Patient Access to Targeted Therapies Updated VOL 1, NO 1

Molecular diagnostics are at the center of personalized healthcare. In July 2012, a rapid molecular test for Kirsten RNA associated rat sarcoma 2 virus gene (KRAS) mutations—the therascreen KRAS RGQ PCR Kit (therascreen KRAS test)—was the first to receive approval from the US Food and Drug Administration (FDA) as a companion diagnostic for detecting the presence of 7 mutations in the KRAS gene in colorectal cancer cells, thus identifying patients with metastatic colorectal cancer who are most likely to respond to cetuximab.¹ If KRAS mutations are absent, patients are candidates for potentially life-prolonging treatment with cetuximab. During the 2013 meeting of the American Society of Clinical Oncology in Chicago, QIAGEN (the manufacturer of the therascreen KRAS test) held a workshop entitled: Will recent changes in companion diagnostic reimbursement put patient access to state-of-the-art therapies at risk? This workshop addressed recent changes in the reimbursement landscape for companion diagnostics and how these changes may ultimately affect patient care and patient access to state of-the-art targeted therapies.

IN VITRO COMPANION DIAGNOSTICS

The FDA recognizes the importance of biomarkers in identifying responders and nonresponders to drugs. “Access to biomarker testing is critical in directing patients toward the best and most appropriate therapies,” said presenters. “A companion diagnostic is an assay that can be used to select in advance which patients are most likely to benefit from a particular therapy or how a therapy might best be administered to an individual patient,” said Tadd S. Lazarus, MD, chief medical officer and head of medical affairs, QIAGEN, Inc. As such, it enables personalization of healthcare. All stakeholders benefit from personalized medicine and companion diagnostics (CDx). Patients can benefit from novel therapeutic strategies, possibly earlier in their disease course compared with trial-and-error approaches to therapy, leading to better treatment outcomes. Healthcare providers can identify active drugs more efficiently and have enhanced confidence in their treatment decisions, and payers can realize cost savings through greater efficiency and the avoidance of ineffective strategies (Figure). “The FDA has encouraged the development of therapeutic products that depend on the use of approved in vitro companion diagnostic devices,” said Dr Lazarus. In the case of cetuximab for the treatment of colorectal cancer, the FDA granted approval for it as a first-line treatment of patients with KRAS mutation-negative (wild-type), epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer as determined by FDA-approved tests.² The use of FDA-approved tests is required for this indication in the cetuximab label. FDA approved the therascreen KRAS test concurrent with this cetuximab approval. This test is the only FDA-approved test for KRAS mutation detection. It is a real-time polymerase chain reaction assay that detects 7 different mutations of the KRAS gene in a formalin-fixed paraffin-embedded (FFPE) tumor specimen.

FDA VALIDATION REQUIREMENTS FOR COMPANION DIAGNOSTICS

An FDA requirement for companion diagnostics is that the clinical utility of the diagnostic has been demonstrated through clinical trial. Once FDA-approved, the drug should not be prescribed without testing with an FDA-approved test. To obtain approval for a companion diagnostic, the sponsor must show that the product is both analytically and clinically validated. Ideally, the diagnostic should be developed and analytically validated early in the development process so that its clinical utility can be assessed in later-stage clinical trials. Analytical validation of a test with multiple biomarkers ideally will occur in clinical trials enrolling patients that are representative of the intended use population.

EGFR PATHWAY CRITICAL TO CANCER CELL SURVIVAL

EGFR is critically involved in the regulation of cell proliferation, survival, and signaling in cancer cells that arise in many anatomical and tissue sites in the body. Key intermediaries of this pathway, such as KRAS and phosphoinositide 3-kinase (PI3K), when mutated, can cause oncogenic signaling, leading to cancer. Tyrosine kinase inhibitors (TKIs) target the various elements of the EGFR pathway. When these drugs are effective in treatment they can lead to prolonged progression-free survival (PFS) in the patient, but in some cases when the mutation is misidentified, these drugs can have adverse effects. KRAS mutations are found in approximately 40% of colorectal cancers.^3-5 Multiple studies have demonstrated that patients with tumors harboring KRAS mutations are unlikely to benefit from anti-EGFR antibody therapy.^2-5 In one such study, the utility of cetuximab in patients with KRAS wild-type EGFR-expressing colorectal cancer was demonstrated in an open-label randomized controlled trial in 1,217 patients, who were randomly assigned to receive either cetuximab in combination with FOLFIRI (leucovorin, 5-fluorouracil, irinotecan) or FOLFIRI alone, irrespective of KRAS mutation status. None of the patients had received prior chemotherapy for metastatic disease. PFS was the primary efficacy end point.² In the overall population, a statistically significant improvement in PFS was observed in patients treated with cetuximab plus FOLFIRI compared with patients treated with FOLFIRI alone (median PFS 8.9 vs 8.1 months; P = .036). Tumor tissue was evaluable for KRAS mutation status assessment in 89% of the patients: 63% had wild-type tumors and 37% had mutant tumors. Retrospective efficacy analyses demonstrated that the median overall survival (OS) for the wild-type subgroup was 23.5 months for patients assigned to cetuximab plus FOLFIRI compared with 19.5 months for patients assigned to FOLFIRI alone (hazard ratio [HR]: 0.80 [95% CI: 0.67 to 0.94]). The median PFS for patients with wild-type KRAS treated with cetuximab plus FOLFIRI was 9.5 months versus 8.1 months for patients treated with FOLFIRI alone (HR: 0.70 [95% CI: 0.57 to 0.86]). The objective response rate (ORR) was 57% in patients with wild-type KRAS treated with cetuximab plus FOLFIRI versus 39% in patients assigned to FOLFIRI alone. In the subgroup of patients with mutant KRAS, there were no improvements in OS, PFS, or ORR with the addition of cetuximab to FOLFIRI.² Retrospective analyses of 2 supportive studies, CA225025 and OPUS, by tumor KRAS mutation status supported cetuximab’s efficacy in the wild-type subgroup.¹

COMPLICATED REIMBURSEMENT LANDSCAPE

“Reductions in reimbursement rates pose significant access problems to FDA-approved testing and new therapies that rely on companion diagnostics,” said Dr Lazarus, “potentially limiting the number of candidates for TKIs.” New Current Procedural Terminology codes were released by the American Medical Association for molecular diagnostics in January 2013. In May 2013, the Centers for Medicare & Medicaid Services (CMS) reduced the average reimbursement rate by 75% to laboratories performing EGFR mutation testing and by 13% to those that perform the KRAS companion diagnostic.⁶ “These reductions are beginning to be a significant disincentive for labs to offer these tests and in turn put the patients at risk in terms of getting access to cancer drugs that rely on companion diagnostic testing,” Dr Lazarus said. Companion diagnostic testing may, therefore, become inaccessible to community laboratories, which cannot bear the cost of running these tests at a loss. “To save money, the labs may resort to performing cheaper lab-developed tests, which are off-label for many of the drugs,” he said. “The trickle-down effect is that companion diagnostic testing will not be widely available and, ultimately, patient care will be compromised.” If companion diagnostic tests become available only to a limited number of laboratories, turnaround time will be increased, delaying prescription of newer therapies. Such a shift also runs the risk of disrupting the local relationship between the oncologist and the pathologist, “which is critical to ensuring cohesive, high-quality patient care,” he said. Following a 60-day comment period on the interim reimbursement amounts, which expired in July 2013, reconsideration requests will be accepted for 30 days, starting in August 2013. The CMS final rule on reimbursement for companion diagnostics will be published in October 2013, and the new national reimbursement figures will become effective in January 2014. “QIAGEN is meeting directly with CMS to discuss the need to expand premium payment for FDA-approved companion diagnostics nationally,” said Dr Lazarus. Such a premium payment will promote access to clinically proven, gold standard assays, in order to secure the highest efficacy of state-of-the-art therapies for patients.

INTIMATE LINK BETWEEN BIOMARKER TESTING AND TARGETED THERAPIES

“The reliability of in vitro diagnostics is critical for accurate diagnosis of disease and appropriate patient management,” said Christine M. Lovly, MD, PhD, assistant professor of medicine and cancer biology, Vanderbilt-Ingram Cancer Center, Nashville, TN. Failure of an in vitro diagnostic to function as intended may result in misdiagnosis and/or insufficient, unnecessary, or even inappropriate treatment, which is why these tests are subject to multiple levels of federal regulation. See some examples of FDA approved in vitro diagnostics in the Table. For example, about 10% of patients with non–smallcell lung cancer (NSCLC) in the United States and about one third in East Asia have EGFR-mutant lung cancer. “In the metastatic setting, EGFR mutations are strong predictors of antitumor efficacy for EGFR TKIs,” said Dr Lovly. “A pivotal trial in 2009 by Mok et al⁷ brought the idea of personalized medicine to the forefront,” she said. The study, conducted in an East Asian population, showed that gefitinib significantly improved PFS in tumors that were positive for EGFR mutation compared with platinum- based chemotherapy. Tumors that were negative for EGFR mutation had significantly longer PFS with platinum-based chemotherapy compared with gefitinib. “Our ability to be more precise in our diagnosis and treatment strategies has improved outcomes, not just in lung cancer but in breast cancer, melanoma, and other cancers,” said Dr Lovly. Among patients with NSCLC in the United States, 2% to 7% have anaplastic lymphoma kinase (ALK) gene fusions,⁸ which, for the most part, are non-overlapping with other oncogenic driver mutations such as EGFR and KRAS. “With more than 200,000 new cases of lung cancer in the United States alone every year,⁹ you’re still talking about tens of thousands of individuals who could benefit from a better understanding of diagnostic tools and therapies for ALK-positive lung cancer,” she said. In addition to NSCLC, ALK fusions can be found in subsets of lymphoma (particularly anaplastic large-cell lymphoma) and inflammatory myofibroblastic tumor. The gold standard assay for detecting ALK gene rearrangements in NSCLC tumor specimens is fluorescence in situ hybridization. Crizotinib is a small-molecule TKI that targets ALK kinase. In the initial phase 1 trial of this agent,¹⁰ patients with ALK-positive advanced NSCLC displayed a 60.8% objective response rate to crizotinib. In a subsequent international phase 3 trial of 347 patients with locally advanced or metastatic ALK-positive lung cancer who had received 1 prior platinum-based regimen,¹¹ PFS was significantly increased with crizotinib compared with single-agent chemotherapy with either pemetrexed or docetaxel—median 7.7 months versus 3.0 months (hazard ratio for progression: 0.49; P <.001).

MOLECULAR TESTING GUIDELINE FOR LUNG CANCER: SENSITIVE ASSAY RECOMMENDED⁸

A molecular testing guideline for the selection of lung cancer patients for EGFR and ALK TKIs has been issued by the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology. The guideline states that EGFR mutation testing should be ordered at the time of diagnosis for patients presenting with advanced-stage disease who are suitable for therapy or at the time of recurrence or progression in patients who originally presented with lower-stage disease but were not previously tested. As Expert Consensus Opinion, the guideline panel encouraged EGFR testing of tumors at diagnosis in patients presenting with stage I, II, or III disease, with the decision to do so made locally by each laboratory, in collaboration with its oncology team. It also recommended that laboratories use EGFR test methods that are able to detect mutations in specimens “with at least 50% cancer content, although laboratories are strongly encouraged to use…more sensitive tests that are able to detect mutations in specimens with as little as 10% cancer cells” (ie, mutant DNA).

IMPACT OF FDA-APPROVED DIAGNOSTICS ON PERSONALIZED HEALTHCARE

The practice of medical oncology has incorporated the use of in vitro diagnostics not only for diagnosis, but also for screening, including or omitting specific therapies for patients, and monitoring the course of a disease. In vitro diagnostics must be fully reliable to support these roles, and FDA-approved in vitro diagnostics have met this standard. The therascreen KRAS test, for example, detects 7 mutations of codons 12 and 13 of the KRAS oncogene, and can recognize mutated cells at concentrations of 0.8% to 6.4%.¹ Better diagnostic tools are expected to help further personalize the practice of medical oncology, with the ultimate goal of improving patient outcomes. FDA approved companion diagnostics and workflows are crucial to providing the most timely and accurate diagnoses, leading to optimum therapy for the patient. However, a reduction in reimbursement will affect access to state-of-the-art therapies that rely on companion diagnostics if changes are not made. Securing a premium payment for approved companion diagnostics is a must to promote access to gold standard assays as the gateway to achieving the greatest efficacy of stateof- the-art therapies. A national coding methodology must be established to distinguish between FDAapproved and less expensive off-label laboratory-developed tests. Providers are urged to join the conversation as CMS finalizes its coverage and payment policies for companion diagnostics.

REFERENCES

1. Center for Devices and Radiological Health, US Food and Drug Administration. Summary of safety and effectiveness data: premarket approval application P110030. http://www.accessdata.fda.gov/cdrh_docs/pdf11/P110030b.pdf. Accessed July 3, 2013.
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5. Tol J, Koopman M, Cats A, et al. Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med. 2009;360: 563-572.
6. Centers for Medicare & Medicaid Services Web site. Gapfill Pricing Inquiries. http://www.cms.gov/Medicare/Medicare-Fee-for-Service-Payment/ClinicalLabFeeSched/Gapfill-Pricing-Inquiries.html.
7. Mok TS, Wu Y-L, Thongprasert S, et al. Gefitinib or carboplatinpaclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361: 947-957.
8. Lindeman NI, Cagle PT, Beasley MB, et al. Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. J Mol Diagn. 2013;15:415-453.
9. US Cancer Statistics Working Group. United States Cancer Statistics: 1999–2009 Incidence and Mortality Web-based Report. Atlanta (GA): Department of Health and Human Services, Centers for Disease Control and Prevention, and National Cancer Institute; 2013. Available at: http://www.cdc.gov/uscs.
10. Camidge DR, Bang YJ, Kwak EL, et al. Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study. Lancet Oncol. 2012;13:1011-1019.
11. Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med. 2013;368:2385-2394.

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