Sarcopenia and Inflammation Associated With Increased Risk of Death in Patients With CRC 

Prediagnosis inflammation was associated with at-diagnosis sarcopenia (low skeletal muscle mass), and the combination of the 2 nearly doubled the risk of death in patients with nonmetastatic colorectal cancer (CRC), according to a study published in 

Sarcopenia and an elevated neutrophil-to-lymphocyte ratio (NLR, a measure of systematic inflammation), have been increasingly recognized as 2 novel prognostic indicators across cancer types, according to the authors. Sarcopenia can be used to predict adverse outcomes such as poor surgical outcomes, treatment toxicity effects, and reduced survival. Similarly, NLR values are utilized to predict treatment response.

“Whereas both sarcopenia and inflammation can be evaluated with existing clinical data and may be modifiable, the relationship between these 2 factors and their independent associations with survival are not well studied,” the authors wrote.

The authors studied 2470 patients from the Colorectal Cancer: Sarcopenia, Cancer, and Near-term Survival (C SCANS) cohort, which included Kaiser Permanente Northern California (KPNC) health plan members who were diagnosed with stage I to III CRC between 2006 and 2011. All participants underwent surgical resection and had abdominal computed tomography (CT) scans at diagnosis.

Using the scans, the authors measured skeletal muscle index. Sarcopenia was defined as less than 52 cm2/m2 for normal or overweight men and less than 38 cm2/m2 for normal or overweight women, and less than 54 cm2/ m2 and less than 47 cm2/m2 for obese men and women, respectively.

Systematic inflammation was measured by NLR from routine blood tests, and the authors averaged all available NLR measures from the 24 months prior to diagnosis. The mean number of NRL measures was 3, and was characterized using standard cut-offs to define normal inflammation as less than 3, moderate inflammation as 3 to less than 5, and high inflammation as 5 or higher.

The results showed that patients with a higher NLR in the 24 months prior to their diagnoses had less favorable values for all other markers of systemic inflammation: higher platelet-to-lymphocyte ratio, lower lymphocyte-to-monocyte ratio, and lower serum albumin level.

The prevalence of an NLR of 3 or greater and sarcopenia were 46% (n = 1133) and 44% (n = 1078), respectively. Over a median of 6 years of follow- up, there were 656 deaths, 357 of which were from CRC. Increasing NLR was associated with sarcopenia in a dose-response manner: compared with patients with NLR of less than 3, the odds ratios (ORs) for sarcopenia were 1.35 (95% CI, 1.10-1.67) for NLR of 3 to less than 5 and 1.47 (95% CI, 1.16- 1.85) for NLR of 5 or greater (

Results also showed that an NLR of 3 or greater and sarcopenia independently predicted overall and CRC-related death. Patients with both sarcopenia and an NLR of 3 or greater had a double the risk of death overall (HR, 2.12; 95% CI, 1.70- 2.65) and CRC related death (HR, 2.43; 95% CI, 1.79-3.29).

“Both sarcopenia and high NLR were independent prognostic indicators in nonmetastatic CRC,” the authors concluded. “If our findings are confirmed by additional studies, these 2 biomarkers are already collected in routine care and thus have high potential for use in clinical prognostication.”

Cespedes Feliciano E, Kroenke C, Meyerhardt J, et al. Associated of systematic inflammation and sarcopenia with survival in nonmetastatic colorectal cancer: results from the C SCANS study. JAMA Oncol. 2017;3(12):e172319. doi:10.1001/jamaoncol.2017.2319.

The Impact High OOP Costs Have on Patients Filling Prescriptions for Oral Cancer Drugs 

Patients with cancer may have more options for oral cancer medica- tions, but high out-of-pocket costs still present a barrier to access, according to a new study in 

Researchers reviewed claims from 2014 to 2015 from a large, proprietary, integrated database that included Medicare and commercial insurance enrollees for 38 oral anticancer agents. They looked at claim reversal (patients failing to purchase an approved prescription), delayed initiation, and abandonment.

The overall abandonment rate was 18% and rates of claim reversal ranged from 13% to 67% depending on the out-of-pocket (OOP) costs. The study found that 10% of patients who had to pay less than $10 did not pick up their prescription, while 32% of those who had to pay between $100 and $500 and nearly 50% of those who had to pay more than $2000 did not pick up their prescription.

“Patients in our study were facing a new cancer diagnosis or a change in their disease that required a new treatment. Imagine leaving your doctor’s office with a plan, ready to start treatment, only to find you can’t afford it,” lead author Jalpa A. Doshi, PhD, a professor in the Perelman School of Medicine at the University of Pennsylvania, and director of Value-Based Insurance Design Initiatives at the Leonard Davis Institute’s Center for Health Incentives and Behavioral Economics, said in a statement. “It adds more stress at what is already a stressful and scary time.”

The researchers also found that the relationship between high OOP costs and patients not filling their prescriptions was consistent across cancers, even for those that have treatments that significantly extend life. Patients with high OOP costs who did fill their prescriptions were more likely to delay it. With oral drugs, more of the medication’s cost is passed to the patient and complete payment is due upfront, which increases the risk of delayed access or abandonment.

The authors determined that if patients currently paying between $50 and $100 for prescription were bumped up to a higher cost category and were responsible for $100 to $500 instead, that the abandonment rates would actually double.

“This shows the importance of discussing financial barriers up front, during conversations about treatment options, even with patients who don’t raise concerns,” Doshi said. “Patients may not be aware of how expensive their prescriptions will be, and physicians may not realize that a patient has opted not to fill the prescription.”

Doshi JA, Li P, Huo H, Pettit AR, Armstrong KA. Association of patient out-of-pocket costs with prescription abandonment and delay in fills of novel oral anticancer agents. 

. 2018;36(5)476-482. doi:10.1200/ jco.2017.74.5091.

Articles

Evidence-Based Oncology

Medical World News: Clinical/Managed Care Updates

Serum Protein Signature Predicts Survival in Patients With Melanoma Receiving Anti-PD-1 Therapy

A pretreatment signature of proteins predicted survival in patients with metastatic melanoma receiving programmed cell death protein 1 (PD-1)— blocking antibodies, according to a December 2017 study published in 

Prior clinical results in patients with metastatic melanoma being treated with the PD-1 inhibitors nivolumab and pembrolizumab have led to substantial improvements in progression-free survival (PFS) and overall survival (OS). According to authors led by Jeffrey S. Weber MD, PhD (see Cover Story), there also have been efforts made toward determining the utility of programmed death ligand-1 (PD-L1) expression on tumor and/or immune infiltrating cells, as measured by immunohistochemistry.

“Correlations between PD-L1 expression and outcome with PD-1/PD-L1 antibodies have been observed in many studies, but melanoma patients with negatively stained tumors may still benefit from anti-PD-1 therapy,” the authors wrote. “A serum-based pre-treatment test of circulating proteins would not require tissue, and if found to be associated with a favorable response to PD-1 blocking antibodies, would be clinically useful.”

The authors conducted the test by collecting sera from 6 sample sets for test development and validation:

A development set of 119 patients with stage IV melanoma prior to treatment, in which the efficacy of nivolumab monotherapy at 1, 3, and 10 mg/kg with or without a multi-peptide vaccine was evaluated

3 validation sets of 101 patients receiving nivolumab or pembrolizumab

A validation set of 48 patients receiving ipilimumab

The sera were obtained with a matrix-assisted laser desorption/ionization time of flight (MALDI-TOF) mass spectrometry. These data, along with clinical data, were used to identify patients with better or worse outcomes. The test, developed with the Diagnostic CortexTM platform, was based on mass spectrometry analysis of patient serum samples. A signature consisting of 209 proteins or peptides was associated with OS and PFS in a multivariate analysis.

For the development set, the test classified 34 patients (29%) as “sensitive” and 85 (71%) as “resistant.” Both OS and PFS showed significant separation (

 = .002 and .016, respectively) by test classification, with substantial effect sizes for each (hazard ratios [HRs] of 0.37 and 0.55, respectively). Patients deemed “sensitive” had a 2-year survival rate of 67%.

The authors found that the test performance across validation cohorts was consistent with the development set results. Results of the pooled analysis showed significantly better OS for patients classified as “sensitive” compared with patients classified as “resistant” (HR, 0.15; 95% Cl, .06-.40; 

< .001). The ipilimumab-treated validation set demonstrated a significant difference in OS between sensitive and resistant groups (HR, 0.40; 

“The serum test described herein might identify patients expressing the ‘sensitive’ serum classification that have long overall survival with PD-1 blockade alone or with the addition of ipilimumab to nivolumab,” the authors concluded.

Weber JS, Sznol M, Sullivan RJ. A serum protein signature associated with outcome after anti—PD-1 therapy in metastatic melanoma. 

. 2017;6(1):79-86. doi:10.1158/2326-6066.cir-17-0412.

Increased CD8+ TIL Counts Linked to Prolonged Survival in Patients With Certain Ovarian Cancers

Epithelial Ovarian Cancer (OC) is responsible for 14,000 deaths each year in the United States, and although initial remission is often achieved, patients often relapse and succumb to the disease. Increasing CD8+ tumor-infiltrating lymphocytes (TILs) in several OC histotypes is associated with an increased rate of survival, according to a study published in 

“Cytotoxic CD8+ TILs participate in immune control of epithelial ovarian cancer,” the study authors wrote. “However, little is known about prognostic patterns of CD8+ TILs by histotype and in relation to other clinical factors.”

The authors assessed a prospective cohort of 5577 women with a primary diagnosis of epithelial ovarian, peritoneal, or fallopian tube cancer. Of the

5577 women, 5078 had tumors of the 5 major histotypes: high-grade serous OC (HGSOC), endometrioid OC (ENOC), clear cell OC (CCOC), mucinous OC (MOC), and low-grade serous OC (LGSOC). The patients were followed until death from any cause. Tumor specimens were taken from an initial debulking surgery, formalin-fixed, paraffin-embedded, and arranged on tissue microarrays.

Epithelial CD8+ TILs were examined using a 4-tiered scoring system. Of the HGSOC cases, 83% had evidence of CD8+ TILs, with lower rates seen in LGSOC (73%), ENOC (72%), CCOC (52%), and MOC (51%).

The results showed a strong association between increasing levels of CD8+ TILs and prolonged survival in HGSOC cases. The median survival was 2.8 years for women negative for CD8+ TILs, 3 years for low levels, 3.8 years for moderate levels, and 5.1 years for high levels. According to the authors, at the extremes, women with high levels of CD8+ TILs had a 43% reduced risk of death compared with women negative for CD8+ TILs. Increasing levels of CD8+ TILs were also linked to prolonged survival for women with ENOC and MOC.

Among HGSOCs, CD8+ TILs were favorable regardless of the extent of residual disease following cytoreduction, known standard treatment, and germline BRCA1 pathogenic mutation. However, they were not prognostic for BRCA2 mutation carriers.

“These large-scale analyses show that CD8+ TILs vary by histotype with HGSOC tumors having the highest levels and a strong association with survival, regardless of extent of residual disease or first-line chemotherapy treatment,” the authors wrote. “We showed for the first time that CD8+ TILs in HGSOC cases with germline BRCA2 mutations may not be associated with survival. Finally, we found that ENOC and MOC tumors show trends associating CD8+ TILs with survival time and that CCOC do not show these trends.”

The authors indicated that a clinically applicable scoring system for CD8+ TILs should be developed and incorporated into clinical trials.

Goode EL, Block MS, Kalli KR, et al. Dose-response association of CD8+ tumor-infiltrating lymphocytes and survival time in high-grade serous ovarian cancer. 

. 2017;3(12):e173290. doi:10.1001/jamaoncol.2017.3290.

Average Profit Margin on Oncology Drugs for 340B Hospitals Nears 50% 

The average profit margin on oncology drugs purchased by hospitals through the 340B program increased to 49% in 2015, subsequently leading to price pressure on cancer drugs, according to new study findings.

“The Oncology Drug Marketplace: Trends in Discounting and Site of Care,” commissioned by the Community Oncology Alliance (COA) and conducted by Berkeley Research Group, expanded upon previous research on the 340B program and assessed the impact the program had on the shift to more expensive hospital outpatient settings for cancer care; the scale of statutory discounts on oncology drugs, specifically 340B drugs; and the part these discounts play in drug pricing.

Currently, nearly half of all cancer patients are treated in hospital outpatient facilities, up from 23% in 2008. While limited research exists on the impact that this shift in site of care has on quality of care and patient outcomes, there is significant evidence of its role in overall healthcare cost increases, according to the authors of the study.

“The continued shift of oncology care to the hospital outpatient setting, combined with increased rates of cancer and rising drug prices, is setting the stage for higher overall costs of oncology care,” the authors wrote.

The authors developed an analysis by utilizing 2 sets of oncology drugs and Medicare fee-for-service claims from 2008 to 2016. Using a combination of IMS wholesale acquisition cost (WAC) sales data from 2010 to 2015 and publicly available pricing data, the authors conducted a financial analysis of sales, discounts, rebates, and 340B margins on a subset of the separately payable oncology drugs that accounted for 85% of total Medicare Part B oncology drug reimbursement in 2015.

340B hospitals have a clear financial incentive to expand oncology services.

 From 2011 to 2016, the average discount of a drug’s list price for Medicaid increased from 44% to 51%. The authors estimate that the average 340B discount from WAC increased from 54% in 2010 to 63% in 2015, which is responsible for keeping the 340B price consistent over that time period. Medicare reimbursement for physician-administered drugs equals 106% of a drug’s average sales price (ASP).

340B hospitals receive over one-third of all Part B oncology drug reimbursement.

 Between 2008 and 2016, the percentage of oncology drug reimbursement to 340B hospitals has more than tripled. According to the authors, there are multiple factors that contributed to the growth: new entity enrollment, growth in contract pharmacy, and expansion of oncology services by 340B hospitals. During the same period, the percentage of oncology drug reimbursement to community oncology practices has declined from 72% to 49%.

A disproportionate share of the shift in site of care is attributable to 340B hospitals. 

The authors analyzed enrollments of 2 cohorts between 2008 and 2016: hospitals that were continuously enrolled in 340B and hospitals that were not enrolled. By 2016, the 340B cohort accounted for over 920,000 oncology claims, a 38% greater growth than the non-340B cohort. “What we saw was that the majority of the growth has come out of existing hospitals through internal growth or acquiring practices,” said Ted Okon, executive director of COA.

Between 2010 and 2015, statutory discounts and rebates paid by manufacturers have almost tripled and put upward pricing pressure on drugs.

 In 2010, the statutory discounts and rebates on oncology drugs included in the analysis were approximately $1 billion and accounted for 7.4% of total gross sales for these drugs. By 2015, statutory discounts and rebates on the same set of drugs surpassed $3 billion and accounted for 14.4% of total gross sales for these drugs. The primary driver of this was the 340B program.

There is a lot that needs to be done, explained Okon, and CMS’ final rule is a step in the right direction. Last month, CMS finalized reform that will adjust payments for the 340B program: the Hospital Outpatient Prospective Payment System (OPPS). The program will adjust payment for drugs purchased through the 340B program to the ASP minus 22.5%, a change from the current rate of plus 6%.

CMS said that the rule will help lower the cost of the prescription drugs and the savings from this will be redistributed equally to hospitals covered by OPPS. In an attempt to create more transparency, 2 modifiers will be put in place in order to identify whether a drug has been purchased under the 340B program. These changes took effect on January 1, 2018.

“What you need next is Congress to shine the light on transparency,” said Okon. “340B is a black hole right now; we have no idea what goes on. Hospitals should be held to the same level of accountability that these federal grantees are.”

The 340B program, which was initiated 25 years ago, requires drug manufacturers participating in the Medicaid Drug Rebate Program to provide a discount to covered safety-net health providers. The program enables these entities to stretch scarce federal resources as far as possible to reach more low- income patients who are uninsured and provide more comprehensive resources.

Medical World News: Clinical Updates

FDA Grants Approval to Pertuzumab for Adjuvant Treatment in Patients with HER2-Positive Breast Cancer 

The FDA has granted approval to pertuzumab (Perjeta) to be used in combination with trastuzumab (Herceptin) and chemotherapy as adjuvant therapy for the treatment of patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer with a high risk of recurrence.

In 2013, the FDA granted accelerated approval to pertuzumab as neoadjuvant treatment. This latest adjuvant approval fulfills the accelerated approval postmarketing process, and regular approval is now granted for pertuzumab as part of treatment for patients with HER2-positive, locally advanced, inflammatory, or early-stage breast cancer (either greater than 2 cm in diameter or node-positive).

The full approval of Roche subsidiary Genentech’s pertuzumab comes after publication of data from the APHINITY (NCT01358877) trial. The multicenter, randomized double-blind, placebo-controlled trial included 4804 patients with HER2-positive early breast cancer who had their primary tumor removed prior to randomization. Following tumor removal, the patients were randomized to receive either pertuzumab or placebo in combination with adjuvant trastuzumab and chemotherapy.

The initial pertuzumab dose is 840 mg administered as a 60-minute intravenous infusion, followed by 420 mg administered as a 30- to 60-minute intravenous infusion every 3 weeks.

The authors assessed for invasive disease-free survival (IDFS), which was defined as the time from randomization to first occurrence of ipsilateral local or regional invasive breast cancer recurrence, distant recurrence, contralateral invasive breast cancer, or death from any cause.

After a median follow-up of 45.4 months, the proportion of IDFS events in the intent-to-treat population was 7.1% (n = 171) in the pertuzumab arm and 8.7% for those administered placebo (hazard ratio [HR], 0.82; 95% Cl, 0.67-1.00; 

 = .047). Patients with hormone receptor—negative or node-positive breast cancer were considered high-risk patients.

The proportion of IDFS events in patients with hormone receptor—negative disease was 8.2% (n = 71) in the pertuzumab arm and 10.6% (n = 91) in the placebo arm (HR, 0.76; 95% CI, 0.56-1.04). The pro portion of IDFS events for patients with node-positive disease was 9.2% (n = 139) and 12.1% (n = 181) in the pertuzumab and placebo arms, respectively (HR, 0.77; 95% CI, 0.62-0.96).

Adverse reactions reported in at least 30% of patients who received pertuzumab included diarrhea, nausea, alopecia, and fatigue. The most common grade 3 to 4 adverse reactions included neutropenia, febrile neutropenia, and leukopenia.

“The goal of treating breast cancer early is to provide people with the best chance for a cure. While we come closer to this goal with each advance, many people still have a recurrence and progress to the metastatic stage,” said Sandra Horning, MD, Roche’s chief medical officer and head of global product development, in a statement. “[The] approval of Perjeta means people with HER2-positive early breast cancer at high risk of recurrence have a new, clinically meaningful treatment option to reduce the chances of their disease returning.”

In 2012, the FDA granted regular approval to pertuzumab for its use in combination with trastuzumab and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer who had not received prior anti-HER2 therapy or chemotherapy for metastatic disease.

FDA grants regular approval to pertuzumab for adjuvant treatment of HER2-positive breast cancer [press release]. Washington, DC: FDA; December 20, 2017. fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm590005. htm. Accessed December 21, 2017.

Von Minckwitz G, Procter M, de Azambuia E, et al; APHINITY Steering Committee and Investigators. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017;377(12):122-131. doi: 10.1056/NEJMoa1703643.

FDA approves Roche’s Perjeta (pertuzumab) for adjuvant treatment of specific type of breast cancer [press release]. Basel, Switzerland: Roche; December 21, 2017. roche.com/media/store/releases/med-cor-2017-12-21b.htm. Accessed January 9, 2018.

Medical World News: Regulatory Updates

In 1970, futurist Alvin Toffler published his book, Future Shock, which explored the idea that the pace of change was accelerating well past the ability of people to assimilate this change.

 The resulting sense of displacement and disorientation was reflected in the book’s title.

We are now in a period of unprecedented rapid change in the domain of medical oncology. From emerging diagnostic technologies that leverage genomic, transcriptomic, and

proteomic assessments of germline and somatic cell mutations to the analogous expanding portfolio of targeted and immuno-oncologic (IO) agents, the very nature of cancer care is changing at a pace that is difficult, at best, to assimilate. As the opportunities for more effective diagnosis and treatment grow at a near-exponential rate, our ability to deliver these therapeutics effectively and efficiently to patients in need is proving to be an increasingly formidable challenge.

The quantum leap in cancer care from the triad of surgery/radiation therapy/chemotherapy toward a new era of therapeutics enriched by IO agents has created both systemic and patient-specific challenges. In a recent paper in the 

“. . . (A)n unprecedented number of new investigational agents and companies are entering the field of IO. As such, it has become challenging for oncology physicians conducting clinical trials, industry veterans developing IO drugs, and even regulators reviewing novel IO agents to keep track of the rapidly evolving landscape.”

These challenges also include the practical issues of how best to select patients for care using these agents, to the systems-based challenges of how best to deliver such highly complex care, at scale, in a financially sustainable way across the American healthcare system.

The proliferation of highly effective targeted therapies has markedly altered the nature of care and outcomes for patients with historically poor prognosis cancers, such as late-stage lung cancer, who may benefit from the use of targeted IO agents, such as the checkpoint inhibitors. For patients with non—small cell lung cancer (NSCLC), the

5-year overall survival for patients responsive to checkpoint inhibitors has quintupled over that of historic controls.

The potential of these agents to markedly improve patient outcomes is just one example of the potential of IO and targeted therapeutics to produce better care outcomes.

™), we review the IO domain from perspectives ranging from that of the evolving standards of care for NSCLC to that of a patient who is undergoing IO treatment. Researchers from the Analysis Group review key changes in the evolving molecular/genomic diagnostic technologies that are

helping to change the prognosis for patients with NSCLC. In an interview, Jeffrey S. Weber, MD, PhD, provides his perspective on IO. And in a remarkable series of interviews, Mary Caffrey brings forth the voices of patients who have navigated the complexities of clinical trials related to immunotherapy. Their courage and resilience in the face of their

respective cancer journeys powerfully conveys the human dimensions of our evolving cancer armamentarium.

As the technologies at the heart of this new era of cancer diagnosis and therapeutics continue to evolve at a rate that is near impossible to assimilate, the challenges to cope with this emerging future will force us to grapple with the effects of our “future shock.” In conversations, such as those fostered by 

stakeholders, we hope to help ground the future in sustainable systems that are dedicated to ensuring the increasing efficiency, effectiveness, and equitability of these life-changing care technologies. 

1. Toffler A. Future Shock. New York, NY: Random House; 1970.

2. Tang J, Shalabi A, Hubbard-Lucy VM. Comprehensive analysis of the clinical immuno-oncology landscape. Ann Oncol. 2018;29(1):84-91. doi:

3. Vermaelen K, Waeytens A, Kholmanskikh O, Van den Bulcke M, Van Valckenborgh E. Perspectives on the integration of immuno-oncology

biomarkers and drugs in a healthcare setting [published online November 21, 2017]. Semin Cancer Biol. doi: 10.1016/j.semcancer.2017.11.011.

4. Goodman A. Five-year survival quadrupled in responders to immunotherapy for non-small cell lung cancer. The ASCO Post. May 10, 2017.

ascopost.com/issues/may-10-2017/five-year-survival-quadrupled-in-responders-to-immunotherapy-for-non-small-cell-lung-cancer/.

Dr Alvarnas is editor in chief and director of Value-Based Analytics at City of Hope, Duarte, California.

Future Shock: Embracing Disruption in the Immunotherapy Revolution

When the FDA approved the chimeric antigen receptor (CAR) T-cell therapy in August 2017, the news made headlines around the world: in this process, a patient’s own genetically modified T-cells are engineered to express receptors that latch on to a specific cell surface protein, connecting them to cancer cells to be destroyed.

 Treatments for individual patients take weeks to create, to say nothing of the costs of care to receive the therapy or the millions to develop it.

It all adds up to some of the most expensive therapies ever invented. The first CAR T-cell therapy, tisagenlecleucel (Kymriah)—a treatment for children and young adults with B-cell acute lymphoblastic leukemia (ALL) developed by Novartis&mdash;was priced at $475,000 for a one-time treatment.

 Axicabtagene ciloleucel (Yescarta), Kite Pharma/Gilead’s treatment for adult patients with relapsed or refractory large B-cell lymphoma, soon followed, priced at $373,000.

 Such ground-breaking therapies, with equally unprecedented prices, would clearly change the way payers did business.

Express Scripts’ chief medical officer Steve Miller, MD, did not hold back in a September blog post, saying the arrival of gene therapies would demand payment models “as novel as the medications themselves.”

 Critics of the cost of the Kymriah, writing in 

) went to press, said the issue of cost matters because CAR T-cell therapies are expected to receive FDA and overseas approval to treat many other blood cancers, including adult ALL, chronic lymphocytic leukemia, and diffuse large B-cell lymphoma. They argue Novartis should be charging only $160,000 per treatment, in part because so many millions in federal research funds helped spark CAR T-cell discoveries.

For now, there’s a lot of uncertainty, as both government and commercial insurers, and a handful of the nation’s leading cancer centers, navigate a reimbursement structure that truly has no precedent. “Ideas on the table include paying for a treatment over time, establishing insurer risk pools and financing one-time payments,” Miller wrote. “A successful model must address patients who change insurers or employers, and tracking their health outcomes over time to ensure payments aren’t being made if the treatment stops being effective.”

Aaron Chrisman, director for Stem Cell Transplant and Cellular Therapy Administration at the University of Chicago Medicine, told 

in an email that the approval and reimbursement process is necessarily painstaking because of the nature of the treatment, not just its high cost. “Because each product is designed for a specific patient, the cells, millions of them, must be produced for 1 patient at a time,” he said. “It can take 2 to 4 weeks to insert the new, molecularly engineered receptor and grow the required number of cells.”

As Chrisman explained, once the customized treatment is returned to the hospital and infused, the modified T-cells multiply and set out to find and attack the cancerous B-cells. Other reports have told of serious short-term side effects, including disorientation and tremors,

 so beyond the cost of therapy itself are the hospitalization costs.

For those on the front lines, connecting very sick cancer patients with a potentially life-saving treatment takes the involvement of the highest levels of leadership at an institution. At this stage, “there is a tremendous amount of oversight in each case,” from the cellular therapy program itself, to managed care, revenue cycle, supply chain, and pharmacy among others, Chrisman said in the email. “This will hopefully lessen over time, but currently it requires a substantial investment in time in order to obtain approvals and to ensure payment happens in a timely and accurate fashion.”

CAR T-cell therapy’s groundbreaking nature—and the learning curve involved for all stakeholders&mdash;makes information on reimbursement hard to pin down. On the day of the FDA approval, Novartis announced an outcomes-based arrangement with CMS, to “eliminate inefficiencies from the healthcare system,” with Kymriah as the first therapy subject to the agreement.

In short, CMS won’t pay for those patients who fail to respond in the first 28 days of treatment.

 A person familiar with CMS reimbursement policy told 

 the following about Medicare reimbursement for CAR T-cell therapy, as of January 19, 2018:

CAR T-cell therapy treatment will only be reimbursed for hospitals or health systems for in inpatient and outpatient settings

Individual or small group practices will not be reimbursed. Those familiar with the treatment said this made sense due to the acute side effects that can occur. 

Inpatient cost for CAR-T will be bundled into the total cost of inpatient stay. If Medicare’s payment does not cover costs, CAR T-cell treatment may qualify under the acute inpatient “outlier” Prospective Payment System (PPS)

As of January 1, 2018, Kymriah, which was the first CAR T treatment to be approved, has an outpatient code: ASP+6% for outpatient prospective payment ($503,500)

As of January 1, 2018, Yescarta did not have an outpatient code; it could be allocated a “not otherwise classified” code

For Kymriah, state-level Medicaid policies matter due to its pediatric indication. Over 2 months, 

 contacted the press office at Penn Medicine, the center for Kymriah’s clinical trials, but received no response to questions about reimbursement. Spokespersons for the New Jersey and Pennsylvania Departments of Human Services, which oversee Medicaid programs closest to Penn, said Kymriah and Yescarta were both covered on an inpatient basis only; in Pennsylvania, Medicaid will only reimburse for FDA-approved indications, not investigational uses.

, Eric Althoff, head of Global Media Relations, Novartis, referenced a Q-code approved for Medicare that became effective January 1, 2018, and said in an email “a number of state Medicaid programs have published Kymriah Medicaid policies,” but offered no specifics.

, spokespersons for both Novartis and Gilead report progress in obtaining commercial coverage; Gilead reported that commercial payers would likely account for between 50% and 60% of Yescarta’s users, and thus far most commercial payers were willing to cover the treatment. The University of Chicago Medicine’s Chrisman said thus far, commercial coverage for CAR T-cell therapy has occurred through individual contracts. “This can be a long process depending on the payer,” he said. “However, we will try our hardest for the sake of all our patients.” As of late January, 4-5 patients were awaiting confirmation of coverage and payment terms at the institution.

Novartis’ Althoff said patient access programs are also available. “Novartis is committed to ensuring eligible patients have access to Kymriah,” he wrote. “This includes co-pay assistance and travel assistance for transportation and accommodations for eligible patients and up to 2 caregivers to support compliance with the safety monitoring period.”

Does the Novartis model need to go a step further, of having billing codes ready when these expensive therapies are approved? “This would likely shorten the time to therapies being widely used, and would certainly help reduce uncertainty around reimbursement and coverage for providers,” Chrisman said. “This would need to go beyond just the creation of billing codes; therapies like CAR T-cell include the product itself as well as a variety of inpatient and outpatient services.” The best bet, he said, would be figuring out how to bill for everything before, or very soon after FDA approval occurs.

FDA approval brings first gene therapy to the United States [press release]. Silver Spring, MD: FDA Newsroom; August 30, 2017. fda. gov/NewsEvents/Newsroom/PressAnnouncements/ucm574058. htm. Accessed February 7, 2018.

Szabo L. Cascade of costs could push new gene therapy above $1 million per patient. Kaiser Health News website. khn.org/news/ cascade-of-costs-could-push-new-gene-therapy-above-1-million-per- patient/. Published October 17, 2017. Accessed February 9, 2018.

At $475,000 per treatment, is Novartis’ Kymriah a bargain, or just another example of skyrocketing prices? Fierce Pharma website. fiercepharma.com/pharma/at-475-000-per-treatment-novartis- kymriah-a-bargain-or-just-another-example-skyrocketing. Published August 31, 2017. Accessed February 6, 2017.

Kite’s Yescarta (axicabtagene ciloleucel) becomes first CAR T therapy approved by the FDA for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy [press release]. Foster City and Santa Monica, CA: Business Wire; October 18, 2017. gilead.com/news/press-releases/2017/10/ kites-yescarta-axicabtagene-ciloleucel-becomes-first-car-t-therapy- approved-by-the-fda-for-the-treatment-of-adult-patients-with- relapsed-or-refractory-large-bcell-lymphoma-after-two-or-more- lines-of-systemic-therapy. Accessed February 6, 2017.

Miller S. Gene therapy holds great promise, but big price. Express Scripts website. lab.express-scripts.com/lab/insights/drug-options/ gene-therapy-holds-great-promisec-but-big-price. Published September 21, 2017. Accessed February 6, 2018.

Kleutghen P, Mitchell D, Kesselheim AS, Najafzadeh M, Sarpatwari A. Drugs won’t work if people can’t afford them: the high price of tisagenlecleucel [published online February 8, 2018]. Health Aff. 10.1377/hblog20180205.292531.

Welch A. Considerations for CAR T-cell therapy in NHL. OncLive website. onclive.com/web-exclusives/considerations-for-car-tcell-therapy-in-nhl. Published January 19, 2018. Accessed February 9, 2018.

Novartis receives first-ever FDA approval for a CAR T-cell therapy Kymriah (CTL019) for children and young adults with B-cell ALL

	that is refractory or has relapsed at least twice [press release]. Basel, Switzerland: Novartis; August 30, 2017. novartis.com/news/media- releases/novartis-receives-first-ever-fda-approval-car-t-cell-therapy- kymriahtm-ctl019. Accessed February 9, 2018.

CAR T- cell therapies are among the most expensive ever invented. For now, there’s a lot of uncertainty, as both government and commercial insurers, and a handful of the nation’s leading cancer centers, navigate a reimbursement structure that truly has no precedent.

With Approval of CAR T-Cell Therapy Comes the Next Challenge: Payer Coverage

first spoke with Jeffrey S. Weber, MD, PhD, about immunotherapy and specifically about ipilimumab (Yervoy, Bristol-Myers Squibb [BMS]).

 At the time, oncologists were still gaining an understanding of this class of cancer treatment, which activates the body’s own immune system by flipping the switches—or checkpoints&mdash;that regulate how the body attacks foreign cells and leaves healthy ones alone. Payers were coming to grips with the price: The drug cost $120,000 a year, an amount that would be eclipsed by combination therapy.

Ipilimumab did not work for everyone. But when it did, patients with the deadliest form of skin cancer—who would have survived just months on chemotherapy&mdash;now survived years. A 2013 article Weber coauthored found survival rates of 37.7% to 49.5% at the 4-year mark for treatment-naive patients in phase 2 trials.

Much has changed since then, both for immunotherapy and for Weber, who has been a leader in bringing basic research into clinical practice for more than 20 years. In November 2015, he left the H. Lee Moffitt Cancer Center & Research Institute in Tampa, Florida, to become deputy director of the Laura and Isaac Perlmutter Cancer Center at New York University Langone Medical Center.

 As Weber points out, today there are more checkpoint inhibitors—including nivolumab (Opdivo, BMS)

— approved for many more cancers, such as non—small cell lung cancer, renal cell cancer, head-and-neck cancers, Hodgkin lymphoma, and colon cancer.

 In the case of ipilimumab, the target is cytotoxic T-lymphocyte antigen-4. Both nivolumab and pembrolizumab target the programmed cell death 1 (PD-1) protein.

, Weber discussed developments in the past year that are rapidly changing immuno-oncology treatment approaches in melanoma. Ipilimumab’s place in the melanoma armamentarium is shifting, thanks in part to research Weber presented in the past year but also because of new combinations in the pipeline. Ipilimumab will still be used, he said, but it will likely be used in new and different ways. And new cost issues are on the horizon, as the prospect of triple therapy is no longer something of the imagination.

Not long after the interview, on December 20, 2017, the FDA approved the use of nivolumab for adjuvant treatment of melanoma,

on the heels of Weber’s presentation of results of the CHECKMATE 238 study at the European Society for Medical Oncology (ESMO). The study found that at 18 months, the difference in relapse-free survival was 66% for those taking nivolumab compared with 53% for ipilimumab, with far fewer immune-related adverse events (AEs) for those taking nivolumab.

 Also in December, Weber was senior author for a study in Cancer Immunology Research showing that a test based on a protein signature associated with metastatic melanoma outcomes can predict patient survival and help oncologists decide which PD-1— blocking antibodies are appropriate for which patients.

 The findings support Weber’s discussion of the growing importance of biomarkers in steering very expensive therapies to patients who will respond to them and for figuring out in advance which patients won’t respond.

Weber and others see a big change ahead: Investigators at ESMO presented results for a combination of pembrolizumab and epacadostat (Incyte), an inhibitor of the enzyme indoleamine 2,3-dioxygenase-1, or IDO1. The overall response rate of 56% and median progression-free survival (PFS) of 12.4 months in the phase 1/2 trial,12 combined with AE rates that are better than the ipilimumab—nivolumab combination, suggest to Weber that a changing of the guard could be on the way in advanced melanoma.

“Based on all the phase 1/2 data, it looks pretty promising,” Weber said. “I would predict if pembro—epacadostat has anywhere near a 12-month PFS and a 50-plus percent response rate, I think people will embrace it,” noting that the ipilimumab–nivolumab combination will become second-line treatment. (Indeed, reports of the early pembrolizumab–epacadostat results have fueled speculation about the future of the Bristol-Myers Squibb [BMS] combination but also about epacadostat and nivolumab.

“You’ll need to look for new [ipilimumab] combinations. Ipilimumab has been kind of ignored in terms of drug development in the last 5 years. But now, all of a sudden [ipilimumab] becomes an important second-line treatment,” Weber said. He rattled off a list of potential combinations: ipilimumab—epacadostat, ipilimumab plus talimogene laherparepvec, or T-VEC; ipilimumab and anti-lymphocyte activation gene-3, known as LAG-3.

“We’ll need to look for all these other combinations,” Weber said. “But it will be good for patients, because if the pembroepacadostat trial pans out, it will become adopted. I’m sure that’s the way it will go in the community.”

The prospect of an alternative to ipilimumab—nivolumab has attracted widespread attention in part because so many patients suffer reactions. “The initial [ipilimumab–nivolumab] combo was, and is, pretty darn toxic,” Weber said. “Whether you give, [the drugs] consecutively—one after the other as we did in a prior study&mdash;or concurrently, you have a 50% to 60% rate of immune- related adverse events. That’s pretty serious.”

And yet, Weber said, there’s been “surprisingly little” research on the etiology and prediction of immune-related AEs over the past decade. But this could be changing. In 2017, Weber noted, the National Cancer Institute (NCI) included an item on this very issue in its Provocative Questions, which are items that investigators are asked to address in grant requests. Precisely, the question is:

“What are the predictive biomarkers for the onset of immune-related adverse events associated with checkpoint inhibition, and are they related to markers for efficacy?”

“I think people are becoming more aware of the issues surrounding immune-related adverse events,” Weber said. “There’s a huge gap in education in how to manage them.” He described a patient he had recently seen who had gone 2 weeks with undiagnosed hypophysitis, an inflammation of the pituitary gland that is a known AE for patients being treated with ipilimumab. The patient’s oncologist had missed it.

As checkpoint inhibitors become approved for other cancer indications, this will become a bigger issue, Weber said. “You’re going to see a lot of approvals coming through in the next couple of years. More and more doctors will be using these drugs in the community. So there will be a big need for education.

“It’s a 2-part process: People will become more experienced; with experience comes some level of expertise. But if your average community physician is treating just a handful [of these] patients a year, experience isn’t going to help that much,” Weber said. “It’s going to take education.”

“That’s an open question, which will be difficult to answer,” Weber said. As patients live longer, however, the question of how long patients should stay on immunotherapy will come up more frequently. The answer isn’t obvious, he said, because it’s not the type of question investigators with funding from the NCI have typically studied— but it’s nonetheless an important one. Weber cited an abstract presented at the annual American Society of Clinical Oncology meeting in 2016 by Caroline Robert, MD, PhD, that found that patients in the KEYNOTE-001 trial who stopped pembrolizumab because of toxicity continued to receive treatment benefits.

“That, I think, will convince people that they should feel comfortable taking patients off [therapy], either after a year or 2 years. Certainly, I think patients will come off by 2 years,” Weber said, although he acknowledged it’s not an easy call. “I tell people if they’ve been on a year and they’ve had a response and the response is stabilized, they should feel comfortable coming off. Now, that’s a tough sales pitch. Imagine you’re the patient and I’m telling you it’s OK to come off a therapy when you’ve had a great response. People get a little concerned about it.”

Considering the chronic AEs, Weber would advise his melanoma patients to stay on immunotherapy “not less than 1 year, not more than 2 years.”

Can Chimeric Antigen Receptor (CAR) T-Cell Successes Seen in Leukemia and Lymphoma Occur in Solid Tumors?

CAR T-cell therapy in solid tumors has been “a huge disappointment,” Weber said, but that starts with the mechanism: “You need a cell surface molecule,” he said. “The CAR T is a fusion of the antigen recognizing region of the antibody with the T-cell transduction molecule. Other than the hematologic malignancies, there aren’t too many dispensable molecules that are present on cells that you can use as a target. In other words, you have too many off- target side effects when you have solid tumors doing CAR strategies.”

Weber noted a promising strategy involving a folate receptor with ovarian cancer,

 “but apart from that, I think it’s going to be a very difficult scenario.”

Optimism in Payer Coverage, but Triple Therapy Awaits 

Weber said his patients at Langone have not had problems gaining coverage for immunotherapy. Not only is the system smooth at his institution, but there are differences from region to region with Medicare—and he finds things better in New York than he did in Florida. “With recent therapies, there have not been any issues at all,” he said. “One nice thing is the big companies like Merck and BMS have tended to have patient assistance programs,” so even though he just presented data on adjuvant nivolumab last fall, “if you can’t get insurance [coverage], you can get it through patient assistance. So I think that’s a good thing.”

Still, the prospect of triple combination therapy concerns him. “Now, we’re talking the kind of money that we were talking about for CAR T cells. And that really flipped everybody out,” he said. The announced price of the first CAR T-cell therapy, tisagenlecleucel (Kymriah, Novartis), was $475,000, although Weber noted reports that Novartis was negotiating an outcomes-based agreement with the CMS that would call for Medicaid to pay only if the treatment worked.

As immunotherapy moves into the adjuvant population, the math becomes more challenging for payers and institutions if “the best you can do is treat 2 patients to benefit 1,” Weber said. That’s why the development of better biomarkers becomes so important. “You’d rather know who are the patients who are going to be cured” and which ones won’t. Thus, targeting the right patients to treat is a huge research focus right now, he said.

“This is the story of where we’re heading,” Weber said. Without better biomarkers, “even if you have the perfect therapy, you’re still going to be treating twice as many patients as you need to.”

1. Peer Exchange. Immunotherapy in cancer care: understanding the impact of shifting treatment paradigms in the managed care setting. Am J Manag Care. 2014;20(SP2):SP38-SP44.

2. FDA approves YERVOY (ipilimumab) for the treatment of patients with newly diagnosed or previously-treated unresectable or metastatic melanoma, the deadliest form of skin cancer [press release]. Princeton, NJ: Bristol-Myers Squibb; March 25, 2011. news.bms.com/press-release/ rd-news/fda-approves-yervoy-ipilimumab-treatment-patients-newly- diagnosed-or-previousl. Accessed January 3, 2018.

3. Gochenauer G. When will the price horizon for oncology drugs top $10,000 a month? Kantar Health website. blog.kantarhealth.com/blog/gordon- gochenauer/2013/02/08/when_will_the_price_horizon_for_oncology_drugs_ top_10000_a_month. Published February 8, 2013. Accessed January 3, 2018.  

4. Wolchok JD, Weber JS, Maio M, et al. Four-year survival rates for patients with metastatic melanoma who received ipilimumab in phase II clinical trials. Ann Oncol. 2013;24(8):2174-2180. doi: 10.1093/annonc/mdt161.  

5. Renowned melanoma and immunotherapy expert joins NYU Langone Medical Center [press release]. New York, NY: PR Newswire; September 9, 2015. prnewswire.com/news-releases/renowned-melanoma-and- immunotherapy-expert-joins-nyu-langone-medical-center-300140023. html. Accessed January 3, 2018.

6. FDA approves Opdivo. Drugs.com website. drugs.com/newdrugs/ fda-approves-opdivo-nivolumab-advanced-melanoma-4133.html. Published December 22, 2014. Accessed January 3, 2018.

7. Merck receives accelerated approval of Keytruda (pembrolizumab), the first FDA-approved anti-PD-1 therapy [press release]. Whitehouse Station, NJ: Merck; September 4, 2014. keytruda.com/static/pdf/KEYTRUDA- Press-Release-ONCO-1120130-0000.pdf. Accessed January 3, 2018.  

8. Immune checkpoint inhibitors to treat cancer. American Cancer Society website.cancer.org/treatment/treatments-and-side-effects/treatment- types/immunotherapy/immune-checkpoint-inhibitors.html. Revised May 1, 2017. Accessed January 3, 2018.

9. FDA grants regular approval to nivolumab for adjuvant treatment of melanoma [press release]. Silver Spring, MD: FDA Newsroom; December 20, 2017. fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ ucm590004.htm. January 3, 2018.

10. Weber JS, Mandala M, Del Vecchio M, et al; CHECKMATE 238 collaborators. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med. 2017;377(19):1824-1835. doi: 10.1056/ NEJMoa1709030.

11. Sznol M, Sullivan RJ, Blackmon S, et al. A serum protein signature associated with outcome after anti-PD-1 therapy in metastatic melanoma [published online December 5, 2017]. Cancer Immunol Res. doi: 10.1158/2326-6066.CIR-17-0412.

12. Dangi-Garimella S. Pembrolizumab plus epacadostat yields durable response in advanced melanoma: ESMO. Am J Manag Care ajmc.com/ newsroom/pembrolizumab-plus-epacadostat-yields-durable-response- in-advanced-melanoma-esmo. Published August 31, 2017. Accessed January 3, 2018.

13. Taylor NP. Early Keytruda combo data paint Incyte’s epacadostat as a threat to Bristol-Myers’ I-O melanoma franchise. Fierce Biotech website. fiercebiotech.com/biotech/early-keytruda-combo-data-paint-incyte- s-epacadostat-as-a-threat-to-bristol-myers-i-o. Published August 31, 2017. Accessed December 19, 2017.

14. Speights K. 3 promising cancer immunotherapies to watch in 2018. The Motley Fool website. fool.com/investing/2017/12/22/3-promising- cancer-immunotherapies-to-watch-in-201.aspx. Published December 22, 2017. Accessed December 27, 2017.

15. Center for Strategic Scientific Initiatives. Provocative Questions. National Cancer Institute website. provocativequestions.nci.nih.gov/ pq-funding-opportunity-information/current-rfas-and-pqs. Accessed December 18, 2017.

16. Robert C, Ribas A, Hamid O, et al. Three-year overall survival for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001. J   Clin Oncol. 2016;34(15)(suppl; abstr 9503). doi: 10.1200/JCO.2016.34.15_suppl.9503.

Ipililumumab's role in treating melanoma will change, as the immunotherapy will likely become part of different combinations than we see today.

February 2018

Medical World News: Clinical/Managed Care Updates

Medical World News: Clinical Updates

Medical World News: Regulatory Updates

Future Shock: Embracing Disruption in the Immunotherapy Revolution

With Approval of CAR T-Cell Therapy Comes the Next Challenge: Payer Coverage

Provocative Questions, Better Biomarkers, and the Prospect of Triple Therapy: A Conversation With NYU's Jeffrey S. Weber, MD, PhD

Recent Approval of Trastuzumab Biosimilar, Ogivri, Has Implications for Patients and Industry

The Clinical Trial and the Patient's Voice: "I'm Extremely Lucky to Be Alive"

Reimbursement Landscape for Molecular Testing in Non-Small Cell Lung Cancer

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