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Saturday, April 6, 2019

Less-Intensive Therapy Impresses in AML for Older Patients

More than half of older patients with untreated acute myeloid leukemia (AML) had rapid attainment of complete remission with the combination of venetoclax (Venclexta) and low-dose cytarabine, data from a single-arm clinical trial showed.
The regimen led to complete remission with or without blood-count recovery in 44 of 82 patients, with a median time to first response of 1.4 months. The cohort had a median response duration of 8.1 months and median overall survival (OS) of 10.1 months.
Patients without prior exposure to hypomethylating agents (HMAs) had a higher response rate, longer response duration, and better survival, Andrew H. Wei, MD, PhD, of the Alfred Hospital in Melbourne, Australia, and co-authors reported online in the Journal of Clinical Oncology.
“The high remission rate, low early mortality, rapid induction of remission, and durable length of remission make the combination with venetoclax an attractive and novel treatment option for older adults not suitable for intensive chemotherapy,” the authors concluded.
The results added to preliminary findings reported at the 2017 American Society of Hematology meeting. Last last year, the FDA approved the venetoclax-cytarabine combination for older patients with AML. Supporting data for the application included the study conducted by Wei and colleagues.
“Some of these patients can have durable responses that can be extended for a long period of time,” said co-author Stephen A. Strickland Jr., MD, of Vanderbilt-Ingram Cancer Center in Nashville, Tennessee. “This is something we haven’t seen a whole lot of in this patient population.”
Patients with newly diagnosed AML have a median age of 68 and often are ineligible for intensive chemotherapy, leaving them with few effective less-intensive options. Partly because of limited expectations for treatment success, many older patients with AML do not receive leukemia treatment, the authors noted.
Members of the B-cell leukemia/lymphoma-2 (BCL-2) family promote cell survival in cancer cells, and BCL-2 mediates chemoresistance and enhances leukemic blast and progenitor cells, Wei and co-authors continued.
Venetoclax, a selective oral BCL-2 inhibitor, achieved an objective response rate of 19% as single-agent therapy for patients with heavily pretreated AML. Resistance to the drug may be mediated by pro-survival proteins, such as MCL1, which is downregulated by HMAs and cytarabine, both of which worked synergistically with venetoclax against AML in preclinical studies. A preliminary clinical trial of venetoclax combined with an HMA showed a 61% complete response rate in older patients with untreated AML.
For the current study, Wei and colleagues reported findings from a prospective phase Ib/II clinical trial involving patients ≥60 with untreated AML. The treatment regimen consisted of venetoclax 600 mg/day and subcutaneous low-dose cytarabine (20 mg/m2 on days 1 and 10 of 28-day cycles). Outcomes of interest included safety, tolerability, response rate, duration of response, and overall survival.
The study population had a median age of 74, 49% had secondary AML, 71% had prior HMA treatment, and 32% had poor cytogenetics. During the dose-escalation phase of the trial, no dose-limiting toxicities occurred at the phase II dose of 600 mg/day.
The most commonly reported grade ≥3 adverse events were febrile neutropenia (42%), thrombocytopenia (38%), and decreased white blood cell count (34%). The most common nonhematologic adverse events (all grades) were nausea (70%), diarrhea (49%), hypokalemia (48%), and fatigue (43%).
The authors reported that 45 patients had venetoclax dose interruptions related to adverse events, most often between 28-day cycles because of delayed neutrophil and platelet recovery. Six patients required venetoclax dose reductions, primarily because of thrombocytopenia.
The 54% rate of complete remission included remission with incomplete hematologic recovery in 28%. The highest rates of complete response occurred in patients with de novo AML, with intermediate-risk cytogenetics, and with no prior HMA exposure (71%, 63%, 62%, respectively). Patients with no prior HMA exposure had a median response duration of 14.8 months and median overall survival of 13.5 months.
Patients who achieved a complete response with or without complete hematologic recovery had an estimated 12-month survival of 73%, as compared with 5% for patients who had no response. The 12-month OS was 100% for patients who had complete response with hematologic recovery and 49% for those who had complete response with incomplete recovery. Most patients who achieved remission became transfusion independent.
Strickland said the “impressive” results compare favorably with reported outcomes achieved with intensive chemotherapy.
“The results with this regimen and with venetoclax and hypomethylating agents look just as good or maybe even better than some intensive approaches,” said Strickland. “The question we’re now having to ask … is should we be changing the paradigm of treatment and looking for lower-intensity therapy first.”
“That’s obviously very controversial and we don’t have head-to-head studies of the less-intensive route versus more intensive treatment options. I think the next step is to try and figure out whether we can do just as well with a low-intensity approach or what is the role or best-identified population for less-intensive therapy.”
AbbVie and Genentech provided financial support and participated in the design, study conduct, and interpretation of data, as well as writing, review, and approval of the manuscript.
Wei disclosed relationships with Amgen, Servier, Novartis, Celgene, AbbVie, Roche/Genentech, Pfizer, and Janssen. Multiple co-authors disclosed relationships with the pharmaceutical industry and other commercial interests.
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AstraZeneca, Merck, Myriad move to test BRACAnalysis in prostate cancer

After attesting to its use in ovarian, breast and pancreatic cancers, the trio of AstraZeneca, Merck & Co. and Myriad Genetics is now bringing the latters companion diagnostic to bear on metastatic castration-resistant prostate cancer.
In a phase 3 study, the BRACAnalysis CDx precision medicine test will be used to hunt for germline BRCA mutations in men eligible for the Big Pharmas PARP-inhibiting Lynparza therapy.
The clinical trial, estimated to wrap up in early 2021, could form the basis of an expanded premarket approval for the BRACAnalysis test in the population, according to Myriad.
AstraZeneca first began working with Myriad on Lynparza in 2007, and has since helped garner U.S. and Japanese approvals for the in vitro diagnostic in ovarian and breast cancersstarting in December 2014, when BRACAnalysis CDx became the first laboratory-developed test approved by the FDA.
Most recently, Japans Ministry of Health, Labour and Welfare approved the blood test in February as a companion diagnostic for first-line Lynparza maintenance therapy in advanced ovarian cancer. The FDA approved BRACAnalysis CDx in a similar indication last December in patients showing a complete or partial response to treatment with platinum-based chemotherapy.
But while the collaboration has led to advances in ovarian and breast cancer, there is a significant unmet medical need in men with metastatic castration-resistant prostate cancer and BRCA1/2 mutations, which is an area where the utility of PARP inhibitors is being explored,” Nicole Lambert, president of Myriad Genetics, said in a statement.
Another area is metastatic pancreatic cancer, where Lynparza and the BRACAnalysis test recently demonstrated positive results in a phase 3 study of patients with germline BRCA mutations following platinum-based chemotherapy.
While Lynparza was beating placebo in progression-free survivaland as the drug moves closer to becoming the first PARP inhibitor approved in pancreatic diseaseMyriads diagnostic showed it could successfully identify patients that would benefit from the treatment, and the company said it plans to file a supplementary approval application with the FDA.
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Pfizer gets EU nod for Tagrisso rival Vizimpro

Pfizers Vizimpro, a drug that could challenge AstraZenecas fast-growing Tagrisso in lung cancer, has been approved for marketing by the European Commission.
Vizimpro (dacomitinib) has been approved in the EU as a first-line, single-agent therapy for locally advanced or metastatic EGFR-positive non-small cell lung cancer (NSCLC), a similar indication to that cleared by the FDA last September.
Dacomitinib has been held up on its way to market significantly, mainly because two phase 3 trials of the drug reported in 2014, which assessed the drug as a second- or third-line treatment option in NSCLC, failed to hit the mark.
Undeterred, Pfizer ran a third trial called ARCHER 1050 that showed Vizimpro was able to extend progression-free survival (PFS) compared to AZs first-generation EGFR inhibitor Iressa (gefitinib), although it was associated with greater toxicity, including skin reactions and diarrhoea.
Now, with approval on both sides of the Atlantic, the drug can mount a stronger challenge against Tagrisso (osimertinib), Iressa, and other EGFR-targeted drugs including Roche/Astellas first-generation drug Tarceva (erlotinib) and Boehringer Ingelheims second-generation Giotrif (afatinib) in the market.
Tagrisso billed as a third-generation drug is already dominating the second-line EGFR-positive NSCLC market, with sales almost doubling to $1.86bn last year and the brand looking likely to become AZs biggest seller in 2019. AZ has been working hard to push Tagrisso into the first-line setting however, based on the results of its FLAURA trial, and seems to be making progress on that front.
Pfizers global president of oncology, Andy Schmeltz, told the Cowen & Co conference last month that there is still plenty of unmet medical need in the EGFR-positive NSCLC category, as the five-year survival rate is still only about 12%.
He acknowledged that the market is very competitive, but suggested Pfizer would be able to position Vizimpro as a first-line option that could then be followed by other EGFR-targeted drugs.
There is one factor that could make that slightly tricky though. The ARCHER 1050 trial design excluded patients with brain metastases, which is a common feature of this patient population, and AZ makes much of Tagrissos ability to cross the blood-brain barrier.
Meanwhile, the hope had been that one of the pivotal trials of Tagrisso and Vizimpro in first-line NSCLC would show a significant impact on overall survival (OS), a secondary endpoint, to help select a preferred option. As it has turned out, neither drug has been able to show a statistically significant on that measure so far.
There is however still some debate about the best order to deliver these drugs, as all EGFR inhibitors eventually succumb to resistance and lose their efficacy over time, and some oncologists have argued Tagrisso should be held in reserve rather than given first-line.
For Pfizer, the Vizimpro approval is another pillar in its bid to rebuild its oncology franchise that has been hit hard by competition to Xalkori (crizotinib) for ALK-positive NSCLC from Roches Alecensa (alectinib), Novartis Zykadia (ceritinib), and Takedas Alunbrig (brigatinib).
Last November, the drugmaker claimed FDA approval for Xalkori follow-up Lorbrena (lorlatinib) in second-line ALK-positive NSCLC and SMO inhibitor Daurismo (glasdegib) for acute myeloid leukaemia, while in October it got a green light for PARP inhibitor Talzenna (talazoparib) for advanced breast cancer.
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Amgen (AMGN) Could See $13 Benefit From NVS Breach – RBC

RBC Capital analyst Kennen MacKay reiterated a Sector Perform rating on Amgen (NASDAQ: AMGN) and sees potential for +$10-$13/share.
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Indivior: New Study Data in Patients with Opioid Use Disorder

Injecting opioid users may benefit from higher maintenance dose of SUBLOCADE™ (buprenorphine extended-release), a once-monthly injection for the treatment of moderate to severe opioid use disorder Indivior also reports results of study showing that therapeutic concentrations of buprenorphine reduce the magnitude of respiratory depression caused by fentanyl.

Indivior PLC (LON: INDV) today announced data from two new studies: the first provides insights into dosing of once-monthly SUBLOCADE™ (buprenorphine extended-release) injection for subcutaneous use (CIII) for the treatment of moderate to severe opioid use disorder in patients who inject opioids, and the second study reports on the impact of therapeutic plasma concentrations of buprenorphine in inhibiting the respiratory depression caused by fentanyl. The results were reported at the 50th Annual Conference of the American Society of Addiction Medicine (ASAM) in Orlando, Florida and follow yesterday’s announcement of results from the RECOVER™ study and the 18-month long-term safety study.
We are generating data to help the healthcare community and others understand the unique challenges faced by patients with opioid use disorder and potential ways to overcome them,” said Christian Heidbreder, Ph.D., Chief Scientific Officer of Indivior. “Addressing this crisis, one patient at a time, means having the necessary information to make individualized decisions about optimal use of medically-assisted treatment to support each patient’s recovery—including proper dosing and length of treatment.”
Opioid injection users may benefit from higher SUBLOCADE maintenance dosesThis post-hoc analysis investigated patterns of abstinence in both injecting and non-injecting opioid users who participated in the SUBLOCADE Phase 3 double-blind, placebo controlled pivotal trial and the subsequent SUBLOCADE open-label long-term safety study (12 months of treatment). Abstinence was defined as negative urine samples plus negative self-reports of illicit opioid use.
Injecting opioid users (based on self-reports) treated with the SUBLOCADE maintenance dose regimen of 300 mg remained in treatment longer and had a higher study completion rate than those treated with the 100 mg maintenance dose. Furthermore, the mean percentage abstinence (Weeks 10–25) was higher among injecting users treated and maintained with SUBLOCADE 300 mg (58%) vs. those maintained with SUBLOCADE 100 mg (43%); the difference in group means was 15%. Among non-injecting users, the percentage with continuous abstinence was the same (28%) in both dose groups.
These findings are consistent with previous reports that injecting opioid drug users may benefit from higher doses of methadone or buprenorphine.1,2 “Indivior is planning additional studies to further characterize the patients for whom a higher maintenance dose of SUBLOCADE may be warranted,” said Dr. Heidbreder.

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Livanova (LIVN) PT Lowered to $100 at Needham, Says Problems Temporary

Needham & Company analyst Mike Matson lowered the price target on Livanova (NASDAQ: LIVN) to $100 (from $120.

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Medicare for All could cut hospital revenues by 16%

Medicare for All could have consequential repercussions for hospital finances, according to a new JAMA report.

KEY TAKEAWAYS

Implementing a “Medicare for All” system that extends the current fee schedule to all patients would result in net revenue losses north of $150 billion.
Hospital profit margins would likely decline from a current average of 7% to a projected negative 9%, representing an annual loss of nearly $86 billion.
On increasing public insurer payment rates to 100%, JAMA calls the approach “very expensive,” adding that it would “do little to encourage hospital efficiency.”
Implementing a “Medicare for All” system that extends the current fee schedule to all patients would result in net revenue losses north of $150 billion for hospitals nationwide, according to a JAMA report released Thursday.
If Medicare for All is implemented, those at greatest risk are hospitals operating with costs significantly higher than the Medicare payment rate, according to the report.
Hospital profit margins would likely decline as drastically as revenues, from a current average of 7% to a projected negative 9%, representing an annual loss of nearly $86 billion.
Similarly, hospitals would expect to fleece 1.5 million clinical and administrative jobs to reduce labor costs in the event of projected revenues shortfalls resulting from Medicare for All.
The JAMA report found that even if hospitals sacrificed their profit margin as a buffer, more than 850,000 jobs would still be lost as a result of outstanding revenue shortfalls.
The findings come as Medicare for All continues to dominate conversation among healthcare policymakers, especially progressive leaders in the Democratic Party, including several presidential candidates who have made it a centerpiece of their respective campaign platforms.

The JAMA report found that expanding Medicare into essentially a single-payer model would adversely affect hospitals which have a disproportionate share of commercially insured patients.
Several variations of Medicare for All call for the eliminationof the private insurance market.
However, more than one-quarter of hospitals that report negotiating with private insurers as the greatest price pressure for the organization also indicate that costs are “7% below the national average and do not lose money treating Medicare beneficiaries,” according to JAMA.
And while Medicare for All would effectively increase payments rates from public insurers to 100%, JAMA calls such an approach “very expensive,” adding that it would “do little to encourage hospital efficiency.”
The report estimates that annual federal Medicare spending would increase $40.7 billion while state and federal Medicare spending would total $25.6 billion.
Last month, a similar study by Navigant examined the potential financial effects on hospitals due to various Medicare expansion policy proposals, including Medicare for All.

In its analysis, Navigant found a medium-sized, nonprofit, multi-hospital system with revenues of more than $1 billion and a current operating margin of 2.3% would see revenues decline by around $330 million under Medicare for All, representing a margin drop of just over 22%.
The JAMA report does highlight some possible positive outcomes from implementing Medicare for All, including that hospitals could find new ways to become more efficient, such as through incurring less debt, negotiating improved rates in supply chain operations, or foregoing planned capital expenditures.
The job losses may even be offset by growth in non-healthcare industries, according to JAMA, meaning reduced healthcare spending under Medicare for All could “could stimulate a growth in employment (or wages) outside of the healthcare industry.”
Still, hospitals leaders have remained openly skeptical about the potential benefits of enacting such a program, with American Hospital Association CEO Rick Pollak rebuffing itin February as a policy that could “do more harm than good to patient care.”
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