of 89 percent. Evaluated patients included those with high-risk genomic factors such as complex karyotype and unmutated IGHV, and more than 70 patients with three to 12 prior lines of therapy. Progression-free survival (PFS) rates were also sustained (estimated seven-year rates of 80% for previously untreated patients; 32% in the highly pre-treated relapsed/refractory [R/R] groups). The analysis also found that PFS trended better for R/R patients when treated with ibrutinib in earlier lines of therapy (after one or two prior lines of therapy versus three or more lines of prior therapy).

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These data were presented today at the 2018 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in San Diego, CA (Abstract #3133). IMBRUVICA 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.

"With up to seven years of follow up, IMBRUVICA monotherapy continues to show long-lasting responses and survival benefits in patients with chronic lymphocytic leukemia and small lymphocytic lymphoma," said Danelle James, M.D., M.A.S., Head of Clinical Science, Pharmacyclics LLC, an AbbVie company. "These results help demonstrate that the benefits of IMBRUVICA can be sustained for many years, which were seen in patients with CLL and SLL that are typically more difficult to treat due to high-risk genomic factors."

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).1 While these cancer cells start in the bone marrow, they then later spread into the blood. The prevalence of CLL is approximately 115,000 patients in the U.S. with approximately 20,000 newly diagnosed patients every year.2,3 SLL is a slow-growing lymphoma biologically similar to CLL in which too many immature white blood cells cause lymph nodes to become larger than normal.4 Both CLL and SLL are predominately diseases of the elderly, with a median age at diagnosis ranging from 65-70 years.5

"The long-term follow-up data with ibrutinib continues to look promising, with remissions that suggest patients are able to live many years beyond what was previously expected," said John C. Byrd, M.D., Warren Brown Chair of Leukemia Research, Professor of Medicine at the Ohio State University and the lead investigator of the seven-year follow-up study. "These data also suggest that starting treatment with ibrutinib as early as possible for CLL and SLL provides the best efficacy over the long-term – an important factor that treating physicians should consider."

About Abstract #3133: Up to 7 Years of Follow-up of Single-Agent Ibrutinib in the Phase 1b/II PCYC-1102 Trial of First Line and Relapsed/Refractory Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Poster presentation: Sunday, December 2 at 6:00 p.m. PST

In the PCYC-1102 and PCYC-1103 studies, newly diagnosed and R/R CLL/SLL patients, including those with high-risk features, received IMBRUVICA with up to seven years of follow up (n=132).

ORR was 89 percent for all patients (complete response [CR], 15%), with similar rates in previously untreated (87%) and R/R patients (89%). CR rates were higher in previously untreated patients (32%) than in R/R patients (10%). Median duration of response (DOR) was not reached (95% confidence interval [CI]: 0+-85+) for newly diagnosed patients but was 57 months (95% CI: 0+-85+) for R/R patients. Median PFS was not reached (95% CI: NE-NE) for newly diagnosed patients and was 51 months (95% CI: 37-70) for R/R patients. Estimated seven-year PFS rates were 80 percent and 32 percent for newly diagnosed and R/R patients, respectively. Median overall survival (OS) was not reached in newly diagnosed (95% CI: 80-NE months) or R/R patients (95% CI: 63-NE months), with estimated seven-year OS rates of 75 percent and 52 percent, respectively.

High grade adverse events (AEs) were reported in 74 percent of newly diagnosed patients and 89 percent of R/R patients. Hypertension (newly diagnosed, 32%; R/R, 26%), diarrhea (newly diagnosed, 16%; R/R, 4%) and hyponatremia (newly diagnosed, 10%; R/R, 0%) were among the most common grade 3 or higher treatment-emergent AEs. Major hemorrhage and grade 3 or higher atrial fibrillation, thrombocytopenia, anemia and arthralgia were observed in 11 percent or less of newly diagnosed and R/R patients. In addition, infection (newly diagnosed, 23%; R/R, 55%) was more common in R/R patients. No new or unexpected AEs were observed, and the occurrence of most grade 3 or higher AEs and serious AEs decreased over time, with the exception of hypertension.

Additional presentation on ibrutinib monotherapy in CLL at ASH (Free ASH Whitepaper) 2018

Additional data presented at ASH (Free ASH Whitepaper) include a sub-analysis derived from patients with R/R CLL enrolled in the RESONATE trial. The sub-analysis assessed the effects of ibrutinib versus ofatumumab on T-cell function (including degranulation and cytokine release) and proliferation. CLL is a B-cell malignancy that is also characterized by profound immune dysregulation, including dysfunctional T cells. These data will also be presented at ASH (Free ASH Whitepaper) on December 2 (abstract #3114).

To view all IMBRUVICA company-sponsored or investigator-initiated studies being presented at ASH (Free ASH Whitepaper) 2018, please visit: View Source

About IMBRUVICA
IMBRUVICA (ibrutinib) is a first-in-class, oral, once-daily therapy that mainly works by inhibiting a protein called Bruton’s tyrosine kinase (BTK). BTK is a key signaling molecule in the B-cell receptor signaling complex that plays an important role in the survival and spread of malignant B cells.6 IMBRUVICA blocks signals that tell malignant B-cells to multiply and spread uncontrollably.

IMBRUVICA is FDA-approved in six distinct patient populations: chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenström’s macroglobulinemia (WM), along with previously-treated mantle cell lymphoma (MCL), previously-treated marginal zone lymphoma (MZL) and previously-treated chronic graft-versus-host disease (cGVHD).7

IMBRUVICA was first approved for adult patients with MCL who have received at least one prior therapy in November 2013.
Soon after, IMBRUVICA was approved in adult CLL patients who have received at least one prior therapy in February 2014. By July 2014, the therapy received approval for adult CLL patients with 17p deletion, and by March 2016, the therapy was approved as a frontline CLL treatment.
IMBRUVICA was approved for adult patients with WM in January 2015.
In May 2016, IMBRUVICA was approved in combination with bendamustine and rituximab (BR) for adult patients with CLL/SLL.
In January 2017, IMBRUVICA was approved for adult patients with MZL who require systemic therapy and have received at least one prior anti-CD20-based therapy.
In August 2017, IMBRUVICA was approved for adult patients with cGVHD that failed to respond to one or more lines of systemic therapy.
In August 2018, IMBRUVICA plus rituximab was approved for adult patients with WM.
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.

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.8 IMBRUVICA was one of the first medicines to receive FDA approval via the new Breakthrough Therapy Designation pathway.

IMBRUVICA is being studied alone and in combination with other treatments in several blood and solid tumor cancers and other serious illnesses. IMBRUVICA has one of the most robust clinical oncology development programs for a single molecule in the industry, with more than 130 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. To date, more than 135,000 patients around the world have been treated with IMBRUVICA in clinical practice and clinical trials.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Hemorrhage: Fatal bleeding events have occurred in patients treated with IMBRUVICA. Grade 3 or higher bleeding events (intracranial hemorrhage [including subdural hematoma], gastrointestinal bleeding, hematuria, and post-procedural hemorrhage) have occurred in 3% of patients, with fatalities occurring in 0.3% of 1,011 patients exposed to IMBRUVICA in clinical trials. Bleeding events of any grade, including bruising and petechiae, occurred in 44% of patients treated with IMBRUVICA.

The mechanism for the bleeding events is not well understood.

IMBRUVICA may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies and patients should be monitored for signs 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 1,011 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 1,011 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 has occurred in 12% of 1,011 patients treated with IMBRUVICA in clinical trials with a median time to onset of 5 months (range, 0.03 to 22 months). Monitor patients for new onset hypertension or hypertension that is not adequately controlled after starting IMBRUVICA. Adjust existing anti-hypertensive medications and/or initiate anti-hypertensive treatment as appropriate.

Second Primary Malignancies: Other malignancies (9%) including non-skin carcinomas (2%) have occurred in 1,011 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%)*, neutropenia (58%)*, diarrhea (42%), anemia (39%)*, rash (31%), musculoskeletal pain (31%), bruising (31%), nausea (28%), fatigue (27%), hemorrhage (23%), 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 (36%)*, thrombocytopenia (15%)*, and pneumonia (10%).

Approximately 6% (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%)*, stomatitis (29%), muscle spasms (29%), nausea (26%), hemorrhage (26%), anemia (24%)*, and pneumonia (21%).

The most common Grade 3 or 4 adverse reactions (≥5%) reported in patients with cGVHD were fatigue (12%), diarrhea (10%), neutropenia (10%)*, pneumonia (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 and adverse reactions.

DRUG INTERACTIONS

CYP3A Inhibitors: Dose adjustments may be recommended.

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 2, 2018 Kite, a Gilead Company (Nasdaq: GILD), reported two-year efficacy and safety data from the pivotal ZUMA-1 trial of Yescarta (axicabtagene ciloleucel) in patients with refractory large B-cell lymphoma (Press release, Kite Pharma, DEC 2, 2018, View Source;p=irol-newsArticle&ID=2378930 [SID1234531786]). With a minimum follow-up of two years after a single infusion of Yescarta (median follow up of 27.1 months), 39 percent of patients were in an ongoing response. This updated analysis with at least 24 months of follow-up was presented at the Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) (ASH; Abstract #2967) and simultaneously published in The Lancet Oncology.

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This press release features multimedia. View the full release here: View Source

In October 2017, Yescarta became the first chimeric antigen receptor T (CAR T) cell therapy to be approved by the U.S. Food and Drug Administration (FDA) 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 (PMBCL), high grade B-cell lymphoma and DLBCL arising from follicular lymphoma. Yescarta is not indicated for the treatment of patients with primary central nervous system lymphoma. The U.S. Prescribing Information for Yescarta contains a Boxed Warning regarding the risk of cytokine release syndrome (CRS) and neurologic toxicities; see below for Important Safety Information.

At two years, the best objective response via investigator assessment (n=101) showed an overall response rate of 83 percent, with 58 percent of patients having achieved a complete response. With a median follow-up of 27.1 months, 39 percent of patients remained in response. Of the patients with an ongoing response at 12 months, 93 percent remained in response at 24 months. The median duration of response was 11.1 months; the median duration of complete response was not reached. Median overall survival was not reached.

"With aggressive cancers such as refractory large B-cell lymphoma, our primary goal is to extend the lives of patients," said Sattva S. Neelapu, MD, ZUMA-1 Co-Lead Investigator and Professor, Department of Lymphoma/Myeloma, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center. "Outcomes with traditional standard of care for this highly refractory patient population have been extremely poor. Nearly 40 percent of patients in ZUMA-1 remain in response and half of the patients are still alive after at least two years of treatment with Yescarta."

In the two-year analysis (n=108), Grade 3 or higher CRS and neurologic events were seen in 11 percent and 32 percent of patients, respectively, and were generally reversible. Four patients developed new serious adverse events (occurring since the previous August 11, 2017 data cutoff), none of which were related to Yescarta. No new Yescarta-related CRS or neurologic events or deaths have occurred since the one-year analysis.

"The two-year point is a another major milestone for Yescarta, which has extended the lives of a significant number of patients in ZUMA-1 and has yielded important learnings that inform further research and development of CAR T therapies," said Alessandro Riva, MD, Executive Vice President, Oncology Therapeutics and Head, Cell Therapy, Gilead Sciences. "These data are not only significant for the lymphoma community, but also reinforce our leadership in cell therapy as we aim to transform the treatment of a variety of cancers with other investigational therapies in our pipeline."

Full study results are available in The Lancet Oncology:

Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1–2 trial: http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30864-7/fulltext

U.S. Important Safety Information for Yescarta

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 REMS.
CYTOKINE RELEASE SYNDROME (CRS): CRS occurred in 94% of patients, including 13% with ≥ Grade 3. Among patients who died after receiving Yescarta, 4 had ongoing CRS at death. The median time to onset was 2 days (range: 1-12 days) and median duration was 7 days (range: 2-58 days). Key manifestations include fever (78%), hypotension (41%), tachycardia (28%), hypoxia (22%), and chills (20%). 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, and hemophagocytic lymphohistiocytosis/macrophage activation syndrome. Ensure that 2 doses of tocilizumab are available prior to infusion of Yescarta. Monitor patients at least daily for 7 days at the certified healthcare facility following infusion for signs and symptoms of CRS. Monitor patients for signs or symptoms of CRS for 4 weeks after infusion. 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: Neurologic toxicities occurred in 87% of patients. Ninety-eight percent of all neurologic toxicities occurred within the first 8 weeks, with a median time to onset of 4 days (range: 1-43 days) and a median duration of 17 days. Grade 3 or higher occurred in 31% of patients. The most common neurologic toxicities included encephalopathy (57%), headache (44%), tremor (31%), dizziness (21%), aphasia (18%), delirium (17%), insomnia (9%) and anxiety (9%). Prolonged encephalopathy lasting up to 173 days was noted. Serious events including leukoencephalopathy and seizures occurred with Yescarta. Fatal and serious cases of cerebral edema have occurred in patients treated with Yescarta. Monitor patients at least daily for 7 days at the certified healthcare facility following infusion for signs and symptoms of neurologic toxicities. Monitor patients for signs or symptoms of neurologic toxicities for 4 weeks after infusion and treat promptly.

YESCARTA REMS: Because of the risk of CRS and neurologic toxicities, Yescarta is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Yescarta REMS. The required components of the Yescarta REMS are: Healthcare facilities that dispense and administer Yescarta must be enrolled and comply with the REMS requirements. Certified healthcare facilities must have on-site, immediate access to tocilizumab, and ensure that a minimum of 2 doses of tocilizumab are available 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.YESCARTAREMS.com or 1-844-454-KITE (5483).

HYPERSENSITIVITY REACTIONS: Allergic reactions may occur. Serious hypersensitivity reactions including anaphylaxis may be due to dimethyl sulfoxide (DMSO) or residual gentamicin in Yescarta.

SERIOUS INFECTIONS: Severe or life-threatening infections occurred. Infections (all grades) occurred in 38% of patients, and in 23% with ≥ Grade 3. Grade 3 or higher infections with an unspecified pathogen occurred in 16% of patients, bacterial infections in 9%, and viral infections in 4%. Yescarta should not be administered to patients with clinically significant active systemic infections. Monitor patients for signs and symptoms of infection before and after Yescarta infusion and treat appropriately. Administer prophylactic anti-microbials according to local guidelines. Febrile neutropenia was observed in 36% of patients 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. 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 or higher cytopenias not resolved by Day 30 following Yescarta infusion occurred in 28% of patients and included thrombocytopenia (18%), neutropenia (15%), and anemia (3%). Monitor blood counts after Yescarta infusion.

HYPOGAMMAGLOBULINEMIA: B-cell aplasia and hypogammaglobulinemia can occur. Hypogammaglobulinemia occurred in 15% of patients. 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: Patients may develop secondary malignancies. Monitor life-long for secondary malignancies. In the event that a secondary malignancy 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%) include CRS, fever, hypotension, encephalopathy, tachycardia, fatigue, headache, decreased appetite, chills, diarrhea, febrile neutropenia, infections-pathogen unspecified, nausea, hypoxia, tremor, cough, vomiting, dizziness, constipation, and cardiac arrhythmias.