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Patient Enrichment to Limit PGx Testing for NSCLC Could Lower Costs, but Miss Responders


By Turna Ray

Results from a recent study indicate that healthcare providers may need to use the clinical and pathological features of patients to enrich the population receiving pharmacogenetic testing in order to ensure that personalized cancer treatment strategies are administered in a cost-effective manner.

Such a strategy has a downside, however, since it increases the likelihood of missing patients who might benefit from a personalized oncology therapy.

In the British Journal of Cancer last month, University of Colorado researchers Adam Atherly and Ross Camidge modeled the health economics of administering Pfizer's non-small cell lung cancer drug Xalkori to patients whose tumors are ALK mutation positive. They found that broadly testing all advanced NSCLC patients in order to identify the small subset of ALK-positive individuals who should be treated with Xalkori did not meet a cost-effectiveness bar of less than $100,000 per quality-adjusted life year gained.

"For assays costing $1,400 per person, cost per QALY gained for ALK screening all advanced NSCLC, excluding treatment cost, is $106,707," Atherly and Camidge wrote in their paper.

More generally, they determined that broad genetic testing is not cost-effective in cases where the biomarker frequency is less than 5 percent and screening costs range from $600 to $1,400 per person.

Their analysis was drawn from literature reviews and expert opinion to try to determine the cost of genetic testing per patient; to compare the cost-effectiveness of various genetic testing platforms to a gold standard, which in this study was fluorescence in situ hybridization-based ALK testing; to identify the extent to which different enrichment strategies involving various clinical and pathological factors can identify the intent-to-treat population; and to characterize the treatment benefit gained by patients who are identified as ALK-positive by testing.

Atherly and Camidge's economic analysis revealed that if doctors were to perform genetic testing in a highly enriched population — for example testing only those NSCLC patients who have adenocarcinoma histology, are non-smokers, and are known to have EGFR and KRAS wild-type tumors — then the "mean health gain" would more than double to around 0.29 QALYs gained per person from 0.013 QALYs gained per person if all advanced NSCLC patients were genetically tested.

Furthermore, the cost per QALY gained would decrease to around $4,756 when an enrichment strategy was used compared to the more than $100,000 per QALY gained when the entire advanced NSCLC patient population is tested.

A downside to such an enrichment strategy, however, is that it would miss around 56 percent of patients with ALK rearrangements, who would have likely benefitted from Xalkori, the researchers pointed out.

As more PGx-guided drugs indicated for small patient subsets come to market, insurers will increasingly need to consider the advantages and disadvantages of various enrichment strategies in order to ensure that the cost of identifying the intent-to-treat population with the help of genetic testing doesn't diminish the potential savings payors are hoping to gain by avoiding giving the treatment to those who are unlikely to see a benefit.

"Medically, to catch all [responders] you have to test all," Camidge told PGx Reporter. In the BJC paper, "economic arguments are overlaid on this [basic premise] depending on the restrictions the payor may or may not impose."

The university hasn't implemented the enrichment strategies for ALK testing that Atherly and Camidge describe in their paper. At UC, "we have routinely tested everyone," Camidge said.

In the paper, "we explain the pros and cons of enrichment to inform its application in different systems where adoption … will be affected by many economic and value judgments," he explained. "It has not affected us [at UC] yet, but we wanted to model it in advance."

National insurer Aetna covers Xalkori under plans that include certain specialty drugs for complex, chronic diseases. Specialty drugs, according to an Aetna brochure, "are often expensive." In order for Aetna to pay for Xalkori within its specialty drug plans, the insurer requires documentation showing that the patient receiving the drug harbors ALK rearrangements.

When it comes to paying for PGx testing in this setting, it seems that Aetna will cover Abbott's Vysis ALK Break Apart FISH Probe Kit for NSCLC patients. According to the Aetna's website, the insurer "considers an FDA-approved test for the ALK fusion gene … medically necessary for persons who are considering … Xalkori for the treatment of NSCLC."

It's not clear from the publically available information on Aetna's website if the insurer encourages enrichment strategies to narrow the patient population receiving ALK testing. Aetna did not respond to questions for this article.

The US Food and Drug Administration simultaneously approved Pfizer's Xalkori and Abbott Molecular's Vysis ALK Break Apart FISH Probe Kit last August. The drug costs more than $115,000 per year. The $1,400 price tag for FISH-based ALK testing cited in the BJC analysis was established by "expert opinion" gathered by the researchers. PGx Reporter has previously reported that Abbott's ALK test is priced at less than $250 per test.

The median age of onset for lung cancer is around 70 years old. As such, most people considered for treatment with Xalkori and companion ALK testing will be covered under Medicare.

Medicare contractor Palmetto is tracking utilization of molecular diagnostics through its MolDx program with the aim of setting reimbursement rates for tests based on the value they provide to patient care. Palmetto hasn't laid out its thinking on the metrics it will use to establish value-based pricing, and so, it's unknown how companion diagnostics, such as ALK testing for Xalkori, will fare (PGx Reporter 2/29/2012).

Palmetto didn't respond to questions ahead of press time.

Although in the study the authors based their analysis on the assumption that the median age for developing lung cancer was at 70 years, they note that actionable molecular abnormalities, such as ALK rearrangements, can show up several years earlier in the overall lung cancer population. "Consequently, in such scenarios there may be additional health benefits that could be addressed in the form of productivity gained" by screening people earlier to consider whether they should receive molecular testing, the researchers suggested.

Enrichment and Dx Platform

Ultimately, as payors become more discriminating in covering PGx testing, they will have to balance a number of factors, including the effectiveness and cost of testing, the prevalence of the marker, the cost of the drug, and the benefit the target population derives from treatment. In this regard, Atherly and Camidge illustrate in their paper the varying cost benefits and outcome risks of applying different enrichment strategies and using different technology platforms for testing.

For example, if healthcare providers cast a wide net, testing all advanced NSCLC patients for ALK mutations by FISH, they have the best chance of identifying all patients who will benefit from Xalkori treatment. However, given that only 1.6 percent of NSCLC patients harbor ALK mutations, the cost per QALY gained of such a broad testing program surpasses the cost effectiveness threshold.

If doctors genetically tested only NSCLC patients with adenocarcinomas, comprising 39 percent of the initial NSCLC population, then the cost per QALY gained drops to around $46,000. Although with this enrichment criteria, nearly 13 percent of likely responders to Xalkori would be missed.

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When the intent-to-treat population is further narrowed to consider never smokers and patients with EGFR and KRAS wild-type tumors, representing 5.8 percent and 2 percent of advanced NSCLC patients, the cost per QALY gained is approximately $12,000 and $4,000, respectively.

But an enrichment plan that accounts for all these factors would overlook 56 percent of patients who would benefit from the drug.

"[A]s the population screened becomes more enriched and the mean health gain increases, the cost per QALY gained decreases," the researchers wrote in their paper. "In addition, beyond increasing the screening 'hit rate,' sequential enrichment provides further absolute cost savings through smaller and smaller proportions of the total population being screened."

In their analysis, Atherly and Camidge also demonstrated that cheaper but less sensitive diagnostic technologies could potentially improve the cost-effectiveness of genetic interventions, but again, the trade-off would be a higher risk of not capturing some patients who might respond to treatment. As such, when comparing the cost-effectiveness of different diagnostic technologies, both their price and their performance must be factored in, the researchers noted.

For example, the cost per QALY gained with an RT-PCR-based test if all advanced NSCLC patients were tested for ALK mutations would be $95,274, below the $100,000 cost-effectiveness threshold. The cost per QALY gained with immunohistochemistry tests would be $57,165.

The researchers estimated in their analysis that an RT-PCR based ALK test cost more than $800, which is cheaper than the $1,400 for a FISH-based assay but could miss up to 30 percent of true ALK positive cases. Meanwhile, IHC testing, at $600 per assay, could fail to pick up 20 percent of ALK-positive patients if such testing was performed alone and if only 3+ IHC staining defined the intent-to-treat population.

"An 'imperfect' test may be more cost-effective than a 'perfect' test, provided the proportion of cases missed remains less than the proportional reduction in the screening cost associated with using the 'imperfect' assay," the study authors wrote in the paper. "For example, although the RT-PCR test misses 30 percent of cases, our estimate is that the test is [approximately] 40 percent less costly ($875 versus $1,400). Thus, the cost per QALY gained is uniformly 10 percent lower than for FISH testing."

Earlier this year, Pfizer inked a collaboration with Roche subsidiary Ventana Medical Systems to develop an IHC-based ALK test for Xalkori (PGx Reporter 1/11/2012).

However, Atherly and Camidge don't advocate using the cheaper, "imperfect" assays when the prevalence of the biomarker of interest is above 5 percent in the disease population. "We would suggest that, with drug and assay costs within the range we have modeled, it makes little sense to potentially miss marker-positive patients through the use of imperfect but cheaper assays, when the biomarker of interest is above a certain threshold ([around] 5 percent)," the researchers said in the paper. "This is because at higher biomarker frequencies, the difference in assay cost makes minimal difference to the overall cost-effectiveness of the screening-treatment pairing."

Even when the biomarker is rare, as ALK rearrangements are in advanced NSCLC patients, the researchers found that "acceptable cost-effectiveness may only be achieved through either reducing the screening price or through adopting clinical enrichment strategies to narrow the focus to populations in which the biomarker exists at higher levels."

Future Savings with Multiplex Tests, NGS

Atherly and Camidge identified other factors that could improve the cost-effectiveness of PGx testing, including increased availability of multiplex tests and wider adoption of next-generation sequencing strategies in healthcare.

The researchers highlighted the use of multiplex tests such as Sequenom's MassArray genotyping system and the SNaPshot PCR assay as examples of how doctors can find multiple, rare mutations of interest in patients in one go when personalizing cancer treatments. "Using these assays, for the cost of one screening test, information may be generated on enough different mutations to produce a hit rate for 'actionable biomarkers' of [greater than] 40 percent in some NSCLCs, well above the level needed to avoid the screening costs being dominant in our modeled cost-effectiveness analysis," the researchers wrote.

Investigators at Massachusetts General Hospital recently published a study in which they tested more than 500 NSCLC patients for 50 known mutations in more than a dozen genes. With this information, researchers were able to recommend personalized treatment strategies for 100 patients with advanced disease (PGx Reporter 12/7/2011).

In lung cancer, tissue biopsies are difficult to obtain and often there may not be enough tissue left over to test for different mutations using single-gene tests. In such situations, with multiplex tests doctors may be able to analyze small biopsies more efficiently. "With the advent of newer technologies, such as next-generation sequencing, there may even be the potential to combine information on mutations, gene rearrangements and gene copy number, together within a single multiplexed platform in the future," Atherly and Camidge added.

Although the main focus of the BJC paper was on the cost-effectiveness of companion diagnostic testing, the researchers also considered the impact that drug price may have on the health economics associated with drug/test combination products. Essentially, the researchers found that when calculating the cost-effectiveness of these products, drug price is the "least impactful" factor after the cost of the assay, the frequency of the biomarker in the screened population, and the extent of treatment benefit in the marker-positive group.

"In the extreme, if the frequency of the marker is 1 percent and the price of the screening test is $1,400, a cost per QALY gained of $100,000 is not achievable at any drug price," the study authors said, adding that when the drug is priced at $1,000 per month and the test price is lowered to $600, the cost-effectiveness for the overall treatment strategy "just becomes achievable."

Comparatively, when the biomarker prevalence increases to greater than 5 percent in the disease population, a cost per QALY gained of less than $100,000 is achievable with a $1,400 test price and a drug price tag between $1,000 and $5,000 per month.

Atherly and Camidge note that when a treatment is targeted for a small genomically defined patient population, a higher drug price is "a precedent already partially established by some cost-effectiveness bodies," reasoning that despite the higher cost "the overall impact on society … will be low, whereas the gain for the individuals affected may be great."

The authors of the BJC paper added that the higher pricing for PGx drugs may incentivize pharma investments in treatments for small patient subsets. Pfizer received orphan drug status for Xalkori, which gives the company additional market exclusivity and tax incentives.

Have topics you'd like to see covered in Pharmacogenomics Reporter? Contact the editor at tray [at] genomeweb [.] com.