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CHMP Recommends Caprelsa Approval in EU on Condition AstraZeneca Conducts PGx Trial


Originally published Nov. 29.

By Turna Ray

Following a conditional recommendation from the European Commission's Committee for Medicinal Products for Human Use, AstraZeneca has decided to conduct additional pharmacogenomic investigations of its drug Caprelsa to ensure that medullary thyroid cancer patients with unknown or negative RET mutations derive benefit from the drug.

CHMP earlier this month proposed a conditional marketing authorization for Caprelsa (vandetanib) for the treatment of aggressive medullary thyroid cancer in patients with unresectable locally advanced or metastatic disease.

The drug label warns that “for patients in whom rearranged during transfection (RET) mutation is not known or is negative, a possible lower benefit should be taken into account before individual treatment decision.” Moreover, CHMP advises that Caprelsa “be prescribed by physicians experienced in treatment of medullary thyroid cancer, the use of anticancer therapies, and the assessment of electrocardiogram.”

The European Commission will now review CHMP's position on Caprelsa and issue a regulatory decision regarding the use of the drug within the European Union. AstraZeneca, meanwhile, believes that MTC patients derive benefit from Caprelsa regardless of their RET mutation status, and is willing to conduct the additional pharmacogenomic investigation hoping to garner a stronger indication for the drug in the general MTC population.

“The CHMP opinion is that approval should be conditional upon AstraZeneca performing a study to gather further evidence of benefit in patients who may not have a RET mutation,” a company spokesperson told PGx Reporter last week via e-mail. “AstraZeneca is committed to perform the actions required for the conditional approval of Caprelsa. Once this trial is completed AstraZeneca will discuss the outcome with regulatory agencies to assess any potential change to the current indication label.”

Counter to AstraZeneca's assertions that all advanced MTC patients would benefit from Caprelsa, data from a pivotal Phase III study published online last month in the Journal of Clinical Oncology suggests that patients with M918T RET mutations may derive greater benefit from the drug than those without this biomarker. However, in that trial, called ZETA, the number of RET mutation negative patients was too small to conclusively discern how these patients respond to Caprelsa.

In reviewing Caprelsa for regulatory approval, both European and US regulators considered data from the ZETA trial, although the US Food and Drug Administration granted the drug orphan status and approved it in April based on less mature study data. The CHMP recommendation stands in stark contrast to the decision of the FDA, which approved Caprelsa for the treatment of adults with metastatic medullary thyroid cancer who are ineligible for surgery. The FDA-approved labeling for the drug states that “there is no evidence of a relationship between RET mutations and the efficacy of Caprelsa.”

According to the JCO paper, in the randomized, double-blind trial of 331 patients with advanced MTC, researchers from AstraZeneca and elsewhere estimated that patients treated with Caprelsa had a median progression-free survival of 30.5 months, while patients in the placebo group experienced 19.3 months of median progression-free survival. “The PFS at six months was 83 percent (vandetanib) and 63 percent (placebo),” researchers, led by Samuel Wells of the National Cancer Institute, wrote in the paper.

At 24 months median follow-up, the researchers found no differences in overall survival between treatment arms. They plan to repeat the survival analysis when 50 percent of study participants have died.

Caprelsa is an inhibitor of the RET, EGFR, and VEGFR tyrosine kinases, which are involved in cell proliferation and angiogenesis in several types of tumors. Approximately 90 percent of patients with familial MTC and multiple endocrine neoplasia type 2 have germline RET mutations. Around 50 percent of those with sporadic MTC harbor mutations in the RET proto-oncogene, the most common being the M918T mutation, which is found in 85 percent of patients with the non-hereditary form of the disease.

ZETA included patients with both hereditary and sporadic MTC. All study participants were required to submit a tumor sample for analysis, except for hereditary MTC patients who had their germline RET mutation status already documented. In the trial, 137 patients in the vandetanib arm were RET mutation positive, two were mutation negative, and 92 had unknown status. In the placebo arm, 50 were mutation positive, 6 were negative, and 44 had unknown status.

According to Wells et al., due to the small number of sporadic MTC patients who were RET negative and the large number of patients with unknown RET status, “subgroup analyses of PFS and objective response rate by RET mutation status are inconclusive."

Mutation status of patients enrolled in ZETA was assessed by an ARMS assay that specifically gauges the M918T mutation and through direct sequencing after PCR amplification of RET at exons 10, 11, and 13 to 16.

When data from this assay was taken into account, "patients with sporadic MTC received benefit from vandetanib whether their tumors were M918T positive or negative,” the researchers concluded, but they highlighted that “the response rate was greater in those who had an M918T mutation” compared to those who didn't. Approximately 55 percent of RET mutation-positive patients had an objective response to Caprelsa, while around 31 percent of mutation-negative patients responded to the drug.

In terms of adverse events, Caprelsa-treated patients experienced more nausea, rash, hypertension, and diarrhea than those in the placebo arm. There was one case of sudden death and one patient died from cardiopulmonary arrest after treatment with the drug. The FDA has included a boxed warning on Caprelsa's label regarding the risk of QT prolongations, torsades de pointes, and sudden death and requires that AstraZeneca educate physicians about these treatment-related risks.

“The potential toxicity associated with long-term administration of vandetanib highlights the importance of appropriate selection of patients for treatment with this agent,” Benjamin Solomon and Danny Rischin from the Peter MacCallum Cancer Centre in Australia wrote in an editorial in JCO accompanying the publication of data from ZETA.

“The shift away from clinical trials in all-comers with thyroid cancer toward studies such as this one that involve clinically and genotypically defined subsets of patients with thyroid cancer will allow more efficient interrogation of other potential molecular targets in thyroid malignancies,” they added.

Awaiting Results

Given CHMP's caveat regarding a pharmacogenomic subset that may not derive benefit from Caprelsa, national regulatory bodies in Europe may decide to await results from AstraZeneca's follow-on study, which will exclusively look at the effect of RET mutation status on Caprelsa's efficacy, before making a marketing authorization or coverage decision regarding the drug.

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For example, the UK's National Institute for Health and Clinical Excellence has increasingly been urging drug developers to use molecular markers and companion diagnostics to hone in on best responder populations for treatments, in an effort to ensure that the right patients are receiving these drugs and that government payors aren't overspending to treat those who won't derive any benefit.

Last month, NICE issued a negative recommendation for Bristol-Myers Squibb's melanoma drug Yervoy. NICE Executive Director Andrew Dillon suggested at the time that Yervoy may have had a better shot at getting a positive recommendation had the sponsor explored a biomarker strategy to identify best responders to the drug (PGx Reporter 10/19/2011).

AstraZeneca has not pursued a biomarker-based strategy for Caprelsa because it believes that the results from the ZETA trial support its decision to seek approval for the drug as a treatment for the general MTC patient population.

The trial shows "that there is evidence of patient benefit independent of RET status, so we did not seek a restriction to RET-positive patients,” the AstraZeneca spokesperson said, adding that the CHMP recommendation, if adopted by European regulators, wouldn't necessarily bar advanced MTC patients with unknown or negative RET mutation status from getting the drug.

Although AstraZeneca is now willing to do additional PGx investigations to appease CHMP and gain greater insight into the effect of RET mutation status on drug response, company officials were previously fairly confident that such an approach would not be needed for Caprelsa.

"It's important to recognize that there is no companion diagnostic with this drug. It's not necessary,” Joe Cordaro, executive director of strategic development at AstraZeneca, told PGx Reporter in April when the FDA approved the drug. A companion test is "not going to be a part of the medullary thyroid cancer" indication for the drug in the US, he added.

AstraZeneca officials feel that RET inhibition is important in MTC regardless of mutation status. "RET in its normal form is important in medullary cancer, and vandetanib blocks both mutated and normal RET, so it gets both forms,” Jim Vasselli, director of clinical research at AstraZeneca, told PGx Reporter in April. “Even in patients with normal RET it's important to block that. So, [vandetanib] gets the EGFR, and VEGFR, and it also gets mutated and normal RET.”

Vasselli noted at the time that in ZETA, patients with both known and unknown RET status derived benefit from the drug. “Efficacy seemed just about equal” between these groups, he said.

According to the JCO paper describing ZETA, however, 34 percent of sporadic MTC patients with unknown RET mutation status who were treated with Caprelsa experienced an objective response rate, while approximately 52 percent of sporadic RET mutation-positive patients responded to the drug.

Although data from the ZETA trial may not be sufficient to draw definitive conclusions about Caprelsa in patients who are RET mutation negative, there are arguments in favor of knowing patients' mutation status when crafting a treatment plan for MTC, a disease that has limited treatment options.

According to Mimi Hu, an MD Anderson Cancer Center researcher who has worked on trials involving vandetanib, knowledge of RET mutation status can help doctors understand the nature of a particular patient's disease, which, in turn, may inform strategies for treating advanced forms of thyroid cancer. "The specific codon mutation can predict the potential aggressiveness of MTC disease course and provide insight into the likelihood of developing other endocrine neoplasias, and it has implications for the … family members” of patients with the hereditary form of the disease, Hu said in an article published in Clinical Advances in May.

"An activating mutation of RET leads to a constitutively active RET tyrosine kinase receptor, which activates intracellular signaling and increased cell proliferation, differentiation, migration, and survival,” Hu added, noting that among non-hereditary MTC patients, a somatic RET mutation in tumors can contribute to the aggressiveness of the disease.

During an advisory committee meeting for Caprelsa in December 2010, some members of FDA's Oncologic Drug Advisory Committee encouraged AstraZeneca to develop a database of patients treated with the drug and track whether patients were more prone to become resistant to treatment based on their RET mutation status.

A new trial with better sample requisition may also help shed light on the role of genomics in MTC patients' response to Caprelsa. In ZETA, researchers analyzed blood samples from patients with the hereditary form of the disease and assessed tumor tissue from patients with sporadic MTC. "Because [MTC] can be an indolent disease, some of the samples [in ZETA] were very old. We weren't able to get good tissue,” Vasselli previously told PGx Reporter. “We were only able to determine the RET mutations in about half of the patients with sporadic disease."

If a companion test should be necessary in order to gain marketing authorization in certain countries in Europe, AstraZeneca has existing diagnostic partnerships that may come in handy. For example, last year, Dako and Quintiles announced they were providing drug-diagnostic co-development services to AstraZeneca involving an unnamed cancer drug (PGx Reporter 11/3/2010).

The National Cancer Institute estimates that approximately 44,600 new thyroid cancer cases were diagnosed in the US in 2010, and nearly 1,700 people died from the disease. Between 3 percent and 5 percent of thyroid cancer cases are MTC, impacting 1,300 to 2,200 people in the US.

Around 40 percent of patients with metastatic MTC have an average survival rate of 10 years. Patients with advanced or aggressive MTC lack treatment options.

Given this unmet medical need, despite the inconclusive data on the effect of Caprelsa on RET mutation-negative patients, Well et al. wrote in the JCO paper that “vandetanib has shown efficacy in patients with locally advanced or metastatic MTC, a challenging group of patients for whom there has been no effective therapy.”

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