On September 30, 2016 CANCER RESEARCH UK reported its first cross-company deal as part of its Experimental Cancer Medicine Centre (ECMC) Combinations Alliance (Press release, Verastem, SEP 30, 2016, View Source [SID:SID1234515522]).

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MSD, Verastem, Inc. and Cancer Research UK will trial a new combination of immunotherapy drugs in mesothelioma, non small cell lung and pancreatic cancers. The trial will run through the ECMC network at centres in Edinburgh-Dundee, Southampton, Glasgow, Leicester and Belfast.

The phase Ib/IIa trial will investigate whether a focal adhesion kinase (FAK) inhibitor drug from Verastem called VS-6063 (defactinib)* can boost the effectiveness of a PD-1 immunotherapy drug from MSD called Keytruda (pembrolizumab).

It is based on discoveries by scientists at the Edinburgh Cancer Research UK Centre at the University of Edinburgh who showed that inhibiting FAK can release the cancer immune response. Defactinib may be able to take down a barrier of immune cells which are tricked into protecting the cancer cells while pembrolizumab can activate cancer-killing immune cells to attack those exposed cancer cells.

Around 50-60 cancer patients will take the drug combination, starting with a small dose and building this up to find what is safe. The scientists will also study how the treatments target the cancers and what effects the drug combination has on the tumours.
The trial will open between late 2016 and early 2017. It will be managed by the Cancer Research UK clinical trials unit in Glasgow and co-sponsored by the University of Glasgow and NHS Greater Glasgow and Clyde.

Dr Mercia Page, medical director of oncology at MSD, said: "We look forward to working with Cancer Research UK and Verastem on this promising combination. Strategic collaborations such as this reinforce the commitment we have to bringing a range of new treatments to the forefront, helping people with cancer who need a number of options available to them."
Dr Greg Berk, Verastem chief medical officer, said: "Combining defactinib and MSD’s pembrolizumab through the Combinations Alliance expands our potential to deliver transformative therapies to patients with many types of cancer.

"We are delighted to be working with the Combinations Alliance, MSD, and world class scientists and medical centres throughout the UK on this trial. This study will build on the single agent activity of defactinib observed in early clinical trials in patients with non-small cell lung cancer and other tumour types, and follows from substantial preclinical research which has demonstrated that FAK inhibition optimizes the tumour immune balance and potentiates efficacy of PD-1 checkpoint inhibition."
Dr Ian Walker, director of clinical research at Cancer Research UK, said: "It’s vital that we find new treatments for these three cancers which take tens of thousands of lives each year in the UK and we’re delighted to be working with MSD and Verastem on this.

"Our Combinations Alliance was set up to help develop partnerships between drug development companies and researchers to try new combinations of drugs in the hope of improving treatments and saving more lives from cancer. This is our first success in bringing together two organisations and we hope that this combination of immunotherapy drugs will benefit patients."
Mesothelioma, pancreatic and non small cell lung cancers have very low survival – with more than half (60 per cent) of mesothelioma patients, more than three quarters (79 per cent) of pancreatic cancer patients and two thirds (68 per cent) of lung cancer patients dying within a year of diagnosis in England and Wales.*

Trial co-lead Dr Stefan Symeonides, from the University of Edinburgh, said: "Immunotherapy is a very exciting area of cancer research and we’ve seen remarkable benefits from pembrolizumab for some patients with hard-to-treat cancers, like melanoma and lung cancer. We’re hoping that the addition of defactinib will extend those benefits to more patients.
"This work could one day give a new treatment option that saves lives for this group of patients who have few options."

On September 30, 2016 Eisai Co., Ltd. (Headquarters: Tokyo, CEO: Haruo Naito, "Eisai") reported the initiation of a global Phase III Clinical Study (Study 307, CLEAR Study) of its in-house developed multiple receptor tyrosine kinase inhibitor lenvatinib mesylate (lenvatinib) in respective combination regimens with the anticancer agent everolimus and the anti-PD-1 antibody pembrolizumab as a potential first-line treatment for advanced renal cell carcinoma (Press release, Eisai, SEP 30, 2016, View Source [SID:SID1234515517]).

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The CLEAR (Comparison of the efficacy and safety of Lenvatinib in combination with Everolimus or pembrolizumab versus sunitinib alone in first-line treatment of subjects with Advanced Renal cell carcinoma) study is a multicenter, randomized, open-label Phase III clinical study to compare the efficacy and safety of lenvatinib/everolimus and lenvatinib/pembrolizumab versus sunitinib alone in first-line treatment in patients with advanced renal cell carcinoma. The primary outcome measure will be progression-free survival.

Non-clinical research into the combination of lenvatinib and everolimus suggested synergistic enhancement of antiangiogenic activity and a stronger antitumor effect than either monotherapy in renal cell carcinoma models through the respective inhibition of signaling pathways which facilitate tumor angiogenesis, upstream (vascular endothelial growth factor receptor [VEGFR] and fibroblast growth factor receptor [FGFR]) with lenvatinib and downstream (mammalian target of rapamycin [mTOR]) with everolimus. 1,2 Furthermore, non-clinical research into the combination of lenvatinib and anti-PD-1 antibody suggested that the combination has a mechanism of action in which lenvatinib enhances the antitumor activity of the anti-PD-1 antibody by reducing immunosuppressive cells. 3

The number of patients with renal cancer is estimated to be approximately 338,000 worldwide, including approximately 115,000 in Europe, 58,000 in the United States and 17,000 in Japan.4 Renal cell carcinoma comprises more than 90% of all malignancies of the kidney, 5 and occurs when malignant cells are found in the lining of the tubules of the kidney. The incidence of renal cell carcinoma in people over 55 years of age is rising, and it is more likely to affect men than women. For advanced or metastatic renal cell carcinoma that is difficult to treat with surgery, the standard treatment is molecular targeted drug therapy, however with low 5-year survival rates, this remains a disease with significant unmet medical need.

Currently lenvatinib has been approved in over 45 countries including the United States, Japan and in Europe as a treatment for refractory thyroid cancer. In May 2016, lenvatinib was approved in combination with everolimus for the treatment of patients with advanced renal cell carcinoma following one prior anti-angiogenic therapy by the U.S. Food and Drug Administration in the United States. Furthermore, lenvatinib was approved in combination with everolimus for the treatment of adult patients with advanced renal cell carcinoma following one prior vascular endothelial growth factor targeted therapy in Europe in August 2016.


Eisai regards oncology as a key therapeutic area and is aiming to discover revolutionary new medicines with the potential to cure cancer. Eisai remains committed to providing further clinical evidence for lenvatinib aimed at maximizing value of the drug as it seeks to contribute further to addressing the diverse needs of, and increasing the benefits provided to, patients with cancer, their families, and healthcare providers.

1. About lenvatinib mesylate ("lenvatinib", generic name, product names: Lenvima , Kisplyx ) Discovered and developed in-house, lenvatinib is an orally administered multiple receptor tyrosine kinase (RTK) inhibitor with a novel binding mode that selectively inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors (VEGFR1, VEGFR2 and VEGFR3) and fibroblast growth factor (FGF) receptors (FGFR1, FGFR2, FGFR3 and FGFR4) in addition to other proangiogenic and oncogenic pathway-related RTKs (including the platelet-derived growth factor (PDGF) receptor PDGFRα; KIT; and RET) involved in tumor proliferation.
Currently, Eisai has obtained approval for lenvatinib as a treatment for refractory thyroid cancer in over 45 countries including in the United States, Japan, in Europe, Korea, Canada, and Mexico, and is undergoing regulatory review in countries throughout the world including South Africa and Malaysia. Specifically, Eisai has obtained approval for the agent indicated in the United States for the treatment of locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer, in Japan for the treatment of unresectable thyroid cancer, and in Europe for the treatment of adult patients with progressive, locally advanced or metastatic differentiated (papillary, follicular, Hürthle cell) thyroid carcinoma (DTC), refractory to radioactive iodine, respectively.
Lenvatinib was also approved in the United States in May 2016 for an additional indication in combination with everolimus for the treatment of patients with advanced renal cell carcinoma following one prior anti-angiogenic therapy. Furthermore, lenvatinib was approved in combination with everolimus for the treatment of adult patients with advanced renal cell carcinoma (RCC) following one prior vascular endothelial growth factor (VEGF) targeted therapy in Europe in August 2016. Lenvatinib will be launched in Europe under the brand name Kisplyx for this indication.
Meanwhile, Eisai is conducting clinical studies of lenvatinib in several other tumor types such as hepatocellular carcinoma (Phase III), endometrial carcinoma (Phase II), biliary tract cancer (Phase II), and in combination with pembrolizumab for various types of cancer (Phase Ib/II).
2. About the Phase III Clinical Study (Study 307, CLEAR Study)
CLEAR Study is a global, multicenter, randomized, open-label, Phase III clinical study to compare the efficacy and safety of lenvatinib in combination with everolimus or pembrolizumab versus sunitinib as first-line treatment of patients with advanced renal cell carcinoma. The study will be initially conducted in the United States and Europe, and Eisai is currently considering adding Japan to the study in the future. Approximately 735 patients aged 18 years or older with histological or cytological confirmation of advanced renal cell carcinoma with a clear-cell component and Karnofsky Performance Status6 of 70 or greater are randomized 1:1:1 to one of three treatment arms to receive either lenvatinib 18 mg (orally, once daily) plus everolimus 5 mg (orally, once daily) [arm A], lenvatinib 20 mg (orally, once daily) plus pembrolizumab 200 mg (intravenously every three weeks) [arm B], or sunitinib 50 mg (orally, once daily) on a schedule of four weeks on treatment followed by two weeks off [arm C]. The primary outcome is to compare progression-free survival between the arm A versus arm C, and the arm B versus arm C. Secondary outcomes are objective response rate, overall survival, and safety.
3. About Non-clinical Research into lenvatinib in Combination with everolimus1,2
It is known that lenvatinib inhibits VEGFR and FGFR which are upstream RTK signaling pathways, and that everolimus suppresses the protein mTOR (mammalian target of rapamycin) found downstream of these signaling pathways. In vitro and animal models have suggested that the combination of lenvatinib and everolimus suppresses RTK signaling pathways, which facilitate tumor angiogenesis, at two points both upstream and down, enabling synergistic signaling inhibition for enhanced antiangiogenesis in vitro. The combination demonstrated stronger antitumor activity than either monotherapy in the in vivo animal model using A498 and Caki-1 human renal cell carcinoma xenograft models.
4. About Non-clinical Research into lenvatinib in Combination with Anti-PD-1 Antibody3
Animal models have shown that lenvatinib activates tumor immunity via the modulation of tumor associated macrophages. Tumor associated macrophages have been reported as a negative regulator of cytotoxic T-cells and a promoter of tumor cell metastasis. Animal models suggest that when lenvatinib is combined with an anti-PD-1 antibody, lenvatinib enhances antitumor activity of the anti-PD-1 antibody by suppressing tumor associated macrophages.

On September 30, 2016 AstraZeneca, along with its global biologics research and development arm, MedImmune, reported that it will showcase the growing potential of its broad portfolio of cancer medicines through 46 scientific presentations, at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2016 Congress in Copenhagen, Denmark, from 7-11 October 2016 (Press release, AstraZeneca, SEP 30, 2016, View Source [SID:SID1234515511]).

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Highlights include new 1st-line data demonstrating superiority of Faslodex (fulvestrant) to a standard-of-care, aromatase inhibitor medicine, Arimidex (anastrazole), in postmenopausal women with HR+ locally-advanced or metastatic breast cancer who have not been previously treated with any hormonal medicine. The Company will also present updated safety and efficacy data from the Study 1108 durvalumab monotherapy cohort in non-small cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSCC), in addition to a comparative analysis of PD-L1 diagnostic assays in 500 HNSCC tumour samples.

Sean Bohen, Executive Vice President, Global Medicines Development and Chief Medical Officer at AstraZeneca, said: "Faslodex is an important treatment option for women with breast cancer. The FALCON trial illustrates how an approved medicine can further improve outcomes in patients with metastatic breast cancer. Additionally, our immuno-oncology presentations demonstrate our commitment to advancing innovation in lung and head and neck cancers, with pivotal data anticipated in the coming year."

Progress in Advanced Breast Cancer
With a strong heritage in breast cancer research, AstraZeneca is addressing the need for treatment advances in this area. Approximately 30% of women with early breast cancer go on to develop advanced/metastatic disease, with median overall survival (OS) of only two to three years. Although advanced breast cancer (Stage III/IV) is generally incurable, it is still treatable and the goal is to improve both the length and quality of life for patients.

Faslodex, a recommended medicine for the three quarters of women with advanced breast cancer whose tumour carries the oestrogen receptor (ER), is the only hormone therapy for advanced/metastatic breast cancer that slows tumour growth by binding to and degrading the ER.

Advanced breast cancer presentations at ESMO (Free ESMO Whitepaper) 2016 Congress will focus on:

New data from the Phase III FALCON trial Faslodex 500mg compared to Arimidex 1mg in the 1st line treatment of women with HR+ locally advanced or metastatic breast cancer (Abstract # LBA14_PR – oral presentation). This trial is included in the official Congress Press Programme.
New insights on the relationship between progression-free survival and OS in HR+ advanced breast cancer using 1st-line treatment data for Faslodex 500mg and Arimidex (Abstract # 250P).
Plans for a Phase II trial to investigate the addition of the PD-L1 antibody, durvalumab, to taxane-anthracycline containing chemotherapy in women with triple-negative breast cancer (TBNC) (Abstract # 221TiP). TNBC tends to occur in younger women and spreads more quickly than most other types of breast cancer.
Advancing medicines in Immuno-Oncology
At ESMO (Free ESMO Whitepaper) 2016 Congress, AstraZeneca will present a range of new and updated data from its Immuno-Oncology programme, including:

Updated results from the Phase I/II trial (Study 1108) of durvalumab in patients with NSCLC (Abstract # 1216PD), and HNSCC (Abstract # 2085 – oral presentation).
Early data from a Phase Ib trial (SCORES) of durvalumab combined with AZD9150 (a STAT3 inhibitor) or AZD5069 (a CXCR2 antagonist) in patients with HNSCC and advanced solid malignancies (Abstract # 1049PD).
A comparative analysis of multiple diagnostic assays used to evaluate PD-L1 expression in HNSCC (Abstract # 955PD).
The Company will also present preliminary findings of a Phase I trial with MEDI0562, a novel anti-OX40 agonistic monoclonal antibody (mAb), in adult patients with advanced solid tumours (Abstract # 1052PD). Activating OX40 boosts anti-tumour immunity by promoting the survival and proliferation of cancer-fighting T cells

Beyond immuno-oncology, AstraZeneca will present data from:

SELECT-1, a Phase III, placebo-controlled trial of the combination of selumetinib and docetaxel in patients with locally advanced or metastatic KRASm NSCLC (Abstract # LBA47_PR).

GOLD, a Phase III trial of Lynparza (olaparib) in combination with paclitaxel in patients with advanced gastric cancer who have progressed following 1st-line therapy (Abstract # LBA25).