The US Supreme Court’s decision to uphold the Affordable Care Act but allow states to decide whether to expand Medicaid

 has raised a question in many states: Where political leaders have been opposed or split on President Obama’s healthcare reforms, is it smart or foolish to cover more people?

While Republicans oppose healthcare reform more often than Democrats, having a Republican in the state house has not always doomed Medicaid expansion. Arizona Governor Jan Brewer, who famously wagged her finger at Obama on an airport tarmac, nonetheless stared down legislators in her own party until they added 300,000 people to the rolls. For New Jersey’s Chris Christie, having a Democratic legislature made Medicaid expansion easier. However, neither Arizona nor New Jersey set up a state-run exchange to enroll people in health plans.

But in other states, philosophical opposition to expanding a government program and concerns about long-term costs forced full-blown rejection of Medicaid Expansion or, in the case of places like Arkansas, Iowa, and Pennsylvania, attempts at hybrid plans. Waivers would allow states to craft their own versions of Medicaid, most with elements of privatization and one, in Pennsylvania, that would require, for the first time, that most new recipients look for work.

On Friday, September 27, Arkansas Governor Mike Beebe received a phone call from US Health and Human Services Secretary Kathleen Sebelius that his state would be the first granted a waiver to pursue a so-called “private option,” which will allow state residents to use Medicaid dollars to subsidize coverage obtained through private insurance. Up to 6 states may pursue some form of Arkansas’ plan with 2, Iowa and Pennsylvania, filing waiver requests.

Beebe, a Democrat, said the waiver would allow about 218,000 Arkansans to receive private coverage. “Our actions have drawn positive attention from across the country, and now we will focus on getting this insuranceto the Arkansans who need it to lead healthier, more productive lives,” he said in a statement.

The Arkansas, Iowa, and Pennsylvania plans all feature free-market aspects to the expansion of coverage—a unique “hybrid” strategy palatable to Republican or conservative Democratic

legislators in their own states, and perhaps to conservative lawmakers elsewhere who have resisted expanding any government program.

  Indeed, at the recent Medicare-Medicaid conference sponsored by America’s Health Insurance Plans, Daniel Crippen, executive director of the National Governors Association, said absent the willingness of the Centers for Medicare & Medicaid Services (CMS) to approve hybrid plans, he did not foresee additional Medicaid expansion until after the 2016 election cycle. “If there’s more flexibility, the sooner the expansion will occur,” he said.

Lack of expansion translates directly into lack of coverage. In June, researchers estimated that if 14 states opted out of Medicaid expansion, as allowed by the 2012 Supreme Court ruling, 3.6 million fewer people would be insured than if all of the states participated. These states would lose out on $8.4 billion in federal transfer payments. Furthermore, uncompensated care could cost these states another $1 billion by 2016.

 In most instances, the states’ healthcare industries have been arguing loudly in favor of Medicaid expansion, based on the forecasts for greater revenues resulting from larger populations having coverage and seeking care. This has been putting state governments at odds with major local and regional businesses in largely Republican areas, an uncomfortable position for business-friendly elected officials.

If Pennsylvania’s waiver is approved by CMS, it would be the 26th state to expand Medicaid, and it could provide other hesitant state governors a usable pathway to not only cover more people and but also to accept federal assistance to take part in the program.

The common element of the hybrid plans is to use the health insurance exchange to increase coverage of the newly insured. Technically, this is not an expansion of Medicaid, though each state would use federal Medicaid dollars to provide subsidies to state residents who would, in turn, use the subsidies to purchase private insurance on the exchanges (now called the marketplace). This is also referred to as a “premium assistance” model.

This approach does not necessarily mean that low-income residents would obtain benefits equal to what they would have received in the traditional Medicaid program. This may be a key objection by critics and CMS alike. To address this gap, CMS would require the states to provide “wraparound coverage,” which would ensure that members have the same level of benefit as any Medicaid beneficiary. This includes paying for any plan cost-sharing requirements above and beyond Medicaid’s own out-of-pocket limits.

 In addition, CMS will require that new beneficiaries have a choice of at least 2 qualified health plans in the marketplace before the agency will approve any section 1115 waiver request.

Arkansas’ plan tightens its eligibility requirements for its state Medicaid program, leaving a greater share of the newly insured population to seek a plan on the exchange (income thresholds

would be ratcheted down to a mere 17% of the federal poverty level, covering those with incomes up to 138% of that benchmark). Arkansas will require those entering the program to use the marketplace to choose a health plan for coverage. If this were voluntary, a section 1115 waiver would not be necessary.

Sandra Cook, consumer assistance specialist for the Arkansas Insurance Department, described the private option as a “win-win” while appearing at Diabetes Innovation 2013, a conference sponsored in Washington, DC, by the Joslin Diabetes Center of Harvard. “Insurers have guaranteed payment for 250,000 lives in Arkansas,” she said, noting it will be at an insurance rate, not the Medicaid rate. This expansion of coverage into areas where the working poor live will encourage young doctors to locate in rural areas, she said, because they will be able to make a living. Private coverage, Cook said, doesn’t carry the “stigma” that some feel when they are on public assistance programs.

Pennsylvania seeks to address Medicaid expansion of the previously uninsured on many levels, including the use of premium assistance and private insurance plans, but notably, Governor Tom Corbett has added a provision onto the state’s section 1115 waiver request: that coverage is contingent on a beneficiary’s actively seeking a job. This may prove to be the most controversial part of Pennsylvania’s application.

Sharon Ward, executive director of the Pennsylvania Budget and Policy Center, issued a white paper September 27 that stated “Federal law and policy prohibit premiums in the Medicaid program for anyone under 100% of the (federal poverty level) and the conditioning of health care coverage on job search and training requirements. The Corbett administration will be applying for a waiver to suspend those provisions of the law. Where CMS comes down on these issues remains to be seen.”

Additionally, Corbett is seeking to keep children in the state Children’s Health Insurance Program, and out of the general Medicaid program, as directed by the ACA.7 It is not known whether these provisions may be deal-breakers for CMS.

According to the Kaiser Family Foundation, CMS is willing to consider these section 1115 waivers as demonstration projects, and as such, may grant approval to a limited number of requests.

Whether this policy continues will determine how many states get the opportunity to pursue waivers.

On September 16, Michigan’s Republican Governor Rick Snyder signed a law altering the state’s Medicaid program that uses similar principles. In the Michigan law, newly insured beneficiaries can receive their health benefits through private insurance plans (not necessarily through marketplace plans, however).

John Z. Ayanian, MD, MPP, from the Institute for Healthcare Policy and Innovation, University of Michigan, wrote in the 

, “The key Democratic goal of expanding Medicaid coverage to low-income adults will be implemented in tandem with Republican objectives to control the state’s healthcare costs, increase the role of private health plans, and require some new Medicaid enrollees to contribute toward the costs of their care.”

Crippen, of the NGA, said governors care about the quality of care, but they have no choice but to look for ways to control costs. “Until recently, states’ top spending item was education,” he said.

“Healthcare, and Medicaid in particular, has crossed that line and is now the most expensive program in the states. “Governors are looking very hard at the patients that cost the most, why

they cost the most, and how we can change those practice or patterns to reduce their costs,” Crippen said. Demonstration projects in states are just now bearing fruit, and governors will implement what they learn over the next few years, he said.

New Hampshire is another state with a Republican-controlled legislature but with a Democratic governor. Local news organizations have reported that the Republican-controlled state senate has formed a commission to determine if Arkansas’ premium assistance—based hybrid plan would work for the state.

New Hampshire Governor Maggie Hassan is seeking quick action, wanting to begin Medicaid expansion by the beginning of 2014 to take advantage of those enticing federal dollars.

1. Kaiser Family Foundation. Focus on health care reform: a guide to the Supreme Court’s Affordable Care Act Decision. July 2012. http://kaiserfamilyfoundation.files.wordpress 2013/01/8332.pdf Accessed October 7, 2013.

2. Radnofsky, L. Arkansas to use Medicaid funds to expand private coverage. The Wall Street Journal. September 27, 2013. http://online.wsj.com/news/articles/ SB10001424052702

304795804579101391947836048 Accessed October 7, 2013.

3. Leusbdorf B. N.H. Medicaid Expansion Study Panel Looks at Arkansas, Iowa Models. Concord Monitor. August 6, 2013. http://www.concordmonitor.com/news7013270-95/nh-medicaidexpansion-study-panel-looks-at-arkansas-iowamodels. Accessed September 24, 2013.

4. Price C, Eibner C. For states that opt out of Medicaid expansion: 3.6 million fewer insured and $8.4 billion less in federal payments. Health Aff. 2013;32:1030-1036.

5. Musumeci M. Medicaid expansion through premium assistance: key issues for beneficiaries in Arkansas’ section 1115 demonstration waiver proposal. Issue brief. Kaiser Commission on Medicaid and the Uninsured. July 2013. http://kff.org/medicaid/issue-brief/medicaid-expansion-through-premium-assistance-key-issues-forbeneficiaries-in-arkansas-section-1115-demonstration-waiver-proposal/. Accessed September 20, 2013.

6. Ward S. Pennsylvania Budget and Policy Center Website. Governor Corbett’s Healthy PA Plan: a summary. September 27, 2013. http://pennbpc.org/governor-corbett%E2%80%99s-%E2%80%98healthy-pa%E2%80%99-plan-summary Accessed October 7, 2013.

7. Worden A, Couloumbis, A, Brubaker H. Gov. Corbett to propose big changes to Pennsylvania Medicaid. Kaiser Health News. September 15, 2013. http://www.kaiserhealthnews.org/Stories/2013/September/15/Pennsylvania-Medicaid-Gov-Tom-Corbett.aspx. Accessed September 20, 2013.

8. Ayanian JZ. Michigan’s approach to Medicaid expansion and reform [published online September 25, 2013]. N Engl J Med.

Articles

Evidence-Based Oncology

New Approaches to Medicaid Expansion: Hybrid Plans Offer Alternatives for Covering More People

The US Food and Drug Administration (FDA) granted accelerated approval September 30 to pertuzumab (Perjeta) in combination with trastuzumab and docetaxel for patients with HER2-positive breast cancer in the neoadjuvant setting.

The vote was not a surprise, as it came after a 13-0 vote, with 1 abstention, on September 12 by the FDA’s Oncologic Drugs Advisory Committee (ODAC) in support of the drug combination.

This pertuzumab regimen is the first neoadjuvant regimen formally approved by the FDA for any type of cancer. The September 12 ODAC meeting was the first in which the committee was asked to consider recommending an oncologic drug for approval on the basis of pathologic complete response (pCR) as the primary end point in the pivotal clinical trials. The committee was asked to consider the question of whether pertuzumab demonstrated “a favorable benefit-to-risk evaluation for the neoadjuvant treatment of early breast cancer.”

“It’s not every day that this committee gets to consider a new indication in breast cancer,” said ODAC chair Mikkael Sekeres, MD, MS, associate professor of cedicine in the Department of Hematologic Oncology and Blood Disorders at the Cleveland Clinic Taussig Cancer Institute in Ohio. The ODAC and subsequent FDA votes could be precedent-setting and result in much earlier approvals for drugs in earlier disease settings. “Early disease is the setting where we can have the biggest impact on long-term survival,” Jose Baselga, MD, PhD, physician-in-chief at Memorial Sloan-Kettering Cancer Center in New York, told the ODAC panel.

Baselga served as primary investigator of the CLEOPATRA trial, which resulted in the FDA’s approval of this same pertuzumab regimen in the metastatic setting, and he is also a primary investigator in the APHINITY trial, which is evaluating the efficacy of this pertuzumab regimen in the adjuvant setting. He said that, typically, the time between a drug’s approval in the metastatic setting and its subsequent approval in an earlier setting is “simply much too long.”

He gave the examples of docetaxel and trastuzumab, where 8 years passed between the approvals of each drug in the metastatic and adjuvant settings, respectively. In the case of pertuzumab, Baselga said that its efficacy has been well established in clinical trials and will continue to be assessed in the APHINITY trial in the adjuvant setting, with results expected to become available in late 2016.However, Baselga indicated that an approval of pertuzumab in the neoadjuvant setting now, a full 3 years prior to when those results will become available, could have an immediate impact on patients. “In terms of survival, even though trastuzumab has had a profound impact, a substantial number of patients are still dying from HER2-positive disease,” Baselga said. “I feel strongly that we should make this therapy available to [patients] now.”

Much of the discussion among ODAC members concerned the potential precedents set by approving an oncologic drug in the neoadjuvant setting. The pivotal trials at the center of this supplemental biologics license application were relatively small compared with many of the clinical trials that have resulted in the approval of drugs for breast cancer in the metastatic setting, enrolling on the order of a couple of hundred patients as opposed to multiple thousands of patients.

Therefore, these trials were not powered to determine survival information. Despite several meta-analyses showing an association between pCR and survival benefits, no definitive answer has been derived from these studies as of yet. “We shouldn’t be assuming what the survival will be when the study is not powered to show that,” said Antonio Tito Fojo, MD, PhD, program direc-tor of medical oncology at the National Cancer Institute and one of the members of ODAC. Fojo abstained from the September 12 vote.

Among the concerns raised by other members of ODAC were the fact that the benefit may be more pronounced in hormone receptor-negative patients; whether docetaxel will be the chemotherapy that oncologists prefer to use with pertuzumab and trastuzumab should the regimen receive approval; and what long-term toxicities might be demonstrated when more data become available. However, in addition to the way the regimen may affect individual patients, Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, asked ODAC to consider the potential benefits to society as a whole if the drug, once approved, did indeed reduce the disease burden in patients with early stage, HER2-positive breast cancer.

The results of 2 trials were at the center of much of the discussion: the NEOSPHERE trial and the supportive TRYPHAENA trial. In the NEOSPHERE trial, a multicenter, open-label, phase II study treatment-naïve patients with HER2-positive breast cancer were randomly assigned in a 1:1:1:1 ratio and stratified by operable, locally advanced, and inflammatory breast cancer as well as hormone receptor expression.

 These patients received 4 neoadjuvant cycles of either trastuzumab (8 mg/kg loading dose, followed by 6 mg/kg every 3 weeks) plus docetaxel (75 mg/m

 every 3 weeks; n = 107; group A); pertuzumab (loading dose 840 mg, followed by 420 mg every 3 weeks) in combination with the group A trastuzumab and docetaxel regimen (n = 107; group B); the pertuzumab and trastuzumab regimens without docetaxel (n = 107; group C); and pertuzumab plus docetaxel (n = 96; group D). The primary end point of the study was pathological complete response (pCR).

Patients who received the combination of pertuzumab, trastuzumab, and docetaxel had a pCR rate of 45.8% (95% confidential interval [CI], 36.1-55.7), a significant improvement over patients who received trastuzumab and docetaxel without pertuzumab, who had a pCR rate of 29% (95% CI, 20.6 -38.5; P = .014). The pCR rates for the remaining 2 groups were 24% in those who received pertuzumab and docetaxel without trastuzumab (95% CI, 15.8-33.7), and 16.8% in patients who received pertuzumab and trastuzumab (95% CI, 10.3-25.3).The most common grade 3 or higher side effects observed in the 4 groups were neutropenia (61, 48, 1, and 52 patients in the 4 groups, respectively), febrile neutropenia (8, 9, 0, and 7, respectively), and leukopenia (13, 5, 0, and 7, respectively).

The number of adverse events was similar in the 3 groups (A, B, and D) that received chemotherapy as part of their treatment regimen, with 15 to 20 serious adverse events per group in 10% to 17% of patients, but was much lower in group C, which did not receive chemotherapy (4 serious adverse events in 4% of patients).

The results of the TRYPHAENA trial were presented at the 2011 CTRC-AACR San Antonio Breast Cancer Symposium, 2 and updated safety results were recently published in the journal Annals of Oncology. This study was a phase II, multicenter, open-label study that enrolled 225 patients with operable, locally advanced, or inflammatory breast cancer. Patients were randomized in a 1:1:1 ratio to receive 6 neoadjuvant cycles every 3 weeks. The first group, Arm A, received a regimen of 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) followed by docetaxel, with trastuzumab and pertuzumab given concurrently throughout the treatment. Arm B received FEC followed by docetaxel plus trastuzumab and pertuzumab. Arm C received docetaxel and carboplatin plus trastuzumab and pertuzumab.

After patients were treated with neoadjuvant therapy, they underwent surgery and continued on trastu-zumab until they completed 1 year of treatment. The study was not powered to compare the 3 study arms. The study found that the pCR rates were 61.6% in the concurrent group (A), 57.3% in the sequential group (B), and 66.2% in the anthracycline-free arm (C). The most common severe adverse events (AEs) observed in the 3 arms were neutropenia (47.2%, 42.7%, and 46.1%, in the 3 arms, respectively), leukopenia (19.4%, 12.0%, and 11.8%), and febrile neutropenia (18.1%, 9.3%, and 17.1%). Additional high AE rates observed with the anthracycline-free arm included anemia (17.1%), thrombocytopenia (11.8%), and diarrhea (11.8%).

While these studies served as the primary basis for the September 12 ODAC vote, a combination of other studies, including the results of the CLEOPATRA trial in the metastatic setting as well as evidence supporting the use of pCR as an end point, served as the basis for the overwhelmingly positive vote. “We need to look at the totality of the evidence…and not just one study,” said Gary Lyman, MD, MPH, professor of Medicine and director of comparative effectiveness and outcomes research at Duke University School of Medicine and the Duke Comprehensive Cancer Center, and a temporary voting member of ODAC.

The ODAC members stressed to Genentech, the drug’s manufacturer, that they are very interested in the results of the APHINITY trial. If the pertuzumab regimen is approved by the FDA but the results of the APHINITY trial are negative, ODAC recommended that the company voluntarily withdraw pertuzumab from the market for use in this neoadjuvant setting. With many members of the public commenting on the life-changing experiences they had with pertuzumab, and others commenting on the need for earlier treatment options, the company is viewing the September 12 decision as a positive step in the future of this drug.

“More than 6000 people in the United States die of HER2-positive breast cancer each year,” said Hal Barron, MD, chief medical officer and head, Global Product Development. “The ODAC’s

recommendation is a step toward bringing Perjeta to people with HER2-positive, early-stage breast cancer, where treatment can potentially prevent the disease from returning and spreading.”

1. Gianni L, Pienkowski T, Im Y-H, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomized, multicenter, open-label, phase 2 trial. Lancet Oncol. 2012;13(1):25-32.

2. Schneeweiss A, Chia S, Hickish T, et al. Neoadjuvant pertuzumab and trastuzumab concurrent or sequential with an anthracyclinecontaining or concurrent with an anthracyclinefree standard regimen: a randomized phase II study (TRYPHAENA). 2011 CTRC-AACR San Antonio Breast Cancer Symposium; December 6-10, 2011; San Antonio, Texas. Abstract S5-6.

In Historic Vote, FDA Backs Perjeta for Pre-surgical Breast Cancer Treatment

Just 3 governors made the Modern Healthcare Top 100 list for 2013, and Louisiana’s Bobby Jindal was among them.

 Jindal was included among the most influential weeks before the start of open enrollment under the Affordable Care Act, which featured elements he refused to roll out in his state. Louisiana would not have its own exchange to sign up enrollees, nor would it expand Medicaid.

That second decision has drawn loud and sustained criticism, given Louisiana’s history of poverty, health disparities, and cancer, much of it linked to oil and chemical interests along the Mississippi River. The corridor between Baton Rouge and New Orleans has long been called “cancer alley,” with many researchers noting the proximity of toxic emissions and cancer clusters among the poor.

Jindal didn’t just opt out of Obamaacare. He crusaded against it, writing op-eds in national publications. As an alternative, he designed a path of privatization to deliver care to the poor, one that retains some elements of Louisiana’s famous two-tiered hospital system while shedding others. Before Jindal’s trusted health and hospitals secretary, Bruce Greenstein, resigned following a scandal, the two brought privatization and managed care elements to Medicaid as well.

While privatization has both fans and critics—it has already resulted in the Louisiana State University hospital system laying off more than 1500 employees

— the bigger tumult came over Jindal’s denial of Medicaid to at least 214,000 Louisianans who might be eligible under the ACA.

 What outrages critics is Jindal’s perceived departure from his original plan, “Louisiana Health First,” unveiled in November 2008.

That blueprint, which came as Louisiana crawled back from Hurricane Katrina, called for expanding Medicaid to more caretakers of eligible children, or at least more additional low-income persons with chronic conditions.

 Offering the poor healthcare choices and providing preventive care at medical homes were seen not as dreams but possibilities, given Jindal’s expertise as a state and federal health official.

As Jindal built a modern academic medical center to replace New Orleans’ battered Charity Hospital, it seemed he would build a healthcare delivery system to match. The announcement came as 4 institutions—Ochsner Health System, and Tulane, Xavier and LSU&mdash; began to show the fruits of investing tobacco tax dollars on the LouisianaCancer Research Consortium (LCRC).

Among its goals, the consortium seeks better screening and earlier diagnosis, to combat a phenomenon common among the poor: cancer mortality is worse than cancer incidence, because too often patients are not seen until their disease has progressed beyond a point where it can be treated effectively.

• In 2011, approximately 22,780 new cancer cases were diagnosed in Louisiana, excluding some skin cancers and carcinomas.

• About 8360 people living in Louisiana died from cancer during 2011.

• Although cancer mortality is improving, rates in Louisiana remain about 30% higher than the rest of the country.

Beyond the political and media uproar, some amazing things are happening in cancer care in Louisiana. The growth of the New Orleans—based Ochsner Health System, its relationships with the state’s medical schools, and its decision to take over struggling institutions has allowed personalized medicine and cancer treatment pathways to take hold in places where change can

Ochsner, LSU, and Tulane collaborate through LCRC, and Ochsner is moving beyond treatment trials to preventive ones for breast and prostate cancer, 

 diseases that hit harder than normal here. So what’s the concern? While Jindal’s approach to upending Louisiana’s one-of-a-kind charity care system could spur even more collaboration, the failure to expand Medicaid means not everyone with cancer will get the same access, at least not now.

Over the past year, the big healthcare story in Louisiana has not involved cancer or the Affordable Care Act. It’s been about the transformation of Louisiana’s unique charity hospital system, which dates to 1736 and flourished under the populist governor Huey P. Long. Under Jindal, 9 of the state’s 10 charity institutions will convert from LSU management into public-private partnerships.

Five such partnerships are in place, with the remaining 4 set to begin in 2014. Proponents, led by Jindal, say the new system will reduce costs, improve care for patients, and offer better training for medical students. In an editorial published in July, Jindal claimed the partnerships were “on target” to save $125 million this year.

Certainly, there is much in Louisiana’s old system to be desired; an Institute of Medicine study released in August found 6 of the 10 highest cost cities for Medicare were in Louisiana.

 (Among the cost drivers was a need to shed retirement obligations for the thousands of public employees in the hospital system; Jindal stated that the changes would wring out $82 million in annual savings.)

For decades, critics of Louisiana’s charity hospital system asked whether the poor were best served with a system of healthcare segregation. The new arrangement does not fully dismantle the divide; the poor are still in separate facilities, but through partnerships these hospitals are now buttressed with private funding, management, and clinical expertise. Some critics predict private partners are biding their time and will absorb losses from the safety-net hospitals until Jindal leaves office, when Louisiana will expand Medicaid.

The partnerships are quite complex. Louisiana retains ownership of safety net hospital buildings, while the private partnership manages them and pay the state lease payments. In return, the private partners receive a share of Medicaid funds, starting with a guaranteed amount.

An interview with 2 top Ochsner physicians revealed the pluses and minuses of Jindal’s approach: Ochsner’s partnership with Leonard J. Chabert Hospital in Houma, Louisiana, gives that safety net hospital access to management and medical expertise it might otherwise lack. According to Ochsner Executive Vice President and Chief Medical Officer Joseph E. Bisordi, MD, FACP, Chabert is run just like any other hospital in Ochsner’s system. Thus, the partnerships can provide a different level of “access” for cancer patients who have coverage through Medicare or Medicaid. But therein lies the issue. For patients with incomes between Medicaid eligibility levels and 133% of the federal poverty line, “I am not sure we have an answer for those folks,” said John Cole, MD, who is Ochsner’s chair for hematology and oncology.

Steve Spires, health policy analyst for the Louisiana Budget Project, a nonpartisan research organization, said that the failure to expand Medicaid has longterm implications for the public-private partnerships, because state taxpayers will continue to experience the fallout of sick people overwhelming hospitals instead of seeking preventative care or catching cancer when it is treatable.

“The taxpayers will end up paying for this care,” Spires said. With cancer in particular, he said, “They will end up paying more than if we had paid for the preventive screening up front.”

The refusal to expand Medicaid frustrates those who have seen positive developments in healthcare over the past decade, including efforts to expand coverage for uninsured children and increase cancer screenings. A decade ago things seemed on the upswing, when Louisiana’s Legislature approved a tobacco tax to create the LCRC and seek a National Cancer Institute (NCI) designation within the state by promoting clinical trials.

Donna Williams, MPH, DrPH, has had a front-row seat for the decline in breast cancer mortality over the past decade.As director of Louisiana Cancer Control Programs for the LSU School of Public Health, she knows that early detection saves lives, because she has the data to prove it.

In 1995, the breast cancer screening rate in Louisiana for African American women was 59.1%, compared with a national average of 70.2%, putting Louisiana 48th among the states. LSU’s screening program launched in 2002, and data from the Centers for Disease Control and Prevention (CDC) revealed an immediate, steep drop in mortality among African American women, which later reversed somewhat after the massive population shifts following Hurricane Katrina.

By 2010, Williams said, Louisiana ranked 22nd among the states for 2-year mammography screening, with a rate of 76.3%, slightly higher than the national average of 75.2%. Louisiana screened 78.3% of African American women in 2010, compared with a national rate of 78.9%.10 Breast cancer mortality rates for all women remain well below 2002 levels, according to CDC data. (Figure 1.)

 But the good news with breast and cervical cancer is not repeated in other cancers, Williams said. Many whospoke with 

 decried Louisiana’s low eligibility levels for Medicaid, which typically leave the uninsured with long waits for care once cancer is diagnosed, assuming it is diagnosed in time.

As Williams and others explained, federal law requires Medicaid coverage once breast or cervical cancer is diagnosed. “They have fast-track qualification,” Williams said. “It’s a 2-pager; the providers attach the medical documentation and it goes through in less than 2 weeks.” By contrast, “If you have prostate cancer, you’re out of luck,” she said. “We don’t have any programs specific to the other cancers.” Much will depend on where a patient lives; those who use New Orleans’ current replacement for the defunct Charity Hospital fare comparatively well to those in remote areas, Williams said. Those familiar with the experiences of Louisiana’s uninsured say long waits and travel times can be as deadly as the cancer itself.

“People die as a consequence of this. That is not an exaggeration,” said Moriba Karamoko, director of the Louisiana Consumer Healthcare Coalition. “You can say people have access to oncology lists, but if the waiting list is so long and people die waiting, what kind of access do people really have?”

The Louisiana lifestyle, one that appreciates drinking, smoking, relaxing, and enjoying rich food (often fried), seems almost tailor-made to promote the kinds of cancers that are common in the state: lung, prostate, colorectal. Overlay an impoverished population, with demographics that tilt toward obesity, diabetes, and other risk factors associated with cancer, and it’s not a surprise that the state’s numbers are so high.

But another factor has been at work for decades: Louisiana’s relationship with industry. Because there are so many demographic and lifestyle factors in play, it has been impossible to prove that oil, gas, and chemical interests are responsible for even higher cancer incidence rates in certain areas of the state. The proximity of industry to cancer clusters in certain zip codes along the Mississippi, as well as western parishes like Cameron and Calcasieu, has long been noted.

Wilma Subra, a Louisiana native and winner of a MacArthur “genius” grant, gave up a career as a chemist for Gulf South Research 30 years ago. She founded a company to gather the science in support of residents who believed toxins from the plants near their homes were making them sick. She was able to document how the burning of toxic waste as fuel contributed to a spike in neuroblastomas in Amelia, Louisiana, and a judge ordered the facility closed.

that she has seen elevated levels of lung, brain, and organ cancers in areas where concentrations of polyvinyl chloride “are way over acceptable standards.” For years, she has worked with residents of Mossville, Louisiana, a community of mostly African Americans surrounded by chemical plants.

Subra says she’s no expert on healthcare policy, but the people she works with need more than they are getting. “We have a desperate need for medical care due to the toxic exposure,” she said. Young doctors rotate in and out, and they don’t always understand what they are seeing. She would like to see toxicologists on hand permanently; specialists are needed to treat the complex conditions that patients experience. But that requires money; either direct funding, or residents with Medicaid or health insurance.

“The community thinks there should be a free clinic,” Subra said. “But when you say ‘free’ industry goes beserk.”

For decades, if you lived in Louisiana, or on the Gulf Coast of Mississippi or Alabama, and your doctor said, “Cancer,” the next word was, “Ochsner.”

The renowned clinic was founded by Alton Ochsner MD, who was among the first to document the link between cancer and cigarette smoking; despite being criticized for this pronouncement, he opened the first group medical practice in New Orleans in 1942.

By fate of geography, Ochsner did not flood in 2005 during Hurricane Katrina and was able to stay open to serve residents after other hospitals went dark. Already a growing presence in Louisiana, it bought 3 hospitals in 2006,

cementing a strong “system” that Bisordi said will be key to delivery cancer care going forward. “One of the advantages we have as a system that you may not have as a small community hospital, you don’t have the structure to be more efficient. We have the resources in our system,” he said.

In addition, Ochsner enjoys good collaborative relationships with LSU and Tulane medical schools, which have programs to boost minority participation in clinical trials, Bisordi said. “Some of the patient samples from clinics at Ochsner go for analysis at LSU,” he said. Today, Bisordi and Cole say their goal is to keep patients as close to home as possible for cancer care. Ochsner does more clinical trials by far than any other cancer center in Louisiana—Bisordi said about 6% of the 2600 new cancer patients who come through its system participate in one. Yet not all come to the main hospital on Jefferson Highway, right outside New Orleans. “Our thinking with the community hospitals is, ‘We don’t want the folks you can take care of.’ Cole said, “care is best delivered closest to home.”

Cole said the Ochsner system is developing consistent, evidence-based pathways for cancer care delivery, which will be shared at the community level with all hospitals and clinics. This is the expressed goal of the Affordable Care Act—to promote cost savings by developing measurable methods to provide care, not by withholding it. If cancer care delivery improves, but a group of Louisianans lacks the means to receive it, what happens?

The Rev. Fred Kammer SJ, a Jesuit priest, Yale-educated lawyer and the former head of Catholic Charities USA now based at Loyola University New Orleans, has written about Medicaid expansion. He said that the discussion of the issue remains elevated among opinion leaders in the state. “It’s a scandal,” he said.

As the exchanges opened, Spires, of the Louisiana Budget Project, agreed. “Once people see the inequity, that people below the 133% of the poverty line get nothing, it’s going to turn up the heat. It’s by no means an issue that’s going to go away.”

1. 100 Most Influential People in Healthcare 2013. Modern Healthcare. August 24, 2013. http://www.modernhealthcare.com/gallery/20130824/PHOTO/824009999/PH&Params=Itemnr=70&Template=galleryzoom Accessed 0ctober 7, 2013.

2. Billings, FT. Cancer corridors and toxic terrors—is it safe to eat and drink? Trans Am Clin Climatol Assoc. 2005;116:115-125.

3. Jindal health secretary resigns amid investigation. March, 30, 2013. Associated Press, via Modern Healthcare. http://www.modernhealth care.com/article/20130330/INFO/303309964. Accessed October 7, 2013.

4. Selvam A. Louisiana’s health system sees massive layoffs. Modern Healthcare. July 18, 2013. http://www.modernhealthcare.com/article/20130718/blog/307189996 Accessed October 7, 2013.

5. Medicaid expansion could help thousands of uninsured Louisiana residents: Editorial. The Times-Picayune. September 15, 2013. http://www.nola.com/opinions/index.ssf/2013/09/medicaid_expansion_could_help.html Accessed October, 7, 2013. (Note: This editorial quotes a state projection of Medicaid expansion at 214,000. Estimates varied; some were in excess of 500,000.)

6. Louisiana Department of Health and Hospitals. Louisiana Health First. November 14, 2008. http://host.antaresnet.com/cabl/uploads/47.pdf. Accessed October 7, 2013.

7. Louisiana Cancer Research Consortium Website. http://www.louisianacancercenter.org/about-lcrc. Accessed August 24, 2013.

8. Jindal B. A new era for health care in Louisiana. Baton Rouge Daily Report. July 25, 2013. http://www.businessreport.com/apps/pbcs. dll/article?AID=/20130725/BUSINESSREPOR T02/130729879&template=printart. Accessed October 7, 2013.

9. Catalanello R. 6 Louisiana cities among 10 most expensive for health care, report says. The Times-Picayune. August 3, 2013. http://www. nola.com/health/index.ssf/2013/08/six_louisiana_cities_lead_the.html. Accessed October 12, 2013.

10. Behavioral Risk Factor Surveillance System data, Centers for Disease Control and Prevention. http://statecancerprofiles.cancer.gov/risk/index.ph.

Status in the States: In Louisiana, Will Privatization Affect Efforts to Stop Cancer?

Last month, the US Food and Drug Administration (FDA) granted Priority Review to dabrafenib (Tafinlar) and trametinib (Mekinist) as a combination treatment for patients with unresectable or metastatic melanoma with a BRAFV600E/K mutation.

According to a September 16 statement from the drugs’ manufacturer, GlaxoSmithKline, the FDA has set target dates in early January 2014 to review the trametinib and dabrafenib supplements. The drugs were approved simultaneously as single agents earlier this year.

Each drug treats melanoma through a different mechanism of action. Dabrafenib is a BRAF inhibitor approved to treat patients who express the BRAFV600E mutation, while trametinib, a MEK 1/2 inhibitor, is approved to treat patients with either the BRAFV600E or BRAFV600K mutation. Both drugs act on the RAS kinase pathway, dabrafenib at an earlier point than trametinib. A patient will typically develop resistance to dabrafenib monotherapy after about 5 to 7 months. The addition of trametinib helps overcome the tumor’s resistance mechanism, allowing for a more durable response to treatment.

The Priority Review was granted based on the results of a randomized phase I/II study that compared combination therapy with dabrafenib and trametinib with dabrafenib monotherapy in adult patients with BRAFV600E/K mutation-positive metastatic melanoma. According to the study that was published in the New England Journal of Medicine, progression-free survival (PFS), response rate, and duration of response favored the combination of dabrafenib and trametinib compared with single agent dabrafenib for patients with BRAFV600E/K—positive metastatic melanoma.

The phase II study randomized 162 patients with BRAFV600E/K—positive metastatic melanoma to 1 of 3 treatment arms: monotherapy with dabrafenib at 150 mg/BID; combination of dabrafenib at 150 mg/BID plus 1 mg of once-daily trametinib; or concurrent full doses of both drugs (dabrafenib at 150 mg/BID; once-daily trametinib at 2 mg). The median PFS for patients who received the full-dose combination was 9.4 months, as compared with 5.8 months with dabrafenib monotherapy (hazard ratio for progression or death, 0.39; 95% confidence interval, 0.25 to 0.62; P <.001).

Side effects associated with MEK inhibitors, including peripheral edema, hypertension, decreased cardiac ejection fraction, and ocular events, had a higher occurrence in the combination therapy, while side effects associated with BRAF inhibitors of hyperproliferative skin lesions occurred less frequently in the combination group compared with the monotherapy group.

In February 2013, the global phase III COMBI-AD study began, aiming to analyze the combination of dabrafenib and trametinib as adjuvant therapy for patients with melanoma.

The study will evaluate whether the combination of agents can delay or prevent the recurrence of melanoma (Relapse Free Survival) in patients with Stage IIIa, IIIb, or IIIc BRAFV600E/K mutation-positive melanoma that has been completely removed by surgery. The study will also evaluate the safety profile of the dabrafenib-trametinib combination in this treatment setting. “The patients included in this trial are at high risk of their melanoma returning after surgery and there are currently few treatment options to reduce this risk,” Rafael Amado, MD, head of Oncology Research and Development for GlaxoSmithKline, said in a statement when the trial was announced.

“Given the efficacy and safety findings observed with combined dabrafenibtrametinib treatment in the metastatic setting, we are investigating whether the combination administered after surgery can help these patients live longer without melanoma recurrence.” There are 2 additional phase III studies ongoing, aimed to evaluate the combination of dabrafenib and trametinib for patients with metastatic BRAFV600 melanoma.

1. Flaherty KT, Infante JR, Daud A, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012; 367:1694-1703. doi:10.1056/NEJMoa1210093

Melanoma Combination Granted Priority Review Designation by FDA

The novel polo-like kinase 1 (PLK1) inhibitor volasertib in combination with low-dose cytarabine (LDAC) received a breakthrough therapy designation September 17 from the US Food and Drug Administration (FDA) for its potential as a treatment for patients with untreated acute myeloid leukemia (AML) who are ineligible for intensive remission induction therapy.

PLKs function as important regulators of the cell cycle and are involved in the activation of cyclin-dependent kinases and maintenance of genomic stability. In preclinical evidence exploring the PLK family, PLK1 was identified as holding the most potential for targeted cancer therapies, since it is commonly overexpressed in many tumor types. As an antimitotic target, PLK1,

which is only expressed in dividing cells, plays an essential role throughout many stages of mitosis. As an antagonist of PLK1, the first-in-class agent volasertib is thought to induce mitotic arrest and apoptosis in cancer cells.

The FDA’s breakthrough therapy designation will help expedite Boehringer Ingelheim’s development of volasertib. The program is intended to potentially speed up the review process for treatments for serious or life-threatening conditions. This relatively new designation provides similar benefits to the FDA’s fast-track designation, although the 2 are separate programs. Unlike the fast-track designation, a breakthroughtherapy must demonstrate preliminary clinical evidence and represent a substantial improvement over available therapies.

“This FDA breakthrough therapy designation provides Boehringer Ingelheim the opportunity to engage in an ongoing dialogue with the FDA to help expedite the development of volasertib as a potential treatment option for these patients with AML,” said Sabine Luik, MD, the senior vice president of Medicine & Regulatory Affairs and the US regional medical director for Boehringer Ingelheim Pharmaceuticals, Inc, in a statement issued by the company.

The breakthrough therapy designation was granted based on results from a phase II study presented at the 2012 American Society of Hematology annual meeting. In this study, patients with previously untreated AML who were ineligible for intensive treatment were randomized to receive either intravenous volasertib in combination with LDAC or LDAC alone. Preliminary results from the trial demonstrated significant improvement in the primary end point of objective response (measured as complete remission (CR) or CR with incomplete blood count recovery (CRi).

Additionally, a trend was observed in favor of the combination for the secondary end point of event-free survival (EFS).

 In the study, 87 patients were randomized in a 1:1 ratio to receive volasertib plus LDAC (n = 42) or LDAC alone (n = 45). Treatment was repeated every 4 weeks until progression for a median of 2 cycles. The maximum tolerated dose for volasertib of 350 mg was administered on days 1 and 15 and LDAC was administered at 20 mg twice daily subcutaneously on days 1 to 10. The median age for patients in the trial was between 75 and 76 years.

At the time of the analysis, 31% of patients receiving the combination achieved a CR or CRi compared with 11.1% in the control arm (odds ratio 3.59; 95% CI, 1.15-11.18]; P = .0277).

The median time to remission in the volasertib arm was 71 days compared with 69 days in the control arm. A trend toward an advantage in EFS was observed in the volasertib arm, with a median EFS of 169 days compared with 69 days for patients who received LDAC alone (hazard ratio [HR] = .61; 95% CI, 0.35 - 1.05; P = .0725). At the time of the analysis, the secondary end point of overall survival was not yet available, since only 2 patients had experienced recurrence or death. In total, the remission duration with the combination was 53 to 407 days compared with 32 to 282 days with LDAC alone. Adverse events were more frequent with the combination of volasertib and LDAC and were in line with those expected with the agent’s myelosuppressive mechanism of action. However, early death rates were similar between the 2 arms at 30, 60, and 90 days.

The most common all-grade events observed in patients who received volasertib combination were febrile neutropenia (50%), constipation (45.2%), nausea (40.5%), and anemia (40.5%). The most common events observed in the LDAC arm were nausea (33.3%), anemia (28.9%), pyrexia (28.9%), constipation (26.7%), asthenia (26.7%), and diarrhea (26.7%) in the LDAC arm. In all, 95.2% of patients experienced grade 3 or higher events with the combination compared with 68.9% with LDAC alone.

Following the presentation of these findings, a phase III confirmatory analysis was initiated in January 2013. In this study, labeled POLO-AML-2, volasertib plus LDAC is being compared with LDAC and placebo as a treatment specifically for patients 65 years or older with previously untreated AML who are ineligible for intensive remission induction therapy. The trial is currently enrolling patients with the first patient entering the trial in February 2013.

In addition to volasertib, Boehringer Ingelheim is investigating several agents in phase III clinical trials for a variety of diseases, including nonsmall cell lung cancer (NSCLC), breast cancer, ovarian cancer, and head and neck cancer. In July 2013, the company received its first oncology approval for afatinib as a treatment for patients with EGFR-mutant advanced NSCLC.

“Volasertib is one of many investigational compounds in Boehringer Ingelheim’s growing oncology pipeline and is an example of our commitment to exploring treatment approaches with the goal of improving patient outcomes,” Luik said in a release.

1. Maertens J, Lübbert M, Fiedler W, et al. Phase I/II study of volasertib (BI 6727), an intravenous polo-like kinase (PLK) inhibitor, in patients with acute myeloid leukemia (AML): results from the randomized phase II part for volasertib in combination with low-dose cytarabine (LDAC) versus LDAC monotherapy in patients with previously untreated AML ineligible for intensive treatment. Presented at: 54th American Society of Hematology Annual Meeting and Exposition; Dec 8-11, 2012; Atlanta, Georgia. Abstract 411.

Volasertib Given Breakthrough Therapy Designation

The monoclonal antibody ofatumumab (Arzerra) has received breakthrough therapy designation from the US Food and Drug Administration (FDA) that could allow for earlier use in patients with chronic lymphocytic leukemia (CLL), according to a joint announcement released by GlaxoSmithKline and Genmab, who have a co-development and commercialization agreement for distributing the drug.

In 2009, ofatumumab was approved for the treatment of CLL that can no longer be controlled by other forms of chemotherapy. This breakthrough therapy designation is for patients who have not received prior treatment and are inappropriate for fludarabine-based therapy.

The breakthrough therapy designation comes on the heels of positive phase III data for ofatumumab that were announced in May. In this study, 447 with previously untreated CLL were randomized to receive either ofatumumab in combination with chlorambucil or chlorambucil alone. The study found that patients in the ofatumumab experienced a median progression-free survival of 22.4 months compared with 13.1 months in the control arm (hazard ratio [HR] = 0.57; P <.001).

The study met its primary endpoint, and there were no unexpected safety findings. Full results for the study have been submitted for presentation at the 2013 American Society of Hematology

(ASH) Annual Meeting and Exposition, taking place in December in New Orleans, Louisiana. Ofatumumab is a human monoclonal antibody that targets the CD20 protein, which is expressed on the surface of both normal and malignant B-cells. This mechanism of action allows for a greater response from the immune system against these cancerous cells.

“We are exceedingly proud to receive the breakthrough therapy designation, the second this year for GSK,” said Kathy Rouan, PhD, vice president and head of biopharmaceutical development at GlaxoSmithKline, in a statement. “This FDA program is intended to expedite not just the development but also the review of drugs for serious or life-threatening conditions. We are actively working on our submission and look forward to the enhanced regulatory interaction allowed for breakthrough therapies.”

Breakthrough therapy designation can be assigned to drugs that appear to be superior to existing treatments for life-threatening conditions. Drugs that receive this designation are allowed an expedited review process, aided by more meetings between the FDA and the manufacturer during the development process, as well as requiring fewer patients for clinical trials and less time

needed to conduct these trials. Ofatumumab is still eligible for fast-track designation, accelerated approval, and priority review, if GlaxoSmithKline and Genmab decide that they want to pursue any of these other designations.

“Both of Genmab’s lead products, ofatumumab and daratumumab, have now been granted breakthrough therapy designations from the FDA,” said Jan van de Winkel, PhD, chief executive officer of Genmab, in a statement. “This designation for ofatumumab reflects Genmab’s mission to create differentiated products aimed at improving the lives of patients suffering from debilitating diseases and for whom existing treatments are inadequate.”

Ofatumumab Receives Breakthrough Therapy Designation for Earlier Use in CLL

The FDA has approved the first generic formulation of capecitabine (Xeloda), an oral chemotherapeutic that is currently approved to treat patients with metastatic colorectal cancer (mCRC) and metastatic breast cancer (MBC).

Genentech manufactures capecitabine, which became the first approved oral chemotherapy in 1998. The generic version of capecitabine will be marketed by Teva Pharmaceuticals USA at 150 and 500 mg doses.According to the FDA, on average, the cost of a generic drug is 80% to 85% lower than the brand name equivalent, amounting to billions of dollars saved on prescription drugs each year.

The patent for capecitabine is set to expire on December 14, 2013. The global sales for the agent have continued to rise since its approval. It is considered a “blockbuster” drug, a distinction reserved for treatments that generate more than $1 billion in annual revenue. To date, a generic version of the drug has not been made available.

“Generic drugs are important options that allow greater access to healthcare for all Americans,” said Kathleen Uhl, MD, the acting director of the Office of Generic Drugs in the FDA’s Center for Drug Evaluation and Research. “This medication is widely used by people living with cancer, so it is important to have access to affordable treatment options.

“Since its initial approval in MBC, capecitabine has become widely utilized in several settings. The drug is most well known for its use in combination strategies, specifically in HER2-positive MBC, where it is commonly administered along with lapatinib (Tykerb). As a single-agent, capecitabine has demonstrated efficacy as a first-line therapy for patients with mCRC, following complete resection of the primary tumor when fluoropyrimidine therapy is preferred, and as a treatment for patients with HER2-negative MBC following prior treatment with anthracyclines and taxanes.

Even though the drug has been widely available for more than a decade, investigators are continuing to assess the drug’s efficacy in multiple ongoing clinical trials. As of today’s approval, the chemotherapy is being examined in combination or as a single-agent in over 300 open studies across a variety of diseases. Although the drug is not specifically FDA approved for other indications outside of breast cancer and colorectal cancer, capecitabine is widely used as a treatment for patients with gastric cancer in the first-line setting and in combination with oxaliplatin for patients with stage II to IIIb disease.

The standard schedule for capecitabine is 8 cycles of 1250 mg/m

 administered orally twice daily for 2 weeks followed by 1 week of rest. The most common adverse reactions with capecitabine are diarrhea, hand-and-foot syndrome, nausea, and vomiting. Additionally, the medication has a boxed warning regarding an adverse capecitabine and anticoagulant interaction.

First Generic Version of Capecitabine Gains FDA Approval

The FDA has placed a partial hold on the clinical development of the BCR-ABL inhibitor ponatinib (Iclusig) as it investigates the high occurrence of arterial thrombosis in patients treated with the drug. As part of this hold, new patient enrollment into all clinical trials investigating ponatinib has been stopped.

Ponatinib was granted accelerated approval in December 2012 at a 45-mg daily dose for patients with chronic myeloid leukemia (CML) or Philadelphia chromosome—positive acute lymphoblastic leukemia (Ph+ALL). This approval was based on data from the phase II PACE trial that enrolled patients who were resistant or intolerant to dasatinib or nilotinib, or harbored a T315I mutation.A Boxed Warning was included in the approval, based on the development of arterial thrombosis in 8% of patients and hepatotoxicity in the trial. However, at an FDA-required median 24-month planned follow-up, the rate of arterial thrombosis had increased to 11.8% in patients treated with ponatinib, warranting the pause in patient enrollment.

Ariad Pharmaceuticals, Inc, the company developing ponatinib, is seeking the approval of dose modification from the FDA, in order to resume its ongoing clinical development program. Additionally, the company is consulting with the FDA on needed adjustments to the drug’s prescribing information to reflect the newly discovered increase in toxicity. “We believe that the actions we are taking will help us ensure the most appropriate and safe use of Iclusig. With 2 years of follow-up, we have learned a great deal about both the efficacy and safety of Iclusig in patients with Philadelphia-positive leukemias,” stated Harvey J. Berger, MD, chairman and chief executive officer of Ariad.

The PACE trial was a single-arm investigation of 449 patients, of which 444 were eligible for efficacy analysis. The primary end point for patients with chronic-phase (CP)-CML (n = 267) was major cytogenetic response (MCyR). The primary end point was major hematologic response (MaHR) for patients with accelerated-phase (AP)-CML (n = 83), blast-phase (BP)-CML (n = 62), and Ph+ALL (n = 32). Ponatinib was approved based on a 10-month analysis of the PACE trial that found that treatment with ponatinib demonstrated a 54% MCyR rate in patients with CP-CML. Specifically, 70% of the 64 patients with the BCR-ABL T315I mutation achieved MCyR. The MaHR rate was 52% in patients with AP-CML, 31% in patients with BP-CML, and 41% in patients with Ph+ ALL.

At this early follow-up, the median duration of MCyR for patients with CPCML had not yet been reached. The median duration of MaHR was 9.5 months in patients with AP-CML, 4.7 months in patients with BP-CML, and 3.2 months in patients with Ph+ ALL. At the 24-month follow-up, the PACE trial data demonstrated continued efficacy, even following dose reductions.

Overall, 190 patients with CP-CML received a reduced dose of either 30 mg or 15 mg. Despite this reduction, 90% of patients who achieved MCyR maintained this response for a median of 19 months. Furthermore, Ariad noted in a release, for the 35 patients reduced to a 15-mg dose, 94% maintained a MCyR. The most common adverse events were thrombocytopenia, rash, and dry skin. The most common serious adverse event was pancreatitis, which led to 1 patient discontinuing the drug. At 24 months, serious venous occlusion occurred in 2.9% of ponatinib-treated patients, compared with 2.2% when the drug was approved. In total, all types of arterial and venousrelated adverse events occurred in approximately 20% of ponatinib-treated patients.

“We are focused first and foremost on the needs of cancer patients—to have new medicines that provide both safe and effective treatment of their malignancies. Our unwavering commitment to patients has led us to promptly take the steps we have outlined,” Berger said in a statement. To support the accelerated approval of ponatinib, the phase III EPIC trial was initiated to compare 45 mg ponatinib with imatinib for patients with newly diagnosed CML. As a result of the new safety findings, Ariad, in collaboration with a data monitoring committee, is proposing that the daily dose of ponatinib be adjusted to 30 mg daily in this trial. However, if patients have already achieved a major molecular response (MMR), the dose will be further reduced to 15 mg daily.

Additionally, the company announced, the eligibility criteria for all ponatinib clinical trials will be modified to exclude patients with prior arterial thrombosis that has resulted in heart attack or stroke. 

Safety Concerns Halt Ponatinib Development

A phase III study of the PI3K-delta inhibitor idelalisib in combination with rituximab (Rituxan) has been stopped early following a positive interim analysis, according to a statement from Gilead Sciences, Inc, the company developing the drug announced October 10.

The randomized trial, labeled Study 116, investigated the combination as a treatment for chemotherapy-ineligible patients with previously treated chronic lymphocytic leukemia (CLL). The decision to stop the trial early followed a recommendation from an independent data monitoring committee that found a highly statistically significant prolongation in the primary end point of progression-free survival (PFS). As a result of the stoppage, patients on the control arm receiving rituximab plus placebo are now eligible for treatment with idelalisib in an extension study.

Idelalisib is a first-in-class selective PI3K-delta inhibitor. This mechanism of action is thought to be effective in B-cell malignancies due to the role of PI3K-delta in the activation, proliferation, and survival of B cells. Prior to the phase III investigation, the treatment was explored in early-stage trials, which seemed to confirm this rationale.

“This is the first phase III study to report positive results for a new class of targeted therapies that inhibit B-cell receptor signaling as a major component of their mechanism of action, an important area of focus in the development of chemotherapy-free regimens in CLL and other B-cell malignancies,” said Norbert W. Bischofberger, PhD, the executive vice president of research and development and chief scientific officer at Gilead, in the statement.

The phase III study enrolled a total of 220 patients, approximately 20 patients more than expected. All patients enrolled on the trial had previously treated recurrent CLL with measurable lymphadenopathy. Patients in the trial were randomized in a 1:1 ratio to receive idelalisib at a 150-mg dose twice daily in combination with intravenous rituximab at an initial dose of 375 mg/

 or rituximab and placebo. Patients who progressed were eligible to receive idelalisib therapy in a double-blind extension study.

Data from the interim analysis are likely to be presented later this year. “Given the significant unmet medical need in CLL, particularly in this population of patients who are not fit for chemotherapy, we are pleased that idelalisib has shown a clinically meaningful benefit for patients,” said Bischofberger in a statement.

The phase III study was launched on the basis of results from a phase I trial examining the combination of idelalisib with rituximab and/or bendamustine for patients with previously treated CLL. Results from this analysis were presented at the 2012 meeting of the American Society of Hematology. In that study, 19 patients who had received a median of 2 prior therapies took idelalisib at 150 mg twice daily in combination with weekly rituximab at 375 mg/m

. In the intent-to-treat to population, the overall response rate (ORR) was 78%. Moreover, the 1-year PFS rate was 74%, and 84% of patients experienced a lymph node response (shrinkage ≥50%) resulting in marked reductions in lymphadenopathy.

The highest level of response in this trial was experienced with the combination of idelalisib, rituximab, and bendamustine (Treanda). This portion of the trial contained 15 patients and found an ORR of 87%, a 1-year PFS rate of 87%, and lymph node response in 87% of patients. A randomized phase III study examining the combination of idelalisib, rituximab, and bendamustine is recruiting patients with previously previously treated CLL (NCT01569295).

The early stop of the phase III trial indicates a promising treatment with the potential for regulatory approval. However, controversy exists in medical research regarding stopping randomized clinical trials early based on evidence of benefit. In many cases, evidence suggests that trials that stop early overestimate treatment effects Moreover, an analysis published in BMJ in 2012 found that large overestimates of benefits were common when less than 200 events were analyzed. Most recently, a large phase III trial analyzing abiraterone acetate for men with metastatic castration-resistant prostate cancer before chemotherapy fell under scrutiny after the trial was halted early following an interim analysis.

As a result of this early unblinding, many questioned the authenticity of the survival advantage experienced in the trial, since statistical significance had not been met. Despite this, the US Food and Drug Administration (FDA) approved abiraterone based on results from this study. In its announcement, Gilead stated that it has informed the FDA of its decision to stop the trial. The company is engaged in conversations regarding a potential regulatory filing for idelalisib in CLL.

In September 2013, Gilead submitted a New Drug Application to the FDA for approval of idelalisib for the treatment of patients with indolent non-Hodgkin’s lymphoma (iNHL). That submission was based on data from a single-arm, open-label phase II study of 125 patients with iNHL who were refractory to rituximab and alkylating-agent-containing chemotherapy. In an interim analysis of this study, single-agent idelalisib achieved an ORR of 53.6%, with a median duration of response of 11.9 months. Additionally, median PFS was 11.4 months with lymph node shrinkage experienced in 89% of patients.

In addition to previously treated patients with CLL and iNHL, idelalisib plus rituximab has demonstrated promising results in treatment-naïve patients with CLL, according to results from a phase II trial that was presented at the 2013 ASCO Annual Meeting. In that study, patients who were ≥65 years old with previously untreated CLL or small lymphocytic lymphoma received idelalisib at 150 mg BID combined with weekly rituximab at 375 mg/m2. At a 24-month analysis, the combination was found to be highly active in treatment-naïve elderly patients. The trial found a Kaplan-Meier estimated PFS benefit of 93%. Moreover, the combination achieved a complete response rate of 19% and an ORR of 97%.

At the time of the presentation, the lead author, Susan M. O’Brien, MD, said, “The high overall response rate and durable disease control observed in this phase II study suggest that idelalisib in combination with rituximab could become an important therapeutic option for CLL patients new to treatment.” O’Brien is the Ashbel Smith Professor of Medicine in the Department of Leukemia at the University of Texas MD Anderson Cancer Center in Houston and was a principal investigator of the phase II study.

Positive Idelalisib Data End Late-Stage CLL Trial

Results from a pooled analysis of data from 12 studies have demonstrated a long-term survival benefit that extends through at least 10 years for patients with advanced melanoma treated with ipilimumab (Yervoy).

The results were announced by the drug’s manufacturer Bristol-Myers Squibb on September 27 and presented the next day at the 2013 European Cancer Congress in Amsterdam. This study, which included 2 phase III trials, 8 phase II trials, and 2 retrospective trials, represents the largest overall survival (OS) analysis to date for patients with advanced or unresectable metastatic melanoma treated with ipilimumab.

The analysis included both patients who were previously treated (n = 1257) and previously untreated (n = 604).

 “This pooled analysis is encouraging, particularly when considering that metastatic melanoma is one of the most aggressive forms of cancer and historically, average survival was just 6 to 9 months,” said F. Stephen Hodi, MD, Department of Medicine, Harvard Medical School, Dana-Farber Cancer Institute, in a statement.

In the 1861 patients treated with ipilimumab, median OS was 11.4 months (95% CI: 10.7—12.1). Researchers noted a distinct plateau in OS at year 3 that extended through year 10, independent of line of therapy, ipilimumab dose, or maintenance therapy. The 3-year OS rates were 22%, in the entire study population, 26% for treatmentnaïve patients, and 20% for previously treated patients. The authors of the study wrote that these OS data should be considered as a benchmark for future melanoma therapies, as they represent a large benefit in a difficult-to-treat disease.

September/October 2013

New Approaches to Medicaid Expansion: Hybrid Plans Offer Alternatives for Covering More People

In Historic Vote, FDA Backs Perjeta for Pre-surgical Breast Cancer Treatment

Status in the States: In Louisiana, Will Privatization Affect Efforts to Stop Cancer?

Melanoma Combination Granted Priority Review Designation by FDA

Volasertib Given Breakthrough Therapy Designation

Ofatumumab Receives Breakthrough Therapy Designation for Earlier Use in CLL

First Generic Version of Capecitabine Gains FDA Approval

Safety Concerns Halt Ponatinib Development

Positive Idelalisib Data End Late-Stage CLL Trial

Pooled Analysis Reinforces Long-Term Survival Benefit With Ipilimumab

Trebananib Shows Promise in Recurrent Platinum-Sensitive Ovarian Cancer

Dual HER2 Blockade Less Effective in PI3KCA-Mutant Breast Cancer

Challenges in Oncology Practice

Melanoma: From Impossible to Treat to Poster Child for Targeted Therapies