Xalkori And Inlyta: NICE Pans Two Pfizer Oncology Drugs In Two Days

Britain’s NICE has rejected Pfizer’s Xalkori (crizotinib) for lung cancer and Inlyta (axitinib) for kidney carcinoma within two days of each other, putting drug discounts back in the spotlight.

Trialing a drug against best supportive care – as sometimes required by the U.K.’s National Institute for Health and Clinical Excellence – could be considered unethical if second, third and fourth-line treatments are already widely available. At least this is the criticism being leveled at the practice by some in the pharmaceutical industry.

Often the low cost of using best supportive care and generics as comparators for innovative drugs will result in a negative NICE decision on cost effectiveness and prompt drug manufacturers to offer a patient access scheme – a manufacturer's discount – in order to secure reimbursement.

While a discount is worth a shot when trying to get a drug approved by NICE, it's no guarantee of automatic success. With two rejections for Pfizer Inc. in two days, Britain’s cost-effectiveness watchdog is giving drug manufacturers pause for thought when agreeing to a price cut.

On March 27, NICE turned down Inlyta (axitinib) for the treatment of adults with advanced renal cell carcinoma after failure of prior treatment with sunitinib or a cytokine. The previous day, it rejected Xalkori (crizotinib) for previously treated anaplastic-lymphoma-kinase-positive advanced non-small-cell lung cancer.

Best Supportive Care Studies Unethical?

Pfizer is clearly concerned about U.K. prospects for its kidney cancer drug Inlyta because the drug was the subject of a Final Appraisal Determination, the last stage in the NICE assessment process. Inlyta is an oral multi-targeted kinase inhibitor with anti-tumor activity. It should be well positioned in the U.K. because there are currently no second-line drugs for renal cell carcinoma approved by NICE.

Within the scope of the appraisal, NICE had requested a comparison of Inlyta with best supportive care, but Pfizer had failed to comply.

Pfizer Oncology U.K.'s medical director David Montgomery in an interview pointed out that “across the world” second, third and even fourth-line treatments for kidney cancer are available and fully funded, “so running a trial against best supportive care is now largely unethical, because there are routinely available alternative treatment options.”

NICE rebuffed this suggestion by Montgomery, saying that relevant comparators are identified, and that consideration is given specifically to routine and best practice used on the publicly-funded National Health Service – including existing NICE guidance – and to the natural history of the condition without suitable treatment.

“There will often be more than one relevant comparator technology because routine practice may vary across the NHS. Potential consultees and commentators, including the manufacturer, are consulted on the content of the scope to ensure all relevant issues have been considered,” a NICE spokesperson said.

Pfizer did in fact manage to submit an indirect comparison against best supportive care. Initial evidence came from the randomized controlled AXIS study, a Phase III, international, multicenter, randomized, open-label, active-controlled trial comparing axitinib with sorafenib for treating advanced or metastatic renal cell carcinoma after failure of prior first-line systemic therapy.

The manufacturer also identified a Phase III, multicenter, randomized, double-blind, placebo-controlled trial comparing sorafenib with placebo for people with metastatic renal cell carcinoma who had received one prior systemic therapy. Proposing that the TARGET trial was suitable for an indirect comparison of axitinib compared with best supportive care, Pfizer used placebo from the TARGET as a proxy for best supportive care.

“But of course, because it relies on modeling, it does lead to some uncertainties,” Montgomery conceded.

The problem is that it is often difficult from such an indirect comparison to calculate an accurate incremental cost-effectiveness ratio (ICER) per quality-adjusted life year (QALY).

On the Cusp Of Being Reimbursable

NICE concluded that Inlyta was only shown to be a life-extending, end-of-life treatment for patients who had previously been treated with sunitinib. Evidence for those previously treated with a cytokine led to too much uncertainty, NICE said. This contrasted significantly with Phase III trial evidence presented to FDA at the end of 2011, in which the benefit to patients previously on cytokines seemed to be greater (Also see "Pfizer’s Inlyta Shows Greater Efficacy In Subpopulation; Will It Be Enough For ODAC And FDA?" - Pink Sheet, 5 Dec, 2011.).

The U.K. reimbursement watchdog considered that the more plausible ICER for the prior-sunitinib group was likely to lie between the base-case estimate with a survival relationship of 1 to 1.6 – approximately £33,500 ($50,800) per QALY gained – and the estimate assuming no survival gain with a survival relationship of 1 to 1 – approximately £52,900 ($80,300) per QALY gained.

The usual threshold below which NICE is comfortable with recommending a drug is an ICER of roughly £30,000 ($45,500) per QALY gained. For life-extending drugs, aimed at small populations, this can be increased to about £50,000 ($75,900).

The Inlyta ICER per QALY gained is therefore within the range for which drugs have previously been approved, when end-of-life criteria are taken into consideration.

“We are genuinely surprised and disappointed by this final appraisal determination,” Montgomery said.

Two options remain available to the company if it wants to save the drug in the U.K.: an appeal, or a rapid reappraisal, following a subsequent further discount. Pfizer is debating how to move forward, Montgomery said.

Progression-Free Versus Overall Survival

Pfizer feels less urgency about its second rejection, because this is only at the early appraisal consultation stage in the U.K. Xalkori has already made a name for itself across the globe, clearing the FDA in August 2011 in less than five months, based on early stage evidence (Also see "Pfizer’s Crizotinib Eases Past FDA With Targeted Population" - Pink Sheet, 29 Aug, 2011.).

Xalkori is a tyrosine kinase inhibitor, which blocks anaplastic lymphoma kinase (ALK), an enzyme prevalent in some non-small cell lung cancers. Given that there are limited treatment options for people with non-small-cell lung cancer whose disease has progressed following chemotherapy, the drug is starting from a favorable position.

This is enhanced by the fact that clinical specialists and patient experts agree that people with ALK-positive non-small-cell lung cancer particularly value the availability of an effective targeted therapy such as Xalkori and the convenience of an oral formulation. Neither of these features apply to docetaxel (Sanofi’s Taxotere and generics), one of the comparators requested by NICE – and a chemotherapy medication – nor do they clearly apply to the other: best supportive care.

The main evidence to support Xalkori came from a single trial, PROFILE 1007, a multicenter, randomized Phase III efficacy and safety study in patients with advanced or metastatic previously treated ALK-positive non-small-cell lung cancer.

There is some uncertainty as to what exact survival gains patients might enjoy with Xalkori. According to PROFILE 1007, the median gains in progression free survival were 4.7 and 5.1 months with Xalkori, when compared with general chemotherapy and docetaxel respectively.

However, there was no statistically significant difference in overall survival between Xalkori and chemotherapy.

The ongoing problem is that NICE still requires evidence of overall survival to include in its QALY calculations, Montgomery said. In order to generate this type of hard evidence, a trial sponsor would have to prevent cross-over between trial arms. This could, however, mean leaving a patient in an arm where a less effective treatment, or placebo, was offered, which could result in reduced overall survival for that patient. “That is not entirely ethical,” Montgomery said. As a result, companies trial and provide results through modeling, but this then leads to uncertainty.

Patients randomized to the chemotherapy arm in the Xalkori trial, after progression, almost universally crossed over to the crizotinib arm, he confirmed.

Still, NICE was prepared to accept that, while treatment with Xalkori would result in an overall survival gain compared with docetaxel, exactly how much remains uncertain given the immaturity of the PROFILE 1007 data and the impact of crossover in the study.

Pfizer said that more mature – and presumably therefore more reliable – overall survival data would be available from PROFILE 1007 at a specific date that it requested NICE to keep confidential. Two problems remain though. The first is that the data would not be ready within the timeframe set out by NICE for the appraisal. The second is that the cross-over issue from one trial arm to the other would still be apparent. It is cross-over that was partly responsible for the drug’s reimbursement rejection in Germany in February this year (Also see "Germany’s IQWiG Pans Pfizer’s Xalkori On Study Results, Side Effects" - Pink Sheet, 20 Feb, 2013.).

Nevertheless, supplying the additional data could increase the cost effectiveness of Xalkori, whose incremental cost-effectiveness ratios per quality adjusted life-year gained are close to NICE’s upper limits – after taking into consideration end-of-life criteria.

NICE concluded that the most plausible cost per QALY for Xalkori would lie somewhere between £63,800 ($96,800) and £181,100 ($274,800) compared with docetaxel, and between £51,700 ($78,400) and £80,500 ($122,100) for crizotinib compared with best supportive care.

It is therefore entirely plausible that a manufacturer’s discount would swing things Pfizer’s way. However, unless it is substantial enough, it may only bring the ICER per QALY relating to best supportive care within the correct range. If this were to be the case and the ICER per QALY compared with docetaxel were to remain above NICE’s threshold, then the reimbursement watchdog could end up narrowing the indication to grant reimbursement for patients who have been treated previously only with best supportive care.