Medical World News: Clinical Updates

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

Jaime Rosenberg

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 Cancer Immunology Research.

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 (P = .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; P < .001). The ipilimumab-treated validation set demonstrated a significant difference in OS between sensitive and resistant groups (HR, 0.40; P = .004).

“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.

Reference:

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

Jaime Rosenberg

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 JAMA Oncology.

“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.

References:

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

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

Jaime Rosenberg

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.

The study had 4 main findings:

1. 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).
2. 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%.
3. 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.
4. 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.

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