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  • PALOMA-1 confirms expectations, but will it support regulatory filing?

    Final progression-free survival (PFS) data from the PALOMA-1 phase II trial was presented at the Plenary Session of the 2014 American Association for Cancer Research (AACR; Finn, abstract CT-101). Observers were expecting positive news, since interim analyses already had shown PFS benefit for palbociclib (PD 0332991, Pfizer/Amgen/Onyx) and Pfizer had indicated via press release that the final PFS results were positive (February 3, 2014). However, the big question wasn’t whether the data would be positive, it was whether the final data would be good enough to support filing for accelerated approval.

    PALOMA-1 (NCT00721409) was an open label trial that randomized 165 patients to letrozole or letrozole plus palbociclib. As part of the trial design, both CCND-1 amplification or p16 loss were prospectively evaluated as biomarkers, but only ER-status was predictive of activity (Finn, Abstract 100O, IMPAKT 2012). An interim analysis based on 61 events presented at the San Antonio Breast Cancer Symposium (SABCS) in 2012 demonstrated a striking 18.6 month improvement in PFS when palbociclib was added to letrozole  (26.1 months versus 7.5 months, HR 0.37, p<0.001; Finn, Abstract S1-6).

    The final analysis consisted of 100 PFS events, and palbociclib maintained the impressive PFS benefit (20.2 months versus 10.2 months, HR 0.488, p=0.0004). All evaluated subgroups showed a strong benefit for palbociclib. Palbociclib plus letrozole also increased objective response rate (ORR; 43% versus 33%; primarily partial responses) and clinical benefit rate (81% versus 56%). The presenter suggested that the lower response rate could be attributed to fact that PALOMA-1 included patients with bone metastases that cannot be easily assessed for response. Further efficacy analysis conducted in patients with measurable disease (n=65 in palbociclib arm and n=66 in letrozole arm) demonstrated an ORR of 55% versus 39%.  Preliminary analysis on overall survival (OS) indicates only a trend to an OS benefit: 37.5 months versus 33.3 months, HR 0.813, 0.2105). The toxicity profile for palbociclib was manageable given that the relative dose intensity was 94% and the discontinuation rate due to adverse events (AEs) was 13% in palbociclib plus letrozole versus 2% in letrozole alone arm. Common Grade 3/4 toxicities in palbociclib plus letrozole versus letrozole alone arm included neutropenia (54% versus 1%), leucopenia (19% versus 0%), fatigue (4% versus 1%) and anemia (6% versus 1%).

    The impressive PFS benefit was definitely well received by those in attendance at the conference. The discussant (Dr. Jose Baselga) stated “these results are strikingly positive and with a large potential impact to patients with ER+ breast cancer.” The important question remains: what will Pfizer do with these data? Palbociclib was awarded “breakthrough therapy” designation in April 2013 based on the interim data from PALOMA-1. Moreover, historical data presented by Dr. Finn suggest that the PFS benefit for palbociclib compares favorably: past trials showed that aromatase inhibitor treatment was associated with a 10-13 month PFS benefit.

    Historically in breast cancer, overall survival has been a major criteria for approval by the U.S. Food and Drug Administration especially given the narrow PFS benefit observed with some agents in this disease. Based on the immature OS results from PALOMA-1, it is unclear if palbociclib will be able to achieve a significant survival advantage. The discussant Dr. Baselga noted caution on accepting the PFS benefits from Phase II data based on recent failures with most recent example of iniparib that failed in Phase III trials following impressive Phase II benefit. Given the small sample size and the aggressive nature of breast cancer,  it might be ideal to await the results of ongoing Phase III PALOMA-2 study (NCT01740427) of palbociclib plus letrozole as first-line therapy or the Phase III PALOMA-3 study (NCT01942135), which is comparing the addition of palbociclib to faslodex in later lines of therapy.

    Dr. Baselga acknowledged the difficulty for Pfizer as they make this this decision, when he noted some of the competition for palbociclib. Eli Lilly’s CDK 4/6 inhibitor bemaciclib (LY2835219) recently presented phase I data in breast cancer patients, and will be examined in a phase II trial in HR+, HER2- patients (NCT02102490). Also, Novartis has recently reported Phase I data for their CDK 4/6 inhibitor LEE011 (Infante, 2014 International Congress on Targeted Anticancer Therapies) that was evaluated in a dose-escalation study in 78 patients with solid tumors. Although the trial had only five breast cancer patients, LEE011 as a monotherapy achieved two partial responses and was well-tolerated. This phase I data supported Novartis’ Phase III trial (MONALEESA-2; CLEE011A2301; NCT01958021) which will evaluate the efficacy of LEE011 in combination with letrozole. Finally, Novaris’s PI3K inhibitor buparlisib (BKM120) is the subject of two phase III trials [BELLE-2 (NCT01610284); BELLE-3 (NCT01633060)] for HER2-positive patients.  This competition highlights Pfizer’s quandary.  If they choose (or the FDA forces them to choose) to wait, they stand a chance of losing their first-to-market advantage. However, it is also hard to ignore such a striking PFS benefit in this patient population. After all, Afinitor® (everolimus, Novartis) was approved in the relapsed/refractory HER2- postmenopausal setting based on a 6-month PFS benefit.

    No matter what happens next for now, it seems CDK inhibitors have gained a slot in physician’s arsenal of options for the treatment of HR+ metastatic breast cancer.  Kantar Health eagerly awaits to hear Pfizer’s future plans for palbociclib.

    by Neesha Suvarna, Ph.D., Consultant, Kantar Health and Arnold DuBell, Ph.D., M.B.A., Consultant, Kantar Health

    COA Meeting Day #2 – Best Of The Day

    As day two of the annual COA conference started, there were still a lot of topics to be covered by the faculty. I began in the clinical track with an interesting lecture on Lynch Syndrome.

    Lynch Syndrome

    Do You Know It When You See It?

    Larry Geier, MD

    Director, Clinical Cancer Genetics

    Kansas City Cancer Center/University of Kansas Cancer Center

    Dr. Geier set the stage by first discussing relatively common hereditary cancer syndromes:

    • Hereditary breast/ovary syndrome (BRCA genes)
      • Breast, ovary, others
        • Lynch syndrome (mismatch repair genes)
          • Colon, uterus, ovary, stomach, others
        • Colon polyposis syndromes (APC, MUTYH genes)
          • Colon, upper GI, others

            What are the hallmarks of hereditary cancers? Some of the more common signals include: family clustering, younger age at diagnosis, multiple cancers in the same person, typical phenotypes, and tumor suppressor genes.

            The nice (maybe “nice” is the wrong word) thing about hereditary cancers is that they may be more preventable. We can identify at-risk patients, and then attempt to prevent the cancer. For example, 5-10% of breast cancers are hereditary and 100% of those cancers are preventable. Another example is colorectal cancer where 5% of CRC cancers are hereditary and 80-90% of those cancers are preventable.

            Importantly, it is becoming increasingly recognized that genetic evaluation, when appropriate, should be done soon after diagnosis in order to optimally manage the patients who have genetically based cancer.

            Dr. Geier spent some time discussing Lynch Syndrome as it relates to management of hereditary cancers. Lynch Syndrome is caused by an inherited defect in any one of several “mismatch repair” genes (MMR). Five genes are currently available for clinical testing:

            • MLH1 (most common gene involved)
            • MSH2 (second most common, often associated with sebaceous neoplasms)
            • MSH6 (excess of uterine cancers)
            • PMS2 (new, prevalence and features uncertain)
            • EPCAM (not MMR, but adjacent to MSH2)

            These MMR genes normally correct DNA mismatch mutations that occur during DNA replication. Cancer occurs when a sufficient number of these mutations occur in critical genes – it’s just a matter of time.

            The problem is that Lynch Syndrome creates genomic instability, which greatly accelerates the timeline from colon polyp to CRC for example. Instead of the usual 7-10 years, it may be only 1-3 years from polyp to CRC. As you can tell, a clean colonoscopy every 10 years is not sufficient to catch CRC in these people, and frequent screening is very important in this group of people.

            So how do we diagnose Lynch Syndrome:

            • Tumor Testing
              • Microsatellite instability
              • Immunohistochemistry for MMR proteins
              • Useful for automatic screening of all CRC patients at the pathology level
            • Germline DNA Testing
              • Direct DNA analysis of one or more of the five genes
              • This is the only way to diagnose Lynch Syndrome

            Ideally, physicians and other care givers will screen for Lynch Syndrome. However, traditional dependence on providers to identify these patients has been largely ineffective, probably for the following reasons:

            There is a wide spectrum of cancers and physicians

            Providers underestimate the prevalence of these syndromes

            Too much reliance on the “slam dunk” family history

            Too little attention to the phenotype that is typical for Lynch colon cancer

            The bottom line is that these syndromes are more common than most realize, and they are easily missed. Physicians need to pay attention to family history of cancers other than CRC such as uterus, ovary, gastric, pancreas, and urothelial cancers. There should be universal IHC screening for MMR proteins on all CRC and endometrial cancer patients. Genetic testing should be considered soon after diagnosis, and along those lines rigorous application of “red flags” will capture the majority of families.

            Integrating Palliative Care and Oncology

            Rebecca Bechhold, MD, Oncology Hematology Care

            Dr. Bechhold describes integrated care as palliative care + oncology care, and integrated care includes: 1) an extensive discussion of the goals of care and 2) superb symptom management.

            Did you know that the US spends 2X more than any other country on cancer care, and that 20-30% of $55 billion in cancer care is spent in the last 6 months of life, without any evidence of improvement in quality of life? How about this one – did you know that a cancer diagnosis is the most common cause of personal bankruptcy in the US, regardless of insurance coverage?

            There is a need for integrated care because the survival time in many cancers is so limited in late stage disease. We have also seen that palliative chemotherapy frequently causes hospitalizations, and that any end of life conversation with a doctor has been shown to lower costs in the last week of life. For these reasons, and because patients express feelings of abandonment when oncologists are not part of their end of life care, there is an established need for integrated care.

            The need for integrated care is there, but how do you make it part of your practice? Consistent with many of the discussions here at the meeting, working with the payer is beneficial to everyone. For example, palliative care can decrease utilization, increase profits, increase outcomes, increase bonus payments, and reduce avoidable admissions. These are all things that should get the attention of payers.

            The point is that end of life care is complex, time consuming, and deserves our best effort. But also we, as physicians, deserve adequate compensation and patient management should be paid for. In the end excellent patient management leads to increased patient and family satisfaction, decreased hospital admissions, and increased QOL for patients.

            Biomarkers in Practice: A Review of Outcomes and Reimbursement Issues

            Ali McBride, PharmD

            Clinical Coordinator Hematology/Oncology

            The University of Arizona

            The first portion of Ms. McBride’s talk gave us a background on biomarkers, including discovery and development of biomarker, definitions, current applications of tumor biomarkers, and limitations of current biomarkers.

            But it was when she started discussing outcomes with biomarkers that the puzzle pieces started to fit together. There are, of course, great examples of clinically successful biomarkers in CML, melanoma, and colorectal cancer for example. Ms. McBride chose CRC as a case study, demonstrating why Kras is a good biomarker for CRC patients while EGFR isn’t. As a case study, the Kras example points to the goals of personalized therapies:

            • Identify patients likely to respond to a drug or treatment
            • Identify patients at risk for adverse reactions
            • Monitor response to treatment and adjust as necessary
            • Identify patients matching the population that was studied in the pivotal therapeutic trial

            All that is well and good, as long as there is reimbursement to make biomarker identification and use economically viable. As Ms. McBride transitioned into the business end, it was easy to see that one needs the other for the concept to work well in practice.
            In theory payers would like biomarkers because there is less risk for them:

            • Prevents the use of ineffective therapies
            • Decreased variation in patient outcomes
            • Adverse outcomes will decrease overall costs for healthcare systems

            But of course there are concerns. Development of these molecular tests is not validated in many instances, and without that there are other problems such as clinical trial development and of course reimbursement.

            To give you an idea of the role of a biomarker in cancer management, nobody argues that the ALK test should not be given and reimbursed in NSCLC patients. The widely reported price of the companion diagnostic test kit for crizotinib, developed by Abbott Molecular, is less that $200, while established reimbursement is $400 – $500. In contrast the reported price of crizotinib is $9,600 per month.

            Meanwhile the FDA expects that companion tests will usually be lab tests that are co-developed with the medication, and approved at the same time. Regarding reimbursement however, if the product label specifies that biomarker testing is required to identify appropriate patients, then it must be ensured that the label reads broad enough to accommodate all current and future methods of testing for the biomarker. The problem is elucidated with the Herceptin example, when some patients had coverage denied because the laboratories contracted to test for HER2 did not have access to the HercepTest or the laboratory used different IHC testing.

            Suddenly even clinically robust personalized therapies are thrown into question because reimbursement is not as straight-forward as one would expect. If the test is not reimbursed by CMS or commercial insurers, market adoption of the new therapy will be impacted. Historically, national coverage decisions have helped establish reimbursement policy for biomarkers.

            CMS determines the national payment limits for 65 genetic tests described by Tier code.

            • Tier 1 lists CPT codes for commonly performed tests
            • Tier 2 lists codes for less commonly performed tests
              • At this time CMS has not finalized reimbursement levels for any Tier 2 codes

            Ms. Mcbride went on to describe examples where reimbursement was higher for an FDA approved Kras test, and an example where the biomarker test under water. In summary, everybody wants personalized cancer therapy, and the scientific advances have been excited and meaningful, but regulation and reimbursement of these tests is still problematic.

            By Don Sharpe

            COA Meeting Day #1 – Best Of The Day

            While attending the annual Community Oncology Alliance (COA) meeting in Orlando I’ve been absorbing content, networking at the breaks, and interviewing faculty. All of it has lead to a lot of new insights that I thought I’d try and summarize here. Note that I’m really only hitting some highlights, and there is nothing like being part of a meeting to really digest all the presentations, especially talking to presenters to put everything presented into context.

            The Emperor of all Maladies: A Biography of Cancer

            Siddhartha Mukherjee, MD, PhD

            The keynote speaker at the meeting was Siddhartha Mukherjee, MD, PhD, the Pulitzer Prize winning Author of The Emperor of All Maladies: A Biography of Cancer. Dr. Mukherjee. Assuming you’re a stakeholder in the cancer industry, it is a book you have to read. Hard for me to do justice here, but Dr. Mukherjee does a terrific job of laying out the history of cancer, all the way back to mummies in fact, through to recent history and today’s understanding of the molecular basis of the disease, and finally looks forward into the future of the disease.

            Dr. Mukherjee began his talk with a surprise for the audience, announcing that for past couple of years he has been working with Ken Burns  on a documentary based on his book. He shared the trailer with us, the first time it has been seen in a public forum.

            Now onto the meeting – I’ll try and share a few of the things I learned and found interesting.

            Molecular Profiling and Circulating Tumor Cells: Challenges as Declining Reimbursement and Clinical Policies Collide

            John Powderly, MD, President, Carolina BioOncology Institute

            The clinical track began with John Powderly, MD, President, Carolina BioOncology Institute presenting his experience with Circulating Tumor Cells (CTCs) and clinical trials at the Carolina BioOncology Institute. The CBI is heavily involved in research, including >40 early phase trials opened since 2005. They have studied products such as ipilimumab, panitumumab, PD1, aflibercept, and so on. Importantly, Dr. Powderly discussed the importance of companion diagnostics, and in particular their experience working with CTCs.

            Companion diagnostics, and their use in clinical trials, are benficial because they match the drug to the patients most likely to benefit, can provide a better clinical response, improvement in attrition rates, and if successful are more likely to get the product approved. For the drug developer, having a companion diagnostic can extend the drug’s life cycle thus producing higher revenue. Dr. Powderly calculates that companion diagnostics can save drug companies as much as $1.8 billion in waste associated with developing drugs without companion diagnostics.

            Dr. Powderly shared his experience with CTCs, what he calls the substrate of personalized medicine. After providing the scientific rationale for CTCs as a surrogate marker, Dr. Powderly was pleased to announce that they had some success presenting CTC data in prostate cancer patients at the recent ASCO GU meeting. Using prostate specific membrane antigen (PSMA) as a marker, they delivered an experimental antibody drug conjugate and saw a significant reduction in CTC percentage, perhaps indicating that they have identified a new prostate cancer marker and perhaps showing that CTCs can be used a surrogate.

            Next Dr. Powderly shared the problem they had with CTCs on the business end. Originally they were on the frontier, bought a veridex machine, and were reimbursed enough with standard codes to make the machine slightly profitable. In 2008 Medicare called CTCs investigational (despite a FDA approval) and reimbursement vanished until Medicare created a NDC code but at that point reimbursement was less than the cost of the test. In the long run the Institute had to change the model and only offer CTC testing in clinical trials where the test is specified as part of the protocol and paid for. Unfortunately a testament to one of the problems with personalized medicine today – a lack of infrastructure  and standardized systems to support development and clinical trials.

            Novel Opportunities for Engagement Utilizing In-House Pharmacy Services

            Angel Aslo, Pharmacy Director, The Zangmeister Center, Columbus, OH

            Ray Bailey, Pharmacy Director, Florida Cancer Specialists

            First a few facts:

            • The cancer drug category is experiencing a 32% – 42% growth rate
            • Oral oncolytics represent 35% of the oncology pipeline
            • FDA approvals of oral oncology meds is surpassing the IV approvals

            As the shift toward oral chemotherapy grows, so does the need for efficient in-house pharmacy functions. In this presentation the faculty discussed their unique pharmacy logistics, and contrasted them between the largest independent practice in the country – Florida Cancer Specialists -  and a stand alone multidisciplinary cancer center – The Zangmeister Center in Columbus, OH.

            Both presenters talked about “speed to therapy”, the need to get the medication in the hands of the patient as quickly as possible. The difference is that Zangmeister is a stand alone cancer center where the patient can fill the prescription within the walls of the cancer center, while Florida Cancer Specialists is a network of offices demanding a central pharmacy serving all the satellite offices.

            Regardless of the setting, both presenters stressed the importance of proper pharmacy workflows, integration with the EMR, and in the case of FCS, downstream logistics to fill prescriptions get the medication directly to patients throughout their network of practices in Florida.

            Not to be overlooked is the importance of compliance/persistence workflows, and great financial counseling.  All patients are followed, whether the prescription is filled through the in-house pharmacy or a different pharmacy, with a pharmacy care plan. There is usually a contact at one week for a review of the care plan, and every 30 days for refills or to assess adherence. There are also considerations for dose reductions or holidays, side effects, or any physician directed changes to therapy.

            Other services provided by in-house pharmacies can include:

            • Developing SOPs for handling of oral oncolytics in the practice
            • Develop practice support tools to understand the SOP
            • Identify pharmaceutical specific assistance programs

            Finally, great financial counseling is also a service provided by the in-house pharmacy. It is vitally important to know the help that is available such as copay assistance foundations, local foundations, copay cards, pharma “free goods”, and practice copay assistance programs.

            Community Oncology 2.0 Information Technology

            A Practical Guide to Where We Are Today and Where We Need to Go

            Lucio Gordan, MD, Co-Director of Integrated Clinical Services and Medical informatics, Florida Cancer Specialists

            Dr. Gordan is a self-described geek, due to his interest at a young age in computers, software, and programming. He began by describing the bright future for oncology, but contrasted that bright future with many challenges too. Dr. Gordan emphasized how information overload is making medicine in general challenging, but also pointed out that oncology is the ideal model for an IT solution.

            In Dr, Gordan’s viewpoint, IT can help oncology with

            • EMRs
            • Patient portals
            • Pathways
            • Data harvesting

            But unfortunately adoption of EMRs is ot going well so far. According to an article published in medical Economics in February 2014, in a survey across all medical specialties:

            • 73% of largest practices would have chosen a different EMR
            • 50% said that “cost is too high”
            • 45% said that “care is worse”

            So far there is about 70% adoption of an EMR in oncology, with about 50% adoption of an oncology-specific EMR. The functionality of EMRs should include:

            • Visit notes
            • Ordering
            • Billing
            • Metrics
            • Content such as diagnosis, regimens, laboratory orders, ancillary medications
            • Research protocols
            • Alerts
            • Connections to resources like uptodate.com, NCCN guidelines, and medical journals
            • Printing of educational materials

            Dr. Gordan also provided some ideas to help choose an EMR such as KLAS Research, the ASCO EMR lab, Oncology Electronic Health Record Field Guide, GPOs, and referrals from other practices. He also said that making sure the vendor does a demo in your office is critically important.

            Is there a best EMR in oncology? Probably not because you need an EMR that fits your unique practice dynamics. The decision could be based on the practice size, number of clinics, and involvement with the local hospital and other local specialties.

            When thinking about the future of EMRs, Dr. Gordan wants to see:

            • Mobile adaptability
            • Improvement in ability to collect data and export metrics
            • Built-in pathways
            • Pre-populated clinical trials
            • Increased efficiencies within offices

            The end of Dr. Gordan’s talk discussed data harvesting. Regarding big data, he said that today big data is a big headache. Right now we have too much data, and it is going to grow 8 fold in 10 years.

            To demonstrate the headache, it is estimated that poor data is costing businesses 20-30% of their revenue and wrong data is costing US business $600 billion annually. “Lack of understanding of data” is cited as the #1 reason for over running project costs.
            The challenge is that much of the data is unstructured i.e. physician notes, but also radiology reports, some labs, and pathology.

            Many physicians think their data is worth something, but don’t understand the nature of unstructured data. So who wants the data?

            • Pharmaceutical R&D
            • Payers
            • Oncologists
            • Research networks
            • Practice management companies
            • GPOs

            It is estimated that the total market value of data is in excess of $300 billion. But Dr. Gordan does not think that data is the gold mine that many think it is.

            by Don Sharpe

            The Evolving Use of White Bagging in Oncology

            Channel dynamics are changing for physician-administered infusible drugs, with implications for practice economics, payer utilization management, site of care, and availability of data for manufacturers. Today, buy and bill’ is the primary method of distribution of IV oncology drugs, whereby oncology practices typically purchase these drugs from specialty distributors/group purchasing organizations (GPOs), which are then billed to payers under the medical benefit. Recently, however, specialty pharmacies are making inroads into the buy and bill model via ‘white bagging’ (Figure 1).

            Figure 1: With the advent of white bagging, drugs flow through SPs, bypassing buy and bill and usually SDs/GPOs

            White bagging is the method of delivery by which physician-administered drugs are dispensed by a specialty pharmacy (SP) for a specific patient, shipped to the physician for administration, and generally paid under the pharmacy benefit rather than the medical benefit. The specialty pharmacy is reimbursed by the payer for the drug; the physician is only paid a drug administration fee.

            Payers and providers have different, and at times, conflicting objectives, but both are finding reasons to adopt white bagging. Providers may elect to have a specialty pharmacy dispense the drugs to eliminate the financial risks and hassles of securing adequate reimbursement for certain drugs. In addition, some payers mandate – or encourage through unfavorable reimbursement structures – white bagging to control utilization and lower costs of selected drugs.

            Manufacturers look to channel partners for product access, quality control through the supply channel, and product data. Although specialty distributors (via buy and bill) or by specialty pharmacies (via white bagging) may both be able to support these objectives, the two models have implications that manufacturers will want to consider. Knowing what the drivers of white bagging are, whether payer or provider instigated, is important to manufactures if they wish to influence distribution dynamics.

            White Bagging Growth Trend

            While most IV drugs continue to flow through the specialty distributor channel, the use of the SP channel is increasing (Figure 2). Similarly, payers report 25% of IV oncologics being dispensed by SPs in 2013 (Figure 3).

            Figure 2: The white bagging channel increases as buy and bill decreases.

            Figure3: Payers report one-quarter of IV cancer drugs are distributed through SPs.

            Payer Drivers

            White bagging may be attractive to payers for a few reasons. Partnership with SPs allows payers to extend the reach and depth of utilization management on the pharmacy benefit. In addition, white bagging may be cost effective if payers are able to negotiate more favorable dispensing rates with SPs than through buy and bill. One-third of respondents in Kantar Health’s 2013 MCO survey reported that they had implemented or expanded their use of specialty pharmacies for office-administered drugs in 2013, with additional increases planned in 2014 (Figure4).

            Figure 4: Payers have increased their use of Specialty Pharmacy for office-administered drugs in 2013, and plan to further increase use of SPs in 2014

            Provider Choice

            Providers, in turn, may choose to white bag to avoid carrying costs and the financial risk associated with expensive drugs (Figure 5).

            Figure 5: Financial considerations and payer mandates drive practice use of white bagging

            Practices are increasingly sensitive to carrying costs and reimbursement risk –indirectly driving white bagging. Financial pressure and risks stem from decreased reimbursement from payers and patients’ inability to pay their cost shares. Growing oncologist comfort with SPs for oral oncolytics may also support increased use of SPs for IVs (Figure 6).

            Figure 6: Practices acknowledge value of SPs in providing administrative assistance

            Conclusion

            The confluence of payer and provider drivers is likely to precipitate a slow but steady growth of white bagging over time. The result will likely be a combination of models in oncology – buy and bill and white-bagging – co-existing across provider segments and even within practices.

            Why should manufactures care whether their IV oncology products are dispensed via buy and bill or white bagging?

            • In using an SP, providers forego the potential margins on buy and bill. Do the differences in margins impact physician choice in treatment options?
            • Unfavorable practice economics, including loss of revenue from buy and bill, and unfavorable reimbursement on some products, is fueling the shift toward the more expensive hospital as site of care. Among other cost implications, patient cost share may be higher in this setting, impacting ability to pay and treatment continuation.
            • Manufacturers’ access to data is more limited through SPs, reducing the ability to track sales.
            • Specialty Pharmacy is a more fragmented channel than SDs, requiring many more relationships and increasing quality control risks.

            In any case, manufacturers of IV products may want to expand relationships with SPs and leverage their relationships with oncology practices.

            By Deni Deasy Boekell, Senior Director, Commercial Planning, Kantar Health

            CTC Testing Coming Under Fire by Medicare Contractor Palmetto GBA

            If Palmetto GBA gets their way, oncologists and cancer patients in West Virginia, Virginia, and North and South Carolina may soon be denied access to Janssen Diagnostics’ CELLSEARCH® CTC test, indicated for use in patients with metastatic breast, colorectal, or prostate cancer.

            The test is used to capture and count circulating tumor cells (CTC) in patients; and in conjunction with all other clinical information collected from a physical examination, a complete medical history, and results from diagnostic tests (e.g. blood, imaging, and/or laboratory tests), a more complete picture to determine a patient’s prognosis can be assessed.

            Does Medicare coverage or lack of coverage impact quality cancer care? Well, if you’re unlucky enough to live in one of these 4 states, you need to know that Medicare is considering discontinuing coverage for the CTC test in your region. The pending Non-Coverage Decision (DL34631, Circulating Tumor Cell Marker Assays) for the test is to be decided on February 24, 2014. While this isn’t a life or death situation, it would be nice to think that eligible patients could get access to technology without having to pay out of pocket. Or at least coverage wouldn’t depend on where your house is.

            The CELLSEARCH CTC test, initially cleared by the FDA in 2004, is the only in vitro diagnostic (IVD) test that has been cleared through the FDA 510(k) review process.

            According to Andrew J. Armstrong, MD, Duke Cancer Center, men with metastatic prostate cancer have a wide range of outcomes that can range from months to many years of life expectancy.

            The CELLSEARCH CTC test is able to provide a more refined prognosis when used in combination with other tests, “and the number of CTCs in the blood at any given time can lead to adjustments in prognosis during therapies with chemotherapy or newer hormonal therapies,” he said.

            “There are some men whose prostate cancers do not produce much PSA, and some men where the CTC test really adds clinical value in the decision to stop an ineffective therapy or continue an effective one.”

            The clinical validity of CTC enumeration tests is well-established in scientific literature, including articles published in respected journals, such the New England Journal of Medicine, Journal of Clinical Oncology, Lancet Oncology, Urology and many other peer-reviewed, highly regarded journals.

            Clinical data from 26 independent prospective studies involving more than 2,800 patients have been published in more than 100 peer-reviewed publications that validate the clinical performance and value of the test.

            On the other hand, we spoke to Dean Gesme, MD, a medical oncologist at Minnesota Oncology, and he told us, “We don’t utilize the test in our practice.  The technology is fascinating but its role in determining treatment or in informing the need for changes of therapy have yet to be validated.”

            “While more studies are needed to understand how to use the CTC to guide therapy decisions, the value that the CTC test provides currently is similar or better than the value that PSA tests, CT scans, and bone scans provide to doctors and patients in the clinic,” Dr. Armstrong went on to say.

            Oncologists and patients are concerned that the draft non-coverage decision, if finalized in its current form, could jeopardize Medicare beneficiary access to the CELLSEARCH® CTC test and consequently impact clinical management of beneficiaries with certain types of metastatic cancer.

            According to a statement from the company, “For patients undergoing cancer treatment, CTC testing provides data on whether their prognosis is changing over time. This allows physicians to make an evidence-based decision regarding whether to continue existing therapy, change therapy, and/or stop therapy. Thus by providing physicians with earlier disease prognosis data, patients can be spared prolonged periods of treatment with ineffective therapy and its cumulative toxicities, and alternative active therapies can be initiated, or options such as hospice care can be contemplated.”

            Janssen Diagnostics is seeking to continue constructive discussions with Palmetto (the regional Medicare carrier) to review data published in peer-reviewed medical journals and presented at major medical meetings that confirm the value of CTC testing.

            From 2010-2012 alone, more than 85,000 U.S. patients and their oncologists used CELLSEARCH® to better understand the progression of disease and make more informed treatment decisions.

            To submit your concerns directly to Medicare about the pending Non-Coverage Decision test, you can go to:

            http://tinyurl.com/savecancertest/

            by John McCleery

            Xtandi PREVAILs in Metastatic Castrate-Resistant Prostate Cancer

            Prostate cancer is the most common cancer in men and the second most common cause of cancer deaths in men in the United States. The incident population of prostate cancer in the United States was above 200,000 patients in 2013.1 The rate of prostate cancer growth varies from very slow to moderately rapid, and some patients may have prolonged survival even after the cancer has metastasized to distant sites such as bone.

            Perhaps the most important recent advances in treatment of prostate cancer are the development and approvals of the next generation anti-androgens, Xtandi® (enzalutamide, Medivation/Astellas), FDA approved in August 2012 for treatment of metastatic castrate-resistant prostate cancer (mCRPC) in the post-docetaxel setting, and Zytiga® (abiraterone, Johnson & Johnson), FDA-approved in April 2011 in the post-docetaxel setting and subsequently approved in December 2012 to include use in the chemotherapy-naïve mCRPC setting. Approval of these two next-generation anti-androgens set the scene for an epic battle for market share between these agents.

            Impressive results from the international Phase III PREVAIL study were presented Thursday January 30, 2014, at the American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium by Dr. Tomasz Beer.2 PREVAIL, a randomized, placebo-controlled Phase III trial was designed to evaluate safety and efficacy of Xtandi versus placebo in patients with mCRPC. A total of 1,717 men who were asymptomatic or mildly symptomatic and chemotherapy-naïve were randomized to receive either Xtandi (n=872) or placebo (n=845). Co-primary endpoints were overall survival and radiographic progression-free survival (rPFS). The trial design included one planned interim analysis at approximately 516 events. The Independent Data Monitoring Committee analyzed the data following 540 deaths and reported significant benefits in overall survival and rPFS for patients in the Xtandi arm. Following this interim analysis, PREVAIL was halted, unblinded, and patients in the placebo arm were offered treatment with Xtandi.

            The median duration of treatment was more than three-fold longer for the Xtandi arm at 16.6 months versus 4.6 months for the control arm. rPFS was estimated at 13.8 months for the Xtandi arm versus 3.9 months for the placebo arm (HR=0.186; p < 0.0001) and this benefit favored Xtandi across all subgroups of patients (including performance status, age, geographic region, and presence of visceral disease). Treatment with Xtandi also provided a significant 29% improvement the risk of death, with an estimated 32.4 months median overall survival in the Xtandi arm compared with an estimated 30.2 months for the placebo arm (HR=0.706; p<0.0001). This improvement in overall survival came despite the fact that more patients from the placebo arm (70.3%) received at least one subsequent life-extending therapy compared with just 40.3% of patients in the Xtandi arm. Again, the survival advantage provided by Xtandi was consistent across all patient subgroups. Xtandi therapy yielded an objective response rate of 58.8%, including a complete response rate of 19.7%, compared with an objective response rate of only 4.9% and a 1% complete response rate in the placebo arm. Xtandi also delayed the median time to initiation of chemotherapy by 17 months (28.0 months versus 10.8 months). Xtandi was well tolerated in this trial, with the most common adverse events reported as fatigue, back pain, constipation and arthralgia, most of which were low grade. Other adverse events of interest that were slightly more prevalent in the Xtandi arm included cardiac adverse events, and hypertension, again, mostly low grade. Seizures were reported in one patient from each treatment arm.

            With strongly positive results from PREVAIL in hand, Medivation and Astellas will waste no time with their regulatory submissions to expand the label of Xtandi to include chemotherapy naïve mCRPC.  Upon approval, Xtandi will join Zytiga and Provenge® (sipuleucel-T, Dendreon) as the only approved agents to treat mCRPC prior to docetaxel therapy.  How physicians will choose which drug to use initially, and the ideal sequence of therapies over the course of the disease, is currently one of the most asked questions in the prostate cancer field.  If we look strictly at clinical outcomes in the two pivotal Phase III trials in chemotherapy-naïve mCRPC (keeping in mind the usual caveats about cross-trial comparisons), both Xtandi and Zytiga significantly improve rPFS (with potentially stronger benefit in the Xtandi trial) but slight differences exist with regard to impact on overall survival ― Zytiga offers a 5.2 month OS benefit that failed to reach statistical significance,3 while Xtandi offers a 2.2 month OS benefit that did reach statistical significance.  Which of these outcomes will prove more meaningful and convincing to physicians and patients who are weighing their options between multiple effective agents, and what other factors will come into play in such decisions?  With both drugs projected to be blockbusters, this truly is the billion dollar question.  Other factors to be considered include:

            • Safety: the toxicity profile of each drug is great in comparison with chemotherapy, but small differences exist between the two with regard to liver, cardiovascular, and seizure events)
            • Use of concomitant corticosteroids: Zytiga requires this, Xtandi does not
            • Cost of therapy: Xtandi is slightly more expensive on a monthly basis
            • Sequencing of the two agents: there remains limited data to understand whether one sequence is more effective than the other, but this is a hotly debated topic
            • Secondary endpoints: time delay to initiation of chemotherapy may hold significant influence with physicians, and the data for this endpoint appear stronger for Xtandi (17.2-month benefit over placebo) than was reported with Zytiga (8.4-month benefit over placebo)
            • Physician specialty: urologists and oncologists are both key treaters of mCRPC, but the influential factors that guide treatment decisions may differ between these specialists

            There remain a lot of unknowns with regard to the future treatment paradigms for mCRPC.  But one thing remains certain: the pace of development, level of competition, and clinical improvements in prostate cancer are growing by leaps and bounds, and the patients will reap the greatest rewards.

            References:

            1 Kantar Health CancerMPact® United States Patient Metrics, accessed January 30, 2014.

            2 Beer TM, et al., Abstract LBA1, ASCO GU Symposium 2014.

            3 Zytiga FDA label, accessed January 30, 2014.

            By: Stephanie Hawthorne, Ph.D., Director, Clinical & Scientific Assessment, Kantar Health and Greg Wolfe, Ph.D., Senior Consultant, Clinical & Scientific Assessment, Kantar Health

            ASCO Genitourinary Cancers Symposium Presscast Highlights Advances in GU Cancers

            January 28, 2014—In a presscast held in advance of the 2014 Genitourinary Cancers Symposium (Jan. 30-Feb 1) in San Francisco, researchers reported survival improvements in genitourinary tumor types, indicating that some aspects of clinical practice could change as a result of the studies.

            • For men with metastatic castration-resistant prostate cancer, enzalutamide improved overall survival in the phase III PREVAIL study, and significantly prolonged the time before chemotherapy was needed
            • For men with locally advanced prostate cancer, radiotherapy plus oral anti-androgen therapy more than halved the 10- and 15-year cancer-specific mortality rate in the Scandinavian Prostate Cancer Group’s Study VII
            • Persons with metastatic renal cell carcinoma who were taking angiotensin system inhibitors had improved survival compared with non-users of these anti-hypertensive agents
            • An analysis of data from the Clinicaltrials.gov web site showed that one in five cancer clinical trials fails to be completed, mostly due to poor accrual of subjects

            Enzalutamide Offers Overall Survival Benefit Prior to Chemo

            In the phase III PREVAIL study, enzalutamide significantly reduced the risk of death, significantly delayed progression, produced meaningful responses in soft tissue disease, significantly delayed the time to initiating chemotherapy, and was well tolerated over an extended period of time in men with castration-resistant metastatic prostate cancer (mCRP) that progressed on androgen-deprivation therapy, according to Tomasz Beer, MD, Professor of Medicine and Deputy Director of the Knight Cancer Institute at Oregon Health and Science University.

            The study enrolled 1,717 men with mCRP who had not received treatment for metastatic disease. The two primary endpoints were overall survival and radiographic progression-free survival (assessed by bone and CT scans).

            Enzalutamide was associated with a 29% reduction in the risk of death (P<0.0001), and an 81% reduction in the risk of radiographic progression (P<0.0001). Treatment with enzalutamide was also associated with significantly greater responses in soft tissue disease that was measurable on imaging, 59% vs 5% for placebo.

            Enzalutamide also prolonged the time before patients needed chemotherapy, which Dr. Beer called a “pragmatic measure of a real-world treatment effect.” Median time to chemotherapy was 28 months with enzalutamide, vs 10.8 months with placebo, a 65% reduction in risk and an absolute benefit of 17 months (P<0.0001).

            Grade 3 and 4 adverse events occurred in 43% of the enzalutamide arm and 37% of the placebo arm. The most common adverse events with enzalutamide were back pain, fatigue, constipation and arthralgias, mostly grades 1 and 2. Only 6% of each arm discontinued due to toxicity.

            “Because of these positive findings, my view is that enzalutamide provides meaningful clinical benefit” in this setting,” he said in the briefing. “If approved for this indication, it will become an important standard option for use before chemotherapy in patients with asymptomatic or minimally symptomatic advanced prostate cancer,” he went on to say.

            Radiotherapy Plus Anti-Androgen Treatment Improves Long-Term Survival

            In an updated analysis of the Scandinavian Prostate Cancer Group’s Study VII, the addition of radiotherapy to oral anti-androgen treatment more than halved the 10-year and 15-year prostate cancer-specific mortality rates for men with locally advanced prostate cancer, compared with anti-androgens alone.

            Compared with radiotherapy alone, the combination treatment “more than doubles the 10-year survival rate and confirms that this approach should be a standard option for men with this type of prostate cancer who are expected to live at least another 10 years,” said Sophie Dorothea Fosså, Professor of Oncology at Oslo University Hospital in Norway.

            The study included 875 patients with locally advanced prostate cancer who received 3 months of total androgen blockade (medical castration); half then received continuous anti-androgen therapy while the other half received continuous anti-androgens plus radiotherapy (70-74 Gy). They were followed for a median of 10.7 years.

            Fosså noted that the radiation dose is higher than is typically used in the United States, which may help explain the benefit observed in this study.

            The cumulative prostate cancer-specific mortality rate at 10 years was 8% with the combination vs 19% with hormonal therapy alone, a 65% reduction, and at 15 years was 12% and 31%, respectively.

            The overall mortality rate was 26% vs 35%, respectively, at 10 years, and 43% and 57%, respectively, at 15 years, she reported. She noted that the 10-year prostate cancer-specific mortality rate of 8% is comparable to results after prostatectomy in comparable patients.

            “In these patients, the combination of radiotherapy and hormones may be considered a standard curative treatment option,” she suggested.

            Anti-Hypertensive Agent Improves Survival in RCC

            A retrospective analysis of patients with metastatic renal cell carcinoma (RCC) found that patients who received an angiotensin system inhibitor (ASI) had improved survival, compared with patients not treated with these agents. When patients also received an agent targeting the vascular endothelial growth factor (VEGF) pathway, survival was further improved, according to Rana McKay, MD, an oncology fellow at Dana Farber Cancer Institute, Boston.

            Dr. McKay said the results support the use of ASIs for metastatic RCC patients who are hypertensive and lack contraindications for their use.

            The findings came from an analysis of 4,736 patients treated in phase II and III clinical trials. Median overall survival for patients receiving ASIs (n=1,487) was 26.7 months, compared with 17.05 months for those not using ASIs (n=3,249) (HR 1.213; P=0.0009).

            Further analysis showed that overall survival was improved in ASI users vs non-users, but was only statistically significant in patients also receiving a VEGF-targeted agent. For this group, median overall survival was 31.12 months versus 21.94 months for non-users (HR 1.380; P=0.0003).

            Differences were not significant for users of mTOR-targeted agents or interferon-alpha.

            One in Five Cancer Clinical Trials Never Completed

            An analysis of cancer clinical trials registered on the web site Clinicaltrials.gov showed that about 20% of trials fail to complete, for reasons unrelated to a drug’s efficacy or toxicity.

            Matthew Galsky, MD, Associate Professor of Medicine at the Icahn School of Medicine at Mount Sinai in New York, reported the findings from an analysis of trials registered on the web site between 2005 and 2011.

            He noted, “Trials that are initiated, but fail to complete—ie, close without enrolling the intended number of subjects—represent an extreme example of inefficiency.”

            Dr. Galsky and colleagues found that of 7,776 phase II or III interventional trials in adult cancer patients, approximately 20% failed to complete for reasons unrelated to efficacy or toxicity. The main reason was failure to accrue.

            Other reasons included inadequate funding, cancellation by the sponsor, and departure of the principal investigator. Fewer than 20% closed because of lack of efficacy or excessive toxicity, and these were excluded from the analysis.

            “These failures represent important barriers to progress in cancer care,” he said.

            Dr. Galsky commented that this research is “not an indictment of any particular stakeholder,” instead, “we want to hold up a mirror” for the entire clinical trials system. “Clearly, there’s work to do,” he said.

            by Caroline Helwick

            Is TGF-β the New Kid on the Block for Nexavar Failures? Or is it More of the Same?

            Clinically speaking, hepatocellular carcinoma (HCC) is a particularly challenging disease. Surgery remains the only curative strategy for patients with HCC, however not all patients are eligible for surgery. The approval of Nexavar® (sorafenib, Bayer/Onyx/Amgen) revolutionized HCC, providing a targeted therapy option for patients with HCC and an advance over de facto standard doxorubicin. The enthusiasm for Nexavar is dampened by the fact that not all patients may be eligible for Nexavar treatment due to poor liver function, and options remain limited for patients whose disease progresses. Since the introduction of Nexavar, other targeted therapies have attempted to carve a place in the HCC treatment landscape, either as frontline agents or in the relapsed setting, only to be met with failure.

            Recent pivotal trial failures include: Sutent® (sunitinib, Pfizer) in comparison with Nexavar in first-line;1 brivanib compared with Nexavar in first-line2 and in Nexavar-refractory patients;3 and most recently Afinitor® (everolimus, Novartis) failed to demonstrate efficacy in Nexavar-refractory HCC patients.4 Despite multiple failures, there is a long list of agents that are currently in active clinical development either in Phase II or Phase III trials, with most agents aiming for the Nexavar-refractory population. Agents currently in pivotal trials in Nexavar-refractory patients include ADI-PEG20 (Polaris Group), Cometriq® (cabozantinib, Exelixis), ramucirumab (Eli Lilly), and Stivarga® (regorafenib, Onyx/Amgen), as well as tivantinib (Arqule/Daiichi Sankyo) that is being studied in a subpopulation of patients with MET overexpression.

            Into this matrix enters LY2157299, a novel transforming growth factor-beta receptor 1 (TGF-β1) kinase inhibitor that Eli Lily is developing in HCC. Elevated TGF-β1signaling promotes liver fibrosis and progression to HCC; hence targeting TGF-β signaling has been proposed as a unique approach in HCC treatment. While limited data is available with LY2157299, this agent prevented HCC cancer cell migration on extracellular matrix substrates in cell culture studies.5 Given the potential importance of this pathway in HCC and some preliminary evidence that inhibition of this pathway can inhibit certain processes in HCC, Eli Lilly is evaluating this compound in an ongoing Phase II study. The trial is evaluating LY2157299 in patients ineligible for Nexavar therapy or who have progressed on Nexavar. While the trial is still recruiting, interim results were presented6 at the American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium on Friday, January 17, 2014. The study accrued 109 patients who were randomized to two arms: Arm A LY2157299 at 160 mg/day and Arm B LY2157299 at 300 mg/day. Primary endpoints were time-to-progression (TTP) and biomarker changes (serum AFP, TGF-β, and e-cadherin). Serum AFP was used as a surrogate marker for clinical efficacy and patients in whom AFP levels decreased greater than 20% compared to baseline were considered “AFP responders.” Of the eligible patients accrued, about 80% were Nexavar-pretreated and 50% had AFP levels greater than 400 ng/ml at baseline. The median TTP was 12.0 weeks in Nexavar-refractory patients (90% CI: 6.6-12.6) and 18.3 weeks in Nexavar-naïve patients (90% CI: 6.6-42.4). About one-quarter of the patients achieved more than a 20% decrease in AFP levels and were categorized as AFP-responders. The drug was very well-tolerated, with the most common grade 3/4 toxicities being neutropenia (2.7%) and fatigue (1.8%). Perhaps the most exciting piece of data from this study was the increase in median OS in the AFP responder population compared to AFP-non-responders (93.1 weeks versus 29.6 weeks; p=0.00006). In contrast, median OS in the entire population was 8.3 mos (36 weeks). Given that Nexavar achieves an OS of about 10 months and given that not all patients can tolerate Nexavar, this appears to be a niche positioning opportunity for Eli Lilly.

            Although this study is very promising, there are a couple of caveats. Key amongst them is the use of AFP as a biomarker. Decreases in AFP levels have been shown to be clinically useful in monitoring tumor response in HCC patients; however, AFP detection is also known to be a poorly reliable marker, particularly in small tumors.7 This may present a challenge in metastatic disease or on small tumors that progress very slowly. Whether AFP is the most appropriate biomarker to use in this context and whether this is an appropriate biomarker to support approval down the line is not known – all biomarkers approved to-date focus on patient selection based on baseline presence of the biomarker; this would pave new ground as a biomarker of response post-therapy, and perhaps would be more useful in guiding decisions of whether to continue treating patients with the drug as opposed to guiding decisions of whether to initiate therapy with the drug. In addition, whether the inhibitor is truly inhibiting the TGF-βpathway is not known, as downstream targets such as phosphor-Smads have not yet been evaluated. The phosphorylation of Smad protein plays an important role in TGF-β signaling and activates a nuclear transduction protein.

            So where does LY2157299 stand in terms of novel agents in HCC? Clearly, it is too early to determine how this compound will fit into the overall picture of HCC therapy. The table below provides a preview of the clinical efficacy of LY2157299 in comparison to the key agents in development in Nexavar-refractory patients.

            Table 1: Efficacy Outcomes in Nexavar-pretreated HCC

            In favor of LY2157299 are its manageable toxicity profile and the fact that it targets a novel pathway. However, the demonstrated efficacy benefit in the general population is not striking compared to the other agents currently in development in the same population. The OS and TTP observed with LY2157299 in AFP responders are particularly intriguing; however, whether the test is appropriate or whether AFP level is an appropriate marker for response remains a concern. While the study is promising, we will have to wait until the data mature and see how this plays out in a larger Phase III trial.

            References:

            1. Cheng et. al., J Clin Oncol,. 31(32): 4067-4075, 2013
            2. Johnson et al., J Clin Oncol, 31(28): 3517-3524, 2013.
            3. Llovet et. al., J Clin Oncol,31(28):3509-16, 2013.
            4. Zhu et al.. Abstract 172, ASCO GI 2014.
            5. Duturi et. al. PLOS One 27;8(6):e67109 2013
            6. Faivre, Abstract LBA 173, ASCO GI 2014
            7. Farinati et. al., Am J Gastroenterol, 101(3):524-32, 2006
            8. Bruix et al., Eur J Canc, 49(16): 3412-3419, 2013
            9. Verslype, Abstract 4007, ASCO 2012

            By Neesha Suvarna, PhD, Consultant, Kantar Health and Len Kusdra, Analyst, Kantar Health

            Noteworthy Studies At ASCO GI Presscast

            January 14, 2014 — The 2014 ASCO Gastrointestinal (GI) Symposium will run from January 16-18, 2014, at the Moscone Center West in San Francisco, CA. More than 2500 medical, surgical, and radiologic specialists will attend and learn about the latest translational science and new approaches to diagnosis and management of GI cancers.

            A pre-meeting Presscast featured 5 important studies: 3 in difficult-to-treat cancers and 2 focusing on more convenient treatments and improved quality of life.

            Anti-Angiogenesis with Ramucirumab

            Second-line treatment with the combination of ramucirumab (an anti-angiogenesis inhibitor) plus paclitaxel increased overall survival (OS) by more than 2 months in patients with metastatic gastroesophageal junction (GEJ) and gastric carcinoma, according to results of the Phase III RAINBOW trial. This trial comes on the heels of the REGARD trial, showing that single-agent ramucirumab improved progression-free survival (PFS) in this setting.

            Median OS is 4-5 months with currently available second-line therapies. In RAINBOW, ramucirumab plus paclitaxel achieved a median OS of 9.6 months versus 7.4 months with paclitaxel (P=.016). Median PFS was 4.4 months for the combination versus 2.9 months with paclitaxel alone (P=.016).

            “These are astonishingly good results in this patient population. The improvement in survival was not only statistically significant, but clinically meaningful as well. The rate of tumor progression was reduced by 36%, and 6-month and 9-month PFS almost doubled [with ramucirumab],” stated lead author Hansjochen Wilke, MD, Kliniken Essen-Mitte, in Essen, Germany.

            RAINBOW, the largest gastric cancer second-line therapy trial conducted to date, enrolled 665 patients who progressed within 4 months of standard first-line platinum- and fluoropyrimidine-based combination chemotherapy. Patients were treated until disease progression, unacceptable toxicity, or death.

            Currently, only about 30% of patients with advanced gastric cancer receive second-line therapy in the U.S. compared with about 80% in Japan. “We expect that more people will be treated with second–line chemotherapy with this effective new drug,” said Dr. Wilke.

            Vaccine Strategy

            Updated results of a Phase II randomized trial found that a double hit with 2 vaccines (GVAX followed by CRS-207) markedly improved OS in patients with metastatic pancreatic ductal carcinoma compared to GVAX alone. Median OS was 6.1 months with the combination versus 3.9 months with GVAX alone (P=.0343).

            After 1 year, about 24% of patients were alive in the combination arm versus 12% of those in the GVAX-alone arm. Among patients who received 2 doses of GVAX and at least 1 dose of CRS-207, median OS was 9.7 months versus 4.6 months, respectively, (the protocol called for 2 doses of GVAX and 4 doses of CRS-207).

            Side effects were related to mode of administration (sub dermal or intra venous) and resolved quickly.

            The study enrolled 90 patients with metastatic pancreatic cancer who failed or refused chemotherapy.

            “This is the first time a randomized study has shown that immunotherapy is effective in pancreatic cancer. This is just a first step, and we plan to take this approach further,” stated lead author Dung T. Le, MD, Sidney Kimmel Comprehensive Cancer Center in Baltimore, MD.

            “This strategy extends survival without encountering the effects of chemotherapy,” stated Smitha Krishnamurthi, MD, Case Western Reserve University, Ohio, who moderated the Presscast.

            An additional 3-arm study is being planned to evaluate the combination compared with CRS-207.

            CAPTEM (Capecitabine and temozolomide)

            The combination of capecitabine and temozolomide (CAPTEM) achieved durable responses and extended PFS in 95% of patients with neuroendocrine tumors (NET) that progressed on standard high-dose octreotide. Responders included patients with carcinoid NET, which are typically chemoresistant.

            A few patients in this small study were able to get off their respirators and resume normal activities, and the remissions are long lasting, said lead author Robert L. Fine, Columbia University Medical Center, New York City.

            “New treatments are sorely needed for this disease,” said Dr. Fine.

            The study included 28 patients with various subtypes of NET. CAPTEM achieved tumor shrinkage in 43% of patients and stopped tumor growth in 54%. High response rates were observed in carcinoid and pituitary NET, typically very difficult to treat tumor subtypes.

            Among 12% of those with carcinoid tumors, 41% had tumor shrinkage; the typical response to chemotherapy in this subgroup is 0%-4%. Among the 4 patients with pituitary tumors, CAPTEM achieved 2 complete remissions, 1 partial remission (75% reduction in tumor size), and 1 had stable disease for 5 years.

            The most recent data capture shows that median PFS approaches 30 months and more than 4 years for 25% of patients. Median OS is longer than 25 months.

            Toxicities were minimal, said Dr. Fine.

            The combination versus temozolomide alone is now being studied in a cooperative group trial.

            “Although small and not randomized, this trial is of great interest because CAPTEM achieved responses in patients we consider chemoresistant,” said Dr. Krishnamurthi.

            Oral Capecitabine

            Oral capecitabine achieved equivalent outcomes as standard continuous infusional 5-FU when combined with neoadjuvant radiation in patients with stage II or III rectal cancer, according to mature results of NSAPB R-04. The study also found that oxaliplatin is of no additional benefit when added to either drug and is associated with increased overall toxicity.

            The study randomized 1608 patients who were receiving 5 weeks of neoadjuvant radiation therapy to 1 of 4 arms: 5-FU; 5-FU + oxaliplatin; capecitabine; capecitabine + oxaliplatin. Results showed no significant differences in loco-regional control rates and other 5-year outcomes, including disease-free survival and OS, among all 4 treatment arms.

            “This study shows you can use an oral drug, capecitabine, or continuous infusional 5-FU plus radiation, with indistinguishable outcomes. The same was true for oxaliplatin, but the side effects, especially increased grade 3 and 4 diarrhea, suggest that this drug should not be used in combination with radiotherapy in the preoperative rectal cancer setting,” stated lead author Carmen J. Allegra, MD, University of Florida in Gainesville.

            “Doctors should be reassured that they are not giving less effective therapy if they prescribe capecitabine. Oral capecitabine is certainly far more convenient for patients than placing an intravenous port for 5-FU and wearing a pump on their belts for 5 weeks.”

            Extended RAS Testing

            A retrospective analysis of a large Phase III study supports the use of extended KRAS testing in patients with metastatic colorectal cancer (mCRC) to identify subgroups that should be treated with panitumumab and other EGFR inhibitors. The study showed that tumors that contain RAS mutations beyond KRAS exon 2 are unlikely to benefit from the addition of panitumumab to second-line FOLFIRI chemotherapy.

            “Testing for RAS mutations will allow doctors to better select patients and only recommend panitumumab treatment to those most likely to benefit. These results confirm that it is RAS status that matters, not just KRAS, when determining if panitumumab therapy could be beneficial. These findings will spare patients with a RAS mutation the costs and side effects of a treatment that will not improve their outcomes,” stated lead author Marc Peeters, MD, PhD, Antwerp University Hospital, Edegem, Belgium.

            The study was based on tumor samples from 1186 patients enrolled in a large, international Phase III study evaluating the addition of panitumumab to FOLFIRI as second-line therapy.

            Forty-five percent of the patient population had mutated KRAS exon 2. Extended RAS testing revealed mutations that predicted for response to panitumumab in another 18%.

            Among patients treated with both panitumumab and FOLFIRI, median OS and median PFS were improved in those with wild-type RAS tumors versus those with RAS mutations: median OS was 16.2 months versus 11.8 months, respectively, and median PFS was 6.4 months versus 4.8 months, respectively. The addition of panitumumab to FOLFIRI was of no added survival benefit versus FOLFIRI alone in those who received panitumumab plus chemotherapy: median OS 11.8 months versus 11.1 months, respectively; median PFS was 4.8 months versus 4.0 months, respectively.

            “These findings support extended RAS testing as standard of care for metastatic CRC to identify patients who will benefit from panitumumab,” said Dr. Krishnamurthi.

            By Alice Goodman

            Impact of 55th ASH Annual Meeting on the Treatment of Chronic Lymphocytic Leukemia

            In an effort to provide you with timely market feedback from ASH 2013, OBR and MDoutlook are pleased to share results from MDoutlook’s second OncoPoll™ from the meeting exploring Chronic Lymphocytic Leukemia.

            Global Response from 24 Countries and 100 Respondents

            ROE

            • Austria, Bulgaria, Croatia, Czech Republic, Greece, Hungary, Lithuania, Norway, Portugal, Romania, Serbia, Spain, Sweden, Switzerland, Turkey

            ROW

            • Argentina, Australia, Uruguay

            Respondent Practice Classification and Meeting Attendance: Higher Attendance Amongst Ex-US Respondents Than US

            Survey Question: How would you classify your practice setting? Did you attend the 55th ASH Annual Meeting in New Orleans, LA?

            Key Conclusions

            • More US respondents practiced in community settings rather than academic ones.
              More than 1/3rd attended the ASH annual meeting
            • Ex-US had a 2:1 split between academic and community settings.
              2/3rd of Ex-US respondents attended the ASH annual meeting

            1) Chronic Lymphocytic Leukemia Patient Flow: “Watch and wait” CLL Patients Represent Largest Proportion for US and Ex-US

            Survey Question: In the past 12 months how many CLL patients have you attended fall into each of these sub-groups?

            Key Conclusions

            • “Watch and wait” CLL patients are largest subset of the patient population seen by both US and
              Ex-US respondents
            • Nearly 50% of the CLL patients seen by both US and Ex-US are in “Go go” and “Slow go” category
            • Patient distribution roughly similar for US and Ex-US respondents

            2) New Therapies: Obinutuzumab Expect to Have Large Impact on Treatment of “Slow go” Chronic Lymphocytic Leukemia

            Survey Question: Based on the data presented at the 55th ASH meeting how impactful do you think Obinutuzumab and Ofatumumab will be for “Slow go” CLL patient group? (Please rate 1=No impact to 5=Great impact)

            Key Conclusions

            • Both US and Ex-US respondents rated the impact of obinutuzumab higher than the impact of ofatumumab for the treatment of “Slow go” Chronic Lymphocytic Leukemia patients
            • Nearly 90% of US and Ex-US respondents rated obinutuzumab 4 or 5

            3) Anti-CD20 Antibody Therapy: Large Shifts Seen in Usage of Obinutuzumab and Ofatumumab

            Key Conclusions

            • US respondents plan to decrease the usage of rituximab by 38% and increase obinutuzumab and ofatumumab almost by 275% and 175% respectively
            • Ex-US respondents plan to decrease the use of rituximab by 20% and increase obinutuzumab and ofatumumab nearly by 375% and 175% respectively

            4) Anti-CD20 Antibody Therapy: Future Usage of Obinutuzumab and Ofatumumab is Higher in US than Ex-US

            Key Conclusions

            • Based on the clinical availability of obinituzumab and ofatumumab, nearly 50% of US respondents plan to use rituximab and obinutuzumab; ~30% will use ofatumumab
            • Nearly 60% of Ex-US respondents plan to use rituximab; ~30% will use obinutuzumab and ofatumumab
            • Anticipated usage of new therapies will be higher in US than Ex-US

            5) New Therapies: Both Ibrutinib and Idelalisib are Expected to Have Large Impact on Treatment of “No go” Chronic Lymphocytic Leukemia

            Survey Question: Based on the data presented at the 55th ASH meeting how impactful do you think ibrutinib and idelalisib will be for “No go” CLL patient group? (Please rate 1=No impact to 5=Great impact)

            Key Conclusions

            • Both US and Ex-US respondents rated the impact of ibrutinib higher than the impact of idelalisib for the treatment of “No go” CLL patients
            • Ibrutinib impact rating is relatively high for a therapy in phase II clinical trials
              • Over 90% of US and Ex-US respondents rated ibrutinib 4 or 5

            6) New Therapies: Majority of Respondents Are Expected to Use Ibrutinib and Idelalisib for CLL Patients with DEL17p and NL17p

            Survey Question: Ibrutinib has recently been granted FDA approval for the treatment of Mantle Cell Lymphoma and Idelalisb looks likely to also to receive FDA approval in the near future.  If these two therapies become available to you, what proportion of your patients do you expect to use these treatments?

            Key Conclusions

            • More than 80% of US and about 70% of Ex-US CLL patients with DEL17p are expected to receive ibrutinib and/or idelalisib
            • Nearly 2/3rd of CLL patients with NL17p are expected to receive ibrutinib and/or idelalisib in the US and Ex-US

            7) New Therapy: ABT-199 Is Expected to Have Large Impact On Treatment of Chronic Lymphocytic Leukemia

            Survey Question: Based on the data presented at the 55th ASH meeting how would you rate the impact of ABT-199 for your CLL patients? (Please rate 1=No impact to 5=Great impact)

            Key Conclusions

            • ABT-199, an inhibitor of Bcl-2, was highly and equally rated by both US and Ex-US respondents for the treatment of previously treated patients with DEL17p as well as relapsed/refractory patients previously treated with fludarabine
            • Nearly 70% of US and Ex-US respondents rated ABT-199 as 4 or 5; considered high for a treatment in Phase 1 clinical development

            For a more detailed analysis, please click here to download the full report.

            Submitted by Jan Heybroek, President, Luan Dao, Sr. Global Medical Analyst, and Raj Manimaran, Global Medical Analyst, MDoutlook