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Chemotalk NewsletterChemotalk Newsletter, Vol. 82: February 1, 2015 Happy New Year to all! Beginning with two promising stories regarding breast cancer: NEW BREAST CANCER DRUG ON THE HORIZON Pfizer Inc has begun talks with the U.S. Food and Drug Administration to finalize the prescription label of its BREAST CANCER drug palbociclib, in an indication the drug was likely closer to regulatory approval. The largest U.S. drugmaker also said there was no plan for the agency to hold an advisory committee meeting to discuss the medicine prior to an approval decision. Pfizer shares rose 2 percent on the news, which was greeted as a sign that FDA approval by the April 13 decision date set by the agency was likely. "The statement from Pfizer that there is no FDA Adcom (advisory committee) planned for palbo reaffirms our high confidence for a first pass approval in April," Jefferies analyst Jeffrey Holford said in a research note. Palbociclib, which would be sold under the proposed brand name Ibrance, is considered one of the most important new medicines in Pfizer's developmental pipeline, with analysts forecasting annual sales of $3 billion. "We think consensus continues to underestimate this opportunity," said Holford, forecasting peak annual sales of $5 billion for the drug. Pfizer, in a statement, said it hopes to bring Ibrance to patients as soon as possible. In a key clinical trial, palbociclib nearly doubled the time it took for breast cancer to worsen. It was not yet known if, or by how much, the drug extends overall survival. * * * MBI BOOSTS CANCER DETECTION IN PATIENTS WITH DENSE BREASTS By Anna Azvolinsky, PhD Mammography alone often doesn't cut it in patients with dense breast tissue Molecular breast imaging (MBI) in addition to mammography resulted in a better BREAST CANCER detection rate compared with mammography alone in women with dense breasts. Adding MBI to mammography increased the overall breast cancer detection rate from 3.2 to 12 per 1,000 women screened (P < .001). The detection rate for invasive cancers increased from 1.9 to 8.8 per 1,000 patients screened (P < .001). A total of 1,585 women, all with dense breast tissue, had a mammogram as well as MBI. Of the tumors detected by MBI, 11 of 14 (79%) were invasive. Of those that were invasive, 82% were node-negative, representing early-stage, treatable disease. The change in detection of ductal carcinoma in situ (DCIS) was not statistically significant when MBI was added. Detection increased from 1.3 to 3.2 cases of DCIS (P = .250). These results are published in the American Journal of Roentgenology. The results are similar to those reported in a 2011 study which showed that MBI is able to detect about three times as many cancers as mammography, said lead study author Michael K. O'Connor, PhD, professor of radiologic physics at the Mayo Clinic in Rochester, Minn. The major difference, O'Connor told Cancer Network, is that the current study used approximately one-third the dose of technetium (99mTc) sestamibi, the radioisotope used for the imaging, as the earlier study. This lower dose reflects a technological advance in MBI, allowing clinicians to use a lower dose while retaining the same image quality, said O'Connor. The sensitivity of mammography alone was 23.8%, 81% for MBI alone, and 90.5% for the combination of both screening techniques. The difference in sensitivity between mammography alone and the combination was statistically significant (P < .001). MBI has been shown to be useful as an additional screening method for the 40% to 50% of women with dense breast tissue as standard digital mammography does not detect breast cancers as well in these women. The current study used both the digital LumaGEM MBI system (Gamma Medica), approved as a medical device by the US Food and Drug Administration in 2011 as well as the GE Discovery NM750b system. But, O¹Connor pointed out that the dose of radioisotope used in this current study are lower than those recommended in the FDA approval of these devices‹4 to 8 mCi dose compared with the approved 20 to 30 mCi. "Lower doses are essential if MBI is to be used for screening," said O'Connor. Adding MBI to mammography increased the recall rate by 6.6%, which is lower than previously published recall rates of 9% to 23% for adjunct MRI or ultrasound for breast cancer screening. Additionally, MBI plus mammography increased the biopsy rate by 2.9%, which compares favorably with the increase in biopsy rates for ultrasound (7.8%) and MRI (8%). While mammography is a way to visualize the anatomy of the breast tissue, MBI is a functional analysis. "Some cancers can be difficult to detect on mammography as they are visually indistinguishable on x-ray from some types of normal breast tissue. However, functionally these cancers can be far more readily detected as their functional signature is very different from that of normal tissue," said O'Connor. Some academic centers, including the Mayo Clinic are offering MBI as a supplement screening. According to O¹Connor, the Mayo Clinic continues to investigate how to further reduce the radiation doses used for MBI and to expand its potential applications. "An important next step for MBI technology is a multicenter prospective randomized trial to assess comparative performance measures," concluded the authors. * * * ELECTRICAL SCALP DEVICE FOR DEADLIEST BRAIN TUMORS CAN PROLONG SURVIVAL By Denise Grady An electrical device glued to the scalp can slow cancer growth and prolong survival in people with the deadliest type of BRAIN TUMOR, researchers reported. The device is not a cure and, on average, adds only a few months of life when used along with the standard regimen of surgery, radiation and CHEMOTHERAPY. Some doctors have questioned its usefulness. But scientists conducting a new study said the device was the first therapy in a decade to extend life in people with GLIOBLASTOMAS, the brain tumors in which median survival is 15 months even with the best treatment. The disease affects about 10,000 people a year in the United and is what killed Senator Edward M. Kennedy in 1009. It is so aggressive and hard to treat that even seemingly small gains in survival are considered important. The new findings mean the device should become part of the standard care offered to all patients with newly diagnosed glioblastomas, the researchers conducting the study said. The equipment consists of four pads carrying transducer arrays that patients glue to their scalps and change every few days. Wires lead to a six-pound operating system and power supply. Except for some scalp irritation, the device has no side effects, the study found. Bur patients have to wear it more or less around the clock and must keep their heads shaved. It generates alternating, low-intensity electrical fields -- so-called tumor-treating fields -- that can half tumor growth by stopping cells from dividing, which leads to their death. The researchers said the technology might also help treat other cancers, and would be tested in MESOTHELIOMA and cancers of the LUNG, OVARY, BREAST and PANCREAS. The equipment is made by Novocure, a company with headquarters on Jersey, an English island off the coast of France. It also has a research center in Israel and operations in the United States. The company is paying for the study, which involves 700 patients in 12 countries. Novocure's device has been approved in the United States since 2011, but only to treat recurrent glioblastomas, not newly diagnosed ones. It costs $21,000 a month, and some insurers cover it. So far, Novocure has been providing it free to patients without insurance coverage according to William F. Doyle, the company's executive chairman. The study tested the device in newly diagnosed cases. The results were presented at a meeting of the Society for Neuro-Oncology, by Dr. Roger Stupp, the study director and chairman of the department of oncology and cancer at the University Hospital in Zurich. The data came from the first 315 patients, who were followed from 18 to 60 months. They were assigned at random to one of two groups: 105 received standard treatment alone, usually consisting of surgery, radiation and the chemotherapy drug temozolomide; the other 210 received standard treatment and the electrical device. Patients who wore the device fared better than those who did not: Their median survival was 19.6 months, compared with 16.6 months in those on standard treatment alone. Among those with the device, 43% survived two years, compared with 29% among those receiving only standard therapy. "It was a surprise, and better than we would have expected," Dr. Stupp said in an interview. The study design called for a data analysis partway through to monitor the patients' safety. When the monitoring board saw how much better patients were doing with the electrical fields it recommended that the study be stopped so that the device could be offered to everyone. It was the first time that a monitoring board had recommended stopping a brain-cancer study because one treatment was so much better than another. Dr. Patrick Y Wen, director of neuro-oncology at Dana-Farber Cancer Institute I Boston, who was not involved with the study, said that until now, there had been some skepticism among doctors about the treatment. "But these results seem real," Dr. Wen said, "With these results, I think more people would definitely use it." Dana-Farber does not use the device, he said, but with the new data, "I think some patients will probably want to have it, and we will probably plan to use it going forward." A three-month increase in survival may not sound like much, he said, "but for our patients, it's not trivial." Another neuro-oncologist not associated with the study, Dr. Nicholas Butowski of the University of California, San Francisco, described the Novocure device as "polarizing" and said, "Some of my colleagues just do not believe it." But Dr. Butowski added: "Perhaps it does work in some patients. T's got logic behind it." He said he would use it, though he suspected that the benefit was relatively small. He also described the device as being in its infancy, and said he expected that Nobvocure would find ways to make it more effective. Maureen Piekanski, 59, a glioblastoma patient and study participant from Throop, Pa., learned about the device from her daughter, a nurse, who had combed the Internet for glioblastoma studies. "It appealed to me because it was noninvasive and it wasn't going to make me sick," Ms, Piekanski said. "It was worth a try. I had nothing to lose." Before making her decision, Ms. Piekanski consulted several doctors, and one told her that she might as well put sewage on her head. She joined the study anyway because she knew that even with the best available treatment her outlook was bleak. "If you get 15 months, you did good." She has been wearing the device since August 2011 -- more than three years. Her tumor is gone, and the disease has not returned. She has M.R.I. scans every two months. "I get two months as a time, always thinking I might have a recurrence," she said. There is no way to tell whether the device has been keeping her alive, or whether she would have done just as well without it. But when she completed the period she had signed up for in the study, and the researchers told her that she could stop wearing the device if she wanted to, she said, "Oh, yeah, I'm keeping it." * * * DISCOVERY RELATING TO PANCREATIC CANCER Researchers have identified one reason PANCREATIC CANCER is so resistant to CHEMOTHERAPY treatment: vitamin D. Only about 5 percent of pancreatic-cancer patients survive beyond five years even with the most aggressive treatment, according to the National Cancer Institute. One big reason is that chemotherapy ‹ including the standard drug, gemcitabine ‹ isn¹t very effective at preventing pancreatic cancer cells from replicating. To understand why, Timothy J. Yen, a professor at Temple University¹s Fox Chase Cancer Center in Philadelphia, removed each of the 24,000 genes, one by one, in pancreatic cancer cells and then doused them with gemcitabine. When some of these genes were ³knocked out,² the gemcitabine was effective. One in particular surprised the researchers. "When we knocked out the gene for a protein that binds to vitamin D, almost all of (the cancer cells) died," said Yen, the leader of the research team. Although vitamin D is important for health, especially for bone health, normal cells do not need vitamin D to survive, said Yen. Apparently, though, pancreatic cancer cells do. That means if scientists can figure out a way to inactivate the vitamin D receptor in pancreatic cancer cells, the main drug used to treat patients would be more effective. "My excitement about making vitamin D receptors a priority is because it is a Œdruggable' target," Yen said. "There are compounds out there that drug companies already make to affect vitamin D," so the apparatus and knowledge already exist. The researchers at Fox Chase Cancer Center, which is part of the Temple University Health System, published their findings in the journal Cell Cycle. Their study took nearly four years to complete, and the initial findings were so unexpected, Yen said, that many more-sophisticated experiments were performed to convince the team that their findings were correct. "I didn¹t believe the results at first," he said, ³because the literature on vitamin D , what does it have to do with cancer? But this wasn't just a fluke." Yen admits that he and his team are novices when it comes to vitamin D, but they did know that it aids functioning in nearly every tissue and organ of the human body, not just the bones. What was so unusual in their genetic experiments was to find that while normal cells do not require vitamin D to survive, pancreatic cancer cells need it to repair the damage caused by chemotherapy. "This in vitro study was quite elegant and suggested that targeting VDR (vitamin D receptors) may show synergistic effect with gemcitabine in pancreatic cancer patients," said Haoqiang Ying, an expert in molecular and cellular oncology at the University of Texas MD Anderson Cancer Center in Houston. "Much more detailed studies are needed." Many researchers have examined how tumor cells hijack genes, according to Yen. "Why they hijack certain genes we don't know," he said. "But they do re-purpose other genes to help the cancer to survive. In the case of pancreatic cancer, it¹s the (gene for the) vitamin D receptor." Another reason pancreatic cancer is so stubborn to treat is that the malignancy creates a kind of moat around itself, making it difficult for chemo drugs to reach the primary tumor. "The possibility is, if we can design something to inhibit vitamin D, we can enhance the sensitivity of the tumor to the limited amount of the drug that gets through," Yen said. "I would love to see the day my research gets to the bedside, but there are so many things to overcome. This is just another light switch we¹ve turned on. We just hope to keep it on as long as we can." * * * FOR FIRST TIME, F.D.A. PANL APPROVES GENERIC COPY OF COSTLY BIOLOGIC DRUG By Sabrina Tavernise An expert panel unanimously recommended that the Food and Drug Administration approve a cheaper copy of a special drug used in CANCER therapy, paving the way for alternatives to an entire class of complex and costly drugs to enter the United States market. Most brand-name drugs eventually lose their patent protection, opening the market to lower-priced generic products. But one class of drugs, known as biologics, which includes some of the most expensive medications in the world has been insulated from the competition of cheaper copies for years. That changed when the 14 members of the panel convened by the F.D.D., recommended approval of a drug known as EP2006, which helps the body make white blood cells and is a close copy of an existing medication called Neupogen, also called filgrastim. EP2006 was approved in Europe in 2009 as Zarzio but has not been use in the United States, I part because no regulatory pathway existed to bring copies of biologic drugs to market. "This is kind of like cutting the ribbon to open a major new road," said Ronny Gal, a senior research analyst who focuses on specialty pharmaceuticals at Sanford C. Bernstein & Company. "It is literally a new concept in medicine." Biologic drugs are so called because they are made out of living cells and not synthesized from chemicals as ordinary drugs are. Some examples of popular biologic drugs are Remicade, Humira and Enbrel for autoimmune disease, and Herceptin, Rituxan and Avastin for cancer. If the F.D.A. Follows the panels advice -- it usually does, though it does not have to -- the move would usher in an era of competition for biologics and would eventually reduce prices, Mr. Gal said. Pharmaceutical companies have been criticized for the high prices of new drugs, and biologics are particularly expensive; Avastin, for example, can cost more than $50,000 a year. Express Scr9pts, the nation's largest manager of prescription drug benefits, estimates that the introduction of EP2006 -- to be called Zarxio in the United States -- could save $5.7 billion in drug costs over the next 10 years. "The need to bring low-cost competition into biologic drugs is critical in making American health care more affordable," Mr. Gal said. Biologics make up about a third of drugs in the United States, he said, and the share is expected to grow. The drug recommended on Wednesday is made by Sandoz, a unit of the Swiss company Novartis. Neupogen, the original, is made by Amgen, an American company. Biologic drugs were first developed in the 1980s and were considered so specialized that making generic versions was seen as most likely impossible. But science has advanced, and as patents began to expire, drug companies started developing lose copies, called biosimilars, and seeking F.D.A. approval for them. Companies with the original patents initially resisted, arguing that their drugs were so complex that it was not possible to make an exact copy, but that position eventually became untenable. Biosimilars are about a third cheaper than brand-name biologic drugs, on average, in countries where they are in use, according to Express Scripts, although some argue the discounts could be much steeper, up to 90%. Express Scripts estimated that $250 billion in drug costs could be saved over the next decade if 11 biosimilars in development were approved. At the meeting experts seemed to be following the thinking of F.D.A. officials, several of whom stated directly that the drug maker had achieved its goal. "The data submitted by Sandoz demonstrated that EP2006 is highly similar to U.S.-licensed Neupogen, and that there are no clinically meaningful differences between the two products," said Dr. Albert Deisseroth, medical officer team leader for the Division of Hematology Products at the F.D.A. Experts voted to recommend approval for all five of Neupogen's licensed uses -- known in medical terms as its indications. That is a victory for Sandoz, and a positive signal for makers of biosimilars, who had worried that approval might only cover a few uses. The F.D.A. is not allowed to consider the price of drugs in its approvals, but even so, a series of outside speakers, including patients, urged approval to make critical treatments more affordable. "We have talked this morning about the elephant in the room -- about cost," said Amye Leong, who identified herself as a patient. "I know that the F.D.A. is not supposed to be talking about this, but it is the cost that we patients daily must deal with." The meeting drew intense interest in the pharmaceutical industry and included prominent speakers like Dr. Janet woodcock, the director of the agency's Center for Drug Evaluation and Research, who spoke about the new regulatory pathway for biosimilars. The blueprint was laid out in 2010 in the Affordable Care Act, and the F.D.A. has issued guidance for companies on how to gain approval for biosimilars. * * * See you next month... This is a short newsletter. I promise to make up for it next month. There's definitely enough to talk about... And if you have any thoughts of how this newsletter could be improved, please email me directly, at Elaine@elainejesmer.com. Elaine Jesmer
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