ASCO, Author Interviews, Biomarkers, Cancer Research, Cost of Health Care, Immunotherapy / 07.06.2016
Chemotherapy and Toxicities of Immune Checkpoint Inhibitors May Be Prohibitively Expensive
MedicalResearch.com Interview with:
Neil T. Mason, MBA
Personalized Medicine Strategist
Personalized Cancer Medicine
Division of Population Science
Moffitt Cancer Center
MedicalResearch: What is the background for this study? What are the main findings?
Response: Immune checkpoint inhibitors targeting PD-1 (nivolumab and pembrolizumab) and CTLA-4 (ipilimumab) have revolutionized the treatment of metastatic disease in melanoma and non-small cell lung cancer with additional indications showing positive results. These drugs have elicited profound and durable responses in a significant number of patients, but have been criticized for their high cost. Though the price of the drugs themselves can reach over $100,000 per year, they can also cause severe, life threatening toxicities that are difficult and expensive manage.
This model utilizes patient data from a large, NCI-designated cancer center to estimate the average cost of treatment with immune checkpoint inhibitors based on average duration of treatment and reported incidence of major toxicities. Based on the model, PD-1 inhibitor therapies are less costly than ipilimumab due to the significantly higher cost per dose of ipilimumab and average treatment duration of less than a year for PD-1 inhibitors. Managing drug-related toxicities were estimated to contribute between $8,200 and $9,600 to the cost of therapy with nivolumab adding the most cost.
Dr. Maria Schwaederle[/caption]
Maria Schwaederle PharmD
Clinical Research Scientist
Center for Personalized Cancer Therapy
UCSD Moores Cancer Center
La Jolla, CA 92093
MedicalResearch.com: What is the background for this study? What are the main findings?
Dr. Schwaederle: We performed this analysis with experts in the field, including but not limited to Drs Schilsky, Lee, Mendelsohn and Kurzrock, all known for their experience in the area of precision/personalized medicine.
Historically, phase I trials (which are often first in human or highly experimental in other ways) were believed to be examining only toxicity. Our meta-analysis of 13,203 patients shows that in the era of precision medicine, this historical belief needs to be discarded. Second, it is the use of precision medicine that makes this belief outdated.
Indeed, Phase I trials that utilized a biomarker-driven approach that is the essence of precision medicine had a median response rate of about 31%, which is higher than many FDA approved drugs, and this is in spite of the fact that phase I patients are a highly refractory group having failed multiple lines of conventional therapy.
Importantly, however, it was not the use of targeted agents alone that was important. It was the biomarker-based approach where patients are matched to drugs. Without matching, response rates were dismal—about 5%.
Dr. Dawn Hershman[/caption]
Dawn L. Hershman, MD MS
Professor of Medicine and Epidemiology
Leader, Breast Cancer Program
Herbert Irving Comprehensive Cancer Center
Columbia University
NY NY
MedicalResearch.com: What is the background for this study? What are the main findings?
Dr. Hershman: Chemotherapy induced peripheral neuropathy is a common side effect of anti cancer therapy and there are currently no ways to prevent it. We used a large clinical trials database, SWOG, and linked it to Medicare claims for patients over the age of 65. We found that age and type of taxane were associated with the development of CIPN. We also found a significant increase when a taxane was given along with a platinum agent. We found a doubling of risk among patients with a prior history of diabetes. No other chronic condition was associated with an increased risk of CIPN. We found a suggestion of a decreased risk among patients with a prior history of auto-immune disease.
Dr. Katie Greenzang[/caption]
Katie Greenzang, MD
Dana-Farber/Boston Children’s Cancer and Blood Disorders Center
MedicalResearch.com: What is the background for this study? What are the main findings?
Dr. Greenzang: Advances made over the last several decades mean that more than 80 percent of children diagnosed with cancer will become long-term survivors. However, many of these survivors experience physical and cognitive late effects of the treatment that cured them. We surveyed 352 parents of children recently diagnosed with cancer to assess how well they understood their children’s risk of future limitations in physical abilities, intelligence, and quality of life. We found that an overwhelming majority of parents (92 percent) are very interested in learning about possible late effects, and most (86 percent) seek detailed information. Yet, parent and physician predictions of a child’s risk of experiencing late effects of treatment often don’t match. Among children identified by their oncologists as being at high risk for such challenges, only 38 percent of parents recognized this risk in physical abilities, 21 percent in intelligence, and 5 percent in quality of life.
Dr. Gregory Idos[/caption]
Gregory Idos MD
Division of Gastroenterology and Hepatology
Keck School of Medicine
University of Southern California
Los Angeles, CA 90033
MedicalResearch.com: What is the background for this study? What are the main findings?
Dr. Idos: Identifying individuals at increased risk for hereditary cancer prompts enhanced cancer surveillance as early detection mitigates disease specific morbidity and mortality. This justifies germ line genetic testing for specific cancer risk alleles. In recent years, the field of cancer genetics has moved from a gene by gene sequencing approach to now having the ability to examine multiple genes concurrently. Multiplex gene panel (MGP) testing allows simultaneous analysis of multiple high- and moderate- penetrance genes. As a result, more pathogenic mutations and variants of uncertain significance (VUS) are discovered. MGP tests are increasingly being used by cancer genetic clinics, but questions remain about the clinical utility and complexities of these tests.
We are conducting a multi center prospective trial to measure the added yield of detecting pathogenic mutations using the MGP approach. In our interim analysis of the first 1000 participants, we found that multiplex gene panel testing increased the yield of detection of pathogenic mutations by 26%. In some cases, we found patient’s who had a mutation in the BRCA gene, but their family history did not indicate a history of breast or ovarian cancer.
Dr. Sarmad Sadeghi[/caption]
Sarmad Sadeghi MD, MS, PhD
Assistant Professor of Medicine
Norris Comprehensive Cancer Center
University of Southern California
MedicalResearch.com: What is the background for this study?
Dr. Sadeghi: Several years ago analyses of outcomes for radical prostatectomy highlighted the significant impact of surgical experience on the oncological outcome for the patients. In this case experience was measured by the number of radical prostatectomies performed by the surgeon, and oncological outcome was measured by treatment failure rates (rising PSA). Despite this data, the move for redirecting patients to “high volume centers” where more experienced surgeons perform the operation has been sluggish. There was insufficient data on what is involved in referring patients to high volume centers and whether or not such action is cost effective.
In a previous study we demonstrated that for every referral to a high volume center, there would be an average of $1,800 over a follow-up period of 20 years in societal cost savings. The main source of these savings is fewer treatment failures.
The next question was who is a good candidate for referral and whether these savings can offset the referral costs.
Dr. Philip McCarthy[/caption]
Philip McCarthy, BA, MD
Professor of Oncology
Director, Blood and Marrow Transplant Program
Roswell Park Cancer Institute
Associate Professor of Medicine
Jacobs School of Medicine and Biomedical Sciences
State University of New York at Buffalo
Buffalo, NY 14263
MedicalResearch.com: What is the background for this study? What are the main findings?
Dr. McCarthy: There have been three Phase III studies that examined the role of maintenance lenalidomide after autologous stem cell transplant (ASCT) for newly diagnosed multiple myeloma patients. IFM 2005-02 (France), CALGB 100104 (Alliance, USA), GIMEMA-RVMM-PI-209 (Italy). All three studies had progression free survival (PFS) as their primary endpoint and all demonstrated a superior PFS when compared to placebo or no therapy after ASCT. However only the CALGB 100104 study demonstrated a statistically superior overall survival (OS). Thus, a meta-analysis was necessary to assess the effect of post-ASCT lenalidomide maintenance on overall survival. This study utilized a pooled analysis of updated primary-source patient data from all three studies after the primary efficacy analyses had been conducted. The meta-analysis demonstrated that there is a statistically superior OS (P value=0.001, HR=0.74 (0.62-0.89)), Median OS for no maintenance or placebo was 86 months and the median OS for lenalidomide had not been reached. The median OS for lenalidomide treatment arm was extrapolated to be 116 months based on median of the control arm and HR (median, 86 months; HR = 0.74). Thus, there is a 26% reduction in the risk of death which is an estimated 2.5 year increase in median OS. There is an increased incidence of second primary malignancies with lenalidomide maintenance when compared to placebo but this risk is less than the risk of dying when not receiving lenalidomide.
Dr. Kenneth Iczkowski,[/caption]
Kenneth A. Iczkowski, M.D.
Department of Pathology
Medical College of Wisconsin
Milwaukee, WI 53226
MedicalResearch.com: What is the background for this study?
Dr. Iczkowski: The International Society of Urological Pathology (ISUP) in 2014 proposed use of a new 5-tier grade grouping system to supplement traditional Gleason grading to facilitate prognosis stratification and treatment1. The 5 categories subsume: Gleason 3+3=6, Gleason 3+4=7, Gleason 4+3=7, Gleason 8, and Gleason 9-10.
We desired to determine whether men with a highest Gleason score of 3+5=8 or 5+3=8 in their set of prostate biopsy specimens, would have differing outcomes from those with Gleason 4+4=8. Because Gleason 5 cancer has been demonstrated to have a higher biologic potential than Gleason 4, it was expected that Gleason score 8 pattern with any Gleason 5 pattern would have a worse outcome.
Dr. Wayne Furman[/caption]
Wayne L. Furman, MD
Department of Oncology
Jude Children's Research Hospital
Memphis, TN 38105-3678
MedicalResearch.com: What is the background for this study? What are the main findings?
Dr. Furman: Despite improvement in 2-yr EFS from 46% to 66% with the inclusion of dinutuximab, a monoclonal antibody that recognizes a glycoprotein on neuroblasts called ‘GD2’ (disialoganglioside), more than one-third of children with high-risk neuroblastoma still are not cured. Therefore novel therapeutic approaches are needed for this subset of patients. The clinical evaluation of various anti-GD 2 monoclonal antibodies in children with neuroblastoma has been exclusively focused on treatment of patients after recovery from consolidation, in a state of ‘minimal residual disease’. This is because traditionally chemotherapy has been thought to be too immunosuppressive to combine with monoclonal antibodies. However recent studies suggest, even in the setting of “bulky” solid tumors, the combination of chemotherapy with monoclonal antibodies can enhance the effectiveness of the antibodies. First, chemotherapy can increase the efficacy of antibodies by depleting cells of the immune system that suppress immune function. Also chemotherapy-induced tumor cell death can trigger tumor antigen release, uptake by antigen processing cells and an enhanced antitumor immune response. There is also data that anti-GD2 monoclonal antibodies can suppress tumor cell growth independent of immune system involvement. Furthermore anti-GD2 monoclonal antibodies and chemotherapy have non-overlapping toxicities. All of these reasons were good reasons to evaluate the addition of a novel anti-GD2 monoclonal antibody, called hu14.18K322A, to chemotherapy, outside the setting of minimal residual disease, in children with newly diagnosed children with high-risk neuroblastoma.
Dr. Andrea Wickremasinghe[/caption]
Andrea C. Wickremasinghe, MD
Neonatologist
Kaiser Santa Clara California
MedicalResearch.com: What is the background for this study?
Response: Neonatal jaundice is common and is often treated with phototherapy. Phototherapy is typically considered to be benign. In the past decade, phototherapy use has increased and it is sometimes started at bilirubin levels below recommended treatment thresholds. Beginning in the 1970’s, in-vitro and in-vivo studies have shown phototherapy to be associated with cellular changes implicated in the pathogenesis of cancer. Epidemiologic studies have yielded mixed results, with some studies showing associations between phototherapy and leukemia and other studies failing to show this association. In this study, we used a large statewide administrative dataset to investigate the relationship between neonatal phototherapy and cancer in the first year after birth.
Dr-Aurora-Perez-Cornago[/caption]
Aurora Perez-Cornago, PhD
Cancer Epidemiology Unit
Nuffield Department of Population Health
University of Oxford
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: Excessive body size and adiposity have been proposed to influence
several metabolic and hormonal mechanisms that can promote cancer development.
We found that men who have greater adiposity have an elevated risk of
high grade prostate cancer, an aggressive form of the disease, and
prostate cancer death.
Dr. Michael Johnson[/caption]
Michael A. Johnson Ph.D
Associate Professor
Department of Chemistry
University of Kansas
MedicalResearch.com: What is the background for this study? What are the main findings?
Dr. Johnson: We undertook these studies because chemotherapy induced cognitive dysfunction, also known as ‘chemobrain’, has become a major health issue in recent years. For example, up to a third of patients who have undergone chemotherapy treatment for breast cancer have reported symptoms of chemobrain. These symptoms may include loss of verbal and visual memory as well as decreased mental flexibility and difficulty focusing.
For this study, we wanted to understand how treatment with chemotherapeutic agents affects the ability of neurons to communicate. An impairment of neurotransmitter release would imply that communication is hindered. This inability to communicate normally could contribute to cognitive dysfunction.
We initially measured the release of dopamine in a region of the brain called the striatum. Our measurement of dopamine in this region was motivated by two key issues: its importance in cognitive function and our ability to measure it with high temporal resolution. From a cognitive standpoint, dopamine is important because the striatum helps translate signals, received from the cortex, into plans by forwarding wanted signals to other parts of the brain and suppressing unwanted signals. Fortunately, we can easily measure dopamine release using an electrochemical technique called fast-scan cyclic voltammetry. This method allows us to not only measure how much dopamine is released from a living brain slice, but also it affords us the capability to measure how quickly dopamine is taken back up. We also measured serotonin release using this method.
Our main finding was that the ability of neurons to release dopamine was impaired after carboplatin treatment. We also found that serotonin release was similarly impaired. These release impairments corresponded to a decrease in cognitive ability of the treated rats.
Dr. Robert Wong[/caption]
Robert Wong, M.D., M.S.
Attending Physician, Gastroenterology & Hepatology
Director, GI Education & Research
Highland Hospital I A member of Alameda Health System
Oakland, CA
MedicalResearch.com: What is the background for this study? What are the main findings?
Dr. Wong: Colorectal cancer is a leading cause of morbidity and mortality in the United States. Early diagnosis through implementation of effective screening and surveillance programs leads to earlier staged tumor at time of diagnosis, which increases the treatment opportunities and improves overall survival. However, disparities in access to effective screening and surveillance can impair timely diagnosis and lead to advanced disease, limited treatment options and poor outcomes. The current study evaluated race/ethnicity-specific disparities in colorectal cancer epidemiology at a large urban safety net hospital and observed African American patients had significantly more advanced cancer stage at the time of diagnosis. Our study observed that African Americans were over 5 times more likely to have advanced stage 3-4 colon cancer at time of diagnosis compared with non-Hispanic white patients with colon cancer. While these findings are likely multifactorial, it sheds important light on race/ethnicity-specific disparities in colorectal cancer epidemiology and helps target future education and research to improve outcomes.
Dr. Sibaji Sarkar[/caption]
Sibaji Sarkar Ph.D
Instructor of medicine
Boston University School of Medicine
Boston
MedicalResearch.com: What is the background for this study? What are the main findings?
Dr. Sarkar: Although breast and ovarian cancers have different clinical presentations, there are certain molecular events that are conserved between the two types of cancers. For example, mutation in a few genes, such as BRCA1, BRCA2, is an indicator of possible development of both breast and ovarian cancers. ARHI, a pro-apoptotic imprinted gene is epigenetically silenced in both breast and ovarian cancers. A similar pattern was observed in microRNA as well. There are also several genes which are differentially expressed in these two types of cancers but few of these striking resemblances led us to investigate whether they have a common origin. In this paper, we compared genetic and epigenetic events in both breast and ovarian cancers and we hypothesize that they may have similar origin (mechanism of formation of cancer progenitor cells), which should be regulated by epigenetic mechanism.
Nana Keum[/caption]
NaNa Keum, ScD|
Harvard T. H. Chan
School of Public Health Department of Nutrition
Departments of Nutrition and Epidemiology,
Harvard T.H. Chan School of Public Health
Boston, MA 02115
MedicalResearch.com: What is the background for this study?
Response: While general health benefits of physical activity are well-known, evidence on its specific benefits on cancer endpoints is limited and physical activity guidelines for cancer prevention lack details in terms of the optimal dose, type and intensity of physical activity.
MedicalResearch.com: What are the main findings?
Response: We found that the optimal exercise regime to prevent overall digestive system cancers may be to accumulate 30 MET-hours/week of physical activity primarily through aerobic exercise and regardless of its intensity.
Dr. Alejandro Sousa[/caption]
Alejandro Sousa, MD, PhD
Department of Urology, Comarcal Hospital
Monforte, Spain
MedicalResearch.com: What is the background for this study?
Dr. Sousa: Bladder Cancer management has remained stable over the past 25 years, with very little in the way of new therapies or approaches being developed. Traditional treatment using intravesical Mitomycin C for Non Muscle Invasive Bladder Cancer (NMIBC) patients is limited due it's low absorption levels. Device assisted therapies that deliver Chemo-hyperthermia offer a new hope, with the potential for improved outcomes and better disease management due the the increased drug activity and better efficacy. We wanted to investigate the optimal treatment regime for this new therapy and whether it provides a safe and effective alternative to current standard treatment.
Dr. James Welsh[/caption]
James S. Welsh, MS, MD, FACRO
President, American College of Radiation Oncology
Professor and Medical Director
Director of Clinical & Translational Research
Department of Radiation Oncology
Stritch School of Medicine Loyola University- Chicago
Cardinal Bernardin Cancer Center
Maywood, IL 60153
Chief of Radiation Oncology
Hines VA Medical Center
MedicalResearch.com: What is the background for this study? What are the main findings?
Dr. Welsh: Cancer immunotherapy could represent a truly powerful means of addressing cancer. Although immunotherapy itself is not new, there are new agents and combinations of older agents (including radiation therapy) that could prove more successful than anything we have seen in many years. The data in melanoma thus far is quite encouraging and this preliminary success could possibly extend to many other malignancies as well.
Dr. Aaron Thrift[/caption]
Aaron Peter Thrift, Ph.D
Assistant Professor
Duncan Cancer Center
Department of Medicine, Gastroenterology Section
Baylor College of Medicine
Houston, TX, US
MedicalResearch.com: What is the background for this study? What are the main findings?
Dr. Thrift: Patients with Barrett’s esophagus are at significantly higher risk of developing esophageal adenocarcinoma. Due to the continued rise in incidence of esophageal adenocarcinoma attention has turned to chemoprevention as a method to delay or halt the progression of Barrett’s esophagus to neoplasia, including invasive cancer. Acid suppressive medications, such as proton pump inhibitors (PPIs) and histamine-2 receptor antagonists (H2RAs), are commonly used in patients with gastroesophageal reflux disease (GERD), the primary risk factor for Barrett’s esophagus.
We contacted a nested case-control study involving 311 patients with Barrett’s esophagus who developed esophageal adenocarcinoma (cases) and 856 matched controls (patients with Barrett’s esophagus but who did not develop esophageal adenocarcinoma). Compared to never users, we found that Barrett’s esophagus patients taking PPIs and H2RAs had 69% and 45% lower risk of esophageal adenocarcinoma, respectively. The associations were independent of other risk factors for progression, including concomitant use of nonsteroidal anti-inflammatory drugs and statins.
Dr. Ze'ev Ronai[/caption]
Ze'ev Ronai, Ph.D.
Chief Scientific Advisor and Professor
Sanford Burnham Prebys Medical Discovery Institute
NCI-designated Cancer Center
MedicalResearch.com: What is the background for this study? What are the main findings?
Dr. Ronai: Our lab has been studying the role of the transcription factor ATF2 in melanoma, demonstrating it's oncogene function and the ability to attenuate melanoma development once inhibiting this transaction factor activity.
We set to examine the role of ATF2 using the genetic melanoma model of BRAF/PTEN to find that inactive ATF2 promotes melanoma development in this model.
To our great surprise the transcriptional-inactive form of ATF2 was sufficient to promote melanoma development when combined with mutant BRAF, pointing to the "super" oncogenic capacity of this protein.
Dr. Uras[/caption]
Dr. Iris Z Uras and Univ.-Prof. Dr. Veronika Sexl
[caption id="attachment_24559" align="alignleft" width="80"]
Dr. Sexl[/caption]
Institute of Pharmacology and Toxicology
University of Veterinary Medicine
Vienna
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults. Patients suffering from AML have poor prognosis and high mortality rate despite considerable advances in chemotherapy and hematopoietic stem cell transplantations. Up to 30% of patients with AML harbor an activating mutation in the FLT3 receptor tyrosine kinase (FLT3-ITD). Such mutations are associated with a high predisposition to relapse after remission. In a simplified way we can say that these tumor cells depend on FLT3: Is FLT3 blocked, cells die. Hence, FLT3 inhibitors are being developed as targeted therapy for FLT3-mutant AML; however, clinical responses are short-lived and their use is complicated by rapid development of resistance. This emphasizes the need for additional therapeutic targets.
Our study represents a novel therapeutic window to specifically target and kill AML cells with FLT3-ITD mutations. We found that the tumor-promoting enzyme CDK6 but not its close relative CDK4 directly regulates and initiates the production/transcription of FLT3 and thus lead to disease. The FDA-approved kinase inhibitor Palbociclib not only blocks the activity of CDK6 but in turn impairs FLT3 expression: Mutant AML cells die immediately. The treatment does not affect cells without the mutation.
The power of CDK6 inhibition in AML cells goes beyond FLT3: Palbociclib also stops production of the PIM1 kinase and thus overcomes the potential activation of survival pathways counteracting the effects of FLT3 inhibition.
Dr. Melissa Wilson[/caption]
Melissa A. Wilson, MD, PhD
Assistant professor of Medical Oncology
NYU Langone Perlmutter Cancer Center
MedicalResearch.com: What are the most common types of skin cancer?
Dr. Wilson: Basal cell carcinoma, squamous cell carcinoma and melanoma. With rare exception, all are related to sun exposure.
MedicalResearch.com: Are some types of skin cancer more serious than others?
Dr. Wilson: Melanoma is the most serious form of skin cancer, with the highest risk of developing into metastatic disease. Most basal cell and squamous cell carcinomas are superficial and not as invasive, so removal is the treatment. Rarely, these can cause invasive and metastatic disease, but this occurs infrequently. Melanoma is much more serious. Of course, the earlier melanoma is detected and the earlier stage that it is, is more predictive of a favorable outcome.
MedicalResearch.com: Who is most prone to skin cancer?
Dr. Wilson: Persons with excessive sun exposure, fair skin, light hair and blue eyes - although it can certainly occur in anyone.
Dr. Kapp[/caption]
Julie M. Kapp, MPH, PhD
Associate Professor
2014 Baldrige Executive Fellow
University of Missouri School of Medicine
Department of Health Management and Informatics
Columbia, MO 65212
MedicalResearch.com: What is the background for this study?
Dr. Kapp: For the past several decades the U.S. has had the highest obesity rate compared to high-income peer countries, and for many years people in the U.S. have had a shorter life expectancy. For female life expectancy at birth, the U.S. ranked second to last. At the same time, the U.S. has the third highest rate of mammography screening among peer countries, and the pink ribbon is one of the most widely recognized symbols in the U.S. While the death rate in females for coronary heart disease is significantly higher than that for breast cancer, at 1 in 7.2 deaths compared to 1 in 30, respectively, women have higher levels of worry for getting breast cancer.