Medical World News®, December 2017

Roche Gets Drug Approvals for First Treatment for a Rare Blood Disorder and NSCLC

AJMC Staff

ROCHE HAD 2 DRUGS approved by the FDA—one for a rare blood disease and the other for first-line treatment for lung cancer.

Vemurafenib (Zelboraf ) is the first FDA-approved drug for Erdheim-Chester disease (ECD), a rare blood disorder. Already approved for the treatment of people with unresectable or metastatic melanoma with the BRAF V600E mutation, the new indication includes patients with ECD who harbor the BRAF V600 mutation. Characterized by an abnormal multiplication of histiocytes, these white blood cells can invade normal tissues and organs.

The drug was approved based on data from the phase 2 VE-BASKET study, which used an innovative clinical trial design that matched a disease’s underlying genetic profile to the mechanism of action of the medicine. For the 22 people with ECD, the trial showed a best overall response rate of 54.5%.

“This FDA decision means people living with Erdheim-Chester disease will now, for the first time, have an FDA-approved treatment option,” Sandra Horning, MD, Roche’s chief medical officer and head of global product development, said in a statement.¹ “We are committed to finding new ways to bring medicines to patients with high unmet need, and we are pleased that this innovative clinical trial helped identify Zelboraf for treatment of this rare disease.”

The second drug approved was alectinib (Alecensa) as a first-line treatment for people with anaplastic lymphoma kinase (ALK )-positive metastatic non—small cell lung cancer (NSCLC). The FDA approved the drug based on results from the phase 3 ALEX study, which showed the drug reduced the risk of disease worsening or death by 47% compared with crizotinib. Median progression-free survival was 25.7 months for people on alectinib, compared with 10.4 months for those on crizotinib.

Alectinib has been recommended in the National Comprehensive Cancer Network guidelines as a treatment option for first-line ALK -positive metastatic NSCLC. “Our goal is to develop medicines that have the potential to significantly improve upon the standard of care,” Horning said in a separate statement.² “In our pivotal study, Alecensa significantly extended the time that people lived without their disease worsening compared to crizotinib and also showed a marked reduction in the risk of their cancer spreading to the brain.”

References:

1. FDA approves Zelboraf (vemurafenib) for Erdheim-Chester disease with BRAF V600 mutation [press release]. Basel, Switzerland: Roche; November 7, 2017. roche.com/media/store/releases/med-cor-2017-11-07b.htm. Accessed November 7, 2017.

2. FDA approves Roche’s Alecensa (alectinib) as first-line treatment for people with specific type of lung cancer [press release]. Basel, Switzerland: Roche; November 7, 2017. roche.com/media/store/releases/med-cor-2017-11-07.htm. Accessed November 7, 2017.

ASCO: Alcohol Linked to Several Types of Cancer

Jaime Rosenberg

ALCOHOL CONSUMPTION, whether light, medium, or heavy, is linked to higher risks of several leading cancers, according to findings released by the American Society of Clinical Oncology (ASCO).¹

ASCO has listed alcohol as a definite risk factor for cancer, saying that it contributed to 5% to 6% of new cancers and cancer deaths globally. The evidence linked alcohol consumption with breast, colon, esophagus, and head and neck cancers.

“People don’t typically associate drinking beer, wine, and hard liquor with increasing their risk of developing cancer in their lifetimes,” said ASCO President Bruce Johnson, MD, FASCO, in the statement. “However, the link between increased alcohol consumption and cancer has been rmly established and gives the medical community guidance on how to help their patients reduce their risk of cancer.”

According to the National Cancer Opinion Survey conducted by ASCO earlier this year,2 70% of Americans do not identify alcohol as a risk factor for cancer, and only 38% are limiting their alcohol intake as a way to reduce the risk of cancer.

In addition to raising awareness of the correlation between alcohol consumption and cancer, ASCO also put emphasis on implementing evidence-based policy recommendations to reduce excessive alcohol consumption:

• Provide alcohol screening and brief interventions in clinical settings
• Regulate alcohol outlet density
• Increase alcohol taxes and prices
• Maintain limits on days and hours of sale
• Enhance enforcement of laws prohibiting sales to minors
• Restrict youth exposure to advertising of alcoholic beverages
• Include alcohol control strategies in comprehensive cancer control plans
• Support efforts to eliminate the use of “pinkwashing” to market alcoholic beverages.

For example, discouraging alcoholic beverage companies from exploiting the color pink or pink ribbons to show a commitment to nding a cure for breast cancer given the evidence that alcohol consumption is linked to an increased risk of breast cancer.

According to ASCO, excessive alcohol consumption can also delay or negatively affect cancer treatment. Oncologists have the ability to identify strategies to help patients reduce their alcohol intake; address racial, ethnic, gender, and sexual orientation disparities that may place these populations at increased cancer risk; and serve as community advisers and leaders to raise awareness of alcohol as a cancer risk behavior.

“ASCO joins a growing number of cancer care and public health organizations in recognizing that even moderate alcohol use can cause cancer,” said Noelle K. LoConte, MD, lead author of the statement and associate professor of medicine at the University of Wisconsin, in the ASCO statement. “Therefore, limiting alcohol intake is a means to prevent cancer. The good news is that just like people wear sunscreen to limit their risk of skin cancer, limiting alcohol intake is one more thing people can do to reduce their overall risk of developing cancer.”

References:

1. Alcohol linked to cancer according to major oncology organization: ASCO cites evidence and calls for reduced alcohol consumption [press release]. Alexandria, VA: American Society of Clinical Oncology; November 7, 2017. asco.org/about-asco/press-center/news-releases/statement-alcohol-linked-to-cancer-november-2017. Accessed November 7, 2017.

2. National survey reveals most Americans are unaware of key cancer risk factors. American Society of Clinical Oncology website. asco.org/advocacy-policy/asco-in-action/national-survey-reveals-most-americans-are-unaware- key-cancer-risk?et_cid=39746367&et_rid=789325918&linkid=National+Cancer+Opinion+Survey.

Published October 24, 2017. Accessed November 7, 2017.

FDA Action on MSK Tumor Profiling Assay Breaks Ground on Multiple Fronts

Mary Caffrey

THE FDA HAS AUTHORIZED a faster approval path for a next-generation sequencing (NGS) assay developed at Memorial Sloan Kettering (MSK) Cancer Center, which represents both a scientific and regulatory breakthrough at the agency.

The diagnostic test, known as IMPACT, identifies more genetic mutations, or biomarkers, for cancer “than any test previously reviewed by the agency,” according to an FDA statement issued November 15.¹ What’s more, the FDA simultaneously announced that it was granting accreditation to the New York State Department of Health (NYSDOH) to act on its behalf, and that tests that passed muster with that agency would not need a separate FDA clearance.

IMPACT, which stands for Integrated Mutation Profiling of Actionable Cancer Targets, allows clinicians to look beyond the mutations in solid tumor cancers—lung, colon, breast, and melanoma—to aid patients with less common solid tumors.² Because NGS casts a wider net than conventional genetic testing, it allows researchers in phase I “basket studies” to find out quickly if cancer therapies can be used in rarer cancers beyond those for which they are already approved.

The test had been submitted through the FDA’s de novo premarket review pathway, reserved for low- to moderate-risk devices. It had previously been reviewed by NY state health regulators, who had cleared it for use. The FDA’s action on November 15 created a Class II pathway for these types of tests, allowing them to be cleared either through the FDA or by an accredited third party.

Third-party accreditation allows the FDA to keep up with the pace of innovation and encourage test develop- ers to voluntary seek 510(k) clearance, FDA Commission- er Scott Gottlieb, MD, said in the statement.

“This is another example of where the FDA is working to nd creative and exible approaches to regulation that spurs development and efficient delivery of innovative technology,” he said. “We’ll continue to look for opportunities to create regulatory efficiencies where possible to drive broader access to tools that improve American health, while maintaining the safety and e cacy standards that patients should expect from their FDA-reviewed products.”¹

“NGS technologies can examine hundreds, if not millions, of DNA variants at a time; and we are only at the beginning of realizing the true potential for these devices to assist patients and their health care providers in learning about the genetic underpinnings of their disease,” said Jeffrey Shuren, MD, director of the FDA’s Center for Devices and Radiological Health, in the statement.

“Recognizing the significant effect information about an individual’s biomarkers can have on their care planning and outcomes, the FDA worked closely with NYSDOH and MSK to help ensure that the IMPACT test is accurate, reliable and clinically meaningful. This collaboration is an excellent example of how the FDA can partner with the medical and development communities to review innovative tests as quickly as possible.”

References:

1. FDA unveils a streamlined path for the authorization of tumor profiling tests alongside its latest product action [press release]. Silver Spring, MD: FDA Newsroom; November 15, 2017. fda.gov/2. NewsEvents/Newsroom/PressAn- nouncements/ucm585347.htm. Accessed November 29, 2017.

2. MSK researchers develop targeted test for mutations in both rare and common cancers. Memorial Sloan Kettering Cancer Center website. mskcc.org/msk-impact. Accessed November 15, 2017.

ASCO’s TAPUR Study Expands to Enroll Patients Receiving Immunotherapy

AJMC Staff

WITH AN EXPANSION THAT includes immunotherapy combination treatments, the American Society of Clinical Oncology (ASCO)’s Targeted Agent and Profiling Utilization Registry (TAPUR) Study has now grown to 500 participants and 16 therapies.

“This study just reached a key milestone and we’re excited to explore these treatments further,” said ASCO chief medical officer Richard L. Schilsky, MD, FACP, FASCO. “While no conclusions about drug efficacy should be drawn at this point, we are very pleased with the growth and expansion of the TAPUR Study.”

The expansion now adds patients to the following study arms to TAPUR:

• Patients with ovarian cancer with KRAS, NRAS, and BRAF wildtype variants treated with cetuximab
• Patients with breast cancer with a high tumor mutation burden treated with pembrolizumab
• Patients with colorectal cancer with a BRAF V600E mutation treated with vemurafenib plus cobimetinib
• Patients with non—small cell lung cancer with CDKN2A deletion or mutation treated with palbociclib as monotherapy

The following study cohort, however, will be permanently closed:

• Patients with pancreatic cancer with CDKN2A loss or mutation treated with palbociclib as monotherapy

TAPUR, which provides patients access to drugs at no cost, is designed to evaluate FDA-approved targeted agents for indications other than those on the drug’s label, with the objective of using real-world evidence to identify alternative options for patients with advanced disease.

According to the ASCO press release, 510 participants are enrolled in the TAPUR Study, which is available at 83 clinical sites in 20 states. The study now includes a

new drug combination, nivolumab plus ipilimumab, an immunotherapy treatment that boosts the immune system to target tumor cells. With this addition, there are a total of 19 drugs yielding 16 different targeted therapy options (some drugs are used in combination).

“The TAPUR trial gives us the chance to [apply] the technology and the science, and apply it to patients in real time, with everybody agreeing that they’re going to have access to the medicine, that they’re going to have payment for the treatments, and that the data are going to be available,” according to Leonard Lichtenfeld, MD, deputy chief medical officer, American Cancer Society.

Reference:

ASCO expands TAPUR study enrollment after promising initial treatment outcomes seen [press release]. Alexandria, VA: American Society of Clinical Oncology; November 16, 2017. asco.org/about-asco/press-center/news-releases/asco-ex- pands-tapur-study-enrollment-after-promising-initial. Accessed November 29, 2017.

Study to Explore Link Between Diabetes, Pancreatic Cancer

Mary Caffrey

A 3 -YEAR STUDY will investigate the link between new-onset diabetes and pancreatic cancer, with the hope of finding ways to detect pancreatic cancer early, when it is at a curable stage.

Richard Frank, MD, director of clinical cancer research for the Western Connecticut Health Network (WCHN), will lead the $2.7 million study, which will ask participants to undergo annual magnetic resonance imaging of the pancreas for 3 years under a protocol developed by network radiologists Ronald Lee, MD, and James Bauman, MD. A gastroenterologist will examine suspicious lesions using endoscopic ultrasound to determine whether cancer is present.

Study participants will also give a blood sample every 6 months to create a serum blood bank, which may later allow investigators to find a biomarker for pancreatic cancer; none currently exists.

Overtaking other types of cancer in overall death rate, pancreatic cancer is projected to be the second-leading cause of cancer death by 2020. A challenge with pancreatic cancer is that it is often detected only at a late stage, when it is difficult to treat.

Rising rates of diabetes and obesity have been linked to increases in pancreatic cancer. Type 2 diabetes is associated with a 1.5- to 2.0-fold increase in pancreatic cancer risk. Although the connection is not fully understood, insulin resistance, in ammation, and resulting hyperglycemia have been implicated in the mechanisms that cause cell proliferation in diabetes-related pancreatic cancer.

In 2012, Donghui Li, PhD, reported in Molecular Carcinogenesis¹ that results from animal studies suggest islet cell turnover, associated with insulin resistance, triggers the initial growth of pancreatic cancer cells. Because the failure of islet beta cells is the hallmark of the onset of obesity-associated type 2 diabetes, it would make sense to closely follow patients with new-onset diabetes for early signs of pancreatic cancer.

Patients in the trial will not have to pay for any tests, as all have been covered by private donations, according to a statement from WCHN. The actor James Naughton and his family raised more than $1 million for pancreatic cancer research in honor of his late wife, Pamela, who died of pancreatic cancer in 2013.

Reference:

Li D. Diabetes and pancreatic cancer. Mol Carcinog. 2012;51(1):64-74. doi: 10.1002/mc.20771.

Fiber Intake Associated With Lower Mortality in Patients With Colorectal Cancer

Jaime Rosenberg

HIGHER FIBER INTAKE after the diagnosis of nonmetastatic colorectal cancer (CRC) is associated with lower CRC-specific and overall mortality, according to a study published in JAMA Oncology.

CRC is the third most common cancer and third-leading cause of cancer death in the United States. While high dietary fiber intake has previously been associated with a lower risk of CRC, there is no known benefit of fiber intake for CRC survivors.

“Due to lack of data on post-diagnostic diet and CRC survival, most dietary recommendations for CRC survivors are primarily based on incidence studies,” wrote the authors. “Therefore, identifying prognostic dietary factors is needed to improve CRC survivorship.”

Authors of the study analyzed 1575 healthcare professionals with stages I to III CRC from the Nurses’ Health Study (NHS) and Health Professionals Follow-up Study (HPFS). Participants were mailed a questionnaire focusing on medical history and lifestyle factors at baseline and every 2 years after.

Dietary data were collected and updated every 4 years using Food Frequency Questionnaires (FFQs). The baseline for NHS was 1980, and the baseline for HPFS was 1986. The study was conducted between December 23, 2016, and August 23, 2017.

Dietary fiber intake data collected by the FFQs inquired about how often, on average, the participant consumed each food of a specific serving size in the prior year. Authors calculated the daily intake for each nutrient by multiplying the reported frequency of consumption by its nutrient content and then summing across all foods.

CRC-specific and overall mortality was determined after adjusting for other potential predictors for cancer survival.

Results showed that high fiber intake was associated with lower mortality. The multivariable hazard ratio per 5-g increase in intake per day was 0.78 for CRC-specific mortality and 0.86 for all-cause mortality. The benefit of increasing fiber intake capped at approximately 24 g/d. Patients who increased their fiber intake after diagnosis had a lower mortality rate, with each 5-g/d increase in intake linked to an 18% lower CRC-specific mortali- ty and 14% lower all-cause mortality.

There was no substantial association between fiber intake and tumor subsite or stage.

With respect to specific sources of fiber:

• Cereal fiber was associated with lower CRC-specific mortality and all-cause mortality.
• Vegetable fiber was associated with lower all-cause mortality but not CRC-specific mortality.
• Whole grain intake was associated with lower CRC-specific mortality.
• No association was found for fruit fiber.

“Our present study adds to the existing literature and suggests that the effect of high fiber intake may extend beyond protection against cancer incidence and contribute to better prognosis after cancer is established,” concluded the authors.

Reference:

Song M, Wu K, Meyerhardt JA, Ogino S, et al. Fiber intake and survival after colorectal cancer diagnosis [published online November 2, 2017]. JAMA Oncol. doi: 10.1001/jamaoncol.2017.3684.

Do Oral Parity Laws Reduce OOP Spending for Patients?

Surabhi Dangi-Garimella, PhD

ACCORDING TO A NEW ANALYSIS by Stacie Dusetzina, PhD, and colleagues, state oral parity laws—devised to equate out-of-pocket (OOP) spending for patients, irrespective of whether their treatment is an oral agent or an infusion—are not consistent with reducing patient OOP costs for oral anticancer agents.

The medical versus pharmacy benefit equation has shifted for these oral agents. John Fox, MD, MHA, senior medical director and vice president of medical affairs, Priority Health, explained during a panel discussion hosted by The American Journal of Managed Care^® that more than 60% of patients on the commercial side

of their plans have significant deductibles and coinsurance. “There is less cost sharing on the pharmacy benefit for an oral cancer drug than on the medical benefit, but an unintended consequence of this is that oral prices may increase for patients.”¹

For the present study, published in JAMA Oncology,² investigators at the University of North Carolina, Harvard Medical School, and Brigham and Women’s Hospital analyzed claims data from 3 insurance plans for the period between 2008 and 2012, aggregated by the Health Care Cost Institute. The nearly 64,000 adults in the study lived in 1 of 16 states that passed the oral parity laws during the study period and had received anticancer treatment for which an oral option was available. Primary outcomes being evaluated were:

• Anticancer medication use
• OOP spending
• Total healthcare spending

The use of oral anticancer agents, measured as a percentage of overall anticancer treatment, rose from 18% to 22% during the study period, in the months prior to and after parity. Prescription fills for oral therapies without a co-pay rose from 15.0% to 53.0% among plans subject to parity, compared with a 12.3% to 18.0% increase in plans not subject to parity (P<.001).

Additionally, patients with monthly OOP spends of over $100 increased from 8.4% to 11.1% in plans subject to parity, while those not subject to parity saw

a slight decline: 12.0% to 11.7% (P = .004). Importantly, patient monthly OOP spending varied based on the actual OOP amount after parity:

• Spending decreased by $19.44 at the 25th percentile.
• Spending decreased by $32.13 at the 50th percentile.
• Spending decreased by $10.83 at the 75th percentile.
• Spending increased by $37.19 at the 90th percentile.
• Spending increased by $143.25 at the 95th percentile.
• The 6-month total spending did not change post parity for oral or any anticancer therapy users.

Based on their results, the authors concluded that, despite the slight financial protection, “parity laws may not be sufficient to ensure that patients are protected from high out-of-pocket medication costs.”

References:

1. Oral parity laws and patient cost sharing. The American Journal of Managed Care^®. ajmc.com/peer-exchange/ oncology-stakeholder-summit-fall-2015/oral-parity-laws-and-patient-cost-sharing. Published January 28, 2016. Accessed November 13, 2017.

2. Dusetzina SB, Huskamp HA, Winn AN, Basch E, Keating NL. Out-of-pocket and health care spending changes for patients using orally administered anticancer therapy after adoption of state parity laws [published online November 9, 2017]. JAMA Oncol. doi: 10.1001/jamaoncol.2017.3598.

Incidence Rates of Early-Stage Breast and Colorectal Cancers Increased Following Enactment of ACA

Jaime Rosenberg

THE INCIDENCE RATES of early-stage breast and colorectal cancers increased after the initiation of the Affordable Care Act (ACA), according to a study published in JAMA Oncology.

In addition to expanding insurance coverage, the ACA puts emphasis on preventive care. Through the ACA, cost sharing for services given an A or a B grade by the US Preventive Services Task Force (USPTF) is eliminated.

“Although these policies have improved preventive care generally, their impact on cancer screening specifically is uncertain,” wrote the authors.

The authors of the study analyzed incidence rates in early-stage breast, colorectal, and cervical cancers following the implementation of major ACA policies on January 1, 2014.

The 3 types of cancers all have A or B screening grades from the USPSTF.

Age-adjusted incidence rates of the 3 types of cancers were compared in the first 9 months of 2013 (pre-ACA) and the last 9 months of 2014 (post-ACA), with an intervening 6-month “wash-in” period.

Incidence rates were per 100,000 person-years and were age adjusted. The authors computed the incidence rate ratios (IRRs) and associated 95% confidence intervals to assess for change between the pre- and post-ACA periods. Weighted least squares with a log link were used to see whether the relative difference in IRRs for early-stage disease varied significantly compared with locally advanced/metastatic disease. To find the relative difference in IRRs, the authors exponentiated the difference-in-differences of the log IRRs.

The authors found that from pre- to post-ACA, the incidence of early-stage breast cancer increased from 55.5 to 56.9 cases per 100,000 person-years, with an IRR of 1.025. The incidence of early-stage colorectal cancer (CRC) increased from 13.5 to 15.3 cases per 100,000 person-years, with a pre- to post-ACA IRR of 1.132.

The difference in IRRs was significantly greater for early versus locally advanced/metastatic stages in both early-stage breast cancer and CRC. However, this pattern was not seen in cervical cancer.

These results showed that following the adoption of the ACA, the incidence of early-stage breast and CRC increased but did not vary for the late stages of the 2 cancer types. Although the screening itself was not assessed, these ndings are consistent with increased breast and CRC screenings since the ACA was enacted.

“These results are consistent with a small but positive impact of the ACA on use of recommended cancer screening, which may vary by cancer site,” concluded the authors.

Reference:

Sun M, Cole AP, Lipsitz SL, Trinh QD. Trends in breast, colorectal, and cervical cancer incidence following the Afford- able Care Act: implications for cancer screening [published online November 2, 2017]. JAMA Oncol. doi: 10.1001/ jamaoncol.2017.3861.

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