Oncology Highlights - March 2016
Reading our newsletter will only take a few minutes and allows you to keep up to date with last month’s news items on oncology drug development.
Kind regards, the SMS-oncology team
Does Viagra encourage melanoma cells to proliferate?
Viagra, also known as sildenafil, is used by men to treat erectile dysfunction and has been on the market since the 1990s. Now, researchers led by Prof. Robert Feil from the University of Tübingen in Germany, have found a signaling pathway in melanoma cells that is affected by the drug, indicating that sildenafil actually stimulates skin tumors to grow. By conducting experiments in animals and human cell cultures, it was found that Sildenafil appears to inhibit the phosphodiesterase PDE5, an enzyme that ensures the constant break down of signaling molecules (cGMP). These signaling molecules play an important part in complex metabolic pathways, including blood vessel cells, the heart, neurons and sensory cells. The inhibition of PDE5 by sildenafil acts "like a brake on cGMP" according to Prof. Feil, and as such he equates taking sildenafil as disabling that brake, allowing melanoma to grow more robustly. Furthermore, this mechanism could explain the increased risk of melanoma in men who take sildenafil, nonetheless it is unlikely that the drug induces new cancers. While further studies are needed to assess these effects in humans, Prof. Feil warns that melanoma patients should consult their doctors before using sildenafil. The study was published in Cell Reports. Read more >
Precision oncology could be tailor-made for metastatic prostate cancer
According to a new study by Dr. Nelson at the Fred Hutchinson Cancer Research Center in Seattle, metastatic prostate cancer appears to be tailor-made for precision oncology. To work effectively, precision oncology requires two conditions: first that tumors from different individuals should be very different in their oncogenic drivers and therapeutic susceptibilities (heterogeneity between patients) and second that tumors within an individual should be quite uniform (homogeneity within patients). To determine whether prostate cancer metastases meet these 2 conditions primary or metastatic tumors from 176 men were removed and analyzed for various genetic and genomic alterations, such as copy number alterations, gene expression and whole-exome sequencing. The research showed that the conditions were met though the metastases are very complex. The presumptive driver mutations generally occurred within all metastases tested from a single individual. The mutations that were found to be unique to specific tumors were generally not predicted to be detrimental. They found that tissue from a single metastasis in prostate cancer could provide consistent molecular information needed to custom-design therapy. Read more >
Single dose of trastuzumab kick starts immune response in certain breast cancers
Only 50% of women with HER2-positive breast cancer treated with trastuzumab will have their tumor completely respond to therapy prior to undergoing surgery (neo-adjuvant) to remove the mass. Therefore, there is a high need to find ways to identify women who are most likely to respond to neo-adjuvant treatment. Prior research has shown that a patient's own immune system can be predictive for trastuzumab response. Vinay Varadan (PhD), assistant professor at Case Western Reserve University School of Medicine and member of the Case Comprehensive Cancer Center, and colleagues used data from two clinical trials to measure the molecular makeup of breast tumors after a single dose of trastuzumab. Their study showed, for the first time, that the immune-cell-activating properties of trastuzumab are likely related to the subtype of HER2-postive breast cancer, as well as that the tumor's immune response to single dose of the HER2 inhibitor can already predict which patient population would respond to the drug on a more long-term basis. Read more >
Study of patients with melanoma finds most have few moles
Studies have suggested that the number of total moles and atypical moles is associated with the risk of melanoma. Yet the relationship of those mole patterns with tumor thickness and cancer prognosis is complex. Alan Geller, of the Harvard T.H. Chan School of Public Health in Boston, and co-authors looked at the association between age and total moles and atypical moles and whether there was a relationship between them and tumor thickness, a very important prognostic indicator for melanoma. A total of 566 melanoma patients were studied. The majority (66.4%) had 0-20 total moles, while 73.3% had no atypical moles. Patients that were younger than 60 and had more than 50 total moles were associated with reduced risk for thick melanoma, while having more than five atypical moles compared with no atypical moles was associated with thicker melanoma. The researchers suggest that physicians and patients should not rely on the total nevus count as a sole reason to perform skin examinations or to determine a patient’s at-risk status. Younger patients should be educated on the increased risk of thicker melanomas associated with having more atypical moles the study, published in JAMA Dermatology, concludes. Read more >
Breakthrough therapies cut development timeline by two years
The US Food and Drug Administration's (FDA) “breakthrough therapy designation” was created in 2012 under the Food and Drug Administration Safety and Innovation Act (FDASIA). Breakthrough designation is granted to products that show potential for "substantial improvement" over existing treatments and provides sponsors with more frequent communication with FDA and intensive guidance on their drug development program. Since creating the scheme the FDA has approved more than 30 drugs under this category, many of which are cancer therapies. A study conducted by the Friends of Cancer Research concluded the amount of time it takes to develop new oncology drugs has been effectively shortened by more than two years and these have faster approval times compared with oncology products without breakthrough therapy status. The study also found that breakthrough drugs were three times more likely to receive accelerated approval. The analysts give a median time of 7.4 years for non-breakthrough products between submission of an investigational new drug application (IND) and a new drug application (NDA) or biologics license application (BLA), whereas only 5.2 years were calculated for products with the designation. Read more >
Standard template issued to boost efficiency of clinical trial protocol review
In order to improve the efficiency of clinical trial protocol reviews, the National Institutes of Health (NIH) has released a draft protocol template for NIH-funded Phase II and III drug and device studies. The template was jointly developed with the FDA and has the potential to "help clinical investigators make clinical trials more efficient, potentially saving development time and money". Peter Marks, director of the Center for Biologics Evaluation and Research (CBER) said the standard template would address gaps in international guidelines and was created because most investigators have insufficient experience in developing clinical trial protocols. FDA hopes that one day similar efforts, such as the common protocol template developed by TransCelerate Biopharma, may afford consistency for the medical product development community. Read more >
EMA / FDA
EMA oncology drug recommendations for approval March 2016:
The Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion for:
- Darzalex (daratumumab, Janssen-Cilag International) for the treatment of adult patients with relapsed and refractory multiple myeloma, whose prior therapy included a proteasome inhibitor and an immunomodulatory agent and who have demonstrated disease progression on the last therapy. The monoclonal antibody binds to CD38, a type II transmembrane glycoprotein highly expressed in hematological malignancies. On 17 July 2013, daratumumab was granted orphan designation by the European Commission.
- Palonosetron Accord (palonosetron, Accord Healthcare) for the prevention of nausea and vomiting associated with cancer chemotherapy. The active substance of Palonosetron Accord is palonosetron (as hydrochloride), belonging to the class of serotonin (5-HT3) antagonists. It acts by blocking serotonin receptors and subsequently the neuronal cascade of events leading to nausea and vomiting caused by cancer chemotherapeutic agents. Palonosetron Accord is a generic of Aloxi, which has been authorised in the EU since 22 March 2005.
- Halaven (eribulin, Eisai Europe) for the treatment of adult patients with unresectable liposarcoma who have received prior anthracycline containing therapy (unless unsuitable) for advanced or metastatic disease. Eribulin is a fully synthetic analogue of the marine natural product halichondrin B, a potent naturally occurring mitotic inhibitor found in the marine sponge Halichondria okadai. By attaching to the protein tubulin in cancer cells, eribulin disrupts the formation of an internal ‘skeleton’ that cells need to assemble when dividing, thereby preventing the division and spread of the cancer cells.
- Opdivo (nivolumab, Bristol-Myers Squibb) as monotherapy or in combination with ipilimumab for the treatment of advanced (unresectable or metastatic) melanoma in adults. The PD-1 inhibitor is already approved for the treatment of non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC).
The FDA adopted an extension of indication for:
- Defitelio (defibrotide sodium, Jazz Pharmaceuticals) for the treatment of adult and pediatric patients with hepatic veno-occlusive disease (VOD), also known as sinusoidal obstructive syndrome, with renal or pulmonary dysfunction following hematopoietic stem-cell transplantation (HSCT). Defibrotide increases the breakdown of clots in the blood. The drug was already approved in Europe by EMA in October 2013 under exceptional circumstances.
- Xalkori (Crizotinib Capsules, Pfizer) for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are ROS1-positive. XALKORI is a tyrosine kinase inhibitor (TKI) and anti-angiogenic agent and was first approved by the FDA in 2011 for the treatment of patients with locally advanced or metastatic NSCLC that is anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test. XALKORI blocks the proteins made by the mutated ALK and ROS1 genes, which may stop the of growth and spread of cancer cells.