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Sunday, June 3, 2018

#ASCO18: Merck beats Roche in big squamous lung cancer survival numbers


Over the last few years, non-squamous non-small cell lung cancer data has grabbed most of the attention in immuno-oncology. Not this ASCO.
It’s the squamous form of lung cancer that’s in the spotlight this time, and on Sunday morning at the American Society of Clinical Oncology annual meeting, Merck & Co. was the star of the show, upstaging Roche with better data.
Both Roche and Merck rolled out positive numbers for their PD-1/PD-L1 checkpoint inhibitors in previously untreated squamous patients, setting them up for a marketplace battle. But Merck one-upped its rival by showing a larger benefit, as well as overall survival data that Roche doesn’t yet have.
Saturday, the Swiss pharma giant got the party started, unveiling results from its ImPower-131 study that showed its Tecentriq, when combined with chemotherapy, reduced the risk of worsening disease or death by 29% compared with chemo alone.
Sunday, though, Merck’s Keytruda, combined with chemo, showed it could cut that same risk by 44% and pare down the risk of death by 36%, according to data from the drugmaker’s Keynote-407 study. That’s a performance Roy Baynes, Merck SVP and head of global clinical development, called “truly remarkable.”

The numbers aren’t directly comparable, of course, because the studies were designed differently. “There were a lot of differences in the way these trials were run,” said Dan Chen, VP and global head of cancer immunotherapy development for Roche’s Genentech unit. And Baynes agreed that “there are all sorts of risks in doing cross-trial comparisons, not least of which” is that the patient populations weren’t exactly the same.
Still, pharma watchers will compare them, and some analysts expect Keytruda to leverage its data to prevail in the market showdown—especially given its positioning in first-line lung cancer on the whole. Right now, it’s the only member of its class to bear the FDA’s blessing for use in previously untreated patients,, and it has not one, but two approvals.

“Barring any surprises, we see Merck in a dominant position going forward,” Credit Suisse analyst Vamil Divan wrote to clients ahead of the data release.
Roche, for its part, eagerly awaits its chance to share overall survival data for the Tecentriq-chemo team in squamous lung cancer. While that data aren’t yet mature, “you can clearly see the start of that separation” in survival when the stats are charted, Chen said.
And in the meantime, he encouraged industry watchers to look at the body of evidence Tecentriq has so far produced across histologies and as part of different regimens.
“To date, all of these studies are positive,” he said. “I think that’s probably the better way to look at all of this.”
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#ASCO18: Array to update on Phase 3 melanoma trial


Array BioPharma Inc. (Nasdaq: ARRY) announced that it will present data from the Phase 3 COLUMBUS trial of encorafenib and binimetinib in advanced BRAF-mutant melanoma in an oral presentation on June 4, 2018, at the 54th Annual Meeting of the American Society of Clinical Oncology (ASCO) in Chicago, Illinois.
“Binimetinib and encorafenib is the first targeted therapy to demonstrate over 30 months median overall survival in a Phase 3 trial and we look forward to presenting the results from the COLUMBUS trial at ASCO,” said Ron Squarer, Chief Executive Officer. “With nearly 15 months median progression-free survival and an attractive tolerability profile, these data underscore the potential of this combination to become an important new treatment option for patients with BRAF-mutant advanced, unresectable or metastatic melanoma.”
As previously announced, the most common Grade 3/4 adverse events (AEs) seen in more than 5% of patients were increased gamma-glutamyltransferase (GGT) (9%), increased creatine phosphokinase (7%), and hypertension (6%) in the encorafenib plus binimetinib group.
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U.S. Supreme Court case could limit physician referral power


A case before the U.S. Supreme Court on how antitrust laws are enforced has the potential to affect health care in a way that would harm patient care and interfere with a physician’s duty to a patient to provide the best medical care.
The case before the nation’s highest court, State of Ohio et al. v. American Express Company et al., involves how a credit card company operates, although this may seem far removed from the practice of medicine, the underlying issue the justices are considering is how federal antitrust laws are applied. Their ruling could upend how the courts determine whether anti-steering provisions are violated under the Sherman Act.
If the nation’s highest court upholds a ruling by the 2nd U.S. Circuit Court of Appeals, it would mean dominant health insurers or dominant hospital systems could create contracts that include anti-referral rules that prohibit physicians from referring patients to out-of-network specialists for innovative or medically-necessary tests that would provide the patient with the best care. So argues an amicus brief the Litigation Center for the American Medical Association and State Medical Societies and the Ohio State Medical Association filed with the U.S. Supreme Court.
“Material interference with physicians’ medical judgments threatens physician autonomy, damages the doctor-patient relationship, decreases medical innovation and lowers the overall quality of patient care,” the Litigation Center brief states. “The antitrust laws have historically played an instrumental role in preventing such outcomes. This court should ensure that antitrust law’s vital role in health care continues.”

Why the ruling would impact medicine

Under the 2nd Circuit’s decision, it would be extremely difficult for a patient or physician to prove to a court that antitrust laws were being violated.
A plaintiff—whether that is the government, physician or a patient—would have to net out the harm to one group of consumers with the potential benefits to another group. For example, if a physician were barred from referring a patient to a particular specialist or if a patient were unable to obtain a particular test, the court would balance that harm against the speculative benefits to other patients and insurance subscribers, the amicus brief tells the court.
If the Supreme Court allows the lower-court decision to stand, “it would provide greater leeway for dominant entities to impose contractual restraints on a physician’s ability to refer their patients for care which the physician deems best in their medical judgment,” the brief states.
“Physicians will have no choice but to accept those restrains because rejecting them means turning away a large number of patients whom physicians would otherwise be able to serve, which is untenable from both a business and ethical standpoint,” the brief says. “Physicians would then have to weigh, against what they deem best for their patients, the consequences of their breaching their contractual obligations. It would be difficult for them to find recourse under the antitrust laws in such situations.”
Physicians would be prevented from making referrals based on their best judgment and on best medical outcomes for their patients, the Litigation Center and OSMA conclude. “In this way, these restrictions could be wholly at odds with the physician’s ethical responsibilities. And because such restrictions could limit quality and choice, they raise competitive concerns that the antitrust laws traditionally have proscribed,” they told the Supreme Court in their brief.
Justices heard oral arguments in February and a ruling is expected by the end of June.
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Becoming Their Own Doctors: Coping With Patient Requests in Information Age


Hello. I’m Dr Charles Vega, and I am a clinical professor of family medicine at the University of California at Irvine. Welcome to Medscape Morning Report, our 1-minute news story for primary care.
It probably comes as no surprise to primary care physicians to learn that the frequency with which patients come in asking for a specific intervention—a drug, a blood test, an imaging study—has increased over the past 30 years.
A large analysis of data from a Dutch primary care network, collected from 1985 to 2014, confirms this trend. Requests for lab tests or an imaging study more than doubled. A request for a specific drug was up more than 20%.
What may be surprising is the percentage of compliance with these requests, which also increased significantly. Physicians are complying 70%-100% of the time. The investigators attributed this increase to a greater sense of patient empowerment and easy access to medical information.
The question is: Is this trend positive or negative? It’s important to have empowered patients involved in active decision-making, but not every patient request is reasonable, or even safe. What do you think? Please use the comment button to voice your opinion on this new research.
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1-Hour Exercise, 3 Times a Week Boosts Cognition in Older Adults


Exercising for 52 hours over a 6-month period may be an optimal dose for cognitive improvement in older adults, a systematic review of 98 randomized clinical trials suggested.
Interventions that averaged 52 hours over a span of 6 months — averaging about an hour, 3 times a week — were linked to specific cognitive improvements in adults with and without cognitive impairment, reported Joyce Gomes-Osman, PT, PhD, of the University of Miami Miller School of Medicine, and colleagues in Neurology: Clinical Practice.
“The constructs of cognition that were most amenable to exercise were processing speed and executive function,” Gomes-Osman told MedPage Today. “This is an encouraging result because those two constructs are among the first that start to go with the aging process. “This is evidence that you can actually turn back the clock of aging in your brain by adopting a regular exercise regimen.”
Interestingly, statistical associations did not hold for memory improvement, noted Art Kramer, PhD, of Northeastern University in Boston, who was not involved in the study. “Despite the fact that animal studies have found robust memory benefits from exercise, memory benefits were not consistently observed in the human studies that were reviewed.”
Gomes-Osman’s group searched medical databases in December 2016 for randomized controlled trials that tested the effect of exercise on cognition. After a review of 4,612 relevant studies, they included 98 trials with a total of 11,061 participants in their review. Participants had an average age of 73 and 67.58% were female. Of the total sample, 59.41% of participants were classified as older healthy adults, 25.74% had mild cognitive impairment (MCI), and 14.85% had dementia.
The clinical trials assessed exercises that included walking, biking, dancing, strength training, tai chi, and yoga over spans from 4 weeks to 1 year. Most participants (58.2%) did not exercise regularly before enrolling in a study. Most studies used either high (37.8%) or medium intensity (36.7%) exercise.
Aerobic exercise, strength training, mind-body exercises like yoga and tai-chi, and combinations of exercises all were linked to improved cognitive skills in both healthy individuals and those with MCI. Only the total length of time over a 6-month period was linked to improved cognitive skills, not weekly exercise minutes.
“Although half of the exercise in the studies we assessed was in support of aerobic exercise, it doesn’t mean that aerobic exercise necessarily was more effective,” said Gomes-Osman. “It just means that more trials have actually studied aerobic exercise.”
Within aerobic exercise interventions, the most common exercise was walking, Gomes-Osman noted. “It’s encouraging to know that you don’t need to be running. If you start walking, you’re going to get benefit. But this is not window-shopping; this is walking. It’s physical exercise, not just physical activity.”
Since most participants did not exercise regularly before joining a trial, this data also “strongly supports that decreasing sedentary behavior is something associated with brain health,” Gomes-Osman said.
The effect of exercise on overall cognition is not clear because so few studies have assessed this, she added. And it’s possible that future trials — ones that compare different types of exercise, or evaluate exercise in both physically fit and sedentary people — may show different results.
Nonetheless, some cognitive benefit is clear. “I believe in giving people knowledge about outcomes,” Gomes-Osman said. “If you tell people to be active, they may be less interested overall than if you say ‘You can do this, this, this, or this, and you need to keep it up a couple times a week for about 6 months, and then you should get a benefit.’ I think that’s a better sell for patients.”
The study was supported by the Evelyn F. McKnight Institute at the University of Miami Miller School of Medicine.
Gomes-Osman and co-authors disclosed relevant relationships with Neosync, Starlab, Neuronix, Neuroelectrics, Constant Therapy, Cognito, and Novavision.
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Twice-weekly interferon called option in MS treatment


Among multiple sclerosis (MS) patients experiencing breakthrough disease on standard-dose once-a-week interferon beta 1-a (IFN-1α), switching to twice-weekly dosing may offer advantages, a researcher reported here.
More than half of patients with breakthrough disease and adequate follow-up (26/52 patients) who were switched to twice-weekly treatment had no further clinical relapses, new T2 lesions, or enhanced lesions on MRI, or worsening of Expanded Disability Status Scale (EDSS) during at least 14 months (range 14 to 192 months) of follow-up, according to Robert Baumhefner, MD, of the VA Greater Los Angeles Healthcare System.
He presented data on a 17-year experience treating MS patients with the twice-weekly dosage of intramuscular IFNβ-1a at the Consortium of Multiple Sclerosis Centers (CMSC) annual meeting.
Baumhefner told MedPage Today that standard practice for experiencing breakthrough disease on interferon treatment is to switch them to another drug. Eighteen drugs have been approved for the treatment of MS, but around half became available within the past decade.
“The long-term side effects of these newer agents are not known, so it might be advantageous to keep many of these patients — if they stabilize — on a drug that has been proven to be safe for 25 years,” Baumhefner said.
Several previous studies, including the PRISMS trial, have suggested a dose-response effect for IFN-β in the treatment of MS, but other studies have failed to show this. Baumhefner noted that prior studies have not addressed the strategy of doubling the IFN dosage and treatment schedule for IFN-treated patients with breakthrough disease.
A total of 107 MS patients were started on intramuscular IFNβ-1a at the MS clinic of the VA West Los Angeles Medical Center from 1995 to 2015, and 59 of these patients with breakthrough disease were switched to twice-weekly intramuscular IFNβ-1a. Fifty-two patients were followed for at least 2 years.
Patients were evaluated, on average, every 4 months. At each visit an interval history of any relapse, Incapacity Status Scale, Functional Systems Scale, Expanded Disability Status Scale (EDSS), and a proprietary graded neurologic examinations were obtained.
Annual MRI of the brain using a contrast-enhanced MS protocol was also obtained for most patients.
Breakthrough disease was defined as continued clinical relapses, new T2 or enhanced lesions on MRI, or worsening of EDSS or neurologic examination.
Five patients did not tolerate the increase in frequency of administration. IFNβ neutralizing antibody testing was performed on 25 patients while on twice-weekly dosing, and one patient who failed twice-weekly IFNβ had consistently elevated titers on two determinations (4%).
African-American patients, patients with a higher EDSS score when switching, and patients with a longer duration of stability on once-weekly treatment were less likely to respond.
Baumhefner said for many patients with breakthrough disease on standard IFNβ-1a, increasing the treatment dosage with twice-weekly therapy may be an acceptable alternative to switching treatments.
June Halper, MSN, MSCN, CMCS CEO, agreed, noting that “it makes a lot of sense for some patients to stay on a drug that has worked for them, and tweak the therapy if there is a breakthrough instead of automatically moving on to another drug,” she told MedPage Today.
Baumhefner said a prospective, blinded, randomized trial comparing once-weekly and twice-weekly intramuscular IFNβ-1a may be warranted.
Baumhefner disclosed no relevant relationships with industry.
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Baby Teeth May Predict Autism


Zinc and copper metabolism cycles in the layers of baby teeth may be able to predict which children will develop autism spectrum disorder, a longitudinal analysis suggests.
This is the first study to generate a 90% accurate fetal and early childhood biomarker of autism by tracking metabolic pathways over time and could lead to new diagnostic tools, reported Paul Curtin, PhD, of Icahn School of Medicine at Mount Sinai in New York City, and colleagues in Science Advances.
Using novel tooth-matrix biomarkers that directly measured uptake of elements, the researchers found that children who later developed autism had disrupted zinc-copper rhythmicity in utero or in their earliest months of life.
“We looked at the naturally shed teeth of children and explored them much as you would explore the growth rings of a tree, using them as a sort of retrospective biomarker to see what children were exposed to in the womb and in early life. When we derived measures of metabolic cycles and used machine-learning algorithms to predict which children would develop autism, we found out we were 90% accurate in our predictions,” he told MedPage Today.
Prenatal and newborn children form a new tooth layer daily, which captures an imprint of chemicals circulating in the body and produces a chronological exposure record. Zinc and copper pathways are central regulators of multiple metals; disruption of the pathways may have downstream effects that may affect the metabolism of other essential elements and toxic metals.
For this study, the researchers analyzed teeth from 193 participants in four case-control samples — a discovery population of twins from Sweden, two similar groups from the United States, and a birth cohort from the United Kingdom — using a laser ablation technique to sample each tooth at an average of 152 locations. “The data from the teeth we analyzed covered primarily the second and third trimesters through a few months after birth,” Curtin said.
In all four study sets and in the pooled analysis, zinc-copper rhythmicity was disrupted in autism cases. The autism cases had three quantifiable characteristics altered: the average duration of zinc-copper cycles, the regularity with which the cycles recurred, and the number of complex features within a cycle.
Using two different classification models, the researchers achieved 90% accuracy in classifying cases and controls, with sensitivity to autism diagnosis ranging from 85% to 100% and specificity ranging from 90% to 100%.
“These cycles haven’t been well documented in the past,” said Curtin. “Here we are showing they are critical to neurodevelopment and when they are disrupted, we find that disruption is linked to autism and in fact, can be used to predict autism.”
The study also represents a new direction in autism biomarker research, he added. While many studies have assessed exposure levels, this analysis examined cycles to see how metabolism might be disrupted.
“With this research, we are shifting the focus to looking at metabolic cycles to understand how children are processing nutrients, as opposed to just looking at their exposure to toxicants.”
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