On July 21, 2017 Merck (NYSE:MRK), known as MSD outside the United States and Canada, reported that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion recommending approval of KEYTRUDA (pembrolizumab), the company’s anti-PD-1 therapy, for the treatment of certain patients with locally advanced or metastatic urothelial carcinoma, a type of bladder cancer (Press release, Merck & Co, JUL 21, 2017, View Source [SID1234519854]). Specifically, KEYTRUDA is recommended for the treatment of locally advanced or metastatic urothelial carcinoma in adult patients who have received prior platinum-containing chemotherapy, as well as adult patients who are not eligible for cisplatin-containing chemotherapy. The recommendation will now be reviewed by the European Commission for marketing authorization in the European Union. A final decision is expected in the third quarter of 2017.

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"There is significant need for new options that address the treatment gaps for patients in Europe with locally advanced or metastatic urothelial carcinoma, especially for those who have failed on prior platinum treatment or are ineligible for cisplatin-containing chemotherapy," said Dr. Roger Dansey, senior vice president and therapeutic area head, oncology late-stage development, Merck Research Laboratories. "We are pleased that the CHMP has provided a positive opinion for KEYTRUDA in these two patient populations and look forward to working with the European Commission to bring forward this new option for patients in need."

The positive opinion is based on data from the KEYNOTE-045 and KEYNOTE-052 trials. KEYNOTE-045 is a phase 3, randomized study investigating KEYTRUDA (pembrolizumab) compared to investigator-choice chemotherapy (paclitaxel, docetaxel, vinflunine) in patients with locally advanced or metastatic urothelial carcinoma that has recurred or progressed on or after platinum-containing chemotherapy. KEYNOTE-052 is a phase 2, open-label study investigating KEYTRUDA in treatment-naïve patients with locally advanced or metastatic urothelial carcinoma who are ineligible for cisplatin-containing therapy.

The KEYTRUDA clinical development program includes more than 30 tumor types in more than 500 clinical trials, including more than 300 trials that combine KEYTRUDA with other cancer treatments. Currently, Merck has the largest immuno-oncology clinical development program in bladder cancer, with 29 trials underway involving KEYTRUDA as monotherapy and in combination, including four registration-enabling studies.

About Bladder Cancer
Bladder cancer begins when cells in the urinary bladder start to grow uncontrollably. As more cancer cells develop, they can form a tumor and spread to other areas of the body. Urothelial carcinoma, the most common type of bladder cancer, starts in the urothelial cells that line the inside of the bladder. In 2012, approximately 430,000 people worldwide were diagnosed with bladder cancer and 165,000 died from the disease. The incidence of bladder cancer is elevated in North America, Europe, North Africa, the Middle East, Australia and New Zealand.

About KEYTRUDA (pembrolizumab) Injection
KEYTRUDA is an anti-PD-1 therapy that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.
Studies of KEYTRUDA – from the largest immuno-oncology program in the industry with more than 500 trials – include a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand factors that predict a patient’s likelihood of benefitting from treatment with KEYTRUDA, including the exploration of several different biomarkers across a broad range of tumors.

KEYTRUDA (pembrolizumab) is administered as an intravenous infusion over 30 minutes every three weeks for the approved indications. KEYTRUDA for injection is supplied in a 100 mg single-dose vial in the U.S.
KEYTRUDA (pembrolizumab) Indications and Dosing in the U.S.

Melanoma
KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma at a fixed dose of 200 mg every three weeks until disease progression or unacceptable toxicity.

Lung Cancer
KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have high PD-L1 expression [tumor proportion score (TPS) ≥50%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA, as a single agent, is also indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.

KEYTRUDA, in combination with pemetrexed and carboplatin, is indicated for the first-line treatment of patients with metastatic nonsquamous NSCLC. This indication is approved under accelerated approval based on tumor response rate and progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

In metastatic NSCLC, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

When administering KEYTRUDA in combination with chemotherapy, KEYTRUDA should be administered prior to chemotherapy when given on the same day. See also the Prescribing Information for pemetrexed and carboplatin.

Head and Neck Cancer
KEYTRUDA (pembrolizumab) is indicated for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy. This indication is approved under accelerated approval based on tumor response rate and durability of response.

Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. In HNSCC, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.


Classical Hodgkin Lymphoma
KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma (cHL), or who have relapsed after three or more prior lines of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. In adults with cHL, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression. In pediatric patients with cHL, KEYTRUDA is administered at a dose of 2 mg/kg (up to a maximum of 200 mg) every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

Urothelial Carcinoma
KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

KEYTRUDA is also indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

In locally advanced or metastatic urothelial carcinoma, KEYTRUDA (pembrolizumab) is administered at a fixed dose of 200 mg every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

Microsatellite Instability-High (MSI-H) Cancer
KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR)
· solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options, or
· colorectal cancer that has progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan.
This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established.
In adult patients with MSI-H cancer, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression. In pediatric patients with MSI-H cancer, KEYTRUDA is administered at a dose of 2 mg/kg (up to a maximum of 200 mg) every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

Selected Important Safety Information for KEYTRUDA (pembrolizumab)
KEYTRUDA can cause immune-mediated pneumonitis, including fatal cases. Pneumonitis occurred in 94 (3.4%) of 2799 patients receiving KEYTRUDA, including Grade 1 (0.8%), 2 (1.3%), 3 (0.9%), 4 (0.3%), and 5 (0.1%) pneumonitis, and occurred more frequently in patients with a history of prior thoracic radiation (6.9%) compared to those without (2.9%). Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 or recurrent Grade 2 pneumonitis.

KEYTRUDA (pembrolizumab) can cause immune-mediated colitis. Colitis occurred in 48 (1.7%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.4%), 3 (1.1%), and 4 (<0.1%) colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis.

KEYTRUDA can cause immune-mediated hepatitis. Hepatitis occurred in 19 (0.7%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.4%), and 4 (<0.1%) hepatitis. Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA.

KEYTRUDA can cause hypophysitis. Hypophysitis occurred in 17 (0.6%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.2%), 3 (0.3%), and 4 (<0.1%) hypophysitis. Monitor patients for signs and symptoms of hypophysitis (including hypopituitarism and adrenal insufficiency). Administer corticosteroids and hormone replacement as clinically indicated. Withhold KEYTRUDA for Grade 2; withhold or discontinue for Grade 3 or 4 hypophysitis.

On July 21, 2017 Merck KGaA, Darmstadt, Germany, which operates its biopharmaceutical business as EMD Serono in the US and Canada, and Pfizer Inc. (NYSE: PFE) reported that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has recommended the approval of avelumab* (BAVENCIO) as a monotherapy for the treatment of adult patients with metastatic Merkel cell carcinoma (mMCC), a rare and aggressive skin cancer (Press release, Pfizer, JUL 21, 2017, View Source [SID1234519853]). The European Commission (EC) will now review the CHMP’s recommendation, with a decision expected in the third quarter of 2017.

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"We welcome the CHMP’s recommendation, as there are currently no approved treatments in Europe for this type of skin cancer, which can be devastating for patients and their families," said Luciano Rossetti, M.D., Executive Vice President, Global Head of Research & Development at the biopharma business of Merck KGaA, Darmstadt, Germany. "This is an important step towards making avelumab available to patients and we look forward to the European Commission’s decision later this year."

"Metastatic Merkel cell carcinoma is a devastating disease and patients in Europe currently have very few treatment options," said Chris Boshoff, M.D., PhD, Senior Vice President and Head of Immuno-Oncology, Early Development, Translational Oncology, Pfizer Global Product Development. "This milestone further demonstrates our commitment to tackle hard-to-treat cancers as we continue to explore the potential of avelumab in other tumors."

The CHMP positive opinion is based on data from JAVELIN Merkel 200, an international, multicenter, single-arm, open-label, Phase II study split into two parts:

· Part A included 88 patients with mMCC whose disease had progressed after at least one chemotherapy treatment, with 59% of patients reported to have had one prior anti-cancer therapy for mMCC and 41% had two or more prior therapies. Data submitted included a minimum of 18 months of follow-up.

· Part B, at the time of the data cut-off, included 39 patients with histologically confirmed mMCC who were treatment-naïve to systemic therapy in metastatic setting, 29 of whom had at least 13 weeks of follow-up.

Enrolment in Part B of the study is ongoing and is planned to include 112 treatment-naïve patients.

The human anti-PD-L1 antibody, avelumab, previously received Orphan Drug Designation (ODD) from the EC for MCC. To qualify for ODD in the EU, a medicine must be intended for the treatment, prevention or diagnosis of a disease that is life-threatening or chronically debilitating, and has a prevalence in the EU of not more than 5 in 10,000 people.

The US Food and Drug Administration (FDA) granted accelerated approval for avelumab in March 2017 for the treatment of mMCC in adults and pediatric patients 12 years and older; and in May 2017 for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy therapy, or who have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.[1] These indications were granted under accelerated approval based on tumor response rate and duration of response data/criteria. Continued approval for these indications may be contingent upon verification and description of clinical benefit in confirmatory trials.

The clinical development program for avelumab, known as JAVELIN, involves at least 30 clinical programs and more than 6,000 patients evaluated across more than 15 different tumor types. In addition to mMCC, these cancers include breast, gastric/gastro-esophageal junction, head and neck, Hodgkin’s lymphoma, melanoma, mesothelioma, non-small cell lung, ovarian, renal cell carcinoma and urothelial carcinoma.

*Avelumab is not approved for any indication in any market outside the US. BAVENCIO is the proprietary name submitted to EMA for the investigational medicine avelumab.

About Metastatic Merkel Cell Carcinoma
Metastatic MCC is a rare and aggressive disease in which cancer cells form in the top layer of the skin, close to nerve endings.[2],[3] MCC, which is also known as neuroendocrine carcinoma of the skin or trabecular cancer, often starts in those areas of skin that are most often exposed to the sun, including the head and neck, and arms.[2],[4] Risk factors for MCC include sun exposure and infection with Merkel cell polyomavirus. Caucasian males older than 50 are at increased risk.[2],[4] MCC is a highly immunogenic cancer, meaning that those with a weak immune system (i.e., solid organ transplant recipients, people with HIV/AIDS and people with other cancers, such as chronic lymphocytic leukemia) are also at a higher risk.[2],[4] MCC is often misdiagnosed for other skin cancers and grows at an exponential rate on chronically sun-damaged skin.[4]-[6] Current treatment options for MCC in Europe include surgery, radiation and chemotherapy.[3] Treatment for metastatic or Stage IV MCC is generally palliative.[3]

About JAVELIN Merkel 200
The efficacy and safety of avelumab was demonstrated in the JAVELIN Merkel 200 trial, an international, multicenter, single-arm, open-label, Phase II study split into two parts:

· Part A was conducted in 88 patients with histologically confirmed mMCC whose disease had progressed on or after chemotherapy administered for distant metastatic disease, with life expectancy of more than 3 months. Overall, in Part A, 59% of patients were reported to have had one prior anti-cancer therapy for mMCC and 41% had two or more prior therapies. Data submitted included a minimum of 18 months follow-up. The major efficacy outcome measures for Part A were confirmed best overall response (BOR) and duration of response (DOR), according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, as assessed by a blinded independent endpoint review committee (IERC); secondary efficacy outcome measures included duration of response (DOR), and progression-free survival (PFS).

· Part B, at the time of the data cut-off, included 39 patients with histologically confirmed mMCC who were treatment-naïve to systemic therapy in the metastatic setting, 29 of whom had at least 13 weeks of follow-up. Enrolment in Part B of the study is ongoing and is planned to include 112 treatment-naïve patients. The major efficacy outcome measure is durable response, defined as objective response (complete response [CR] or partial response [PR]) with a duration of at least 6 months; secondary outcome measures include BOR, DOR, progression-free survival (PFS) and overall survival (OS).

The trial excluded patients with active or a history of central nervous system (CNS) metastasis, active or a history of autoimmune disease, a history of other malignancies within the last 5 years, organ transplant, and conditions requiring therapeutic immune suppression or active infection with HIV, or hepatitis B or C. Patients received avelumab 10 mg/kg as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity.

About Avelumab
Avelumab is a human antibody specific for a protein called PD-L1, or programmed death ligand-1. Avelumab is designed to potentially engage both the adaptive and innate immune systems. By binding to PD-L1, avelumab is thought to prevent tumor cells from using PD-L1 for protection against white blood cells, such as T cells, exposing them to anti-tumor responses. Avelumab has been shown to induce antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro. In November 2014, Merck KGaA, Darmstadt, Germany, and Pfizer announced a strategic alliance to co-develop and co-commercialize avelumab.

Indications
The US Food and Drug Administration (FDA) granted accelerated approval for avelumab (BAVENCIO) for the treatment of (i) mMCC in adults and pediatric patients 12 years and older and (ii) patients with locally advanced or metastatic UC who have disease progression during or following platinum-containing chemotherapy, or who have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. These indications were approved under accelerated approval based on tumor response rate and duration of response. Continued approval for these indications may be contingent upon verification and description of clinical benefit in confirmatory trials.

Important Safety Information
BAVENCIO can cause immune-mediated pneumonitis, including fatal cases. Monitor patients for signs and symptoms of pneumonitis and evaluate suspected cases with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold BAVENCIO for moderate (Grade 2) and permanently discontinue for severe (Grade 3), life-threatening (Grade 4), or recurrent moderate (Grade 2) pneumonitis. Pneumonitis occurred in 1.2% (21/1738) of patients, including one (0.1%) patient with Grade 5, one (0.1%) with Grade 4, and five (0.3%) with Grade 3.
BAVENCIO can cause immune-mediated hepatitis, including fatal cases. Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater hepatitis. Withhold BAVENCIO for moderate (Grade 2) immune-mediated hepatitis until resolution and permanently discontinue for severe (Grade 3) or life-threatening (Grade 4) immune-mediated hepatitis. Immune-mediated hepatitis was reported in 0.9% (16/1738) of patients, including two (0.1%) patients with Grade 5 and 11 (0.6%) with Grade 3.

BAVENCIO can cause immune-mediated colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold BAVENCIO until resolution for moderate or severe (Grade 2 or 3) colitis and permanently discontinue for life-threatening (Grade 4) or recurrent (Grade 3) colitis upon re-initiation of BAVENCIO. Immune-mediated colitis occurred in 1.5% (26/1738) of patients, including seven (0.4%) with Grade 3.
BAVENCIO can cause immune-mediated endocrinopathies, including adrenal insufficiency, thyroid disorders, and type 1 diabetes mellitus.

Monitor patients for signs and symptoms of adrenal insufficiency during and after treatment, and administer corticosteroids as appropriate. Withhold BAVENCIO for severe (Grade 3) or life-threatening (Grade 4) adrenal insufficiency. Adrenal insufficiency was reported in 0.5% (8/1738) of patients, including one (0.1%) with Grade 3.
Thyroid disorders can occur at any time during treatment. Monitor patients for changes in thyroid function at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation. Manage hypothyroidism with hormone replacement therapy and hyperthyroidism with medical management. Withhold BAVENCIO for severe (Grade 3) or life- threatening (Grade 4) thyroid disorders. Thyroid disorders including hypothyroidism, hyperthyroidism, and thyroiditis were reported in 6% (98/1738) of patients, including three (0.2%) with Grade 3.

Type 1 diabetes mellitus including diabetic ketoacidosis: Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Withhold BAVENCIO and administer anti-hyperglycemics or insulin in patients with severe or life-threatening (Grade ≥ 3) hyperglycemia, and resume treatment when metabolic control is achieved. Type 1 diabetes mellitus without an alternative etiology occurred in 0.1% (2/1738) of patients, including two cases of Grade 3 hyperglycemia.

BAVENCIO can cause immune-mediated nephritis and renal dysfunction. Monitor patients for elevated serum creatinine prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater nephritis. Withhold BAVENCIO for moderate (Grade 2) or severe (Grade 3) nephritis until resolution to Grade 1 or lower. Permanently discontinue BAVENCIO for life-threatening (Grade 4) nephritis. Immune-mediated nephritis occurred in 0.1% (1/1738) of patients.

BAVENCIO can result in other severe and fatal immune-mediated adverse reactions involving any organ system during treatment or after treatment discontinuation. For suspected immune-mediated adverse reactions, evaluate to confirm or rule out an immune-mediated adverse reaction and to exclude other causes. Depending on the severity of the adverse reaction, withhold or permanently discontinue BAVENCIO, administer high-dose corticosteroids, and initiate hormone replacement therapy if appropriate. Resume BAVENCIO when the immune-mediated adverse reaction remains at Grade 1 or lower following a corticosteroid taper. Permanently discontinue BAVENCIO for any severe (Grade 3) immune-mediated adverse reaction that recurs and for any life-threatening (Grade 4) immune-mediated adverse reaction. The following clinically significant immune-mediated adverse reactions occurred in less than 1% of 1738 patients treated with BAVENCIO: myocarditis with fatal cases, myositis, psoriasis, arthritis, exfoliative dermatitis, erythema multiforme, pemphigoid, hypopituitarism, uveitis, Guillain-Barré syndrome, and systemic inflammatory response.

BAVENCIO can cause severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions. Patients should be premedicated with an antihistamine and acetaminophen prior to the first 4 infusions and for subsequent doses based upon clinical judgment and presence/severity of prior infusion reactions. Monitor patients for signs and symptoms of infusion-related reactions, including pyrexia, chills, flushing, hypotension, dyspnea, wheezing, back pain, abdominal pain, and urticaria. Interrupt or slow the rate of infusion for mild (Grade 1) or moderate (Grade 2) infusion-related reactions. Permanently discontinue BAVENCIO for severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions. Infusion-related reactions occurred in 25% (439/1738) of patients, including three (0.2%) patients with Grade 4 and nine (0.5%) with Grade 3.

BAVENCIO can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risk to a fetus including the risk of fetal death. Advise females of childbearing potential to use effective contraception during treatment with BAVENCIO and for at least 1 month after the last dose of BAVENCIO. It is not known whether BAVENCIO is excreted in human milk. Advise a lactating woman not to breastfeed during treatment and for at least 1 month after the last dose of BAVENCIO due to the potential for serious adverse reactions in breastfed infants.
The most common adverse reactions (all grades, ≥ 20%) in patients with metastatic Merkel cell carcinoma (MCC) were fatigue (50%), musculoskeletal pain (32%), diarrhea (23%), nausea (22%), infusion-related reaction (22%), rash (22%), decreased appetite (20%), and peripheral edema (20%).

Selected treatment-emergent laboratory abnormalities (all grades, ≥ 20%) in patients with metastatic MCC were lymphopenia (49%), anemia (35%), increased aspartate aminotransferase (34%), thrombocytopenia (27%), and increased alanine aminotransferase (20%).

The most common adverse reactions (all grades, ≥ 20%) in patients with locally advanced or metastatic urothelial cancer (UC) were fatigue (41%), infusion-related reaction (30%), musculoskeletal pain (25%), nausea (24%), decreased appetite/hypophagia (21%) and urinary tract infection (21%).

Selected laboratory abnormalities (grades 3-4, ≥ 3%) in patients with locally advanced or metastatic UC were hyponatremia (16%), gamma-glutamyltransferase increased (12%), lymphopenia (11%), hyperglycemia (9%), increased alkaline phosphatase (7%), anemia (6%), increased lipase (6%), hyperkalemia (3%), and increased aspartate aminotransferase (3%).
Please see full US Prescribing Information and Medication Guide.

Alliance between Merck KGaA, Darmstadt, Germany, and Pfizer Inc., New York, US
Immuno-oncology is a top priority for Merck KGaA, Darmstadt, Germany, and Pfizer Inc. The global strategic alliance between Merck KGaA, Darmstadt, Germany, and Pfizer Inc., New York, US, enables the companies to benefit from each other’s strengths and capabilities and further explore the therapeutic potential of avelumab, an anti-PD-L1 antibody initially discovered and developed by Merck KGaA, Darmstadt, Germany. The immuno-oncology alliance will jointly develop and commercialize avelumab and advance Pfizer’s PD-1 antibody. The alliance is focused on developing high-priority international clinical programs to investigate avelumab as a monotherapy, as well as in combination regimens, and is striving to find new ways to treat cancer.

All Merck KGaA, Darmstadt, Germany Press Releases are distributed by e-mail at the same time they become available on the Merck KGaA, Darmstadt, Germany Website. Please go to View Source to register online, change your selection or discontinue this service.

On July 21, 2017 Novartis reported that the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion recommending approval of Rydapt (midostaurin) for the treatment of adults with newly diagnosed acute myeloid leukemia (AML) who are FLT3 mutation-positive (Press release, Novartis, JUL 21, 2017, View Source [SID1234519852]). If approved by the European Commission (EC), Rydapt will be indicated in combination with standard daunorubicin and cytarabine induction and high-dose cytarabine consolidation chemotherapy, and for patients in complete response, followed by Rydapt single agent maintenance therapy, for adult patients with newly diagnosed AML who are FLT3 mutation-positive. Rydapt was also recommended for approval as monotherapy for the treatment of adult patients with aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated hematological neoplasm (SM-AHN) or mast cell leukemia.

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If approved, Rydapt will be the first targeted treatment available in the European Union (EU) for newly diagnosed FLT3 mutation-positive AML patients and advanced systemic mastocytosis (SM) patients. The opinion follows the recent US Food and Drug Administration (FDA) 2017 approval of Rydapt for FLT3-mutated AML and advanced SM on April 28 and the Swissmedic approval on May 4.

"Novartis is dedicated to bringing new treatment options to patients with rare diseases, including AML and advanced SM, which have seen limited treatment developments in the past 25 years," said Bruno Strigini, CEO, Novartis Oncology. "We are pleased with the positive recommendation from the CHMP and excited to move a step closer to bringing this much-needed treatment to these patients across Europe."

AML is a rare and aggressive cancer of the blood and bone marrow[2]. In the EU, there are over 18,000 estimated new cases of AML each year[3]. Approximately one-third of AML patients will have a FLT3 gene mutation[4].

FMS-like tyrosine kinase 3 (FLT3) is a type of cell-surface receptor which plays a role in increasing the number of certain blood cells[5] and the FLT3 gene mutation can result in faster disease progression, higher relapse rates and lower rates of survival than other forms of AML[4],[5],[6]. Prior to the approval of Rydapt in the US, the AML therapeutic strategy had remained relatively unchanged for more than 25 years[7],[8].

Advanced SM is a rare blood disorder characterized by uncontrolled growth and accumulation of mast cells – mediators of allergic responses – in one or more organs[9]. In advanced SM, mast cells accumulate in such high quantities that they begin to cause organ damage[9]. Median overall survival is currently less than six months for mast cell leukemia[10], two years for SM-AHN and 3.5 years for ASM[11].

The EC typically adheres to the recommendation of the CHMP and delivers its final decision within approximately two to three months. The decision will be applicable to all 28 EU member states, plus Iceland, Liechtenstein and Norway.

The positive opinion is based on the Phase III RATIFY (CALGB 10603 [Alliance]) clinical trial, which was conducted in collaboration with the Alliance for Clinical Trials in Oncology and 13 international cooperative groups. In the trial, newly diagnosed FLT3 mutation-positive patients who received Rydapt plus standard chemotherapy experienced significant improvement in overall survival with a 23% reduction in the risk of death compared with placebo plus standard chemotherapy, with median overall survival of 74.7 months and 25.6 months, respectively (hazard ratio [HR] = 0.77, 95% CI, 0.63, 0.95; one-sided p=0.0078)1. The full data from the RATIFY trial were recently published in the New England Journal of Medicine (NEJM)[12].

Event-free survival (EFS; event defined as no complete remission within 60 days of the start of induction therapy, relapse or death) was significantly longer for Rydapt plus chemotherapy versus placebo plus standard chemotherapy (median of 8.2 months compared to 3.0 months, HR = 0.78, 95% CI 0.66, 0.93 and one-sided p=0.0024). RATIFY is the largest worldwide clinical trial in newly diagnosed FLT3-mutated AML to date, as 3,277 AML patients were screened for the FLT3 mutation and 717 patients were enrolled[1].

In the Phase III AML RATIFY trial, the most frequent adverse reactions (incidence greater than or equal to 30%) in the Rydapt plus standard chemotherapy arm were febrile neutropenia, nausea, exfoliative dermatitis, vomiting, headache, petechiae (small red skin spots) and pyrexia. The most frequent non-hematologic Grade 3/4 adverse reaction was febrile neutropenia[1].

The recommendation in advanced SM is based on two single-arm open-label multicenter trials, including the Phase II study (CPKC412D2201), which was the largest prospective trial ever conducted in this rare disorder. The efficacy of Rydapt was established using modified Valent criteria, with patients demonstrating an overall response rate, defined as a major or partial response, of 59.6% (95% confidence interval [CI], 48.6, 69.8%). Efficacy was also assessed in a post-hoc analysis using the 2013 International Working Group-Myeloproliferative Neoplasms Research and Treatment-European Competence Network on Mastocytosis (IWG-MRT-ECNM) consensus criteria (n=113). This assessment estimated an overall response rate of 28.3% (95% CI, 20.2, 37.6)[1].

In advanced SM, the most frequent adverse reactions were nausea, vomiting, diarrhea, peripheral edema and fatigue. The most frequent Grade 3/4 adverse reactions were fatigue, sepsis, pneumonia, febrile neutropenia and diarrhea[1].

Rydapt Ongoing Clinical Development
In order to further investigate the potential of Rydapt in AML, Novartis is planning a Phase III study in newly diagnosed AML patients without a FLT3 mutation (wildtype).

About AML
AML is the most common acute leukemia in adults; it accounts for approximately 25% of all adult leukemias worldwide, with the highest incidence rates occurring in the US, Europe and Australia[13]. It also has the lowest survival rate of all adult leukemias[13].

AML prevents white blood cells from maturing, causing an accumulation of "blasts," which do not allow room for the normal blood cells[2]. Mutations in specific genes are found in many cases of AML[4], and genetic testing for mutations in newly diagnosed AML patients can help to determine prognosis and potential treatment strategies[14].

About Advanced SM
In advanced SM, the uncontrolled growth of neoplastic mast cells causes organ damage (e.g., liver dysfunction), low blood counts and weight loss[9]. Patients also suffer from debilitating systemic symptoms, such as pruritus (severe itching of the skin) caused by mast cells releasing inflammatory mediators, such as histamine, into the blood[9].

The uncontrolled proliferation of mast cells is caused in many people by a KIT gene mutation – the most common mutation, encoding the D817V substitution, occurs in approximately 90% of patients[15]. The KIT gene mutation results in activation of the KIT enzyme, which triggers the abnormal proliferation and survival of mast cells[16].

About Rydapt (midostaurin)
Rydapt (midostaurin) is an oral, multi-targeted inhibitor of multiple kinases, including FLT3 and KIT, which help regulate many essential cell processes, interrupting cancer cells’ ability to grow and multiply[17].

In the US, Rydapt is FDA-approved for the treatment of adults with newly diagnosed AML who are FMS-like tyrosine kinase 3 mutation-positive (FLT3+) as detected by an FDA-approved test, in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation chemotherapy[17]. Rydapt is not indicated in the US as a single-agent induction therapy for the treatment of patients with AML. For a description of the experience with single-agent treatment beyond induction and consolidation, healthcare professionals in the US should refer to the Clinical Studies section of the US Prescribing Information (14.1)[17]. Rydapt is also approved to treat adult patients with aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated hematological neoplasm (SM-AHN) or mast cell leukemia, collectively referred to as advanced systemic mastocytosis (SM)[17].

The full US Prescribing Information for Rydapt can be found at: View Source

Rydapt is also approved in Switzerland, for use in combination with standard induction and consolidation chemotherapy, followed by maintenance monotherapy for treatment of newly diagnosed adult AML patients who have an FLT3 mutation. Rydapt is indicated in Switzerland for the treatment of adult patients with advanced SM.

Indications vary by country and not all indications are available in every country. The safety and efficacy profile of Rydapt has not yet been established outside the approved indications. Because of the uncertainty of clinical trials, there is no guarantee that Rydapt will become commercially available for additional indications anywhere else in the world.

Rydapt Important Safety Information FROM THE US PRESCRIBING INFORMATION
Patients who are allergic to midostaurin or any of the ingredients in Rydapt should not take Rydapt. If a patient taking Rydapt develops signs of an allergic reaction, they should seek medical help immediately. Signs of an allergic reaction include trouble breathing, flushing, chest pain, throat tightness, and swelling of lips, mouth or throat.

Rydapt should be not be used during pregnancy since Rydapt may harm an unborn baby. Pregnancy testing should be conducted for women who might become pregnant. Effective birth control should be used during treatment and for at least four months after stopping Rydapt. If a patient becomes pregnant or thinks she may be, the patient should tell their doctor right away. Women should not breastfeed during treatment with Rydapt and for at least four months after the final dose. Men taking Rydapt who have female partners that are able to become pregnant should use effective birth control during his treatment with Rydapt and for at least four months after the last Rydapt dose. Rydapt may cause fertility problems in women and men, which may affect their ability to have children.

Rydapt may cause lung problems that may lead to death. Patients on Rydapt who develop a new or worsening cough, shortness of breath, or chest discomfort should get medical help right away. These may be signs of serious lung problems.

Common sides effects reported during Rydapt treatment for AML included low level of white blood cells with fever (febrile neutropenia); nausea; redness, pain or ulcers inside the mouth (mucositis); vomiting; headache; bruising; muscle or bone pain; nose bleeds; device-related infection; high blood sugar levels (hyperglycemia) and upper respiratory infections.

Common side effects reported during treatment for ASM, SM-AHM or mast cell leukemia included nausea; vomiting; diarrhea; swelling of the hands, feet or ankles; muscle or bone pain; stomach-area pain; tiredness; upper respiratory infection; constipation; fever; headache and trouble breathing.

If side effects including nausea, vomiting, and diarrhea occur, get worse or do not go away during treatment with Rydapt, patients should contact their doctor. Depending on the side effect and/or severity of the side effect that occur, their doctor may decrease their dose, temporarily stop, or completely stop treatment with Rydapt.

Patients should tell their doctor about all the medicines they take, including prescription and over-the-counter medicines, vitamins and herbal supplements. Rydapt may affect how these medicines work or these other medicines may affect how Rydapt works.