Crizotinib Not Cost-Effective, Says Canadian Study

Roxanne Nelson

February 28, 2014

The targeted therapy crizotinib (Xalkori,Pfizer) has been hailed as a major therapeutic breakthrough for the small subgroup of patients with non-small cell lung cancer (NSCLC) whose tumors test positive for ALK gene rearrangement.

However, as with many of the new cancer drugs, crizotinib comes with very high price tag. In addition, because the biomarker is found in only 3% to 5% of patients with lung cancer, all patients need to be screened.

Therefore, the economic burden of crizotinib on the healthcare system might be too high, Canadian researchers report.

The results of their study were published online February 24 in the Journal of Clinical Oncology.

Although the findings are preliminary, Natasha B. Leighl, MD, from the Princess Margaret Cancer Center in Toronto, and colleagues note that "EML4-ALK fusion molecular testing and targeted crizotinib treatment for patients with advanced nonsquamous NSCLC are currently not likely to be considered cost effective."

Making this strategy more economically feasible would require lower drug costs, more targeted molecular testing, or improved effectiveness, they add.

At least one healthcare system agrees that the drug is too expensive. Last year, the National Institute for Health and Care Excellence (NICE) in the United Kingdom decided not to recommend coverage of crizotinib by the National Health Service (NHS).

"Having already recommended a number of treatments for the various stages of non-small cell lung cancer, we are disappointed not to be able to add crizotinib as a treatment option for patients," Sir Andrew Dillon, chief executive of NICE, said in a statement.

"Although the independent committee that considered the evidence found crizotinib to be clinically effective treatment for ALK-positive non-small cell lung cancer, crizotinib could not be considered a cost-effective use of NHS resources, even when taking into consideration the manufacturer's patient-access scheme," he added.

Dr. Leighl and colleagues look beyond crizotinib. They note that new targeted therapies are changing the paradigm of cancer care, but their cost not only places a crushing burden on healthcare systems, it also limits access to patients who are able to pay for them. In addition, the overall drug benefit might offer only a small survival benefit.

High-Priced Poster Child

In the United States, crizotinib costs roughly $115,000 per year.

"If we accept that we cannot pay $10,000 a month for each new drug, then we have to make decisions about prices using some type of system, rather than let the increasingly small number of people who can afford it to buy it," Thomas Smith MD, Hopkins, from the Sidney Kimmel Comprehensive Cancer Center of Johns Hopkins, Baltimore, MD, told Medscape Medical News.

Lung cancer is currently the "poster child" for personalized medicine, because identifying targetable oncogenic drivers is now considered the standard of care in stage IV disease, write Dr. Smith, Ronan Kelly, MD, also from Hopkins, and Bruce Hillner, MD, from the Massey Cancer Center of Virginia Commonwealth University in Richmond, in an accompanying editorial.

Notably, the ALK gene has emerged as an important oncogenic driver in a small subgroup of patients with adenocarcinoma.

A pivotal phase 3 head-to-head comparison demonstrated that median progression-free survival was twice as long with crizotinib as with standard chemotherapy of pemetrexed or docetaxel (7.7 vs 3.0 months). Experts declared that these data were "practice changing" and that crizotinib "is the best option for treatment in these patients."

Crizotinib subsequently received accelerated approval from the US Food and Drug Administration (FDA) for use in conjunction with a companion diagnostic test (Vysis ALK Break Apart FISH Probe Kit, Abbott Molecular) to identify appropriate patients, which was approved at the same time.

"Targeting ALK is the second significant breakthrough in the treatment of lung cancer after the development of EGFR-directed therapies," Dr. Kelly told Medscape Medical News. "More work needs to be done, but crizotinib certainly represents an incremental breakthrough after decades of no major advances."

Crizotinib is superior to standard chemotherapies in this population, he explained. "The vast majority of patients feel dramatically better and we see significant responses on CT scans. The data to date show progression-free survival that is longer than that with older-style chemotherapies."

However, because study designs to date have permitted crossover, "we await official confirmation of what the overall survival benefit is," he noted.

Dr. Smith pointed out that the survival benefit estimated for crizotinib is only 4 months, and after 2 years in second-line trials, only about 15% of patient were still alive, whether they received crizotinib second-line or after progression. "This is different from [trastuzumab] in breast cancer, which clearly changed overall survival," he said.

Can We Afford It?

As practice changing as crizotinib might be, the editorialists ask whether we can afford to screen everyone with lung cancer and whether we can afford to pay for crizotinib.

Dr. Leighl and colleagues answer no to both questions.

Aside from the drug price, they point out the challenges in implementing molecular testing with the companion test for ALK fusion. These include the high incidence of NSCLC, the low frequency of ALK fusion, and the cost, complexity, and tissue requirements for testing.

The researchers note that of the approximately 8000 new cases of lung cancer diagnosed in Ontario annually, about 6880 patients (86%) have nonsquamous NSCLC. Most of these patients will present with advanced disease (approximately 5160) and be eligible for testing. In this cohort, an estimated 175 patients would have an ALK gene rearrangement and meet the criteria for crizotinib treatment.

Using a less expensive and more widely available testing method — ALK immunohistochemistry with fluorescence in situ hybridization (FISH) confirmation — would run about US$277,674 annually, whereas the total cost of crizotinib treatment would be approximately US$18 million.

In terms of quality-adjusted life-years (QALYs), molecular testing with first-line targeted crizotinib therapy would result in a gain of 0.011 QALYs over standard care.

The incremental cost would be US$2425 per patient, with an incremental cost-effectiveness ratio (ICER) of US$230,728 per QALY gained. In this patient subgroup, crizotinib therapy would provide 0.379 additional QALYs for an additional US$85670 over standard care. In turn, this would produce an ICER of US$225,916 per QALY gained.

The major driver of cost-effectiveness, the researcher note, is the price of the agent.

American Perspective

The editorialists point to other data that give an "American perspective" on the cost-effectiveness of screening patients with lung cancer for targeted therapy (Br J Cancer. 2012;106:1100-1106). The results, they note, are "remarkably similar" to those from the current study.

If 1.6% of patients are found to be positive after screening all patients with FISH and gain 0.83 QALYs each, the total gain is only 0.013 QALYs (5 extra days of quality life) at a cost of $106,700 per QALY per screened individual.

But at a cost of $9600 per month, even if the frequency of ALK-positive patients is more than 50%, the cost-effectiveness is still more than $100,000 per QALY, the editorialists point out. "If the frequency is 1.0%, then the drug price needs to be lowered to less than $2300 per month to meet recognized cost-effectiveness criteria."

Center Stage

The editorialists emphasize that the "debate as to how we can continue to pay for each breakthrough medication without bankrupting patients or society while continuing to incentivize research and development needs to take center stage."

Cost-effectiveness analyses must be used to form policy around national healthcare, and that will differ from country to country. In the United States, where drug costs are higher than anywhere else, there needs to be a federal price commission for drug — one that is public and transparent, with social justice as an intention and inclusive of all involved.

"We need transparency in the development costs," Dr. Smith explained. "This was FDA approved on the basis of 1 or 2 trials, and the equipment to design the drug can be used for many other drugs."

The manufacturers will say that these high prices are necessary to "make up for drugs that don't pan out," he said. "But when the best predictor of the price is the price of the last 5 drugs coming to market.... Well, let's just say 'prove it' by showing us the development costs."

Another suggestion is to allow Medicare to bargain for lower prices, in a manner similar to the Veterans Administration. Currently, Medicare is forbidden to do so.

Dr. Smith emphasized the importance of using crizotinib only with ALK-positive patients. "With [trastuzumab], there was a high percentage of patients getting it who were negative or status unknown until proof was demanded."

Specialty pharmacies can be used to dispense the drug that will allow for tracking compliance. Adherence needs to be monitored and physicians need to make sure that adverse effects are managed, he said.

Other general measures include improving end-of-life care, providing more and longer hospice, giving patients the care they need to stay out of the hospital, using less expensive drugs, ending fee for service, and using less expensive scans (CT vs PET).

These are just a few suggestions, Dr. Smith explained. "We are open to better suggestions, we just have not seen any."

The Cancer Care Ontario Pharmacoeconomics Research Unit is supported by Cancer Care Ontario, and the Canadian Centre for Applied Research in Cancer Control is supported by the Canadian Cancer Society. Study authors Ming-Sound Tsao and Jean-Claude Cutz report relationships with Pfizer, the manufacturer of crizotinib. Dr Kelly reports a consulting role with Novartis.

J Clinical Oncol. Published online February 24, 2014. Abstract, Editorial

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