On April 8, 2015 Roche reported that the European Commission (EU) approved Avastin (bevacizumab) in combination with standard chemotherapy (paclitaxel and cisplatin or, alternatively, paclitaxel and topotecan in patients who cannot receive platinum therapy) for the treatment of adult patients with persistent, recurrent or metastatic carcinoma of the cervix(Press release, Hoffmann-La Roche , APR 8, 2015, View Source [SID:1234502964]).1

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Unlike the majority of cancers, cervical cancer is most commonly diagnosed in younger women, between the ages of 35 and 44.2 Each day it is estimated that 90 women are diagnosed with cervical cancer in Europe, and around 35 of these women will die from the disease.3 Avastin’s EU approval in persistent, recurrent or metastatic carcinoma of the cervix is an important development in a disease area where, until now, treatment options were limited to chemotherapy.

"We are pleased that women in Europe now have a much needed new treatment option that is proven to help them live longer lives compared to chemotherapy alone," said Sandra Horning, M.D., Chief Medical Officer and Head of Global Product Development. "Currently, fewer than one in six women with this disease are alive five years after diagnosis. Avastin’s approval is a welcome advance for women with persistent, recurrent or metastatic carcinoma of the cervix".

The EU approval was based on the significant survival benefit in the pivotal GOG-0240 study, which showed that women who received Avastin plus chemotherapy had a statistically significant 26 percent reduction in the risk of death, representing a median improvement in survival of nearly four months, compared to women who received chemotherapy alone (median overall survival: 16.8 months vs. 12.9 months; Hazard Ratio (HR)=0.74, p=0.0132).1

Also based on the GOG-0240 data, Avastin in combination with paclitaxel and cisplatin or paclitaxel and topotecan chemotherapy was approved in the U.S. in August 2014, in Switzerland in December 2014, and in six other countries worldwide, for the treatment of women with persistent, recurrent or metastatic carcinoma of the cervix.
About the GOG-0240 study1

GOG-0240 is an independent, National Cancer Institute (NCI)-sponsored study of the Gynecological Oncology Group (GOG) that assessed the efficacy and safety profile of Avastin plus chemotherapy (paclitaxel and cisplatin or paclitaxel and topotecan) in women with persistent, recurrent or metastatic carcinoma of the cervix.

Study data from 452 women showed:

The study met its primary endpoint of improving overall survival (OS) with a statistically significant 26 percent reduction in the risk of death, representing a median gain in survival of 3.9 months, compared with those who received chemotherapy alone (median overall survival: 16.8 months vs. 12.9 months; (HR)=0.74, p=0.0132).1
The study showed that women who received Avastin plus chemotherapy had a significantly higher rate of tumour shrinkage (objective response rate, ORR) compared with those who received chemotherapy alone (45 percent [95% CI: 0.39%-0.52%] vs. 34 percent [95% CI 0.28%-0.40%]).1
Overall, the safety profile in the study was consistent with that seen in previous pivotal studies of Avastin across tumour types, except for an increase in gastrointestinal-vaginal fistulae observed in patients who received Avastin plus chemotherapy compared to those who received chemotherapy alone (8.3% vs. 0.9% respectively). All patients with gastrointestinal-vaginal fistulae after treatment with Avastin plus chemotherapy had a history of prior pelvic radiation.1

About cervical cancer

It is estimated that over 33,000 women will be diagnosed with cervical cancer in the EU this year and about 13,000 women will die from the disease.3 While the chances of survival are higher if the disease is caught early (at least nine out of 10 women survive for five years or longer following early diagnosis), the symptoms of early-stage cervical cancer can be easily missed, and many women are not diagnosed until their cancer has already progressed to an advanced stage.2,4 At this stage, the survival rates are reduced and fewer than one in six women survive for five years or longer.2,4

Worldwide, it is estimated there are more than half a million cases of cervical cancer every year and over 260,000 deaths from the disease, making it the fourth leading cause of cancer death in women globally.5
About Avastin

With the initial approval in the United States for advanced colorectal cancer in 2004, Avastin became the first anti-angiogenic therapy made widely available for the treatment of patients with an advanced cancer.

Today, Avastin is continuing to transform cancer care through its proven survival benefit (overall survival and/or progression free survival) across several types of cancer. Avastin is approved in Europe for the treatment of advanced stages of breast cancer, colorectal cancer, non-small cell lung cancer, kidney cancer, ovarian cancer, and now cervical cancer, and is available in the United States for the treatment of colorectal cancer, non-small cell lung cancer, kidney cancer, cervical cancer and platinum-resistant, recurrent ovarian cancer. In addition, Avastin is approved in the United States and over 60 other countries worldwide for the treatment of patients with progressive glioblastoma following prior therapy. Avastin is approved in Japan for the treatment of the advanced stages of colorectal, non-small cell lung cancer, breast cancer, ovarian cancer and malignant glioma, including newly diagnosed glioblastoma.

Avastin has made anti-angiogenic therapy a fundamental pillar of cancer treatment today. Over 1.5 million patients have been treated with Avastin so far. A comprehensive clinical programme with more than 500 ongoing clinical trials is investigating the use of Avastin in over 50 tumour types.
About Avastin – mechanism of action

An independent blood supply is critical for a tumour to grow beyond a certain size (2mm) and spread (metastasise) to other parts of the body. Tumours develop their own blood supply in a process called angiogenesis by releasing vascular endothelial growth factor (VEGF) – a key driver for tumour growth. Avastin is an antibody that precisely targets and inhibits VEGF. Precise VEGF inhibition by Avastin allows it to be combined effectively with a broad range of chemotherapies and other anti-cancer treatments with limited additional impact on the side effects of these therapies.

On April 7, 2015 Merck KGaA and Pfizer reported the finalization of the co-promotion agreement allowing the companies to co-promote Pfizer’s anaplastic lymphoma kinase (ALK) inhibitor XALKORI (crizotinib) (Press release, Pfizer, APR 7, 2015, View Source [SID:1234502955]). This agreement showcases the alliance’s commitment to establishing a combined oncology sales organization in key markets in advance of the potential launch of avelumab*-based treatment regimens in the future.

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XALKORI is the first ALK inhibitor approved in the United States, Japan and the European Union (EU) and is supported by two positive global randomized trials in the first- and second-line ALK-positive advanced non-small cell lung cancer (NSCLC) treatment settings. To date, globally more than 8,000 patients have been treated with XALKORI, including those who received XALKORI in clinical trials.

Under the agreement, XALKORI will be co-promoted in two waves, the first of which will begin in the second and third quarters of 2015 in the United States, Canada, Japan and five European Union countries (France, Germany, Italy, Spain and the United Kingdom). In the United States and Canada, XALKORI will be co-promoted by EMD Serono, the US and Canadian biopharmaceutical businesses of Merck KGaA, Darmstadt, Germany. The second wave will begin in 2016 and includes China and Turkey.

In 2015, Merck KGaA, Darmstadt, Germany, will receive a reimbursement associated with its promotion of XALKORI, followed by an 80 percent (Pfizer), 20 percent (Merck KGaA, Darmstadt, Germany) profit sharing on the product starting in 2016. The co-promotion term will last through December 31, 2020 for the United States, Canada, Japan, France, Germany, Italy, Spain and the United Kingdom, and from January 1, 2016 through December 31, 2021 in China and Turkey. Pfizer will report the sales of XALKORI in countries where it is co-promoted with Merck KGaA, Darmstadt, Germany.

"We are proud and excited to share the legacy of XALKORI, a medicine that changed the treatment paradigm for patients with ALK-positive metastatic NSCLC, with Merck KGaA, Darmstadt, Germany," said Liz Barrett, president and general manager, Pfizer Oncology. "Through our co-promotion of XALKORI, we will establish a best-in-class global sales organization that will be exceptionally prepared for the potential launches of our future oncology medicines."

"As we progress our robust program to co-develop and co-commercialize avelumab, the co-promotion agreement is an exciting milestone for the alliance between Merck KGaA, Darmstadt, Germany, and Pfizer, allowing us to establish our combined oncology sales organization in key markets for the program," said Dr. Andrew Schiermeier, head of Global Oncology and general manager for the Alliance for Merck KGaA, Darmstadt, Germany, adding: "For Merck KGaA, Darmstadt, Germany, this agreement is particularly important as it accelerates the establishment of our United States and Canada oncology sales organization ahead of our potential avelumab launches and positions us for future success in this market."

This co-promotion relationship is related to the announcement in November 2014 of a global strategic alliance between Merck KGaA, Darmstadt, Germany, and Pfizer to jointly develop and commercialize avelumab, an investigational anti-PD-L1 monoclonal antibody, to accelerate the development of immuno-oncology medicines for patients with cancer. The immuno-oncology alliance will also advance Pfizer’s PD-1 antibody.

About Non-small Cell Lung Cancer

Globally, lung cancer is the most common cause of cancer-related deaths in men and the second most common in women, responsible for almost twice as many deaths as both breast and prostate cancer combined1. Non-small cell lung cancer is the most common type of lung cancer, accounting for 85 to 90 percent of all lung cancers2. Locally advanced and metastatic disease account for approximately 35 to 40 percent3 and 70 percent4 of patients, respectively with NSCLC.

About XALKORI (crizotinib)

XALKORI is a kinase inhibitor indicated in the US for the treatment of patients with metastatic non-small cell lung cancer whose tumors are anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test. The US indication is not limited to any specific line of therapy. In the EU, XALKORI is indicated for the treatment of adults with previously treated ALK-positive advanced NSCLC. XALKORI has received approval in more than 80 countries.

XALKORI Important Safety Information

Hepatotoxicity: Drug-induced hepatotoxicity with fatal outcome occurred in 0.2% of patients treated with XALKORI across clinical trials (n=1225). Transaminase elevations generally occurred within the first 2 months of treatment. Monitor with liver function tests including ALT and total bilirubin every 2 weeks during the first 2 months of treatment, then once a month and as clinically indicated. Permanently discontinue for ALT or AST elevation greater than 3 times ULN with concurrent total bilirubin elevation greater than 1.5 times ULN (in the absence of cholestasis or hemolysis), otherwise temporarily suspend and dose reduce XALKORI as indicated.

Pneumonitis: Severe, life-threatening, or fatal interstitial lung disease (ILD)/pneumonitis can occur in patients treated with XALKORI. Across clinical trials (n=1225), 2.5% of XALKORI-treated patients had any grade ILD, 0.9% of patients had Grade 3 or 4, and 0.5% had fatal cases. These cases generally occurred within 2 months after the initiation of treatment. Monitor patients for pulmonary symptoms indicative of pneumonitis. Exclude other causes and permanently discontinue XALKORI in patients with drug related pneumonitis.

QT Interval Prolongation: QTc prolongation can occur in patients treated with XALKORI. Across clinical trials (n=1225), QTc prolongation (all grades) was observed in 2.7% of patients and QTc greater than 500 ms on at least 2 separate ECGs occurred in 1.4% of patients. Avoid use of XALKORI in patients with congenital long QT syndrome. Consider periodic monitoring with electrocardiograms and electrolytes in patients who have a history of or predisposition for QTc prolongation, or who are taking medications that prolong the QT interval. Permanently discontinue XALKORI in patients who develop QTc greater than 500 ms or greater than or equal to 60 ms change from baseline with Torsade de pointes, polymorphic ventricular tachycardia, or signs/symptoms of serious arrhythmia, otherwise temporarily suspend and dose reduce XALKORI as indicated.

Bradycardia: Symptomatic bradycardia can occur in patients receiving XALKORI. Across clinical trials, bradycardia with a heart rate less than 50 beats per minute occurred in 11% of patients treated with XALKORI (n=1174). Monitor heart rate and blood pressure regularly. Avoid using XALKORI in combination with other agents known to cause bradycardia to the extent possible. Permanently discontinue for life-threatening bradycardia due to XALKORI; however, if associated with concomitant medications known to cause bradycardia or hypotension, hold XALKORI until recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above. If concomitant medications can be adjusted or discontinued, restart XALKORI at 250 mg once daily with frequent monitoring. Otherwise temporarily suspend and resume or dose reduce XALKORI as indicated.

Embryofetal Toxicity: XALKORI can cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised to avoid becoming pregnant while receiving XALKORI. If the patient or their partner becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus.

Adverse Reactions: Safety was evaluated in a phase 3 study in patients with ALK-positive metastatic NSCLC randomized to XALKORI (n=172) or chemotherapy (n=171). Serious adverse reactions were reported in 37.2% patients treated with XALKORI. The most frequent serious adverse reactions reported in patients treated with XALKORI were pneumonia (4.1%), pulmonary embolism (3.5%), dyspnea (2.3%), and ILD (2.9%). Fatal adverse reactions in XALKORI-treated patients occurred in 9 (5%) patients, consisting of: acute respiratory distress syndrome, arrhythmia, dyspnea, ILD, pneumonia, pneumonitis, pulmonary embolism, respiratory failure, and sepsis. Common adverse reactions occurring in ≥25% included vision disorder (diplopia, photophobia, photopsia, vision blurred, visual acuity reduced, visual impairment, vitreous floaters), diarrhea, nausea, vomiting, constipation, edema, decreased appetite, fatigue, upper respiratory infection, and dysgeusia. Grade 3 or 4 events occurring at a higher incidence with XALKORI than with chemotherapy and at greater than 2% incidence were syncope (3%), QT prolongation (3%), and pulmonary embolism (5%). Elevation of ALT of any grade occurred in 76% of patients and grade 3 or 4 in 17% of patients. Neutropenia of any grade occurred in 49% of patients and grade 3 or 4 in 12% of patients. Lymphopenia of any grade occurred in 51% of patients and grade 3 or 4 in 9% of patients. Renal cysts occurred in 4% and neuropathy in 19% of patients treated with XALKORI.

Drug Interactions: Exercise caution with concomitant use of moderate CYP3A inhibitors. Avoid grapefruit or grapefruit juice which may increase plasma concentrations of crizotinib. Avoid concomitant use of strong CYP3A inducers and inhibitors. Dose reduction may be needed for coadministered drugs that are predominantly metabolized by CYP3A.

Nursing Mothers: Given the potential for serious adverse reactions in nursing infants, consider whether to discontinue nursing or discontinue XALKORI.

Hepatic Impairment: XALKORI has not been studied in patients with hepatic impairment. As crizotinib is extensively metabolized in the liver, hepatic impairment is likely to increase plasma Crizotinib concentrations. Use caution in patients with hepatic impairment.

Renal Impairment: Administer XALKORI at a starting dose of 250 mg taken orally once daily in patients with severe renal impairment (CLcr<30 mL/min) not requiring dialysis. No starting dose adjustment is needed for patients with mild and moderate renal impairment.

For more information and full prescribing information, please visit www.XALKORI.com.