Testing for ALK-Positive NSCLC

Recent studies offer new insights into ALK detection methods and related treatments. Screening for the non-small cell lung cancer (NSCLC) subtype has been at the forefront of NSCLC research, and numerous published studies have established meaningful results spanning a vast spectrum of testing approaches. While fluorescence in situ hybridization (FISH) has been the “gold standard” of detecting ALK gene rearrangement, several clinical trials evince limitations in this method—in terms of both cost and effectiveness—and oncologists and other medical professionals suggest administering a combination of screening methods to adequately identify ALK-positive NSCLC. The US Food and Drug Administration (FDA) has recently approved FISH as the sole testing method for ALK gene rearrangement. Further, it is also the prescreening step for ALK treatment eligibility. Crizotinib (Xalkori), an orally taken ALK inhibitor, is currently the only FDA-approved drug treatment for ALK non-small cell lung cancer, and since its prescription is entirely contingent upon positive FISH results, many researchers promote the standardization of other screening methods, which could be more accurate and cost efficient. Many payers, however, argue that the efficacy of FISH is enough to validate its usage, and that this current trend of companion diagnostic devices will, in the long run, promote more efficient use of treatment and better patient outcomes.

Anaplastic Lymphoma Kinase

Anaplastic lymphoma kinase, or ALK, is a subset of non-small lung cancer that represents about 4% of lung adenocarcinomas.¹ This subset was discovered in a 2007 Japanese study that identified “a fusion gene comprising portions of the echinoderm microtubuleassociated protein-like (EML4) gene and the anaplastic lymphoma kinase (ALK) gene….”² Interestingly, ALK rearrangement is almost exclusively found in non-smokers, or light smokers (less than 10 packs a year). Further, researchers have identified at least 13 known variants of the EML4-ALK fusion gene, a characteristic often cited as diagnostically problematic, especially given the rareness of ALK rearrangement.

In August 2011, the FDA approved the oral ALK inhibitor crizotinib (licensed by Pfizer under the brand name Xalkori), and it is currently considered the standard method of treatment for ALKpositive NSCLC. Prescription, though, is contingent upon the testing for and subsequent positive identification of ALK rearrangement. To meet this requirement, the FDA approved Abbott Laboratories’ Vysis Break Apart FISH Probe Kit as the sole companion test to crizotinib treatment. This test-treatment combination is part of the larger trend of personalized medicine development, and it represents what Jenifer Antonacci, director of media relations, Pfizer Inc, calls “a shift away from a one-size-fits-all approach, toward biomarker-based treatment decisions.” But with FISH’s high up-front costs and wavering results, many still question the viability of offering the FISH kit as the sole screening method for NSCLC patients.

Testing for and Treatment of ALK-Positive Non-Small Cell Lung Cancer

FISH continues its reputation as the “gold standard” for ALK screening. Being the only FDA-approved companion diagnostic test to crizotinib treatment, its diagnostic merit and cost are sources of much controversy among medical professionals. The test’s diagnostic challenges are often cited in the literature. For instance, a 2011 multi-institutional study by Paik et al reported that out of 735 NSCLC patients, FISH identified ALK-gene rearrangement in only 28 patients (3.8%), while immunohistochemistry (another ALK testing method currently under evaluation) identified 55 patients (7.5%) as ALK positive.³

More important, FISH is an expensive procedure, its steep cost further compounded by laboratory fees. A 2011 Forbes article prices a FISH test at ~$1500, which includes the cost of the test (~$250) and pathology services.⁴ Further, because Abbott’s FISH kit is biomarker-based (the Vysis FISH kit is optimized to locate only ALK gene mutations), it supposes a potential waste of resources; the same Forbes article finds that only 1 out of 25 ALK-tested patients actually test positive for ALK gene rearrangement. As a result, oncologists and subspecialists are working to standardize a more diagnostically effective and economical method for ALK screening. When asked about the economic implications of FISH, Joanne E. Yi, MD, anatomic pathology and clinical pathology, Mayo Clinic, had this to offer: “Most community pathology laboratories do not have the equipment or personnel to perform this test, and they usually send out to reference laboratories. FISH probe for ALK translocation in a lung cancer setting is now more expensive since the FDA approved the drug with the (FISH) companion test…the prevalence of ALK translocation is so low, and if you do cost analysis it (alternative testing and treatment) will be still much cheaper even if you reflex to more FISH.”

Nonetheless, proponents of FISH cite the method’s newly improved assays and ability to positively identify ALK translocation without further validation by other diagnostics as acceptable reasons for its standardization.1 Many also propose administering a combination of screening methods should FISH produce a false negative.

Health plan professionals, as well, are championing the apparent success of companion diagnostic devices like FISH. They argue that the potential effectiveness of a biomarker-based test like FISH outweighs its high cost, and that as a prescreening step before treatment, it enables payers and patients to avoid much higher expenditures on what would be unnecessary treatment.

Table

Crizotinib (Xalkori) was approved by the FDA in August 2011, and is targeted therapy for the treatment of ALK-positive NSCLC. Responses to the drug have been mostly favorable, with the results of the initial drug trials showing a 57% response rate after just 8 weeks of treatment.⁵ While adverse effects have been reported, all are relatively mild, with the most severe being temporary visual impairment ().⁶

Much like its companion FISH test, however, crizotinib comes with a high cost. In 2011, Emaxhealth.com reported that crizotinib costs approximately $9600 a month, and with its reliance on the FISH probe kit as a companion test, the total cost of ALK screening and treatment would be “prohibitive for many.”⁷

In an effort to make crizotinib more affordable and accessible, Pfizer is offering a copay assistance program that enables privately insured, eligible patients to pay no more than $100 per prescription.⁸ It is important to note, though, that both the drug and copay assistance are only available at participating specialty pharmacies. The company is also offering its First Resource counselors to help uninsured or ineligible patients find other crizotinibgranting assistance programs.

Additionally, other treatments for ALK-positive NSCLC are currently under evaluation. A recent study identified 18 ALK-positive patients with an acquired resistance to crizotinib.⁹ Recent papers have noted the efficacy of pemetrexedbased therapies¹⁰ and ganetespib (a heat shock protein 90 inhibitor)¹¹ in treating the ALK subset.

Payer Perspective

Will the current trend of personalized medicine ultimately engender a future of improved healthcare? In a recent interview, Robert McDonough, MD, Clinical Policy Research & Development, Aetna, discussed the impact of ALK testing and other companion diagnostics on policy making and patient outcomes:

EBO:

Does Aetna currently cover the costs of both FISH testing and crizotinib treatment?

Dr McDonough:

This is an interesting treatment, because you have an oral medication that’s covered under your pharmacy benefits, and then you have a companion diagnostic that would be covered under medical benefits. Yes, we would cover both for their approved indications at this time.

EBO:

Do you see other health plans jumping on board with offering both of these recently FDA -approved components?

Dr McDonough:

I think that you’re going to see pretty uniform coverage for the test and the treatment. It is an FDA-approved treatment for cancer. I believe the National Comprehensive Cancer Network has (also) endorsed the use of this for the treatment of people with NSCLC…. To ensure that the product is working appropriately, you would cover, under the medical benefits, the FISH test that’s used.

EBO:

To what extent does the cost of FISH factor into your coverage decisions?

Dr McDonough:

This is an important point—we make the coverage decision based on the evidence of effectiveness. The cost-effectiveness is factored into the coverage decision only after you’ve made the coverage decision….Aetna has agreed to cover cancer drugs with indications that are recognized by the NCCN of level II/B or greater. So in addition to FDA approvals, the NCCN guidelines are factored into our coverage decision.

EBO:

So with research indicating that only 1 out of 20 or 25 patients will actually test positive for ALK gene rearrangement, do you find covering the costs of FISH is in any way a waste of resources? Is it problematic?

Dr McDonough:

The nice part about this (FISH) test is that it allows you to focus on the 1 out of 20 patients that would actually benefit from this (Xalkori) drug. It actually allows for more efficient use of resources. Also, the drug has adverse effects, some that are potentially serious. So in using this test, you’re able to focus the use of the drug on the people that benefit, and not expose the 19 out of 20 patients who will not benefit, from the risks, including the adverse reactions, by exposure to this drug.

EBO:

Pfizer is currently offering the Xalkori drug in conjunction with a $100 copay assistance program for underinsured patients whose health plans do not offer coverage. Do you think it is in these patients’ best interest to pay out of pocket for the FISH test?

Dr McDonough:

Yes. It (the cost of FISH) is minimal to the cost of the drug. You would want to know if you’re 1 out of 20.

EBO:

A stipulation of that Pfizer program is that it only allows a maximum annual savings of $24,000, which is approximately 2 months’ worth of treatment. Isn’t this an inadequate amount of treatment for the average ALK-positive patient? What does the underinsured patient do in this scenario?

Dr McDonough:

Yes. The average patient is on the drug for about 10 to 11 months…But I imagine that the program is allowing coverage with the idea that in the meantime, the patient will be getting coverage, or getting on Medicaid, or some other arrangement where they will get coverage for continued treatment.

EBO:

Both Abbott’s FISH kit and Pfizer’s Xalkori represent a recent breakthrough in personalized cancer treatment. Do you foresee an emergence of potential competitors?

Dr McDonough:

Not so much competitors. What I see is that this is a trend. The idea of having tests that determine whether someone should be eligible for certain treatments…I think in the future we’re going to see many more examples of drugs that are developed in tandem with diagnostic tests, or also the development of diagnostic tests after drugs come out. I think you will see both. The idea is that you can focus treatment on the subgroup of patients who would benefit the most.

EBO:

So, to conclude, you view this trend of personalized medicine as beneficial to patient outcomes overall?

Dr McDonough:

I think it will benefit patient outcomes, and also lead to a more efficient use of resources…The development of these companion diagnostics is essential to be able to demonstrate the benefits of a specific therapy, especially a specific therapy that only benefits a small subgroup of patients with a particular condition. So I do think we’re going to see more development of these companion diagnostic devices. In fact, the FDA has offered some direct guidance for industry on the development of these companion diagnostics, so it’s definitely going to be a trend in the future.

Funding Source: None.

Author Disclosure: The author reports no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.

Authorship Information: Acquisition of data; analysis and interpretation of data; and drafting of the manuscript.1. Just P-A, Cazes A, Audebourg A, et al. Histologic subtypes, immunohistochemistry, FISH or molecular screening for the accurate diagnosis of ALK-rearrangement in lung cancer: a comprehensive study of caucasian non-smokers [published online ahead of print December 6, 2011]. Lung Cancer. Accessed January 27, 2012.

2. Soda M, Choi YL, Enomoto M, et al. Identification of the transforming EML4-ALK fusion gene [published online ahead of print July 11, 2011]. Nature. 2007;448(7153):561-566. Accessed January 27, 2012.

3. Paik JH, Choi CM, Kim H, et al. Clinicopathologic implication of ALK rearrangement in surgically resected lung cancer: a proposal of diagnostic algorithm for ALK-rearranged adenocarcinoma [published online ahead of print November 28, 2011]. Lung Cancer. Accessed January 27, 2012.

4. Gene test for Pfizer cancer drug to cost $1,500 per patient. Forbes website. http://www.forbes.com/sites/matthewherper/2011/08/29/gene-test-for-pfizer-cancer-drug-to-cost-1500-per-patient/. Accessed February 1, 2012.

5. Solomon B, Bang Y-J, Camidge DR, et al. Timing of responses to crizotinib (PF-02341066) in anaplastic lymphoma kinase-positive patients with advanced non-small cell lung cancer. Paper presented at the 22nd EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics; November 16-19, 2010; Berlin, Germany. Accessed January 28, 2012.

6. Camidge DR, Bang Y-J, Iafrate AJ, et al. Clinical activity of crizotinib (PF-02341066) in ALK-posi-tive patients with advanced non-small cell lung cancer [Abstract 366PD]. Presented at the 35th European Society of Medical Oncology Congress; Milan, Italy; October 8-12, 2012. Ann Oncol.21(suppl 8):viii123.

7. Mitchell D. FDA approves lung cancer drug crizotinib, costs nearly $10K monthly. Emax- Health website. http://www.emaxhealth.com/1274/fda-approves-lung-cancer-drug-crizotinibcosts-nearly-10k-monthly. Published August 26, 2011. Accessed January 28, 2012.

8. Pfizer for Professionals (Pfizer Pro) website.http://pfizerpro.com/resources/minisites/xalkori_home/docs/PatientAssistance.pdf.Accessed January 29, 2012.

9. Katayama R, Shaw AT, Khan TM, et al. Mechanisms of acquired crizotinib resistance in ALKrearranged lung cancers [published online ahead of print June 25, 2012]. Sci Transl Med [abstract]. Accessed February 1, 2012.

10. Takeda M, Okamoto I, Sakai K, et al. Successful long-term treatment with pemetrexed of NSCLC associated with EML4-ALK and low thymidylate synthase expression [published online ahead of print November 6, 2011]. Clin Lung Cancer. Accessed February 1, 2012.

11. Jhaveri K, Taldone T, Modi S, Chiosis G. Advances in the clinical development of heat shock protein 90 (Hsp90) inhibitors in cancers [published online ahead of print October 29, 2011]. Biochim Biophys Acta. 2012;1823(3):742-755. Accessed January 29, 2012.

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