Immunotherapy adoption in community setting hindered by costs, biomarker identification

Advances in immunotherapy have dramatically expanded the treatment armamentarium for both solid tumors and hematologic malignancies.

Monoclonal antibodies such as ipilimumab (Yervoy, Bristol-Myers Squibb), pembrolizumab (Keytruda, Merck), nivolumab (Opdivo, Bristol-Myers Squibb) and daratumumab (Janssen and Genmab) have changed the therapeutic landscape for cancers as diverse as melanoma, multiple myeloma and non–small cell lung cancer.

As the list of FDA-approved agents continues to grow, the focus has shifted from evaluation in clinical trial and academic settings toward their integration into community practices, which treat an estimated 85% of cancer patients in the United States.

Photo courtesy of Amy Cloud and PeaceHealth.

“Patients are coming to us now with information about this modality of treatment,” Jennie Crews, MD, director of medical oncology at PeaceHealth St. Joseph Cancer Center in Bellingham, Washington, and president-elect of the Association of Community Cancer Centers, told HemOnc Today. “They are hearing information on the news, or they may have friends who have been on these agents in clinical trials, and they are asking if they are candidates for these treatments.”

Although enthusiasm for immunotherapies is high, several factors — such as the potential for more severe adverse events outside academic practice, the need for applicable treatment biomarkers, and steep costs — could limit their utilization and accessibility in community practices.

Thus, experts have questioned whether patients treated outside of clinical trials and academic centers will be eligible for immunotherapy treatment.

HemOnc Today spoke with several community oncologists and researchers about safety concerns related to the introduction of immunotherapies into community practices, the need to identify biomarkers to make use of these agents more cost-effective, and how patient and oncologist education is key for successful communitywide implementation.

Efficacy vs. safety

Promising immunotherapy research — especially data presented at this year’s ASCO Annual Meeting — has fostered tremendous excitement among community practitioners who wish to incorporate immunotherapy into their patients’ treatment plans, particularly those with few other options.

“With the more recent data coming out, especially in melanoma and non–small cell lung cancer, I believe that in our community practice we will see some of these agents routinely, and rapidly, implemented into our treatment pathways,” Jai N. Patel, PharmD, chief of pharmacology research and phase 1 trials at Carolinas HealthCare System’s Levine Cancer Institute in Charlotte, North Carolina, as well as a HemOnc Today Editorial Board member, said in an interview. “As soon as immunotherapies become fully assimilated into treatment pathways, we are going to see a lot more community practitioners and programs using these agents; therefore, clinician education on drug administration and management of toxicities will be key.”

Results of a phase 3 trial presented at ASCO by Wolchok and colleagues showed nivolumab plus ipilimumab conferred a significantly higher PFS among patients with melanoma than either agent alone (11.5 months vs. 6.9 months for nivolumab monotherapy vs. 2.9 months for ipilimumab monotherapy). The combination also induced an overall response rate of 57.6% (95% CI, 52-63.2) and an average reduction in tumor burden of 52%.

Other study results have been similarly impressive. Lonial and colleagues presented phase 2 data at ASCO that showed single-agent daratumumab yielded an ORR of 29.2% and an expected 1-year OS rate of 65% among patients with heavily pretreated multiple myeloma.

Sapna Patel, MD, assistant professor in the department of melanoma medical oncology at The University of Texas MD Anderson Center, said these study results are exciting because of their potential to produce long-lasting responses, potentially without constant treatment.

“Immunotherapy can lead to long-lasting stability and responses in cancer, as study results have shown,” she told HemOnc Today. “Chemotherapy is generally effective only as long as you are giving it — then a month or 2 months after chemotherapy ceases, it is no longer really working in the body. The immune system is quite different, and immunotherapies that educate the immune system and produce memory cells against the cancer can live in perpetuity. A finite amount of treatment may produce a durable response.”

Despite the long-term benefit, some experts have acknowledged the possibility for more severe and unexpected adverse events from immunotherapies.

Skin rashes often are the first adverse effect to appear after treatment with immunotherapies, followed by gastrointestinal, hepatic, pulmonary, endocrine and renal adverse events.

In the study by Wolchok and colleagues, the rates for grade 3 to grade 4 adverse events were 55% for patients assigned nivolumab plus ipilimumab, 27.3% for patients assigned ipilimumab and 16.3% for patients assigned nivolumab. Approximately 36% of patients assigned the combination discontinued treatment due to adverse events.

In the study by Lonial and colleagues, at least one-quarter of daratumumab-treated patients experienced fatigue (39.6%), anemia (33%), nausea (29.2%) and thrombocytopenia (25.5%); further, 42% of patients experienced infusion-related reactions.

“An important issue moving forward — particularly in the community setting, where it is likely that oncologists are not as familiar with utilizing immunotherapies — is how to manage toxicities,” Jai Patel said. “Immunotherapies, particularly when used in combination regimens, are going to bring a whole new set of toxicities that we have not seen with chemotherapies or targeted agents.”

Although adverse events will likely differ from those associated with more standard approaches to cancer care, community oncologists have the resources and expertise to recognize and treat them, according to Jeffrey Vacirca, MD, FACP, CEO and managing partner of North Shore Hematology and Oncology Associates in East Setauket, New York, as well as vice president of Community Oncology Alliance.

“We have been through these evolutions before,” Vacirca said in an interview. “When the first of the monoclonal antibodies came out, such as rituximab [Rituxan; Genentech, Biogen Idec], it came with a whole different side-effect profile than what we had seen.”

It is important to remember that the vast majority of the clinical development of these drugs takes place in the community, Vacirca said.

“We have participated in the trials to develop most of these drugs, as do a lot of community cancers centers,” Vacirca said. “We are as adept as anyone when it comes to taking care of the side effects of any immunotherapy.”

Despite clinical trial reports, community oncologists should not view immunotherapies as dangerous, according to Jeffrey S. Weber, MD, PhD, a tumor immunologist and immunotherapist at Moffitt Cancer Center in Tampa, Florida.

“It has always been my belief that drugs like ipilimumab, nivolumab and pembrolizumab — and even the combinations — are inherently safe,” Weber told HemOnc Today. “They require a learning curve. We have a lot of smart and well-trained medical oncologists practicing in the U.S. and around the world, and anyone who can learn how to deal with myelosuppression and stem cell transplantation can learn to deal with immunotherapies, because the adverse events we see are nothing compared to that.”

Cost of care

Because the financial burden of cancer care continues to rise, the cost of integrating immunotherapy into the community setting has become a key consideration.

During the plenary session at ASCO, Leonard Saltz, MD, chief of gastrointestinal oncology at Memorial Sloan Kettering Cancer Center and a HemOnc Today Editorial Board member, derided the cost of the nivolumab–ipilimumab combination investigated by Wolchok and colleagues. The cost for an entire year of treatment with this combination for one person would equate to $295,566, Saltz said.

In another example, Saltz noted the approved 2-mg/kg dose of pembrolizumab costs $14,500 for 1 month of treatment. However, a 10-mg/kg dose — evaluated in many abstracts presented at ASCO — would equate to a $1 million yearly cost per individual.

“Cancer drug prices are not related to the value of the drug,” Saltz said. “Rather, prices are based on what has come before and what the seller believes the market will bear.”

Although immunotherapies may become a standard of care, their initial costs likely will be steep, Bruce J. Gould, MD, medical director of Northwest Georgia Oncology Centers in Marietta, Georgia, and president of the Community Oncology Alliance, told HemOnc Today.

“The cost issue is always a tough question,” Gould said. “Based on my calculations, the average wholesale pricing for an average-sized patient on nivolumab would be approximately $156,000 per year. For pembrolizumab, it would be about $122,000 per year.”

Due to the relative novelty of immunotherapies, the optimal length of treatment has not been established. Thus, indefinite treatment could lead to dramatically higher costs.

“Right now, many immunotherapies are given until a patient no longer benefits,” Gould said. “That can be months or it can be years. We may determine that a patient can be given a drug for a shorter time and experience a lasting benefit, but that is not currently known. If we could determine that, it could positively impact the costs associated with immunotherapies.”

Crews agreed that cost is foremost on the minds of many community oncologists who are eager to add immunotherapies to their armamentarium.

“Community oncologists are very concerned about issues of coverage and reimbursement,” Crews said. “This is especially going to be an issue once we start combining these treatment modalities, which will escalate costs even more. We have concerns about our patients being able to afford these drugs, and we have concerns about the ability for our patients to access these drugs.”

Further, the trend toward value-based cancer care could impact immunotherapy use in the community, Crews noted.

“A question that comes up relates to how we are going to manage these concerns over cost in practice,” Crews said. “Are we going to need additional resources in our practices? Is this going to require additional authorizations and approvals? How does this fit into a larger context of value-based care reform, which is of great interest and importance to the community?”

The cost conversation should begin long before the agents hit the market, according to Sapna Patel.

“Once the drugs are through the approval process, it is far too late for us to engage in this discussion,” she said. “We as oncologists need to engage with the pharmaceutical companies during drug development and have a conversation about where we think these prices could land. The difficulty from the pharmaceutical perspective is that they are a business and need to recoup their years of research and development.”

Price issues might be assuaged as the drugs become more widely used, Weber said.

“At some point, insurance companies will balk as prices go up and up,” Weber said. “There is only so much money in the U.S., and the drug companies aren’t crazy. Between the government, the providers and the insurance companies, a strategy will be developed that will ameliorate the price to some degree.”

A greater number of available immunotherapies also may have a positive impact on pricing.

“When you have competition, you have to be competitive,” Weber said. “You have to make your product appealing. As more drugs enter the market and patients have a choice, we might see cuts in price.”

However, not all patient experiences with drug costs have been negative.

“I recently attended a patient symposium on immunotherapy, and because in the U.S. everyone’s insurance is a little bit different, somebody asked what the panel’s experience had been with bills,” Sapna Patel said. “Almost all of them said that their insurance did a great job jumping in and covering costs. Within the indications on the drug label, they had no issues. Still, if you have an 80/20 insurance plan, 20% of six figures is still going to be quite a bit out of pocket.”

Search for biomarkers

Because the cost of immunotherapy could be exponentially high, the identification of biomarkers to better select patients for treatment is essential.

“The way for a patient to get the most bang for their buck would be to determine a consistent biomarker for response,” Gould said. “That way, we would know whether giving a patient a particular drug would be a waste of their time and money, and we don’t have to spend $150,000 for a patient who is not going to benefit. We could work on finding a different, better treatment for them.”

Jai Patel agreed, although he noted that studies of biomarkers thus far have offered mixed results.

“There have been studies looking at PD-L1 as a biomarker, and they have been pretty challenging,” he said. “PD-L1 negativity seems to be unreliable — we still occasionally see response from patients with PD-L1–negative tumors.”

Spigel and colleagues presented data at ASCO that indicated nivolumab benefited patients with squamous NSCLC regardless of PD-L1 expression.

Conversely, Garon and colleagues presented data at the American Association for Cancer Research Annual Meeting that showed patients with NSCLC whose tumors exhibit strong PD-L1 tumor expression may derive particular benefit from pembrolizumab.

Biomarker testing should occur more frequently than it currently does, according to Vacirca, who hopes to see expanded testing as immunotherapies are introduced to the community.

“Community and academic centers understand what the rationale behind the companion diagnostic is,” Vacirca said. “We have been doing it for years. It started with chronic myeloid leukemia and BCR-ABL, where it was necessary to have a Philadelphia chromosome in order to see a distinct response to imatinib [Gleevec, Novartis]. These tests should be done reflexively, but they are not. That is not a problem with oncology. It is a problem with pathology.”

The potential for biomarkers to evolve during the treatment process may explain variant results.

“We are not sure if the biomarkers will exist in the blood after several rounds of treatment or whether they will be detected in the actual tumor,” Sapna Patel said. “Immune molecules are very dynamic. If someone is widely metastatic but you are using a sample from 2 years ago when he or she was first diagnosed, it is not clear if the original sample will hold the biomarker that tells you if they will respond now.”

The amount of research into biomarker identification, as well as the FDA’s strong push to define biomarkers for immunotherapies under review, could expedite biomarker identification.

“So far, what we have seen are associations, not absolute predictions,” Weber said. “The biomarkers cannot give you the level of information that says a patient will not respond to drug X, so let’s try drug Y. But, I am confident that, within the next 5 years, we will see some real predictive biomarkers for checkpoint inhibition.”

Crews had hoped that more research would become available as immunotherapeutic regimens received FDA approval.

“We in the community are really just awaiting more clarification from those who are doing the research,” Crews said.

Education key to acceptance

Clinicians with whom HemOnc Today spoke agreed that education will form the initial cornerstone of acceptance in the community setting.

“Education for clinicians and patients is going to be huge for immunotherapies,” Jai Patel said. “That way, the clinician can be well informed of all the risks and benefits of a therapeutic choice, and can present a confident treatment plan to the patient.”

Organizations such as the Association for Community Cancer Centers and the Institute for Clinical Immuno-Oncology already have begun to educate providers about immunotherapies, Crews said.

“We are holding webinars about the use of immuno-oncology,” Crews said. “We have professional meetings scheduled that will focus on important topics, as well as practice issues like coverage and reimbursement.”

Partnerships between community practices and academic centers could be the key to immunotherapy education, Sapna Patel said.

“We in the academic community can aid in bringing information to frontline community doctors,” she said. “Ideally, a community provider would have an academic expert whom they could call directly.”

Weber agreed.

“There are people like me out at meetings and lectures who are happy to harangue colleagues about the benefits of these therapies,” Weber said. “Doctors will figure out that it is just something different, something new to get excited about. As someone who has spent a lot of time in the immunotherapy world, there have been instances where these therapies have required me to consider things I have not touched since medical school.”

Further, education should extend beyond doctors.

“If we stop only at the oncologists, then we are leaving out a huge segment of our providers: the nurse practitioners, the physician assistants,” Sapna Patel said. “Those advanced practice providers are really in partnership with oncologists across the country and make up an essential part of treatment teams. We make a lot of assumptions that our advanced practice professionals know what we mean when we say ‘checkpoint inhibitor’ or ‘PD-1,’ but it is our job to make sure that they are educated on the finer points of immunotherapy.”

Although patients enrolled on immunotherapy clinical trials may not adequately represent those treated in community practices, community oncologists are eager to translate information gained through clinical trials to their general patient populations, Vacirca said.

“The reality is that few patients seen in true clinical practice, whether in an academic center or in the community, are going to meet every one of those historic criteria used in trials,” Vacirca said. “For example, patients in lung cancer trials tend to be about 10 years younger than the majority of patients. Does that mean that we cannot use those therapies on these patients? Certainly not. It just means that patients enrolled in clinical trials tend to be healthier than those we see in everyday practice. But they can still benefit.”

Gould is confident that — sooner rather than later — immunotherapies will be folded into the standard, widely accepted cancer treatment armamentarium.

“There is no doubt about it,” Gould said. “We are on the tip of the iceberg. Immunotherapy is a game-changer in oncology, and it is going to allow us in the community to produce dynamic results for our patients.” – by Cameron Kelsall

References:

Awad MM and Hammerman PS. J Clin Oncol. 2015;doi:10.1200/JCO.2015.61.4172.

Garon EG, et al. Abstract CT10. Presented at: AACR Annual Meeting; April 18-22, 2015; Philadelphia.

Horvat TZ, et al. J Clin Oncol. 2015;doi:10.1200/JCO.2015.60.8448.

Larkin J, et al. JAMA Oncol. 2015;doi:10.1001/jamaoncol.2015.1184.

Lokhorst HM, et al. N Engl J Med. 2015;doi:10.1056/NEJMoa1506348.

Ribas A, et al. Lancet Oncol. 2015;doi:10.1016/S1470-2045(15)-00083-2.

The following were presented at: ASCO Annual Meeting; May 29-June 2, 2015; Chicago:

Lonial S, et al. Abstract LBA8512.

Spigel DL, et al. Abstract 8009.

Wolchok JD, et al. Abstract LBA1.

For more information:

Jennie Crews, MD, can be reached at PeaceHealth St. Joseph Cancer Center, 3301 Squalicum Parkway, Bellingham, WA 98225; email: jcrews@hotmail.com.

Bruce J. Gould, MD, can be reached at Northwest Georgia Oncology Centers, 340 Kennestone Hospital Blvd., Suite 200, Marietta, GA 30060.

Jai N. Patel, PharmD, can be reached at Levine Cancer Institute, Carolinas HealthCare System, 1021 Morehead Medical Drive, Charlotte, NC 28204; email: jai.patel@carolinashealthcare.org.

Sapna Patel, MD, can be reached at The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030; email: sppatel@mdanderson.org.

Jeffrey Vacirca, MD, FACP, can be reached at North Shore Hematology Oncology Associates, 235 North Belle Mead Road, East Setauket, NY 11733; email: jeffvacirca@gmail.com.

Jeffrey S. Weber, MD, PhD, can be reached at Moffitt Cancer Center, 12902 USF Magnolia Drive, Tampa, FL 33612; email: jeffrey.weber@moffitt.org.

Disclosure: Crews reports an advisory role with the Institute for Clinical Immuno-Oncology, which is sponsored by Bristol-Myers Squibb. Sapna Patel reports advisory roles with Amgen and Genentech; clinical trial support from Bristol-Myers Squibb, Genentech, Merck, Novartis and Prometheus; and a speakers bureau role with Dava. Weber reports consultant roles with AstraZeneca, Bristol-Myers Squibb, Genentech and Merck. Gould, Jai Patel and Vacirca report no relevant financial disclosures.

 

 

Are older patients with cancer at an increased risk for immunotherapy-related adverse events?

Preclinical studies indicate age may increase risk for immunotherapy-related toxicity.

As the majority of patients with cancer are aged older than 55 years, it is imperative to understand the potential impact of age when attempting to apply immunotherapeutic approaches. There are several important caveats to consider. First, it must be understood that the term “immunotherapy” covers a wide range of approaches. These approaches can exert markedly different effects depending on their mode of action as well as how they are applied (locally vs. systemically), and this can also markedly impact potential adverse events where the extent of immune activation tends to correlate with increased risk for toxicities. The goal of the majority of cancer immunotherapeutics is to augment antitumor T-cell responses that can be sustained and be specific for the cancer. These approaches have included:

Direct immunostimulatory agents ranging from systemic cytokine administration (eg, IL-2, IL-12, etc), toll receptor engagement (eg, CpG), or use of agonist antibodies to costimulatory molecules such as CD40, 4-1BB and OX40;

Adoptive cellular immunotherapy with dendritic cells, natural killer cells and/or T cells, including modified cells such as chimeric antigen receptor T cells; and

Reversal of immune suppression including antagonism of checkpoint blockade (eg, targeting CTLA-4, PD-1), indoleamine 2,3-dioxygenase inhibition and T-regulatory cell removal.

Looking at application of all these approaches, one can find extensive literature demonstrating considerable ranges of toxicities from simple fever and rash to life-threatening autoimmune attack and death from cytokine storm that leads to vascular leak and organ failure. Many of these sequelae are inflammatory in nature and can relate to extent of immune activation and inflammatory cytokine production as well as tumor cell kill. Aside from the approaches used, there are also significant variables related to inherent differences in immune status and response among a population based on immune history and concurrent subclinical infections as well as overall health that can affect therapy outcome.

One critical variable is the impact of age on the immune system, intensively studied but still poorly understood. It is clear that many changes occur with aging that in part are due to dysregulation of the immune system, predominance of skewing toward certain pathogens (eg, cytomegalovirus, Epstein-Barr virus) as well as the occurrence of “inflammaging,” in which chronic inflammatory conditions exist. In addition, cytoreductive conditioning regimens used in the majority of front-line cancer treatments also alter immune status and contribute to parenchymal organ damage and overall frailty. A key feature of human aging is its heterogeneity. For any measured variable, the scatter in values in a normal aged population is much wider than the variability of that parameter among younger people. This further complicates our capacity to predict how a particular person will respond to an immune intervention.

Recently, we demonstrated that a variety of systemic immunostimulatory regimens that could mediate protective antitumor effects in young mice instead resulted in rapid death to aged mice. This was due to multiorgan pathology resulting from an inflammatory “cytokine storm,” largely due to activated macrophages and their products. Normal aged inbred mice tend toward obesity. The use of caloric-restricted aged mice could obviate the inflammatory responses and pathology from the regimens. Conversely, young obese mice also demonstrated this heightened toxicity from immunotherapy, indicating the critical role that body fat can play in exacerbating inflammatory responses following immunostimulatory therapy. Interestingly, in these studies it appeared as though both age and adiposity contributed to the extent of inflammatory responses observed. Recent literature also indicates extent of tumor burden contributes toward increased inflammatory responses as tumor cells are killed and release their cellular contents.

Thus, based on preclinical data it would appear that factors such as immune status, high tumor burden, adiposity and increasing age can predispose toward increased toxicities from immunotherapy, particularly systemic immunostimulatory therapies. However these observations must be confirmed with careful clinical assessment. Further, this highlights the critical need for more accurate preclinical modeling to mirror the clinical scenario. As a practical matter, today it remains difficult to predict which patients will have serious toxicity and which will sail through therapy with mild or no side effects.

 

References:

Bouchlaka MN, et al. J Exp Med. 2013;doi:10.1084/jem.20131219.

Davila ML, et al. Sci Transl Med. 2014;doi:10.1126/scitranslmed.3008226.

Dutcher J, et al. Med Oncol. 2001;18:209-219.

Kammula US, et al. Cancer. 1998;83:797-805.

Mirsoian A, et al. J Exp Med. 2014;doi:10.1084/jem.20140116.

Tarhini A. Scientifica (Cairo). 2013;doi:10.1155/2013/857519.

William J. Murphy, PhD, is professor and acting chair of the department of dermatology at University of California Davis. He can be reached at wmjmurphy@ucdavis.edu. Disclosure: Murphy reports no relevant financial disclosures.

Dan L. Longo, MD, is deputy editor of The New England Journal of Medicine and professor of medicine at Harvard Medical School. He can be reached at dlongo@nejm.org. Disclosure: Longo reports no relevant financial disclosures.

Chronological age should not limit use of immunotherapy.

The first question to ask when considering the effects of a medical treatment on the elderly population is, “Who is elderly?” Chronological age does not always correspond with biological age. A person can be aged 70 years with chronic diseases, whereas someone else can be the same age, active and working. As such, it is important to understand “elderly” as a relative term.

For clinical trials, older patients are usually defined as age 60 years or older. However, other factors need to be considered for anyone around that age. The main factor that we consider is performance status, meaning general health. Someone who is generally healthy will have a lower risk profile for any treatment, whether standard therapies or immunotherapies. On the other hand, an older patient who — for example — has heart disease or diabetes, or who takes many medications, will face an increased risk. From a clinical standpoint, people aged 75 years or older inherently face a higher risk for adverse events. But from the ages of 60 years to 75 years — a period during which patients may be defined as “elderly” regardless of performance status — it is truly relative.

I treat patients with acute lymphoblastic leukemia. One of the immunotherapies approved by the FDA for relapsed and refractory ALL — blinatumomab (Blincyto, Amgen) — is approved for Philadelphia chromosome-negative patients. However, the National Comprehensive Cancer Network guidelines actually include all patients with ALL, including patients who are Philadelphia chromosome-positive (Ph+). More than half of patients aged older than 50 years with ALL are Ph+. Blinatumomab is given as a continuous IV infusion over 28 days, with the first 7 to 9 days spent in the hospital to observe for adverse events that occur early on in treatment. The main side effect is cytokine release syndrome (CRS), which is not common, but in severe cases can cause drops in blood pressure. People who are older and not in good health will have difficulty tolerating these adverse events. But over time, these issues resolve, and overall the drug is quite safe for most patients. This drug also carries the risk for infections; however, it is important to note that risk for infection is part of ALL in general. It could occur whether or not the patient receives the drug.

There are multiple clinical trials ongoing that are studying the use of genetically engineered T cells derived from the patient. This is far more experimental and carries more risks, notably CRS. However, the severity is related to tumor build-up prior to treatment. If a patient has a little tumor, the adverse event will probably be small or mild. In a larger tumor, it always appears and may be severe, requiring treatment to support blood pressure, or respiration assistance by intubation. An elderly patient with heart disease might not be able to withstand these risks. But for a similarly aged patient with good performance status, the benefits can outweigh the risks.

Older patients with low performance status or cardiac diseases are likely to be at greater risk for intolerable adverse events. This suggests that we should consider patients for immunotherapies based on their characteristics, not on their chronological age.

 

Dan Douer, MD, is the leader of the acute lymphoblastic leukemia program at Memorial Sloan Kettering Cancer Center. He can be reached at douerd@mskcc.org. Disclosure: Douer reports research funding from and advisory roles with Amgen and Pfizer.