On December 9, 2017 Alpine Immune Sciences, Inc. (NASDAQ:ALPN), a leading immunotherapy company focused on developing treatments for autoimmune/inflammatory diseases and cancer, reported results from a preclinical study of the company’s ALPN-101 program in a humanized model of graft vs. host disease (GvHD) (Press release, Alpine Immune Sciences, DEC 9, 2017, View Source [SID1234522455]). Results showed Alpine’s ICOSL vIgD-Fc fusion proteins demonstrated therapeutic efficacy, including suppressing an allogeneic immune response in vitro, improving survival, and reducing GvHD disease activity. The data were presented in a poster session, titled "Experimental Transplantation: Basic Biology, Pre-Clinical Models: Poster I" (poster #1892) during the 59th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition in Atlanta.

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"These preclinical data showing activity with novel ICOS/CD28 dual antagonists from our vIgD platform in a humanized model of GvHD are encouraging because of the ongoing unmet medical need in GvHD," said Stanford Peng, M.D., Ph.D., Executive Vice President of Research and Development and Chief Medical Officer of Alpine. "These preclinical findings suggest our platform can generate novel immuno-oncology molecules with potential broad clinical therapeutic utility."

GvHD, a complication that can occur after stem cell or bone marrow transplants, has a major impact on survival following transplantation. Transplant-related mortality is as high as 92 percent in grade IV acute GvHD. Approximately 30 to 50 percent of bone marrow transplant patients will develop clinically significant GvHD – or 2,500 to 4,200 patients per year in the United States.

Background on Alpine’s ICOSL vIgD-Fc Fusion Proteins

The immunoglobulin superfamily (IgSF) is a large, diverse family of proteins expressed on immune cells collectively playing a critical role in immune regulation. Well-known IgSF proteins include PD-1, PD-L1, CTLA-4, CD28, CD80/CD86 (B7-1/2), inducible T cell costimulator (ICOS), and TIGIT. Most therapeutic strategies targeting this family of proteins for the treatment of cancers and autoimmune/inflammatory diseases have employed monoclonal antibodies binding to a single target.

Alpine’s vIgD platform, in contrast, transforms natural IgSF proteins into multifunctional protein domains. CD28 and ICOS are expressed on T cells, interacting with CD80/CD86 and ICOS ligand (ICOSL), respectively, and play critical roles in T cell activation. Alpine’s ICOSL vIgD-Fc bind and inhibit both ICOS and CD28 co-stimulatory pathways.

Preclinical Study Design and Results

The preclinical study presented at ASH (Free ASH Whitepaper) 2017 evaluated the function of Alpine’s ICOSL vIgD-Fcs both in vitro and in a humanized mouse model of GvHD. Belatacept, an immunosuppressive T cell co-stimulation blocker approved by the U.S. Food and Drug Administration (FDA) to prevent kidney transplant rejection, was used as a comparator.

Results showed Alpine’s ICOSL-vIgD-Fc:

Demonstrated superior efficacy to belatacept in vitro in inhibiting T cell proliferation (CD4 and CD8 T cells) and cytokine production, including interferon gamma and tumor necrosis factor alpha, two key cytokines induced in a GvHD response
Significantly protected against GvHD at levels comparable to or better than belatacept in the humanized model
Significantly prolonged survival and greatly reduced GvHD disease activity in the humanized model as assessed by a disease activity score and weight loss compared with saline and wild-type ICOSL-Fc

On December 9, 2017 AbbVie (NYSE: ABBV), a global biopharmaceutical company, reported pooled analysis results of the longest follow-up data to date in Bruton’s tyrosine kinase (BTK) inhibition for relapsed/refractory (R/R) mantle cell lymphoma (MCL) patients treated with IMBRUVICA (ibrutinib) (Press release, AbbVie, DEC 9, 2017, View Source [SID1234522454]). The analysis found that, at three years, 45 percent of patients were able to achieve overall survival (OS) and 26 percent had disease progression-free survival (PFS). The pooled analysis also found that patients who were treated with ibrutinib earlier, after their first relapse/progression, experienced higher rates of OS and PFS.1 The analysis is comprised of data from a total of 370 patients in three different clinical trials: SPARK, RAY and PCYC-1104, and one ongoing Phase 3b extension study, CAN3001, which is eligible to patients who continue to benefit from ibrutinib therapy upon completing a previous ibrutinib clinical trial.2 MCL is an aggressive B-cell malignancy in which most patients relapse after their first line of therapy and receive a poor prognosis.

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These data will be presented in an oral presentation at the 59th Annual American Society of Hematology (ASH) (Free ASH Whitepaper) Meeting and Exposition on Dec. 9 at 12:00 p.m. ET in Atlanta (abstract #151).1 IMBRUVICA is a first-in-class BTK inhibitor jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and Janssen Biotech, Inc.

"IMBRUVICA continues to provide a beneficial treatment option for patients with relapsed/refractory mantle cell lymphoma," said Thorsten Graef, M.D., Ph.D., Head of Clinical Development at Pharmacyclics LLC, an AbbVie company. "Prior to the discovery and introduction of IMBRUVICA, people diagnosed with MCL had limited treatment options. This long-term data analysis adds to our growing understanding of IMBRUVICA’s potential treatment benefits for previously-treated MCL patients."

MCL is one of several subtypes of B-cell non-Hodgkin’s lymphoma (NHL) and represents about six percent (about 4,200) of new cases of NHL each year in the U.S. MCL usually begins with lymph node enlargement and can potentially spread to other tissues such as the bone marrow and liver.3 Median overall survival for MCL patients is three to four years.4

To view all IMBRUVICA company-sponsored or investigator-initiated studies being presented at ASH (Free ASH Whitepaper) 2017, which includes 12 oral presentations, please click here.

Abstract #151: Median 3.5-year Follow-Up of Ibrutinib Treatment in Patients with Relapsed/Refractory Mantle Cell Lymphoma: A Pooled Analysis
Oral presentation: Saturday, December 9, 2017, 12:00 PM ET

The pooled analysis includes results from a total of 370 patients from two Phase 2, open-label studies (SPARK and PCYC-1104), one Phase 3, open-label study (RAY), and an additional follow-up of 87 patients across these studies who enrolled in a long-term open-label extension study (CAN3001). Patients enrolled in SPARK, RAY and PCYC-1104 received ibrutinib 560mg orally once daily until progressive disease or unacceptable toxicity. Study inclusion and exclusion criteria were similar across SPARK, PCYC-1104 and RAY, requiring patients to have received at least one prior therapy for MCL and be chemotherapy-free for at least 3 weeks. However, patients in SPARK were required to have already received rituximab and bortezomib, and patients in RAY were required to have already received rituximab. Patients who continued to benefit from ibrutinib therapy at the end of the studies were eligible to enroll in CAN3001, a Phase 3b open-label study, which provides continued access to ibrutinib for patients who have completed an ibrutinib clinical study. Safety reporting in CAN3001 was limited to grade 3/4 adverse events (AEs) and serious adverse events (SAEs). This pooled analysis was limited to patients on ibrutinib therapy, excluding crossover patients. Investigator-assessed tumor response, progression-free survival (PFS), and overall survival (OS) were evaluated. PFS and OS were analyzed by number of prior lines of therapy and best tumor response. Patients in CAN3001 were censored from OS analysis upon treatment or study discontinuation.

With 3.5 years (41 months) of follow-up, the proportion of patients achieving complete response (CR) increased to 26.5%. In addition, 36% (95% CI, 0.31-0.42) and 26% (0.20-0.32) of patients treated with ibrutinib were progression free at 2 and 3 years, respectively, and the median PFS was 13 months. The median PFS in patients with one prior line of therapy was 33.6 (range, 19.4-42.1) months. The median period for patients achieving CR was 46.2 (range, 42.1-not estimable) months. Patients with favorable baseline disease characteristics were more likely to remain on ibrutinib for more than 3 years. Overall, 53% (95% CI, 0.47-0.58), 45% (0.39-0.50), and 37% (0.25-0.49) of patients were alive at 2, 3, and 5 years, respectively, and the median OS was 26.7 months.

In the pooled analysis, the median duration of follow-up was 41.1 months (95% CI, 37.3-42.5) and median exposure to ibrutinib was 11.1 months (range: 0.03-72.1). Eighty-three patients were treated with ibrutinib for 3 or more years, and 40 patients were treated with ibrutinib for 4 or more years. Fifty-four of 87 (62.1%) patients enrolled in CAN3001 remain on ibrutinib. Patients had a median of 2 (range: 1-9) prior lines of therapy before receiving ibrutinib.

Grade 3 or higher treatment-emergent adverse events (TEAEs) occurred in 79.7% of patients, with the new onset events decreasing after the first year. Cumulative incidence of any major hemorrhage was 7.3%, and new onset events decreased after the first year. The most common grade 3 or higher TEAEs were neutropenia (17.0%), thrombocytopenia (12.2%), pneumonia (11.9%), anemia (9.5%), atrial fibrillation (5.9%) and hypertension (5.1%). Most of these AEs were more common during the first year of ibrutinib treatment. Treatment-emergent SAEs occurred in 61.9% patients and new onset SAEs decreased over time (incidence: 47.3%, 33.9%, 29.6%, 25.3%, and 12.5% for Years 1, 2, 3, 4, and > 4, respectively). The data from this pooled analysis have not been reviewed by the U.S. Food and Drug Administration and they are not in the approved label for IMBRUVICA.

About the U.S. Food and Drug Administration (FDA) Approval of IMBRUVICA to Treat R/R MCL
The FDA approved IMBRUVICA (ibrutinib) as a single agent for the treatment of adult patients with MCL who have received at least one prior therapy based on the overall response rate (ORR) seen in the Phase 2 study, PCYC-1104, an open-label, multi-center, single-arm trial of 111 previously-treated MCL patients. IMBRUVICA was administered orally at 560-mg once daily until disease progression or unacceptable toxicity. Tumor response was assessed according to the revised International Working Group (IWG) for non-Hodgkin’s lymphoma (NHL) criteria.5 The efficacy results, which were published in the New England Journal of Medicine in 2013, demonstrated a 68% overall response rate with 47% of patients having a partial response and 21% having a complete response. The median duration of response was 17.5 months.5

About IMBRUVICA
IMBRUVICA (ibrutinib) is a first-in-class, oral, once-daily therapy that mainly works by blocking 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 as well as other serious, debilitating conditions.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 initially 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 previously treated 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.
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 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, 90,000 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 up to 6% of patients. Bleeding events of any grade, including bruising and petechiae, occurred in approximately half 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 14% to 29% of patients. 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 (range, 13 to 29%), thrombocytopenia (range, 5 to 17%), and anemia (range, 0 to 13%) based on laboratory measurements occurred in patients with B-cell malignancies treated with single agent IMBRUVICA.

Monitor complete blood counts monthly.

Atrial Fibrillation: Atrial fibrillation and atrial flutter (range, 6 to 9%) have occurred in patients treated with IMBRUVICA, particularly in patients with cardiac risk factors, hypertension, acute infections, and a previous history of atrial fibrillation. Periodically monitor patients clinically for atrial fibrillation. Patients who develop arrhythmic symptoms (e.g., palpitations, lightheadedness) or new onset dyspnea should have an ECG performed. Atrial fibrillation should be managed appropriately, and if it persists, consider the risks and benefits of IMBRUVICA treatment and follow dose modification guidelines.

Hypertension: Hypertension (range, 6 to 17%) has occurred in patients treated with IMBRUVICA with a median time to onset of 4.6 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 (range, 3 to 16%) including non-skin carcinomas (range, 1 to 4%) have occurred in patients treated with IMBRUVICA. The most frequent second primary malignancy was non-melanoma skin cancer (range, 2 to 13%).

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 (62%), neutropenia (61%), diarrhea (43%), anemia (41%), musculoskeletal pain (30%), rash (30%), bruising (30%), nausea (29%), fatigue (29%), hemorrhage (22%), and pyrexia (21%).

The most common Grade 3 or 4 adverse reactions (≥5%) in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were neutropenia (39%), thrombocytopenia (16%), and pneumonia (10%).

Approximately 6% (CLL/SLL), 14% (MCL), 11% (WM) and 10% (MZL) of patients had a dose reduction due to adverse reactions. Approximately 4%-10% (CLL/SLL), 9% (MCL), and 9% (WM [6%] 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 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.

DRUG INTERACTIONS

CYP3A Inducers: Avoid coadministration with strong CYP3A inducers.

CYP3A Inhibitors: Dose adjustment may be recommended.

SPECIFIC POPULATIONS

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

On December 9, 2017 AbbVie (NYSE: ABBV), a global biopharmaceutical company, reported new three-year follow-up data from the RESONATE-2 study (PCYC-1115/1116), which found that previously-untreated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) patients reported sustained improvements in measures of well-being with IMBRUVICA (ibrutinib) versus chemotherapy with chlorambucil (Press release, AbbVie, DEC 9, 2017, View Source [SID1234522453]). These new data provide the longest quality of life follow up for ibrutinib to date using patient-reported outcomes (PRO). Patients reported their quality of life outcomes for fatigue, mobility, self-care, usual activities, pain/discomfort and anxiety/depression. At 30 months, ibrutinib was also associated with a greater progression-free survival (PFS) rate of 85 percent versus chlorambucil, which had a PFS rate of 28 percent.

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The new RESONATE-2 data will be presented at the 59th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition on Dec. 9 in Atlanta (abstract #1746). IMBRUVICA is a first-in-class Bruton’s tyrosine kinase (BTK) inhibitor jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and Janssen Biotech, Inc.

"In the RESONATE-2 study, patients who were treated with ibrutinib reported greater and sustained improvements in overall health and well-being and experienced decreased disease-related symptoms," said Danelle James, M.D., M.A.S., Head of Clinical Science, Pharmacyclics LLC, an AbbVie company. "For patients with chronic lymphocytic leukemia, a disease that affects primarily older patients, quality of life is an important consideration that should be factored into treatment choices initially and throughout long-term use."

CLL is the most common form of leukemia in adults and is a type of cancer that can form from cells in the bone marrow that later mature into certain white blood cells (called lymphocytes). While these cancer cells start in the bone marrow, they then later spread into the blood. The prevalence of CLL is approximately 115,000 patients in the U.S.1 with approximately 19,000 newly diagnosed patients every year.2 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.3 CLL/SLL are predominately diseases of the elderly, with a median age of 71 at diagnosis.

About the Presentation

Abstract #1746: Prolonged Improvement in Patient-Reported Outcomes (PROs) and Well-being in Older Patients With Treatment-Naïve (TN) Chronic Lymphocytic Leukemia Treated With Ibrutinib (Ibr): 3-Year Follow-up of the RESONATE-2 Study
Poster Presentation; Saturday, December 9, 5:30 – 7:30 p.m. ET

At a median follow up of three years, ibrutinib treatment resulted in significantly longer PFS (median, not reached versus 15 months with chlorambucil), with an 87% reduction in risk of progression or death versus chlorambucil (HR 0.130; 95% CI: 0.081, 0.208). The PFS rate for ibrutinib was 85% versus 28% with chlorambucil. Greater and sustained improvements in PROs were observed with ibrutinib, resulting in significantly greater improvements over time versus chlorambucil (via FACIT-F and EQ-5D-5L Visual Analogue Scale by repeated measures).

In chlorambucil patients with progressive disease, PROs improved after crossing over to ibrutinib. Approximately 87% of patients on ibrutinib (versus 52% on chlorambucil) had decreased/normalized lymphadenopathy within 2 months, which was sustained through 36 months, and disease symptoms, including fatigue and night sweats, improved more frequently for patients on ibrutinib. A greater proportion of patients with baseline cytopenia showed sustained hematologic improvement with ibrutinib versus chlorambucil for hemoglobin (90% versus 45%) and platelets (83% versus 46%).

Patients 65 years and older (median age 73) were randomized to receive 420mg ibrutinib once daily until progressive disease or chlorambucil for up to 12 months. Median treatment duration was 34.1 months on ibrutinib versus 7.1 months on chlorambucil. Further data showed the burden of hematologic support medical resource utilization was less with ibrutinib versus chlorambucil in the first year and subsequently continued to decrease.

The most common adverse events (AEs) of any grade with ibrutinib were diarrhea (47%), fatigue (33%), and cough (30%). Eight Grade 3 or higher AEs had a prevalence of less than 3% in ibrutinib patients and generally decreased or were stable over time. During the first year of treatment, patients on ibrutinib versus chlorambucil experienced less Grade 3 or higher neutropenia (8% and 18%), anemia (6% and 8%), and thrombocytopenia (2% and 5%); other common Grade 3 or higher AEs were pneumonia (5% and 2%), hypertension (4% and 0%), and infections as combined term (17% and 8%). Grade 3 or higher bleeding occurred in 7% of ibrutinib patients over the 3-year follow up. AEs leading to treatment discontinuation occurred in 16% with ibrutinib over 3 years versus 23% for chlorambucil over 7 months of therapy, respectively.

Additional Presentation on RESONATE-2 at ASH (Free ASH Whitepaper) 2017

A separate presentation at ASH (Free ASH Whitepaper) this year will also discuss the RESONATE-2 clinical trial (with a median follow up of 35.7 months) as part of a cross-trial comparison. The data compares ibrutinib as a single-agent therapy and six different chemoimmunotherapy regimens from additional Phase 3 studies in patients with CLL as a first-line therapy, reviewing results in PFS, overall survival (OS) and safety measures. The six chemoimmunotherapy regimens included as part of the cross-trial comparison are fludarabine, cyclophosphamide and rituximab (FCR); bendamustine and rituximab (BR); obinutuzumab and chlorambucil; rituximab and chlorambucil; and ofatumumab and chlorambucil. This data will also be presented at ASH (Free ASH Whitepaper) on Dec. 9 (abstract #1750).

To view all IMBRUVICA company-sponsored or investigator-initiated studies being presented at ASH (Free ASH Whitepaper) 2017, which includes 12 oral presentations, please click here.

About IMBRUVICA
IMBRUVICA (ibrutinib) is a first-in-class, oral, once-daily therapy that mainly works by blocking 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 as well as other serious, debilitating conditions.4 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).5

IMBRUVICA was first approved for adult patients with MCL who have received at least one prior therapy in November 2013.
Soon after, IMBRUVICA was initially 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 previously-treated 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.
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.6 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, 90,000 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 up to 6% of patients. Bleeding events of any grade, including bruising and petechiae, occurred in approximately half 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 14% to 29% of patients. 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 (range, 13 to 29%), thrombocytopenia (range, 5 to 17%), and anemia (range, 0 to 13%) based on laboratory measurements occurred in patients with B-cell malignancies treated with single agent IMBRUVICA.
Monitor complete blood counts monthly.

Atrial Fibrillation: Atrial fibrillation and atrial flutter (range, 6 to 9%) have occurred in patients treated with IMBRUVICA, particularly in patients with cardiac risk factors, hypertension, acute infections, and a previous history of atrial fibrillation. Periodically monitor patients clinically for atrial fibrillation. Patients who develop arrhythmic symptoms (e.g., palpitations, lightheadedness) or new onset dyspnea should have an ECG performed. Atrial fibrillation should be managed appropriately, and if it persists, consider the risks and benefits of IMBRUVICA treatment and follow dose modification guidelines.

Hypertension: Hypertension (range, 6 to 17%) has occurred in patients treated with IMBRUVICA with a median time to onset of 4.6 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 (range, 3 to 16%) including non-skin carcinomas (range, 1 to 4%) have occurred in patients treated with IMBRUVICA. The most frequent second primary malignancy was non-melanoma skin cancer (range, 2 to 13%).

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 (62%), neutropenia (61%), diarrhea (43%), anemia (41%), musculoskeletal pain (30%), rash (30%), bruising (30%), nausea (29%), fatigue (29%), hemorrhage (22%), and pyrexia (21%).

The most common Grade 3 or 4 adverse reactions (≥5%) in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were neutropenia (39%), thrombocytopenia (16%), and pneumonia (10%).

Approximately 6% (CLL/SLL), 14% (MCL), 11% (WM) and 10% (MZL) of patients had a dose reduction due to adverse reactions. Approximately 4%-10% (CLL/SLL), 9% (MCL), and 9% (WM [6%] 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 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.

DRUG INTERACTIONS

CYP3A Inducers: Avoid coadministration with strong CYP3A inducers.

CYP3A Inhibitors: Dose adjustment may be recommended.

SPECIFIC POPULATIONS

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

On December 7, 2017 Sandoz, a division of Novartis and the global leader in biosimilars, reported data demonstrating the pharmacokinetics (PK), pharmacodynamics (PD), safety and immunogenicity of proposed biosimilar pegfilgrastim as compared to the reference biologic, Neulasta*[1] (Press release, Novartis, DEC 7, 2017, View Source [SID1234522450]). The Phase I study, conducted in healthy volunteers, confirmed that Sandoz biosimilar pegfilgrastim matches the reference biologic in terms of PK, PD, safety and immunogenicity profiles[1]. The data were presented during the 2017 San Antonio Breast Cancer Symposium.

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"At Sandoz, we are committed to developing high-quality biosimilar and generic medicines that provide the oncology community with treatment options to help manage their patients," said Mark Levick, MD PhD, Global Head of Development, Biopharmaceuticals, Sandoz, "And it starts with following the science. These findings add to the totality of evidence supporting our proposed biosimilar pegfilgrastim."

Sandoz biosimilar pegfilgrastim is currently under review by the European Medicines Agency (EMA) for use in the same indication as the reference biologic. Pegfilgrastim is a long-acting formulation of filgrastim (granulocyte colony-stimulating factor [G-CSF])[2].

About the study
Study participants were randomized to receive a single 6 mg subcutaneous injection of biosimilar pegfilgrastim or reference medicine on Day 0[1]. After dosing, study participants underwent a 4-week assessment period followed by a 8-week washout period before crossing over to receive the other medicine, and were assessed for a further 4-weeks[1].

The results demonstrated that Sandoz proposed biosimilar pegfilgrastim matched the reference medicine in the PK and PD comparisons as primary endpoints, in terms of absolute neutrophil count (maximum effect attributed to study medication) (95% CI: [0.97, 1.02]) and maximum serum concentration of study medication after administration (90% CI: [1.03, 1.19])[1]. Secondary endpoints of safety and immunogenicity were comparable between both groups[1].

Disclaimer
This press release contains forward-looking statements within the meaning of the United States Private Securities Litigation Reform Act of 1995. Forward-looking statements can generally be identified by words such as "potential," "can," "will," "plan," "expect," "anticipate," "look forward," "believe," "committed," "investigational," "pipeline," "launch," or similar terms, or by express or implied discussions regarding potential marketing approvals, new indications or labeling for the investigational or approved generic or biosimilar products described in this press release, or regarding potential future revenues from such products. You should not place undue reliance on these statements. Such forward-looking statements are based on our current beliefs and expectations regarding future events, and are subject to significant known and unknown risks and uncertainties. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those set forth in the forward-looking statements. There can be no guarantee that the investigational or approved products described in this press release will be submitted or approved for sale or for any additional indications or labeling in any market, or at any particular time. Neither can there be any guarantee that, if approved, such generic or biosimilar products will be approved for all indications included in the reference product’s label. Nor can there be any guarantee that such products will be commercially successful in the future. In particular, our expectations regarding such products could be affected by, among other things, the uncertainties inherent in research and development, including clinical trial results and additional analysis of existing clinical data; regulatory actions or delays or government regulation generally; the particular prescribing preferences of physicians and patients; competition in general, including potential approval of additional generic or biosimilar versions of such products; global trends toward health care cost containment, including government, payor and general public pricing and reimbursement pressures; litigation outcomes, including intellectual property disputes or other legal efforts to prevent or limit Sandoz from selling its products; general economic and industry conditions, including the effects of the persistently weak economic and financial environment in many countries; safety, quality or manufacturing issues, and other risks and factors referred to in Novartis AG’s current Form 20-F on file with the US Securities and Exchange Commission. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise.

On December 5, 2017 Eli Lilly and Company (NYSE: LLY) reported top-line results from its Phase 3 RAINFALL study of CYRAMZA (ramucirumab) in combination with cisplatin and capecitabine or 5-FU (5-fluorouracil) in the first-line treatment of patients with HER2-negative metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma (Press release, Eli Lilly, DEC 8, 2017, View Source [SID1234522477]). The trial met its primary endpoint of progression-free survival (PFS) but did not improve overall survival (OS), a secondary endpoint. The results will be submitted for presentation at a future medical meeting.

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The safety profile observed in the RAINFALL study was consistent with what has been previously observed for ramucirumab. Grade ≥3 adverse events occurring at a rate of five percent or greater and that were higher on the ramucirumab-plus-cisplatin-and-capecitabine/5-FU arm compared to the placebo-plus-cisplatin-and-capecitabine/5-FU arm were hypertension, hand-foot syndrome, and fatigue.

"While we hoped that the positive PFS outcome would have translated into an OS benefit, these RAINFALL results highlight the challenges associated with improving outcomes for people with advanced gastric cancer," said Levi Garraway, M.D., Ph.D., senior vice president, global development and medical affairs, Lilly Oncology. "This is underscored by the fact that there have been no major advances over standard chemotherapy in the first-line HER2-negative gastric cancer treatment setting in the last decade."

Dr. Garraway added, "Lilly is deeply committed to patients with this aggressive disease, and CYRAMZA remains a standard of care in the second-line treatment paradigm for advanced gastric cancer patients around the world. We thank the patients, their caregivers and investigators for their support of and participation in the RAINFALL study."

The company does not intend to seek regulatory approval based on the results of the RAINFALL study. The outcome of RAINFALL does not have any impact on current ramucirumab approvals.

After becoming the first FDA-approved agent to treat advanced gastric cancer after prior chemotherapy in 2014 based on two pivotal Phase 3 studies, ramucirumab is now a standard of care in this setting around the world. This is supported by global and local treatment guidelines, including NCCN, JGCA and ESMO (Free ESMO Whitepaper).

Overall, there have been six positive Phase 3 trials of ramucirumab to date. Previously completed Phase 3 studies of ramucirumab have demonstrated benefit in advanced forms of gastric, non-small cell lung and colorectal cancer – three of the world’s leading causes of cancer-related death. An ongoing Phase 3 trial in advanced urothelial carcinoma has also met its primary endpoint of PFS; those initial data were presented at the ESMO (Free ESMO Whitepaper) 2017 Congress and OS data are expected in mid-2018. Two other ongoing Phase 3 studies of ramucirumab – in hepatocellular carcinoma and EGFR-positive non-small cell lung cancer – are ongoing, with expected data readouts in 2018.

Notes to Editors

About RAINFALL
RAINFALL is a global, randomized, double-blinded, placebo-controlled Phase 3 study of ramucirumab in combination with cisplatin and capecitabine as a first-line treatment in patients with metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma. Study participants unable to take capecitabine (tablets) were given 5-fluorouracil (5-FU).

Initiated in 2015, the study enrolled 645 patients across 19 countries in North America, Asia (Japan), Europe and Latin America. The primary endpoint of the RAINFALL trial is progression-free survival and key secondary endpoints include: overall survival; objective response rate; and safety.

About Gastric Cancer
Gastric cancer, also known as stomach cancer, is a major global health problem. Globally, it is the fifth most common cancer in the world, with one million new cases annually.1 Gastric cancer originates in the stomach. Cancer cells typically develop slowly and symptoms often do not appear until the disease is advanced and has already spread to other organs such as the liver, lungs and bones.2,3 Stomach cancer is the third leading cause of cancer deaths in the world, resulting in 723,000 deaths each year.1 The five-year survival rate for stomach cancer is 31 percent and five percent for advanced cases.4

Stomach cancer is much more common in the Far East than in the Western world.1 In the U.S., it is estimated that approximately 28,000 people will be diagnosed with stomach cancer and nearly 11,000 people will die from this type of cancer in 2017.5 In Japan, the incidence of stomach cancer is high. Of all cancers in Japan, stomach cancer is the second most common and it is the second-leading cause of cancer-related deaths, affecting approximately 108,000 people and killing approximately 52,000.

About Angiogenesis and VEGF Protein
Angiogenesis is the process of making new blood vessels. In a person with cancer, angiogenesis creates new blood vessels that give a tumor its own blood supply, allowing it to grow and spread.

Some tumors create proteins called VEGF. These proteins attach to the VEGF receptors of blood vessel cells causing new blood vessels to form around the tumors, enabling growth. Blocking the VEGF protein from linking to the blood vessels helps to inhibit tumor growth by slowing angiogenesis and the blood supply that feeds tumors. Of the three known VEGF receptors, VEGF Receptor 2 is linked most closely to VEGF-induced tumor angiogenesis.

About CYRAMZA (ramucirumab)
In the U.S., CYRAMZA (ramucirumab) is approved for use as a single agent or in combination with paclitaxel as a treatment for people with advanced or metastatic gastric (stomach) or gastroesophageal junction (GEJ) adenocarcinoma whose cancer has progressed on or after prior fluoropyrimidine- or platinum-containing chemotherapy. It is also approved in combination with docetaxel as a treatment for people with metastatic non-small cell lung cancer (NSCLC) whose cancer has progressed on or after platinum-based chemotherapy. Additionally, it is approved with FOLFIRI as a treatment for people with metastatic colorectal cancer (mCRC) whose cancer has progressed on or after therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine.

Ramucirumab is being investigated in a broad global development program that has enrolled more than 10,000 patients across more than 70 trials worldwide. There are several studies underway or planned to investigate ramucirumab as a single agent and in combination with other anti-cancer therapies for the treatment of multiple tumor types.

Ramucirumab is an antiangiogenic therapy. It is a vascular endothelial growth factor (VEGF) Receptor 2 antagonist that specifically binds and blocks activation of VEGF Receptor 2 by blocking the binding of VEGF receptor ligands VEGF-A, VEGF-C, and VEGF-D. Ramucirumab inhibited angiogenesis in an in vivo animal model.

INDICATIONS

Gastric Cancer
CYRAMZA, as a single agent or in combination with paclitaxel, is indicated for the treatment of patients with advanced or metastatic, gastric or gastroesophageal junction (GEJ) adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy.

Non-Small Cell Lung Cancer
CYRAMZA, in combination with docetaxel, is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with disease progression on or after platinum-based chemotherapy. Patients with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving CYRAMZA.

Colorectal Cancer
CYRAMZA, in combination with FOLFIRI (irinotecan, folinic acid, and 5-fluorouracil), is indicated for the treatment of patients with metastatic colorectal cancer (mCRC) with disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine.

IMPORTANT SAFETY INFORMATION FOR CYRAMZA

WARNING: HEMORRHAGE, GASTROINTESTINAL PERFORATION, AND
IMPAIRED WOUND HEALING

Hemorrhage: CYRAMZA increased the risk of hemorrhage and gastrointestinal
hemorrhage, including severe and sometimes fatal hemorrhagic events. Permanently
discontinue CYRAMZA in patients who experience severe bleeding.

Gastrointestinal Perforation: CYRAMZA can increase the risk of gastrointestinal
perforation, a potentially fatal event. Permanently discontinue CYRAMZA in patients who
experience a gastrointestinal perforation.

Impaired Wound Healing: Impaired wound healing can occur with antibodies inhibiting
the VEGF pathway. Discontinue CYRAMZA therapy in patients with impaired wound
healing. Withhold CYRAMZA prior to surgery and discontinue CYRAMZA if a patient
develops wound healing complications.
Warnings and Precautions

Hemorrhage

In study 1, which evaluated CYRAMZA as a single agent in advanced gastric cancer, the incidence of severe bleeding was 3.4% for CYRAMZA and 2.6% for placebo. In study 2, which evaluated CYRAMZA plus paclitaxel in advanced gastric cancer, the incidence of severe bleeding was 4.3% for CYRAMZA plus paclitaxel and 2.4% for placebo plus paclitaxel. Patients with gastric cancer receiving nonsteroidal anti-inflammatory drugs (NSAIDs) were excluded from enrollment in studies 1 and 2. In study 3, which evaluated CYRAMZA plus docetaxel in metastatic non-small cell lung cancer (NSCLC), the incidence of severe bleeding was 2.4% for CYRAMZA plus docetaxel and 2.3% for placebo plus docetaxel. Patients with NSCLC receiving therapeutic anticoagulation or chronic therapy with NSAIDs or other antiplatelet therapy other than once-daily aspirin or with radiographic evidence of major airway or blood vessel invasion or intratumor cavitation were excluded from study 3. In study 4, which evaluated CYRAMZA plus FOLFIRI in metastatic colorectal cancer, the incidence of severe bleeding was 2.5% for CYRAMZA plus FOLFIRI and 1.7% for placebo plus FOLFIRI. Permanently discontinue CYRAMZA in patients who experience severe bleeding.
Arterial Thromboembolic Events (ATEs)

Serious, sometimes fatal, ATEs including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia occurred in clinical trials. Permanently discontinue CYRAMZA in patients who experience a severe ATE.
Hypertension

An increased incidence of severe hypertension occurred in patients receiving CYRAMZA as a single agent (8%) as compared to placebo (3%), in patients receiving CYRAMZA plus paclitaxel (15%) as compared to placebo plus paclitaxel (3%), and in patients receiving CYRAMZA plus docetaxel (6%) as compared to placebo plus docetaxel (2%), and in patients receiving CYRAMZA plus FOLFIRI (11%) as compared to placebo plus FOLFIRI (3%). Monitor blood pressure every 2 weeks or more frequently as indicated during treatment. Temporarily suspend CYRAMZA for severe hypertension until medically controlled. Permanently discontinue CYRAMZA if medically significant hypertension cannot be controlled with antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy.
Infusion-Related Reactions (IRRs)

Prior to the institution of premedication recommendations across clinical trials of CYRAMZA, IRRs occurred in 6 out of 37 patients (16%), including 2 severe events. The majority of IRRs across trials occurred during or following a first or second CYRAMZA infusion. Monitor patients during the infusion for signs and symptoms of IRRs in a setting with available resuscitation equipment. Immediately and permanently discontinue CYRAMZA for grade 3 or 4 IRRs.
Gastrointestinal Perforations

Four of 570 patients (0.7%) who received CYRAMZA as a single agent in advanced gastric cancer clinical trials experienced gastrointestinal perforation. In study 2, the incidence of gastrointestinal perforation was 1.2% for CYRAMZA plus paclitaxel as compared to 0.3% for placebo plus paclitaxel. In study 3, the incidence of gastrointestinal perforation was 1% for CYRAMZA plus docetaxel as compared to 0.3% for placebo plus docetaxel. In study 4, the incidence of gastrointestinal perforation was 1.7% for CYRAMZA plus FOLFIRI and 0.6% for placebo plus FOLFIRI. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation.
Impaired Wound Healing

CYRAMZA has not been studied in patients with serious or nonhealing wounds. CYRAMZA has the potential to adversely affect wound healing. Discontinue CYRAMZA therapy in patients with impaired wound healing. Withhold CYRAMZA prior to surgery. Resume CYRAMZA following the surgical intervention based on clinical judgment of adequate wound healing. If a patient develops wound healing complications during therapy, discontinue CYRAMZA until the wound is fully healed.
Clinical Deterioration in Child-Pugh B or C Cirrhosis

Clinical deterioration, manifested by new onset or worsening encephalopathy, ascites, or hepatorenal syndrome, was reported in patients with Child-Pugh B or C cirrhosis who received single-agent CYRAMZA.
Reversible Posterior Leukoencephalopathy Syndrome (RPLS)

RPLS has been reported at a rate of < 0.1% in clinical studies with CYRAMZA. Discontinue CYRAMZA in patients who develop RPLS. Symptoms may resolve or improve within days, although some patients with RPLS can experience ongoing neurologic sequelae or death.
Proteinuria Including Nephrotic Syndrome

In study 4, severe proteinuria occurred more frequently in patients treated with CYRAMZA plus FOLFIRI compared to patients receiving placebo plus FOLFIRI. Severe proteinuria was reported in 3% of patients treated with CYRAMZA plus FOLFIRI (including 3 cases [0.6%] of nephrotic syndrome) compared to 0.2% of patients treated with placebo plus FOLFIRI. Monitor proteinuria by urine dipstick and/or urinary protein creatinine ratio for the development of worsening of proteinuria during CYRAMZA therapy. Withhold CYRAMZA for urine protein levels that are ≥2 g over 24 hours. Reinitiate CYRAMZA at a reduced dose once the urine protein level returns to < 2 g over 24 hours. Permanently discontinue CYRAMZA for urine protein levels > 3 g over 24 hours or in the setting of nephrotic syndrome.
Thyroid Dysfunction

Monitor thyroid function during treatment with CYRAMZA. In study 4, the incidence of hypothyroidism reported as an adverse event was 2.6% in the CYRAMZA plus FOLFIRI-treated patients and 0.9% in the placebo plus FOLFIRI-treated patients.
Embryofetal Toxicity

Based on its mechanism of action, CYRAMZA can cause fetal harm when administered to pregnant women. Animal models link angiogenesis, VEGF, and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with CYRAMZA and for at least 3 months after the last dose of CYRAMZA.
Most Common Adverse Reactions—Single Agent

The most commonly reported adverse reactions (all grades; grade 3/4) occurring in ≥5% of patients receiving CYRAMZA and ≥2% higher than placebo in study 1 were hypertension (16% vs 8%; 8% vs 3%), diarrhea (14% vs 9%; 1% vs 2%), headache (9% vs 3%; 0% vs 0%), and hyponatremia (6% vs 2%; 3% vs 1%).
The most common serious adverse events with CYRAMZA in study 1 were anemia (3.8%) and intestinal obstruction (2.1%). Red blood cell transfusions were given to 11% of CYRAMZA-treated patients vs 8.7% of patients who received placebo.
Clinically relevant adverse reactions reported in ≥1% and < 5% of CYRAMZA-treated patients vs placebo in study 1 were: neutropenia (4.7% vs 0.9%), epistaxis (4.7% vs 0.9%), rash (4.2% vs 1.7%), intestinal obstruction (2.1% vs 0%), and arterial thromboembolic events (1.7% vs 0%).
Across clinical trials of CYRAMZA administered as a single agent, clinically relevant adverse reactions (including grade ≥3) reported in CYRAMZA-treated patients included proteinuria, gastrointestinal perforation, and infusion-related reactions. In study 1, according to laboratory assessment, 8% of CYRAMZA-treated patients developed proteinuria vs 3% of placebo-treated patients. Two patients discontinued CYRAMZA due to proteinuria. The rate of gastrointestinal perforation in study 1 was 0.8% and the rate of infusion-related reactions was 0.4%.
Most Common Adverse Reactions—Combination With Paclitaxel

The most commonly reported adverse reactions (all grades; grade 3/4) occurring in ≥5% of patients receiving CYRAMZA plus paclitaxel and ≥2% higher than placebo plus paclitaxel in study 2 were fatigue/asthenia (57% vs 44%; 12% vs 6%), neutropenia (54% vs 31%; 41% vs 19%), diarrhea (32% vs 23%; 4% vs 2%), epistaxis (31% vs 7%; 0% vs 0%), hypertension (25% vs 6%; 15% vs 3%), peripheral edema (25% vs 14%; 2% vs 1%), stomatitis (20% vs 7%; 1% vs 1%), proteinuria (17% vs 6%; 1% vs 0%), thrombocytopenia (13% vs 6%; 2% vs 2%), hypoalbuminemia (11% vs 5%; 1% vs 1%), and gastrointestinal hemorrhage events (10% vs 6%; 4% vs 2%).
The most common serious adverse events with CYRAMZA plus paclitaxel in study 2 were neutropenia (3.7%) and febrile neutropenia (2.4%); 19% of patients treated with CYRAMZA plus paclitaxel received granulocyte colony-stimulating factors.
Adverse reactions resulting in discontinuation of any component of the CYRAMZA plus paclitaxel combination in 2% or more patients in study 2 were neutropenia (4%) and thrombocytopenia (3%).
Clinically relevant adverse reactions reported in ≥1% and < 5% of the CYRAMZA plus paclitaxel-treated patients in study 2 were sepsis (3.1% for CYRAMZA plus paclitaxel vs 1.8% for placebo plus paclitaxel) and gastrointestinal perforations (1.2% for CYRAMZA plus paclitaxel vs 0.3% for placebo plus paclitaxel).
Most Common Adverse Reactions—Combination With Docetaxel

The most commonly reported adverse reactions (all grades; grade 3/4) occurring in ≥5% of patients receiving CYRAMZA plus docetaxel and ≥2% higher than placebo plus docetaxel in study 3 were neutropenia (55% vs 46%; 49% vs 40%), fatigue/asthenia (55% vs 50%; 14% vs 11%), stomatitis/mucosal inflammation (37% vs 19%; 7% vs 2%), epistaxis (19% vs 7%; < 1% vs < 1%), febrile neutropenia (16% vs 10%; 16% vs 10%), peripheral edema (16% vs 9%; 0% vs < 1%), thrombocytopenia (13% vs 5%; 3% vs < 1%), lacrimation increased (13% vs 5%; < 1% vs 0%), and hypertension (11% vs 5%; 6% vs 2%).
The most common serious adverse events with CYRAMZA plus docetaxel in study 3 were febrile neutropenia (14%), pneumonia (6%), and neutropenia (5%). The use of granulocyte colony-stimulating factors was 42% in CYRAMZA plus docetaxel-treated patients versus 37% in patients who received placebo plus docetaxel.
In patients ≥65 years of age, there were 18 (8%) deaths on treatment or within 30 days of discontinuation for CYRAMZA plus docetaxel and 9 (4%) deaths for placebo plus docetaxel. In patients < 65 years of age, there were 13 (3%) deaths on treatment or within 30 days of discontinuation for CYRAMZA plus docetaxel and 26 (6%) deaths for placebo plus docetaxel.
Treatment discontinuation due to adverse reactions occurred more frequently in CYRAMZA plus docetaxel-treated patients (9%) than in placebo plus docetaxel-treated patients (5%). The most common adverse events leading to treatment discontinuation of CYRAMZA in study 3 were infusion-related reaction (0.5%) and epistaxis (0.3%).
For patients with nonsquamous histology, the overall incidence of pulmonary hemorrhage was 7% and the incidence of grade ≥3 pulmonary hemorrhage was 1% for CYRAMZA plus docetaxel compared to 6% overall incidence and 1% for grade ≥3 pulmonary hemorrhage for placebo plus docetaxel. For patients with squamous histology, the overall incidence of pulmonary hemorrhage was 10% and the incidence of grade ≥3 pulmonary hemorrhage was 2% for CYRAMZA plus docetaxel compared to 12% overall incidence and 2% for grade ≥3 pulmonary hemorrhage for placebo plus docetaxel.
Clinically relevant adverse reactions reported in ≥1% and < 5% of CYRAMZA plus docetaxel-treated patients in study 3 were hyponatremia (4.8% CYRAMZA plus docetaxel versus 2.4% for placebo plus docetaxel) and proteinuria (3.3% CYRAMZA plus docetaxel versus 0.8% placebo plus docetaxel).
Most Common Adverse Reactions—Combination With FOLFIRI

The most commonly reported adverse reactions (all grades; grade 3/4) occurring in ≥5% of patients receiving CYRAMZA plus FOLFIRI and ≥2% higher than placebo plus FOLFIRI in study 4 were diarrhea (60% vs 51%; 11% vs 10%), neutropenia (59% vs 46%; 38% vs 23%), decreased appetite (37% vs 27%; 2% vs 2%), epistaxis (33% vs 15%; 0% vs 0%), stomatitis (31% vs 21%; 4% vs 2%), thrombocytopenia (28% vs 14%; 3% vs < 1%), hypertension (26% vs 9%; 11% vs 3%), peripheral edema (20% vs 9%; < 1% vs 0%), proteinuria (17% vs 5%; 3% vs < 1%), palmar-plantar erythrodysesthesia syndrome (13% vs 5%; 1% vs < 1%), gastrointestinal hemorrhage events (12% vs 7%; 2% vs 1%), hypoalbuminemia (6% vs 2%; 1% vs 0%). Twenty percent of patients treated with CYRAMZA plus FOLFIRI received granulocyte colony-stimulating factors.
The most common serious adverse events with CYRAMZA plus FOLFIRI were diarrhea (3.6%), intestinal obstruction (3.0%), and febrile neutropenia (2.8%).
Treatment discontinuation of any study drug due to adverse reactions occurred more frequently in CYRAMZA plus FOLFIRI-treated patients (29%) than in placebo plus FOLFIRI-treated patients (13%). The most common adverse reactions leading to discontinuation of any component of CYRAMZA plus FOLFIRI as compared to placebo plus FOLFIRI were neutropenia (12.5% versus 5.3%) and thrombocytopenia (4.2% versus 0.8%). The most common adverse reactions leading to treatment discontinuation of CYRAMZA were proteinuria (1.5%) and gastrointestinal perforation (1.7%).
Clinically relevant adverse reactions reported in ≥1% and < 5% of CYRAMZA plus FOLFIRI-treated patients in study 4 consisted of gastrointestinal perforation (1.7% CYRAMZA plus FOLFIRI versus 0.6% for placebo plus FOLFIRI).
Thyroid-stimulating hormone (TSH) was evaluated in 224 patients (115 CYRAMZA plus FOLFIRI-treated patients and 109 placebo plus FOLFIRI-treated patients) with normal baseline TSH levels. Increased TSH was observed in 53 (46%) patients treated with CYRAMZA plus FOLFIRI compared with 4 (4%) patients treated with placebo plus FOLFIRI.
Drug Interactions

No pharmacokinetic interactions were observed between ramucirumab and paclitaxel, between ramucirumab and docetaxel, or between ramucirumab and irinotecan or its active metabolite, SN-38.
Use in Specific Populations

Pregnancy: Based on its mechanism of action, CYRAMZA can cause fetal harm. Animal models link angiogenesis, VEGF, and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. There are no available data on CYRAMZA use in pregnant women to inform any drug-associated risks. No animal studies have been conducted to evaluate the effect of ramucirumab on reproduction and fetal development. Advise females of reproductive potential of the potential risk for maintaining pregnancy, risk to the fetus, and risk to newborn and pediatric development, and to use effective contraception during CYRAMZA therapy and for at least 3 months following the last dose of CYRAMZA.
Lactation: Because of the potential risk for serious adverse reactions in nursing infants from ramucirumab, advise women that breastfeeding is not recommended during treatment with CYRAMZA.
Females of Reproductive Potential: Advise females of reproductive potential that based on animal data CYRAMZA may impair fertility.
Please see full Prescribing Information for CYRAMZA, including Boxed Warning for hemorrhage, gastrointestinal perforation, and impaired wound healing.

RB-P-HCP ISI 16FEB2017

About Lilly Oncology
For more than 50 years, Lilly has been dedicated to delivering life-changing medicines and support to people living with cancer and those who care for them. Lilly is determined to build on this heritage and continue making life better for all those affected by cancer around the world. To learn more about Lilly’s commitment to people with cancer, please visit www.LillyOncology.com.