FDA advisers pile on Clovis’ rociletinib, turn thumbs down on fast OK

Kapil Dhingra
Breaking

After hearing a carefully crafted argument from regulators citing Clovis’ lung cancer drug rociletinib for dangerous side effects and a poorly defined efficacy profile, the FDA’s advisory committee on cancer came down squarely against an accelerated approval.

The vote was 12 to 1 in favor of requiring Clovis to finish its randomized Phase III study before the FDA considers again whether to approve the drug for marketing. Most panelists concluded that it was just too early to define the risks and benefits of the drug, particularly with potentially better drugs to choose from.

The formal decision on rociletinib's fate now passes to the regulators. But given their critical internal review and today's stance, their rejection appears to be a formality. And that would mean Clovis won't have a chance to move ahead at the FDA until 2019.

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"Ironically, from a pure corporate strategic perspective, the ODAC rejection may prove to be a blessing in disguise for Clovis and its shareholders," noted drug development expert and Clovis critic Kapil Dhingra after he saw the vote. "At least now the company can focus its resources on other assets in its portfolio rather than undertake the expensive and arduous task of marketing a drug that does not appear to be commercially viable with the data in hand and the unresolved issues to be tackled in the future."

Dhingra sharply criticized Clovis for "misrepresenting" its overall response data in an initial NDA in a recent interview with FierceBiotech following his review of the drug in the Annals of Oncology.

Clovis’ team, led by Lindsey Rolfe, started the day at the Oncologic Drugs Advisory Committee (ODAC) facing an uphill fight on rociletinib, an EGFR inhibitor designed to target lung cancers with a T790M mutation.

Right from the beginning, FDA officials raised questions about the serious dangers facing patients taking the drug, the company’s attempted use of unconfirmed responses in its data and whether the drug was superior to existing therapies, a requirement for accelerated approval. Its execs also had to start with an explanation  of why they suddenly switched from a recommended 500 mg dose--which was in their original NDA last fall--to a 625 mg dose.

The company hit hard on a point that usually wins the day at the FDA’s cancer committee: Oncologists like to have alternative therapies in making a last-ditch fight against cancer, especially a disease like lung cancer. And they’re willing to put up with considerable toxicity and uncertainty if a new drug can offer some hope of extending survival when all else has failed.

But more than half of the patients taking any of the doses of rociletinib experienced an adverse event. Nearly half experienced a serious adverse event and 17% of the patients in the 625 mg arm died due to an adverse event. Evidence of hyperglycemia and QT prolongation--lethal heart arrhythmia--were the two leading causes of dose modification.

Clovis' team highlighted the FDA’s recommendation for a black-box warning as part of its risk mitigation strategy. The FDA, however, wasn’t happy with the single arm study used to support the NDA, noting the absence of comparative data.

“We don’t know what is going on with this drug as regards QT,” noted FDA cancer czar Richard Pazdur, who took a direct role in the review. And regulators were particularly unhappy at the prospect of seeing patients taken off one of the “available” therapies and put on rociletinib,

The FDA also noted that other drugs--including AstraZeneca’s newly approved Tagrisso, which technically can’t be included as an “available” drug because it was approved under the agency’s accelerated pathway--have better safety and efficacy profiles. And some panel members objected to “gaps” in the company’s data.

Clovis faces a tough fight if it expects to eventually get this drug approved. In February, the FDA told Clovis that the available PK data did not support a switch from 500 mg to 625 mg. But Clovis amended its ongoing study anyway to concentrate on 625 mg. That Phase III trial will be completed in 2018.

The rejection today, following sharp criticism of the company's use of data, could apply severe pressure on Clovis' board and executive team to respond in some fashion. I asked for an interview with CEO Patrick Mahaffy, but was told by a spokesperson that he is not taking questions today.

At the beginning of last week, Dhingra stirred considerable discussion with a new analysis which questions Clovis' use of unconfirmed data long after most investigators would have nailed down a final confirmed response. 

"The issues uncovered by the FDA were deeper and more complex than discussed in my article in Annals of Oncology that was based on the information widely available in the public domain," Dhingra tells me today. "Rociletinib has poor pharmaceutical properties, complex pharmacology, and unique pharmacogenetic issues that were generally not well understood until the FDA briefing documents were posted last week. These issues required a systematic and thoughtful mitigation as part of a carefully orchestrated clinical development strategy. It is clear, at least in retrospect, this is not the type of drug that lends itself to a 'Damn the torpedoes, full speed ahead!' type of development strategy."

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