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Chemotalk NewsletterChemotalk Newsletter, Vol. 51: July 1, 2012 Hello, Everyone .. I'm tempted to copy every major article from the ASCO Convention's daily paper, but I've seen some of this information on other sources. This news sounds really good. It's a bit technical, but you'll get the point: DABRAFENIB EXTENDS PROGRESSION-FREE SURIVAL IN METASTATIC MELANOMA HAS HIGH CLINICAL ACTIVITY IN BRAIN METASTASES Utilization of dabrafenib, the selective BRAF kinase inhibitor, has produced positive results compared with dacarbazine for the treatment of METASTATIC MELANOMA and has high clinical activity in BRAIN METASTASES. Updated results from the phase II BREAK-3 trial were presented on behalf of the trial group during ASCO'S Melanoma Oral Abstract Session by Axel Hauschild, MD, of University Hospital, Schleswig-Holstein, Germany. At the same session, John M. Kirkwood, MD, of the University of Pittsburgh Cancer Institute, reported the final data from BREAK-MB, a phase II trial in patients with brain metastases. Both studies included patients with confirmed BRAFV600E mutations. The BREAK-MB phase II protocol for stage IV BRAF-positive melanoma enrolled patients with one or more intracranial metastases who had no prior brain therapy (Cohort A) or patients with disease progression following prior brain therapy (Cohort B). Overall, 325 patients were screened and 172 patients were enrolled. Demographics and clinical characteristics were similar for the two cohorts: 70% male, 54% with elevated lactate dehydrogenase levels (LDH) levels, and 46% with two to four target brain metastases. Thirty-eight percent had received prior chemotherapy and 30% had received prior immunotherapy. Dr. Kirkwood announced an unprecedented overall intracranial disease control rate of 81% in Cohort A and 89% in Cohort B for patients with V600E mutations, with a median duration of intracranial response of 20.1 weeks and 28.1 weeks, respectively. Both cohorts had an overall survival rate over 30%. Results were positive for overall intracranial response, overall response, and median progression-free survival. A subset of 33 patients with BRAFV600K mutations had more limited responses to dabrafenib with an overall response rate of 7% for Cohort A and 50% for Cohort B; the overall disease control rate was 33% and 50%, respectively. Serious adverse events occurred in 30% of the patients in both cohorts, 17% were related to study treatments. Only 2% of patients discontinued treatment due to toxicity and no deaths were attributable to dabrafenib therapy. Dr. Kirkwood concluded that dabrafenib is safe, with unprecedented responses and overall survival, supporting its use as first-line therapy. This shifts the current paradigm of treatment for brain metastases to systemic therapy. In BREAK-3, patients with previously untreated, unresectable stage III or IV disease were stratified by stage after random allocation at a ratio of 3:1 to oral dabrafenib or intravenous dacarbazine. Patients in the dacarbazine arm were allowed to cross over once progression was confirmed by independent review. The primary endpoint was investigator assessed progression-free survival. The trial enrolled 250 patients, 187 were allocated to the dabrafenib arm and 63 were given dacarbazine. Demographic and clinical characteristics were well-balanced between the two treatment groups. Approximately 60% of the patients were men, 65.6% had stage IV (M1c) disease, and 34.4% had elevated LDH levels. Median investigator-assessed progression-free survival was 5.1 months for patients taking dabrafenib and 2.7 months for those receiving dacarbazine. Results from independent review were similar (6.7 months and 2.9 months, respectively. Dr. Hauschild commented that the progression-free survival curves were similar whether the data were censored for crossover patients or not. Subgroup analysis demonstrated dabrafenib to be superior regardless of performance status, LDH levels, age, gender, or disease stage. The confirmed overall response rate was 53% for patients taking dabrafenib and 19% for patients receiving dacarbazine. The most common adverse events for patients taking dabrafenib were skinrelated (hyperkeratosis [51%], palmarplantar hyperkeratosis [21%], and squamous cell carcinoma/keratoacanthoma [7%]), headache (17%), arthralgia (16%), and pyrexia (15%). Photosensitivity was seen in 3% of patients taking dabrafenib and 5% of patients receiving dacarbazine. Few serious adverse events were reported, mainly squamous cell carcinomas (5%), pyrexia (4%), and new primary melanomas (2%). Both dabrafenib and dacarbazine were well-tolerated, with only 3% of patients discontinued due to adverse events in each group. Dr. Hauschild noted that the positive results from BREAK-3 have opened the pathway to combination trials with dabrafenib for stage IV melanoma, as well as adjuvant trials. Discussant Michael B. Atkins, MD, of Georgetown Lombardi Comprehensive Cancer Center, commented that, based on the data from BREAK-MB, there is no reason to exclude patients with melanoma brain metastases from studies of dabrafenib; however, the study design did not address the use of stereotactic radiosurgery, an important therapeutic approach for these patients and one that should be explored in a clinical trial. Dr. Atkins noted that BREAK-3 establishes dabrafenib as the second BRAF inhibitor with proven efficacy and competition is good for patients and the oncology field. In his closing remarks, Dr. Atkins said, ³Despite recent advances, metastatic melanoma is still a bad disease. We need to pause to celebrate but then begin work to raise the bar higher.² * * * And in a related story ... FDA FORESEES JUMP IN APPLICATIONS FOR CANCER DRUGS By Ryan McBride U.S. regulators expect to review lots of cancer drugs this year. With developers finding ways to get early readouts on efficacy, companies are expediting programs to set the stage for rapid development and speedy approvals of new anti-cancer therapies. In an interview with Reuters, FDA oncology chief Dr. Richard Pazdur predicts that the agency will receive 20 submissions for cancer drugs in 2012. It's too early to tell whether that will lead to an increase in approvals this year, but the number says a lot about intense participation in cancer drug research around the biopharma industry. The FDA has only fueled activity in oncology with its growing track record of green-lighting cancer drugs in short order when the treatments show evidence of benefiting patients with life-threatening malignancies. A recent example was the agency's approval last summer of Seattle Genetics' lymphoma drug Adcetris based on small, single-arm studies with impressive results. "It is much easier to approve drugs that have greater efficacy," Pazdur told Reuters. "Our staff is interested getting the drugs out earlier ... it has to be [a] drug that we really think is important." As Reuters notes, a third of the 30 new drugs approved last year in the U.S. were cancer treatments. What's behind the numbers? For one, researchers have drilled deeper into the biology of cancer, uncovering a wealth of disease-related gene targets that can be bull's-eyed with new drugs, and patients can be screened for the genes before they get the treatments. Developers have been able to move fast in the clinic with targeted cancer drugs and seek approvals earlier than they could for treatments against other diseases. Rather than the standard decade-long development timeline for drugs, companies have been able to jump from initial human studies to regulatory submissions for cancer meds in just a few years. Take GlaxoSmithKline's experimental MELANOMA drugs for patients with BRAF mutations. As reported, the London-based drug giant expects to file for U.S. and European approvals of the pair of targeted drugs later this year, little more than three years after kicking off early-stage studies of the treatments. "It has been the fastest experience of my entire career," Paolo Paoletti, the president of GSK Oncology, said in the interview. Pazdur makes clear in his Reuters interview that the FDA pays special attention to game-changing therapies. And in recent weeks U.S. lawmakers have backed proposals to give the agency the flexibility to use a variety of tools to fast-track programs for drugs against serious and deadly diseases. In oncology, there are plenty such cases. * * * CELLS MOST VULNERABLE TO HPV ARE IDENTIFIED By Nicholas Bakalar Scientists hae located the cells in the cervix that give rise to CANCER when attacked by the human papillomavirus, a discovery that may lead to new methods of preventing and treating the disease. Even though the virus pervades the entire genital tract, HPV infection causes precancerous and cancerous lesions in just one part of the cervix, called the ectoendocervical squamocolumnar junction, or SC junction. Now researchers have found that cervical cancers are linked to a small population of distinct cells in that region. The researchers began by examining cells from the SC junction in the cervices of patients not infected with HPV. Among the samples they found some cells that under a microscope looked different from those in adjacent areas. Then they looked at the cells of precancerous and cancerous lesions, comparing the form and genetic makeup of those cells with the SC junction cells. They matched, and so the scientists believe that they have found the cells in which most, if not all, cervical cancers arise. Dr. Christopher P. Crum, the senior author, said that the discovery follows findings in a 2011 study led by Frank McKeon and Wa Xian at Harvard, who found the same cells in Barrett esophagus, a precursor of ESOPHAGEAL CANCERS. (Research has linked these cancers, too, to HPV infection.) The new study was published in the journal Proceedings of the National Academy of Sciences. "These markers could be used to more clearly define which precancers need to be treated versus those that need to be followed, so you don't go doing surgery on women who have innocuous infections," said Dr. Crum, a professor of pathology at Harvard. Dr. Mark H. Einstein, a gynecologic oncologist at Montefiore Medical Center in the Bronx who was not involved in the study, agreed that this could be an important clinical application of the finding "The procedures that treat the precancerous cells can lead to preterm birth in some women, so we want to avoid them if possible," he said. "Sometimes doing less is more." Although the researchers say they cannot rule out that SC junction cells might develop spontaneously, they are almost certain that they appear during fetal development an exist in all women, regardless of age. Markers of SC junction cells are always present in high-grade precancerous and cancerous lesions, and they are absent in most low-grade lesions. In this study, their presence accurately predicted the precancerous lesions most likely to become malignant, those infected by HPV Type 16. The discovery might also lead to prophylactic treatment, at least in areas of the world when routine care like cervical cancer screening is unavailable. "Given how small the area is that these cells occupy," Dr. Crum said, "they might very easily be removed or ablated by some means which could be a cost-effective way of preventing cervical cancer. There are people who claim anecdotally that this would work, and it's a concept worth thinking about." The cells do not regenerate after they are cut away. Clinical application of the discovery could be very close, Dr. Einstein said. "This is something that could probably be adopted by clinicians and pathologists pretty soon," he said. "These investigators have actually identified the type of cells which can then be used to target new methods of testing, treatment and screening. It's fantastic." * * * A ONE-TWO PUNCH A New Class of Cancer Drugs May Be More Effective and Less Toxic By Andrew Pollack Fern Saitowitz's advanced BREAST CANCER was controlled for about a year by the drug Herceptin and a CHEMOTHERAPY agent. But her hair fell out, her fingernails turned black and she was constantly fatigued. She switched to an experimental treatment, which also consisted of Herceptin and a chemotherapy agent. Only this time, the two drugs were attached to each other, keeping the toxic agent inactive until the Herceptin carried it to the tumor. Side-effects, other than temporary nausea and some muscle cramps, vanished. "I'm able to live a normal life," said Ms. Saitowitz, 47, a mother of two young children on Los Angeles. "I haven't lost any of my hair." The experimental treatment, called T-DM1, is a harbinger of a new class of cancer drugs that may be more effective and less toxic than many existing treatments. By harnessing antibodies to deliver toxic payloads to cancer cells, while largely sparing healthy cells, the drugs are a step toward the "magic bullets" against cancer first envisioned by Paul Ehrlich, a German Nobel laureate, about 100 years ago. "It's almost like we're masking the chemotherapy," said Dr Edith Perez, a breast cancer specialist at the Mayo Clinic in Jacksonville, Fla. One such drug, Adcetris, developed by Seattle Genetics, was approved last August to treat HODGKIN'S LYMPHOMA and another rare cancer. TDM-1, developed by Genentech, could reach the market next year. Numerous other companies, from pharmaceutical giants to tiny start-ups, are pursuing the treatments, which are known variously as antibody-drug conjugates, armed antibodies or empowered antibodies. "I don't think there is a major pharma or a midsized pharma with interest in caner that doesn't have a program or isn't scrambling to put one together," said Stephen Evans-Freke, a managing general partner at Celtic Therapeutics, an investment firm that recently committed $50 million to create a new company, ADC Therapeutics, to develop antibody-drug conjugates. About 25 such drugs from a variety of companies are in clinical trials, according to Alain Beck, French pharmaceutical researcher who closely tracks the field. Genentech alone has eight in clinical trials besides T-DM1, and another 17 in earlier stages of development. Many of the drugs use technoloy from either Seattle Genetics, ased in Bothell, Wash, or ImmunoGen of Waltham, Mass., which supplied the toxin and linker used in T-DM1. The armed antibodies do not work for all patients and they are not totally free of side effects. T-DM1, for instance, can lower lood platelet leels. The drugs are also likely to be expenive. Adcetris costs more than $100,000 for a typical course of treatment. Biotechnology drugs called monoclonal antibodies, like Herceptin, Rituxan and Erbitux, are already mainstays of what is called targete cancer therapy. These laboratory-produced molecules mimic the antibodies made by a person's immune system to fight infection. But instead of attacking pathogens these antibodies attach to specific proteins on the surface of cancer cells. But antibodies by themselves have a limited ability to kill tumors. So the antibodies are usually given with more conventional cell-killing chemotherapy drugs, which cause side effects because they can also attack healthy cells. The new approach chemically attaches a toxin to the antibody, increasing its killing power while reducing the need to give toxic drugs separately. After the antibody binds to a cancer cell, it is taken inside the cell like a Trojan horse, and the toxin is released. While armed antibodies are sometimes likened to guided missiles with toxic warheads, they actually cannot guide themselves to tumors. Rather, they float through the bloodstream, bumping against various cells. But they stick only to the cells bearing the target protein "These are like floating sea mines," said K. Dane Wittrup, a professor of chemical and biological engineering at the Massachusetts Institute of Technology. "But when they end up in a particular harbor, they blow up." Less than 1% of the drug actually makes it to the tumor, he estimated. The antibody used in Adcetris, which binds to a protein on malignant cells called CD30, had little effect on cancer when tested alone, even at doses 20 times as high as used now. But when linked to a toxin, it shrank tumors in 75% of those with Hodgkin's lymphoma. Aimee Blaine, a petroleum engineer from Bakersfield, Calif., who has had Hodgkin's lymphoma since 2004, was virtually out of options after traditional chemotherapy and a stem cell transplant failed to cure her disease. Ut four days after taking Adcetris in a clinical trial, the unbearable itching that accompanied her disease vanished, she said. Eventually, so did the cancer. Ms. Blane, 40, has been in remission since her last dose in January 2011 and recently returned to work for the first time in seven years. Like Herceptin, T-DM1 binds to what is known as the KER2 protein and is meant to treat only the roughly 20% of breast cancer cases characterized by an abundance of that protein. In one trial involving 137 women, including Ms Saitowitz, T-DM1 proved both more effective and less toxic than a combination of of Herceptin and the chemotherapy drug docetaxel as an initial treatment for metastatic breast cancer. Those who received T-DM1 went a median of 14.2 months before their disease worsened, compare with 9.2 months for those getting the two-drug combination Yet only 46% of the T-FM1 patients suffered a severe side effect, half the rate of the other group. At the ASCO conference, researchers presented results of a pivotal trial involving nearly 1,000 women. Though armed antibodies are easy to enision, it has taken more than three decades to make them practical, with many failures along the way. With the first armed antibody to reach the market, Mylotarg, the toxin sometimes fell off the antibody prematurely, causing side effects. Approved in 2000 to treat ACUTE LYELOID LEUKEMIA, Mylotarg was removed from the market by its manufacturer, Pfizer, in 2010 after new studies showed it did not prolong lives and had safety problems. Since then, two antibodies linked to radioactive isotopes have been approved to treat NON-HODGKIN'S LYMPHOMA -- Bexxar from GlaxoSmithKline and Zevalin fro Spectrum Pharmaceuticals. These drugs, while effective, are more cumbersome to use than antibodies linked to chemical toxins. Researchers first tried to use existing chemotherapy drugs as the payloads, but they were simply not toxic enough. That is because less of a drug gets to the tumor when carried on an antibody than when the drug floods the body by itself. Seattle Genetics and ImmunoGen use toxins that are hundreds of times as potent as typical chemotherapy agents. They are too toxic to be given by themselves. The linkers have proved even trickier to develop since they must keep the toxin attached to the antibody while in the bloodstream, but then release the toxin insid the cancer cell. Dr. John Lamert, executive vice president for research and development at ImmunoGen, was in the audience at the cancer conference as the fruits of 30 years of work were presented. "To get to this point is a indescribable feeling, actually," he said. * * * MAYO CLINIC USES NEW APPROACH TO REVERSE MS IN MICE MODELS Mayo Clinic researchers have successfully used smaller, folded DNA molecules to stimulate regeneration and repair of nerve coatings in mice that mimic MULTIPLE SCLEROSIS. They say the finding suggests new possible therapies for MS patients. "The problem has been to find a way to encourage the nervous system to regenerate its own myelin (the coating on the nerves) so nerve cells can recover from an MS attack," says L. James Maher III, Ph.D., Mayo Clinic biochemist and senior author on the paper. "We show here that these small molecules, called aptamers, can stimulate repair in the mice we are studying." More than 200,000 people have multiple sclerosis. There is no cure and no effective therapy to stop progression or repair damage to the myelin sheath that surrounds and protects the nerves. Without that protection, nerve fibers will be damaged, leading to declining mobility and cognitive function, and other debilitating complications. MS researchers, including Mayo neurologist Moses Rodriguez, M.D., a co-author on this paper, have focused on monoclonal antibodies in mice to stimulate myelin repair. The Rodriguez and Maher teams, working together, have determined that the aptamers are not only effective, but they are easy and cheap to synthesize -- an important point for drug developers. They also are stable and not likely to cause an immune response. This new approach must be validated in other mouse models to see if it might be a candidate for human clinical trials. The monoclonal antibodies used in earlier research are large and complex, but were shown to promote both cell signaling and remyelination of central nervous system lesions in mice. The aptamers used in this study are less than one-tenth the size of antibodies and are single-strands of DNA containing only 40 nucleotide units. * * * Stay cool. * * * 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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