The OBR Blog

April 07, 2014 - 11:04 am Posted in AACR Conference Coverage comments0 Comments

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.


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

April 06, 2014 - 12:04 pm Posted in COA Conference Coverage comments0 Comments

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

          April 05, 2014 - 12:04 am Posted in COA Conference Coverage comments0 Comments

          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

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