 The identification of oncogenic genomic alterations and the development of matched targeted therapies have made molecular testing an increasingly important approach to treat non—small cell lung cancer (NSCLC). However, little information is available concerning use of molecular testing in clinical practice and about coverage of these novel tests.

 In particular, clinical guidelines and consensus recommendations, currently available molecular tests along with their associated advantages and disadvantages, the use of molecular testing in clinical practice, and current managed care coverage policies.

 The landscape for molecular testing in NSCLC is evolving rapidly. Although targeted therapy in patients with specific oncogenic genomic alterations is associated with superior outcomes, the use of molecular testing in clinical practice is hindered by several factors, including long turnaround times and tissue sample requirements. Clinical guidelines support the use of broad molecular testing in NSCLC, but most US health plans cover testing only for a limited number of genomic alterations. Nevertheless, as testing technology improves and targeted therapies become more available, molecular tests are expected to eventually become the standard of care in NSCLC treatment.

LUNG CANCER IS THE leading cause of death from cancer worldwide.

 In the United States, more than 225,500 new lung cancer cases and 155,870 lung cancer—related deaths were expected in 2017, making lung cancer the second most prevalent cancer among both men and women.

 Non—small-cell lung cancer (NSCLC) is the most common form of lung cancer, representing approximately 85% of all cases.

 NSCLC is characterized by a number of genomic alterations (mutations, rearrangements, and amplifications), and these alterations are responsible for initiating and maintaining tumor growth through constitutive activation of oncogenic signaling pathways.

 Oncogenic genomic alterations (hereafter referred to as driver mutations) in lung cancer have been identified in genes encoding

The development of therapies targeting known driver mutations has permanently altered the treatment landscape of NSCLC.

 The use of targeted therapies in patients harboring specific genomic alterations for which a specific therapy was developed is associated with improved treatment response and survival.6 Indeed, in recent studies, patients with NSCLC who received targeted therapy were shown to have a higher overall response rate—both in first- and second-line settings

 and overall survival compared with patients not receiving targeted therapy.

 Currently, FDA-approved targeted therapies for NSCLC are available targeting

Other therapies are in development for targets such as 

Targeted therapies first approved for other tumor types have also demonstrated clinical benefit in alterations existent in NSCLC. For example, the combination of dabrafenib (Tafinlar) and trametinib (Mekinist) was initially approved for 

 mutations in metastatic melanoma but now is also approved for 

) are present in approximately half of all cases of metastatic melanoma

 but in just 1% to 4% of patients with NSCLC, with 

Similar to other NSCLC subtypes, patients with 

-positive NSCLC receiving targeted therapy experience improved clinical outcomes as demonstrated by the interim results of a phase II trial.

 Based on the results of this ongoing trial, the dabrafenib/trametinib combination received breakthrough therapy designation, followed by FDA approval for the treatment of 

In addition, National Comprehensive Cancer Network (NCCN) guidelines for NSCLC have recently been updated to include 

mutation testing in the standard set of biomarkers that should be assessed for patients with NSCLC, with the recommendation to use dabrafenib plus trametinib in first-line therapy for 

The identification of novel driver mutations defining clinically relevant molecular subtypes of NSCLC has made molecular testing and subtyping an increasingly important diagnostic tool. Molecular testing using next-generation sequencing (NGS) technology has emerged as a tissue- and time-efficient testing approach as it allows an entire panel of genotypes to be tested simultaneously, typically requiring a small tissue sample.

 Accordingly, several clinical guidelines now endorse the use of broad molecular testing to identify actionable driver mutations for which targeted agents may be available.

In light of the accumulating evidence for the value of molecular testing in NSCLC, it is important to understand current patterns in molecular testing in lung cancer in US clinical practice, particularly the use of multiplex testing by NGS. Testing in actual clinical practice may be particularly important in NSCLC and for patients with relatively rare genomic alterations, given the increasing number of available targeted therapies. Considering the need to identify the appropriate targeted therapy for the right NSCLC patients, and the risk of running out of tissue in sequential testing modalities, multiplex testing may be even more important in NSCLC because of its many less-common actionable driver  mutations/alterations, such as BRAF mutations. Anecdotally, patient access to molecular testing for both established and emerging NSCLC driver mutations also varies, with medical coverage policies that may not reflect current scientific and medical consensus in this rapidly changing area. To address this knowledge gap and better understand the current molecular testing landscape for NSCLC in the United States, this targeted literature review included the following 4 objectives:

1. Describe published clinical guidelines and consensus recommendations related to the use of molecular testing in patients with NSCLC.

2. Describe molecular diagnostic tests currently available in the United States for the detection of the BRAF mutations, their use in clinical practice, and their associated

advantages and disadvantages from the point of view of both patients and physicians.

3. Describe current managed care policies regarding the coverage of molecular testing for NSCLC.

4. Identify policies and barriers regarding the use of molecular testing in clinical practice, and the implications and ramifications they present to the molecular

To identify relevant information regarding the 4 study objectives listed above, a targeted literature review was conducted using the following data sources: 1) MEDLINE and EMBASE (via Ovid); 2) published abstracts from the American Society of Clinical Oncology (ASCO); (3) published treatment and diagnostic oncology guidelines from ASCO, the NCCN, and the College of American Pathologists (CAP)/International Association for the Study of Lung Cancer (IASLC)/Association for Molecular Pathology (AMP); 4) published or otherwise publicly

available care pathways including diagnostic testing for NSCLC; 5) medical policies describing coverage for molecular diagnostic tests for NSCLC tumor samples that include BRAF mutations; 6) grey literature, including pharmaceutical, molecular diagnostic and managed care industry websites, white papers, trade press, and newsletters (eg, PinkSheet,  GreySheet, GenomeWeb, Oncology Times, 

™, Managed Care magazine), describing relevant molecular tests and their coverage and reimbursement; and 7) ad hoc Internet and PubMed searches.

Peer-reviewed articles identified during the targeted literature review were selected based on their potential relevance to the 4 study objectives. The search focused on articles published between January 1, 2011, and June 6, 2016, and was limited to English articles focusing on the United States. The search strings used to conduct the target literature review in Ovid MEDLINE and EMBASE contained the terms BRAF, B-RAF, or B RAF and 1) carcinoma, non—small-cell lung/ or non–smallcell lung cancer$.mp. or NSCLC.mp. or ((lung neoplasms/ or bronchial neoplasms/ or carcinoma, bronchogenic/) and (adenocarcinoma/ or adenocarcinoma, bronchioalveolar/ or carcinoma, large cell/ or carcinoma, squamous cell/)) or 2) lung or NSCLC or non–small-cell lung cancer. 

The 3 main US oncology guidelines for the diagnosis and treatment of NSCLC were selected a priori: ASCO, NCCN, and CAP/IASLC/AMP guidelines. Searches for current guidelines were conducted initially in June 2016 and updated in November 2017.

Molecular diagnostic tests that detect the 

mutation and other genomic alterations using NGS were selected based on Internet searching. To be eligible for inclusion, the tests were required to be marketed for diagnostic use in lung cancer, commercially available in the United States, and used or produced by large central/national laboratories, molecular diagnostics specialty companies, or academic laboratories. It should be noted that, because of the nonsystematic nature of the search, the tests that were selected for this study are not necessarily representative and/or inclusive of all the tests that are currently available on the US market.

Payer medical policies (ie, coverage polices) were identified by searching the websites of small and large US healthcare plans. Searches for publicly available medical policies were conducted initially in June and July of 2016.

A total of 73 articles relevant to the study objectives were identified and selected: 1 was related to objective 1,

 A total 19 currently available molecular tests for the detection of the 

 mutation were selected and reviewed: 3 were from large central/national laboratories, 14 from molecular diagnostics specialty companies, and 2 from academic laboratories. A total of 16 healthcare plans were selected and their

medical policies regarding the coverage of molecular tests for patients with NSCLC were reviewed. The results obtained by reviewing the above selections are presented below for each of the 4 study objectives.

 Clinical guidelines and consensus recommendations for molecular tests in NSCLC

The 2016 draft guidelines from CAP/IASLC/AMP support BRAF testing in NSCLC (

 More specifically, they recommend molecular testing be performed to identify genomic alterations in 

 It should be noted that the CAP/IASLC/AMP guidelines were first published online in 2013. Revised 2016 draft recommendations were anticipated for publication in early 2016, however, as of November 2017 updated guidelines have not been published.

NCCN guidelines continue to support broad molecular profiling (Table 1), and they recommend testing for 

mutations (category 1 for both) in the NSCLC algorithm for patients with nonsquamous NSCLC or NSCLC not otherwise specified so that patients with these genetic abnormalities can receive effective treatment with targeted agents such as ceritinib, erlotinib, gefitinib, afatinib, and crizotinib. The NCCN guidelines also recommend testing for 

rearrangements (category 2A) as well as for 

 mutations for patients with metastatic NSCLC. These guidelines also state that other driver mutations and gene rearrangements (ie, driver events) are being

identified, such as RET gene rearrangements, high-level MET amplification or 

).Targeted agents are available for patients with NSCLC who have these other genetic alterations, although they are FDA approved for other indications.

ASCO guidelines date back to 2014, when the ASCO staff reviewed and endorsed the 2013 CAP/IASLC/AMP guidelines (Table 1). At that time, the CAP/IASLC/AMP guidelines only addressed the use of molecular testing for the selection of patients with lung cancer with genomic alterations in 

There are a variety of NSCLC care pathways. Anthem Cancer Care Quality Program Treatment Pathways do not specify which protocols should be used for molecular testing. Overall, care pathways were not publicly available and mostly focused on chemotherapy, targeted therapy, and supportive care regimens

V600E Mutation: Practical Advantages and Disadvantages

A description of the characteristics of a selection of currently available molecular tests for the detection of the BRAF V600E mutation in patients with NSCLC is presented in 

 tests are available both as single analyte tests and as part of multigene panels.

 a growing number of lung cancer panels also assess genomic alterations in several other genes, including 

 mutations, various test technologies are used, with detectable classes of genomic alterations varying with the tests.

As illustrated in Table 2, some tests detect only point mutations while others are more comprehensive and detect genomic alterations such as insertion and deletions (indels),  chromosomal rearrangements, and copy number alterations. One implication of this variability across tests is that not all the actionable—and thus treatable–driver mutations in NSCLC are identified by all available tests. Not surprisingly, the cost of comprehensive panel testing appears to be substantially higher than the cost of single nucleotide polymorphism tests. 

Sample requirements for available tests vary, as summarized in 

. While most tests require formalin-fixed paraffin-embedded tissue, some also accept a blood/liquid biopsy sample, or purified DNA. Several tests have been developed/validated specifically for lung cancer, while other tests may be applied to any solid tumor or are specific to hematologic malignancies.

Test turnaround time from sample collection to availability of results varies widely across tests, ranging from 1 to 4 days to 4 to 6 weeks (

). Test performance also varies and, in addition, is not reported consistently. Similarly, the information available for each test was often incomplete and not reported consistently. For instance, the sensitivity, specificity, and sequencing depth and coverage of the tests were rarely provided.

Very little was found regarding testing patterns in clinical practice. In particular, no information directly related to the clinical practice of 

testing was found. The information available was related only to 

 and did not encompass all types of genomic alterations. Anecdotal evidence suggests a rapid increase in the availability of comprehensive genomic profiling tests and their use by physicians in treatment selection. As a case in point, Foundation Medicine conducted more than 8000 FoundationOne and FoundationHeme NGS tests in the third quarter of 2015, a 25% increase from the previous year. In addition, a global survey conducted by Kantar Health between December 2014 and January 201525 found that overall 81% of newly diagnosed patients with stage IIIb/IV NSCLC received testing for 

 prior to first-line therapy; this percentage was lower among patients treated by US and European oncologists (77%).

  Practical advantages and disadvantages Comprehensive genomic profiling tests that assay and detect various types of driver mutations have substantial advantages for patients and physicians (Table 2). As long as the information provided by these tests is actionable—and thus has clinical utility&mdash;clinical outcomes are likely to improve. Several studies have investigated the utility of molecular testing in patients with NSCLC by comparing different tests and methods.

 In 1 of these studies, evidence for the utility of targeted NGS assays was obtained by comparing the information obtained from a single gene assay and NGS assays. The study showed that 50-gene panel assays were able to identify at least 1 actionable gene variant in almost twice as many specimens than single gene assays.

However, the practical implications of the potentially useful clinical information provided by molecular testing remain unclear, as no studies quantifying the benefit of improved test performance for patients and/or payers were identified. However, time to results for all actionable genomic alterations and technical improvements related to diminished sample requirements with a 50-gene panel may have substantial advantages for both patients and physicians (Table 3). Newer tests are becoming more efficient in detecting NSCLC genomic variants and they require gradually smaller amounts of sample tissue. This is particularly important given that the limited amount of tissue typically available from a lung biopsy needs to be used in multiple histological and pathological tests, including resampling, following a diagnosis of NSCLC.

Importantly, tests can now be performed using samples that require less invasive procedures, such as a liquid biopsy. Several articles assessed the use of these less invasive procedures.

Although liquid biopsy has been validated for 

 its reliability for NSCLC panel tests compared with direct analysis of tumor tissue has not been established.

A fast test turnaround time may be critical to inform clinical decision making (Table 4). Reported turnaround times varied widely. No studies assessing real-world turnaround times or the impact of turnaround time on clinical outcomes were identified. However, it is obvious that assessing 50 genes at once will be faster than analyzing multiple genes in sequence, as is common in many laboratories.

As of December 2017, other approved NGS tests included Oncomine Dx as well as the broader FoundationOne CDx (F1CDx) and Memorial Sloan Kettering Cancer Center’s Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT), which are both approved to detect mutations in more than 300 genes in any solid tumor type, including NSCLC, melanoma, and breast cancer, enabling the identification of patients who may benefit from at least 15 different FDA-approved targeted therapies.

In terms of coverage, managed care policies regarding molecular testing in NSCLC vary considerably (

). Most of the medical policies identified in this review cover only 

testing. For example, a number of Blue Cross Blue Shield medical policies are similar and usually consider only 

 testing as medically necessary. A few plans, such as Health Net, Inc, and CMS, cover testing for genomic alterations in 

NCCN guidelines are typically cited in medical policies as the reason some tests are deemed medically necessary and others are not. 

Although most plans align medical policies with anatomical tumor location, some payers such as Health Net, Inc, UnitedHealthcare, Aetna, and several CMS Local  Coverage/Medicare contractors have issued medical policies covering comprehensive genomic profiling of tumors using NGS. Standard guidelines for coverage of molecular diagnostic tests have been proposed by the Center for Medical Technology Policy, but they have not generally been put into practice. Similarly, in 2011, the Molecular Diagnostic Services (MolDX) Program was created to establish clear expectations for coverage and reimbursement of molecular diagnostic tests.

Based on this review of managed care policies for diagnostic tests, adherence to MolDx recommendations on the part of diagnostic developers and application of these guidelines by payers is not apparent.

Landscape in NSCLC The technology to detect genomic alterations continues to improve, and several studies have shown that NGS-based assays are capable of more

precisely detecting a wider range of alterations than are standard non-NGS tests.

 These findings underscore not only the greater efficiency of NGS testing in the detection of genomic alterations, but also the importance in identifying the right patients who could benefit from targeted therapies.

Articles

Evidence-Based Oncology

This review assesses the current molecular testing landscape for non–small-cell lung cancer in the United States.

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

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

eAppendix

Wesley Hall sounds remarkably calm for someone about to start his fourth course of cancer treatment. His conversation with

) took place just after Thanksgiving, after Hall learned that his stage IV stomach cancer diagnosed in 2013 had metastasized to his liver.

At first, doctors feared the cancer had also spread to Hall’s spine and his rib, but that turned out to be a false alarm. “I was never so glad just to have liver cancer in my life,” Hall says with a laugh.

That positive outlook is hard won, for Hall has been on quite a journey. “I’m calm, because I’m extremely lucky to be alive,” Hall says. He credits oncologist Nuruddin Jooma, MD, MPH, and the team at Florida Cancer Specialists & Research Institute,

 with “not letting any grass grow under [my] feet,” and getting him into a clinical trial within weeks of diagnosis.

By December 19, 2017, Hall had started his third clinical trial in 4 years, and the second involving immunotherapy. He is among several dozen patients taking Lycera’s investigational oral agent LYC-55716, a RORγ agonist that attacks the tumor in multiple ways. The therapy is described as a master switch, simultaneously regulating the activity of both Th17 (helper) T cells and Tc17 (cytotoxic) T cells; the manufacturer says the approach “both ‘removes the brake’ and ‘pushes on the accelerator’ of immune function.”

For Hall, the idea of immunotherapy in a pill was a revelation. But based on experience, he still saw taking part in a clinical trial as a big responsibility—one with long days and travel at the outset for tests at Florida Cancer Specialists’ research facility in Sarasota, some 60 miles from his home in Dunedin. It’s worth it, however. Despite the adverse effects he experienced in a previous trial, and all the driving, Hall knows that he’s beaten the odds.

He is serious about his part in the scientific process. “You have to keep a log,” Hall says, because researchers want to know exactly when medications are taken. “You have to be honest.” And there’s much a person can’t consume, ranging from vitamins and herbal supplements to Florida grapefruit.

It’s not just about what the trials have done for him. Hall knows what he’s doing is part of something bigger, and the prospect of helping younger cancer patients motivates him to take part in early-phase studies. “I’ve been married 3 times so I’m not good at that,” he says. “I’m 74 years old. I figure if I can [participate in] research to help someone else, that’s fine with me. I have young friends with cancer, and my heart bleeds for them.”

Didn't know how to spell lymphoma at diagnosis

It’s been nearly 20 years since Robert Mesloh noticed what appeared to be a small cyst on his right temple one morning while shaving. He was on a business trip in Singapore, and upon returning home to New Jersey he went to his family doctor, who referred him to a dermatologist, who sent him to a surgeon to have it removed. Two weeks later came the pathology report and a late night phone call about a term Mesloh had never heard: follicular indolent non-Hodgkin lymphoma.

“I didn’t even know how to spell lymphoma, much less that it was a cancer,” Mesloh says. “But then, being a double type A personality, I had to find out as much about it as I could.”

It was the early days of the internet, but Mesloh didn’t want to rely only on that, so he connected with the group that would become the Lymphoma Research Foundation (LRF). In time, he became an LRF ambassador, testifying before Congress, traveling to annual meetings, and interacting with researchers from around the world. He’s now retired and has moved from Parsippany, New Jersey, to The Villages, Florida, but his charitable work continues.

Through the LRF, Mesloh serves as a consumer representative—a patient voice&mdash;on one board that awards research grants for cancer prevention and research within the state of Texas,

and on another board that awards grants on behalf of the Department of Defense.

His activism, and his own deep dive into understanding lymphoma, have shown Mesloh how fortunate he was to initially find an excellent oncologist, Charles Farber, MD, PhD, who not only specialized in lymphoma but also excelled in explaining the available treatment options, limited as they were at the time.

When I had my original diagnosis in 1998, I was what they called pre-stage I,” Mesloh says, and there was a 12% chance that the surgery had removed all the cancer; Mesloh also received radiation. Five years later in 2003, he had a recurrence in the abdominal area. In that span, a “miracle” therapy had arrived: the regimen known as R-CHOP (rituximab with cyclophosphamide, doxorubicin [hydroxydaunorubicin], vincristine sulfate [Oncovin], and prednisone) had made a splash at the 2002 meeting of the American Society of Hematology.

 After treatment with R-CHOP, Mesloh received rituximab maintenance therapy for 2 years.

“Currently, knock on wood, I’m still in complete remission,” he says.

Mesloh was among the first group of patients to gain access to R-CHOP under general availability. Having Farber as his oncologist made all the difference, and Mesloh encourages lymphoma patients to seek a specialist. “Back in 1998, there wasn’t very much that was available,” he says, likening the era to the Dark Ages, compared with what Mesloh sees today as the Golden Age of lymphoma research.

When he was diagnosed, Mesloh says, Farber told him there were 3 to 4 types of Hodgkin lymphoma and 22 to 24 types of non-Hodgkin lymphoma. Now, “to date, we know categorically, there are 80-plus types of non-Hodgkin’s lymphoma,” he says. The completion of the human genome project and other technological advances have yielded more details about cancer subtypes, human DNA, and cancer-cell DNA, and each subtype requires a different approach.

Mesloh is keenly aware how timing worked in his favor. If his lymphoma had shown up just a few years earlier, he would have missed the broader availability of rituximab and R-CHOP “specifically for this 1 form of the 80-plus types of lymphoma.” At one point, Mesloh may not have known how to spell lymphoma, but he can now explain in detail how a monoclonal antibody attaches to the antigen on a cancer cell and “chokes it, so it can’t get any more nourishment.”

Still, those people treating Mesloh have stopped short of saying he is cured. “To this very day, I still think about it, though it’s not in the forefront of my mind,” Mesloh remarks.

Could "set the clock" by symptoms from study drug 

Within weeks of his 2013 diagnosis, Hall was enrolled in a phase 2 clinical trial involving folinic acid and oxaliplatin (FOLFOX) and tivantinib, under the care of Sarasota- based researcher Manish Patel, MD.5 “That worked for 2-and- a-half years,” Hall says. (The trial results were reported this summer in 

) However, Hall says, “I had some pretty bad neuropathy in my hands and feet from the platinum-based drugs.”

By the end of 2015, Hall’s cancer had progressed, so he was taken off the trial and put on regular chemotherapy, staying closer to home for care. In January 2016, Patel offered Hall an opportunity for another clinical trial, this time a phase 1 study involving the immunotherapy durvalumab, the programmed cell death ligand—1 inhibitor that a year later would be granted accelerated FDA approval for certain patients with metastatic urothelial carcinoma.

Hall had heard about adverse effects (AEs) from immunotherapy, but durvalumab turned out not to be the problem, although he ran a high fever of about 104 degrees for the first month or so as his immune system adjusted to the treatment. That didn’t bother him. The targeted therapy he took alongside the durvalumab was another story. The other drug, an as-yet unnamed oral WEE1 kinase inhibitor,

caused intestinal AEs so toxic and predictable, Hall says, that “I could set the clock by when the symptoms were going to start [and] when they were going to stop.”

According to trial information from AstraZeneca, the WEE1 kinase inhibitor is designed to target a protein that plays a role in cell cycle progression and protein phosphorylation—a pharmacologically targetable mechanism that lets cells respond to conditions around them.

that at the time he stopped taking the combination in November 2016—when a stomach mass reappeared after 11 months&mdash;he was the only person who had stuck with the WEE1 kinase inhibitor beyond 2 months. The trial is still recruiting patients, and notes on ClinicalTrials.gov reveal that the drug was so difficult to tolerate that the original dosing schedule was amended; it now includes 2 new schedules that add dexamethasone on the first day of the WEE1 kinase inhibitor, because patients on the first schedule experienced “dose-limiting toxicity.”

In early 2017, Hall returned to Jooma’s practice just minutes from home, where he started on a series of radiation and chemotherapy treatments: carboplatin plus taxol. “That kind of killed everything,” Hall says.

By April 2017 he had no signs of cancer in his stomach, but once again he’d experienced neuropathy. That is why when a new tumor emerged in November 2017, Jooma and Patel wanted to try “something my body hadn’t already seen,” as Hall puts it. And so, as Christmas approached, Hall was preparing for a half-dozen trips from Dunedin to Sarasota in January, where he would put in 12-hour days having his blood drawn and getting other lab work done at the Sarasota research facility, to meet the standards needed for a clinical trial.

Each of those would be a long day for someone who doesn’t have cancer, much less someone who does, but Hall doesn’t mind. After more than 4 years, he feels a bond with both his community oncology team and his caregivers at the research center. Hall “never would have survived” at a large academic institution, he claims, and he raves, for instance, about the Thanksgiving dinner that Florida Cancer Specialists hosted for patients, complete with valet parking. “When I’m not sick, I go there and take them cookies and muffins,” he says. “They’re my family.”

In his own family, he has experienced great loss. When Hall was in elementary school, his father died; in December 2016, Hall’s middle son died of an illness caused by his work as a park ranger. Cancer has changed and shaped Hall’s reality as well, but the disease has also led to positive changes. He’s become a “gym rat,” and he enjoys advocacy work with the Community Oncology Alliance. While he doesn’t have grandchildren, he loves playing Santa for his neighbors’ children.

“I have a real calmness about the whole thing,” he says. “It is what it is. You just have to make the best of it.”

Too few patients take part in clinical trials

From his work with the LRF, Mesloh meets young researchers who are devoting their lives to finding cures for lymphoma and other cancers. “The research grants that are coming through, actually for all forms of cancer, are looking down at the molecular level of how to attack the specific forms of cancer,” Mesloh says. Studies that look to use older medications in new ways, along with genetic testing that allows for personalized medicine in cancer care, are gaining traction. By these developments, he says, “I’m very encouraged.”

Less encouraging, Mesloh says, are frustrations like the “archaic system of billing,” including the disparity between the ways infusion and oral medications are treated in some health benefit plans. (Oral therapies are sometimes treated as a pharmacy benefit with high out-of-pocket costs for patients, while infusion is treated as a medical benefit). There’s also not enough progress on sharing information among institutions, despite much talk of doing so during former Vice President Joe Biden’s Moonshot initiative.

The biggest challenge Mesloh hears about is the tiny share of patients willing to take part in clinical trials. “In the United States, only about 5% of our population who are diagnosed with a cancer will go on to a clinical trial. That disappoints me,” he says. To bring precision medicine to its potential, that percentage must grow, and it will take oncologists educating their patients and referring them outside their practices. “Too many people believe they are going to get a placebo,” Mesloh says, even though that will not happen in most cases.

In lymphoma, “we are probably a decade away from being able to manage many of these [subtypes], based on the research that is in the [pipeline] now,” Mesloh says. With the right funding, the field could see improvement on a trajectory that Mesloh calls “hockey-stick” exponential improvement, for the shape of the graph, instead of linear improvement.

For all he’s learned since his diagnosis, some of the most important conversations at Mesloh’s grant meetings come during the breaks, and they epitomize why he is there. Researchers who spend their days locked in a laboratory come talk to him, to quietly thank him for sharing what it’s like to be a patient living with the disease. “They tell me, ‘Bob, I need to be made aware of that issue. I don’t hear enough of that,’” Mesloh relates.

Hall was feeling good during the latest trial as he headed into his first scan on February 6, 2018. But 2 days later, he learned the news “was not what I had hoped.”

The lesion in his liver had spread, and he would have to come off the trial. Hall told 

he remains at the top of the list for any new trial that covered his situation, and he wasted no time getting in to see Jooma the day after learning the news.

Given Hall’s history with neuropathy from platinum-based chemotherapy, Jooma made plans to start a targeted therapy, to be followed by radiation.

Through it all, Hall’s optimism came through as he described “seeing my old friends,” at his appointment. He sounded hopeful about the next chapter of his journey, which would start in just 12 days.

“I’m confident he will take good care of me.”

 would like to thank Rose Gerber of the Community Oncology Alliance Patient Advocacy Network (CPAN) for her assistance with this article. For more about CPAN, visit http://cpan.communityoncology.org/.

1. Where hope is powered by science [home page]. Florida Cancer Specialists & Research Institute website. flcancer.com/en/. Accessed January 28, 2018.

2. LYC-55716 (RORγ agonist) investigational compound. Lycera website. lycera.com/scientific-approach/immune-activation/ror%CE%B3-agonists. Updated January 2018. Accessed January 27, 2018.

3. Advocate reviewers. Cancer Prevention and Research Institute of Texas website. cprit.state.tx.us/grants-process/peer-review-committees/advo- cate-reviewers/. Accessed January 27, 2018.

4. Coiffier B, Lepage E, Briere J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. 2002;346(4):235-242.  

Two stories--of taking part in clinical trials, and of serving as a voice for patients among scientists who run them--highlight how the advances in cancer are built on the trust between those living with the disease and the clinicians on the frontiers of care. 

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

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.”

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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.

17. Zhu X, Cai H, Zhao L, Lang J. CAR T-cell therapy in ovarian cancer: from the bench to the bedside. Oncotarget. 2017;8(38):64607-64621. doi: 10.18632/oncotarget.19929.

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

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

Nearly 20 years after Genentech set a new standard for treatment of patients with breast cancer whose tumors overexpress human epidermal growth factor receptor 2 (HER2),

Last year's approval of trastuzumab biosimilar, Ogivri, will be the first competitor to blockbuster drug, Herceptin, for the treatment of HER2-positive breast cancer since its discovery. 

February 2018

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

eAppendix

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

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

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

Medical World News: Regulatory Updates

Medical World News: Clinical Updates

Medical World News: Clinical/Managed Care Updates

Future Shock: Embracing Disruption in the Immunotherapy Revolution