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The U. S. Food and Drug Administration approved CYRAMZA® (ramucirumab) for use in combination with FOLFIRI for the treatment of patients with metastatic colorectal cancer (mCRC) whose disease has progressed on a first line bevacizumab-, oxaliplatin- and fluoropyrimidine-containing regimen

On April 24, 2015, the U. S. Food and Drug Administration approved ramucirumab (CYRAMZA, Eli Lilly and Company) for use in combination with FOLFIRI for the treatment of patients with metastatic colorectal cancer (mCRC) whose disease has progressed on a first line bevacizumab-, oxaliplatin- and fluoropyrimidine-containing regimen (Press release, Eli Lilly, APR 24, 2015, View Source [SID:1234503178]). Ramucirumab is a recombinant human monoclonal IgG1 antibody that binds to the human vascular endothelial growth factor- receptor 2 (VEGF-R2), preventing the interaction of VEGF-R2 to its ligands.

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This approval is based on the results of a randomized, double-blind, multinational trial enrolling patients with mCRC that progressed during or within 6 months of discontinuation of bevacizumab-, oxaliplatin- and fluoropyrimidine-based combination chemotherapy.

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The clinical trial accrued 1072 patients who were randomly allocated (1:1) to receive FOLFIRI plus placebo or FOLFIRI plus ramucirumab (N=536 per arm). Treatment cycles on both arms were repeated every 2 weeks and ramucirumab was administered at a dose of 8 mg/kg by intravenous infusion every two weeks. Ramucirumab was continued until disease progression or unacceptable toxicity.

The primary efficacy endpoint was overall survival (OS). Treatment assignment was stratified by geographic region (North America vs. Europe vs. other regions), KRAS status (wild-type vs. mutant) and time to progression for the beginning of first-line treatment (< 6 months vs. greater than or equal to 6 months).

The median age of the study population was 62 years, 57% were men, and 99% had an ECOG performance status of 0 or 1. A statistically significant OS improvement was observed in patients receiving FOLFIRI plus ramucirumab compared to those receiving FOLFIRI plus placebo [HR 0.85 (95% CI: 0.73, 0.98), p=0.023, stratified log-rank test]. Median OS was 13.3 and 11.7 months for patients on the FOLFIRI plus ramucirumab and FOLFIRI plus placebo arms, respectively. PFS was also significantly improved in patients who received ramucirumab in combination with FOLFIRI [HR 0.79 (95% CI: 0.70, 0.90), p<0.001]. Median PFS was 5.7 and 4.5 months, respectively.

In general, the safety data was consistent with the known safety profile established in previously approved indications. However, thyroid dysfunction (hypothyroidism) was reported in 2.6% of patients based on thyroid monitoring in patients with mCRC.

The recommended dose and schedule in patients receiving ramucirumab in combination with FOLFIRI after progression on a first-line bevacizumab containing regimen is 8 mg/kg administered every 2 weeks as a 60-minute IV infusion.

Full prescribing information is available at:
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Bristol-Myers Squibb Receives Positive CHMP Opinion in the European Union for Opdivo (nivolumab) for the Treatment of Advanced Melanoma in Both First-Line and Previously Treated Patients

On April 24, 2015 Bristol-Myers Squibb reported that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion recommending that Opdivo (nivolumab), a PD-1 immune checkpoint inhibitor, be granted approval for use in both first-line and previously treated patients with advanced (unresectable or metastatic) melanoma (Press release, Bristol-Myers Squibb, APR 24, 2015, View Source [SID:1234503174]). This is the first positive opinion given by the CHMP for a PD-1 immune checkpoint inhibitor, and it will now be reviewed by the European Commission, which has the authority to approve medicines for the European Union (EU).

The EMA granted Bristol-Myers Squibb accelerated assessment of Opdivo based on current regulations that fulfills its guidance about "medicinal products of major interest from the point of view of public health and in particular from the view point of therapeutic innovation."

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"We are pleased with today’s CHMP positive opinion, as it is a step closer to us bringing this important medicine for those advanced melanoma patients in Europe in need of new options," said Michael Giordano, senior vice president, Head of Development, Oncology. "Our vision is to transform how we approach cancer – from clinical practice to improved patient outcomes. We continue to expand the breadth and depth of our immuno-oncology portfolio across the continuum of melanoma and multiple other cancers, to provide more patients with the potential opportunity for long-term survival."

Positive Opinion based on CheckMate -066, -037

The CHMP positive opinion is based on data from two Phase III studies (CheckMate -066 and -037), demonstrating the efficacy and safety of Opdivo in advanced melanoma patients with important unmet needs. CheckMate -066, a Phase III randomized double-blind study, comparing Opdivo to the chemotherapy dacarbazine (DTIC) in patients with treatment-naïve advanced melanoma, is the first Phase III trial of an investigational PD-1 immune checkpoint inhibitor to demonstrate an overall survival benefit in advanced melanoma, as well as a higher objective response rate. A second study, CheckMate -037, is a Phase III randomized, controlled open-label study of Opdivo versus investigator’s choice chemotherapy in patients with advanced melanoma who were previously treated with Yervoy (ipilimumab), which showed improvement in objective response rates. These data are supported by a Phase Ib study (Study -003) in relapsed advanced or metastatic melanoma, which demonstrated the first characterization of Opdivo benefit/risk in advanced melanoma. There was consistent Opdivo dosing of 3 mg/kg every two weeks across all three trials.

About Opdivo

Bristol-Myers Squibb has a broad, global development program to study Opdivo in multiple tumor types consisting of more than 50 trials – as monotherapy or in combination with other therapies – in which more than 7,000 patients have been enrolled worldwide.

Opdivo became the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world on July 4, 2014 when Ono Pharmaceutical Co. announced that it received manufacturing and marketing approval in Japan for the treatment of patients with unresectable melanoma. In the U.S., the U.S. Food and Drug Administration (FDA) granted its first approval for Opdivo for the treatment of patients with unresectable or metastatic melanoma and disease progression following Yervoy (ipilimumab) and, if BRAF V600 mutation positive, a BRAF inhibitor. On March 5, 2015, Opdivo recently received its second FDA approval for the treatment of patients with metastatic squamous non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy.

About Advanced Melanoma

Melanoma is a form of skin cancer characterized by the uncontrolled growth of pigment-producing cells (melanocytes) located in the skin. Metastatic melanoma is the deadliest form of the disease, and occurs when cancer spreads beyond the surface of the skin to the other organs, such as the lymph nodes, lungs, brain or other areas of the body. The incidence of melanoma has been increasing for at least 30 years. In 2012, an estimated 232,130 melanoma cases were diagnosed globally. Melanoma is mostly curable when treated in its early stages. However, in its late stages, the average survival rate has historically been just six months with a one-year mortality rate of 75%, making it one of the most aggressive forms of cancer.

Bayer Submits Marketing Authorization for Radium-223 Dichloride to Treat Prostate Cancer with Bone Metastases in Japan (for specialized target groups only)

On April 24, 2015 Bayer reported Bayer HealthCare has submitted an application for marketing authorization to the Ministry of Health, Labour and Welfare (MHLW) in Japan for radium-223 dichloride (radium-223) solution for injection for the treatment of prostate cancer patients with bone metastases (Press release, Bayer, APR 24, 2015, View Source [SID:1234503173]).

"The number of patients suffering from prostate cancer has steadily increased in Japan over the past years, and for patients with advanced disease, there are limited options," said Dr. Joerg Moeller, Member of the Bayer HealthCare Executive Committee and Head of Global Development. "With its specific mode of action and the proven clinical benefit, radium-223 reflects our commitment to developing innovative cancer treatments for patients for whom only limited therapy options are available today."

The regulatory submission is based on data from the pivotal Phase III ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer) trial as well as data from additional trials to evaluate the safety and efficacy of radium-223 in Japanese patients. At the interim analysis of the ALSYMPCA trial, radium-223 significantly improved overall survival (OS) [HR=0.695 (95% CI 0.552-0.875), p=0.00185]. Median OS was 14.0 months with radium-223 plus best standard of care vs. 11.2 months with placebo plus best standard of care. Additionally, at the interim analysis there was a delay in the time to first symptomatic skeletal event (SSE) for patients treated with radium-223 vs. placebo. An updated analysis conducted after the study was unblinded showed a further improvement in OS for patients treated with radium-223 vs. placebo, with a median OS of 14.9 months vs. 11.3 months [HR=0.695 (95% CI 0.581-0.832)].

The most common adverse reactions (occurring at a rate of 10% or greater) in patients receiving radium-223 in the ALSYMPCA trial were nausea, diarrhea, vomiting and peripheral edema. The most common hematologic laboratory abnormalities (occurring at a rate of 10% or greater) were anemia, lymphocytopenia, leukopenia, thrombocytopenia and neutropenia.

About the ALSYMPCA Trial
The ALSYMPCA trial was a Phase III, randomized, double-blind, placebo-controlled international study of radium-223 with best standard of care vs. placebo with best standard of care in symptomatic castration-resistant prostate cancer (CRPC) patients with bone metastases. The trial enrolled 921 patients in more than 100 centers in 19 countries. The study treatment consisted of up to six intravenous injections of radium-223 or placebo each separated by an interval of four weeks.

The primary endpoint of the study was OS. A key secondary endpoint was time to first SSE, as defined as external beam radiation therapy (EBRT) to relieve skeletal symptoms, new symptomatic pathologic bone fracture, occurrence of spinal cord compression or tumor-related orthopedic surgical intervention.

About Castration-Resistant Prostate Cancer (CRPC) and Bone Metastases
Prostate cancer is the second most commonly diagnosed malignancy in men worldwide. In 2012, an estimated 1,111,000 men were diagnosed with prostate cancer and 307,000 died from the disease worldwide. In Japan, an estimated 47,000 men were affected with prostate cancer and 12,000 died from the disease in 2013. Prostate cancer is the fifth leading cause of death from cancer in men worldwide, and the sixth leading cause of death from cancer in Japanese men.

CRPC is an advanced form of prostate cancer. A majority of men with CRPC have symptomatic bone metastases resulting in pain, skeletal events such as fractures or spinal cord compression, and/or reduced survival. In fact, bone metastases lead to an increased risk of morbidity and death in patients with CRPC.

About Radium-223 Dichloride
Radium-223 dichloride (radium-223) is a therapeutic alpha particle-emitting pharmaceutical with an anti-tumor effect on bone metastases. Radium-223 mimics calcium and selectively targets bone, specifically areas of bone metastases, by forming complexes with the bone mineral hydroxyapatite. The high linear energy transfer of alpha emitters leads to a high frequency of double-strand DNA breaks in adjacent tumor cells, resulting in a potent cytotoxic effect. The alpha particle range from radium-223 is less than 100 micrometers, which minimizes damage to the surrounding normal tissue.

Radium-223 has been approved under the brand name Xofigo in more than 40 countries worldwide, including the U.S. and the EU.

AstraZeneca enters strategic immuno-oncology collaboration with Celgene Corporation to develop PD-L1 inhibitor programme for patients with serious blood cancers

On April 24, 2015 AstraZeneca and MedImmune, the Company’s global biologics research and development arm, reported that they have entered into an exclusive collaboration agreement with Celgene Corporation, a global leader in hematological cancers, for the development and commercialisation of MEDI4736 across a range of blood cancers including non-Hodgkin’s lymphoma, myelodysplastic syndromes and multiple myeloma (Press release, AstraZeneca, APR 24, 2015, View Source;astrazeneca-enters-strategic-immuno-oncology-collaboration-Celgene-PD-L1-inhibitor-programme [SID:1234503171]).

MEDI4736 is an investigational immune checkpoint inhibitor, directed against programmed cell death ligand 1 (PD-L1). Signals from PD-L1 help tumours avoid detection by the immune system. MEDI4736 blocks these signals, countering the tumour’s immune-evading tactics. Within the collaboration, MEDI4736 will be assessed both as monotherapy and in combination with other AstraZeneca and Celgene potential and existing cancer medicines. Over time, the collaboration could expand to include other assets.

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Under the terms of the agreement, Celgene will make an upfront payment of $450 million to AstraZeneca in relation to MEDI4736. Celgene will lead on development across all clinical trials within the collaboration and will take on all research and development costs until the end of 2016, after which they will take on 75 percent of these costs. Celgene will also be responsible for global commercialisation of approved treatments. AstraZeneca will continue to manufacture and book all sales of MEDI4736 and will pay a royalty to Celgene on worldwide sales in haematological indications. The royalty rate will start at 70 percent and will decrease to approximately half of the sales of MEDI4736 in haematological indications over a period of four years.

Dr. Bahija Jallal, Executive Vice President at MedImmune, said: "We are excited about our strategic collaboration with Celgene, a globally recognised leader in treatments for haematological cancers. This agreement is a great example of how we are accelerating the development of medical innovation in our portfolio in collaboration with other experts, in order to bring life-enhancing new medicines to patients faster. Together with Celgene, we are designing a programme for our anti-PD-L1 that will explore its full potential as a game-changing treatment that could activate the patients’ immune system to fight and change the course of blood cancers in this area of high unmet need."

"The potential of rationally combining immunotherapies such as MEDI4736 with existing and novel haematology compounds creates new opportunities for patients with blood cancers to live longer, better lives," said Jacqualyn A. Fouse, Ph.D., President, Global Haematology and Oncology for Celgene. "This strategic collaboration leverages the deep expertise of AstraZeneca/MedImmune in immuno-oncology along with the experience of Celgene in the study and treatment of blood cancers. This collaboration advances Celgene’s already deep, diverse scientific platform to include checkpoint inhibitors, an area of significant promise in haematology."

The collaboration agreement will become effective upon the expiration or termination of applicable waiting periods under all applicable antitrust laws, if any, and is expected to become effective in the second quarter of 2015. AstraZeneca’s 2015 financial guidance is unaffected by today’s announcement.

NOTES TO EDITORS

About MEDI4736

MEDI4736 is an investigational human monoclonal antibody directed against programmed cell death ligand 1 (PD-L1). Signals from PD-L1 help tumours avoid detection by the immune system. MEDI4736 blocks these signals, countering the tumour’s immune-evading tactics.

MEDI4736 was accelerated into Phase III clinical development in non-small cell lung cancer and head and neck cancer. The OCEANS clinical development programme will evaluate MEDI4736 as monotherapy and in combination with a CTLA-4 (tremelimumab) in lung cancer, across the spectrum of the disease. In head and neck cancer, MEDI4736 is being investigated both as monotherapy and in combination with tremelimumab, looking at patients with different PD-L1 expression status who have failed on chemotherapy.

AstraZeneca and Innate Pharma announce global co-development and commercialisation collaboration for IPH2201 in immuno-oncology

On April 24, 2015 AstraZeneca and MedImmune, the Company’s global biologics research and development arm, reported that they have entered into a collaboration to accelerate and broaden the development of Innate Pharma SA’s proprietary anti-NKG2A antibody, IPH2201, including in combination with MEDI4736, an anti-PD-L1 immune checkpoint inhibitor developed by MedImmune (Press release, AstraZeneca, APR 24, 2015, View Source;astrazeneca-and-innate-pharma-announce-global-co-development-and-commercialisation-collaboration-IPH2201 [SID:1234503170]). Currently in Phase II development, IPH2201 is a potential first-in-class humanised IgG4 antibody. NKG2A is a checkpoint receptor that inhibits the anti-cancer functions of Natural Killer (NK) and cytotoxic T-cells.

The initial development plan includes: Phase II combination clinical trials with MEDI4736 in solid tumours; multiple Phase II trials planned by Innate to study IPH2201 both as monotherapy and in combination with currently approved treatments across a range of cancers; and the development of associated biomarkers.

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The combination of IPH2201 with MEDI4736 adds to the broad programme of immuno-oncology combination trials that AstraZeneca and MedImmune have planned and underway. The studies aim to address multiple immune pathways, harnessing AstraZeneca’s own extensive pipeline and working in partnership to explore the significant potential of immunotherapies in transforming the way cancer patients are treated.

Under the terms of the agreements, AstraZeneca will make an initial payment to Innate of $250 million, which includes the consideration for exclusive global rights to co-develop and commercialise IPH2201 in combination with MEDI4736, as well as access to IPH2201 in monotherapy and other combinations in certain treatment areas. AstraZeneca will pay a further $100 million prior to initiation of Phase III development, as well as additional regulatory and sales-related milestones. AstraZeneca will book all sales and will pay Innate double-digit royalties on net sales. The arrangement includes the right for Innate to co-promote in Europe for a 50% profit share in the territory.

Pascal Soriot, Chief Executive Officer of AstraZeneca, said: "We are pleased to collaborate with Innate Pharma to bring this prospective first-in-class treatment to cancer patients, further strengthening our broad immuno-oncology pipeline. We believe that combination therapy in immuno-oncology has the potential to be one of the most effective ways of treating cancer and that by targeting both innate and acquired immunity we have the opportunity to deliver important clinical benefit to patients across a range of cancers."

Hervé Brailly, CEO and co-founder of Innate Pharma, said: "This agreement allows Innate Pharma to broaden and accelerate the development of anti-NKG2A while preserving our innovative development plan. It provides Innate Pharma with the capabilities and resources to transform the company towards late stage development and potential commercial stage with co-promotion rights. We look forward to partnering with AstraZeneca and MedImmune, leaders in immuno–oncology, in this transforming transaction for Innate Pharma."

The transaction is subject to customary terms and conditions, including the expiration or termination of the waiting period under the Hart-Scott-Rodino Antitrust Improvements Act, and is expected to become effective in the second quarter of 2015. AstraZeneca’s 2015 financial guidance is unaffected by today’s announcement.

NOTES TO EDITORS

About Innate Pharma’s anti-NKG2A

IPH2201 is a first-in-class immune checkpoint inhibitor targeting NKG2A receptors expressed on tumor infiltrating cytotoxic NK and CD8 T lymphocytes.

NKG2A is an inhibitory receptor binding HLA-E. By expressing HLA-E, cancer cells can protect themselves from killing by NKG2A+ immune cells. HLA-E is frequently up-regulated on cancer cells of many solid tumors or hematological malignancies. IPH2201, a humanized IgG4, blocks the binding of NKG2A to HLA-E allowing activation of NK and cytotoxic T cell responses. Hence, IPH2201 may re-establish a broad anti-tumor response mediated by NK and T cells. IPH2201 may also enhance the cytotoxic potential of other therapeutic antibodies.

About MEDI4736

MEDI4736 is an investigational human monoclonal antibody directed against programmed cell death ligand 1 (PD-L1). Signals from PD-L1 help tumours avoid detection by the immune system. MEDI4736 blocks these signals, countering the tumour’s immune-evading tactics.

MEDI4736 was accelerated into Phase III clinical development in non-small cell lung cancer and head and neck cancer. The OCEANS clinical development programme will evaluate MEDI4736 as monotherapy and in combination with a CTLA-4 (tremelimumab) in lung cancer, across the spectrum of the disease. In head and neck cancer, MEDI4736 is being investigated both as monotherapy and in combination with tremelimumab, looking at patients with different PD-L1 expression status who have failed on chemotherapy.