Adcom could kill off Clovis’s rociletinib

It was expecting a grilling, and it got one – and now it’s back to the drawing board for Clovis Oncology and its lung cancer candidate rociletinib. An FDA advisory panel has recommended that a decision should be delayed until results from the Tiger-3 phase III study are available, pushing possible approval out to 2019.

Delayed approval is probably the best-case scenario for rociletinib, which now looks “dead in the water”, according to Mizuho analysts. One question is whether Clovis has enough cash to fund the trial to completion. At the end of the year it had $529m in cash and a $280m convertible debt, and it is unlikely to be able to raise more money.

Even if rociletinib does eventually get approved, “competitive pressures feel insurmountable”, the Mizuho analysts wrote. By then, AstraZeneca’s rival EGFR inhibitor, Tagrisso, will have had several years to make its first-mover advantage count. It was approved last November for T790m-mutated non-small cell lung cancer, without the need for an adcom.

Clovis had been hoping to get the nod in the same indication, and all had been going well until November when the FDA asked for more clinical data, sending its stock down 70% (FDA hands Astra a lung cancer edge over Clovis, November 16, 2015). 

The problem, it turned out, was that interim datasets from the Tiger-X trial included responses from patients who were not later confirmed as responders. This slashed response rates from 60% with the 500mg dose, when Clovis first reported data at Asco 2015, to 28%.

Clovis began its rolling submission for rociletinib in July, before this development, probably explaining why the project got as far as an adcom. The number of negative panel votes seems to be coming down, presumably thanks to greater communication between companies and the FDA earlier in the drug development process.

Year Number of negative advisory panels
2012 13
2013 10
2014 8
2015 2
Data according to EvaluatePharma's calendar of events

And for rociletinib matters are even worse: as well as efficacy not being as good as the company had initially touted, there are safety concerns, too. The advisory panel proposed a black box warning over a heart-related side effect, QTc prolongation, and focused on progression to Torsade de Pointes. Meanwhile, a high incidence of hyperglycaemia has also been seen with the drug.

EvaluatePharma’s sellside consensus forecast for rociletinib is $525m, down from a peak of $830m in early 2015, and expectations look set to fall further still. Clovis’s shares closed down just 5% yesterday, suggesting that the negative outcome had been expected.

Rucaparib silver lining?

The way forward for Clovis might lie with its PARP inhibitor rucaparib, which is in phase III development for ovarian cancer. The Mizuho analysts believe that, instead of spending money on the Tiger-3 rociletinib study, “a better use of cash would be to focus on commercialising rucaparib”, which they forecast could bring in sales of $650m by 2023.

However, it is difficult to see how Clovis can ethically stop a trial that is already under way for financial reasons, and this puts the group's cash reach into serious doubt. Moreover, the PARP inhibitor field is becoming increasingly crowded, with AstraZeneca’s Lynparza already approved in ovarian cancer, and Tesaro and AbbVie also with agents in phase III (Therapy focus – Ovarian cancer field readies for phase III readouts, March 18, 2016). 

“Clovis will need significant R&D and marketing resources to gain approvals and remain competitive in the marketplace,” the Mizuho analysts wrote. Maybe it is time to ditch rociletinib, though how the company can do this is a harder question to answer.

Project Study Trial ID Primary completion
Rociletinib Tiger-3 NCT02322281 Sep 2018
Rucaparib Ariel 3 NCT01968213 Mar 2017

To contact the writers of this story email Madeleine Armstrong or Edwin Elmhirst in London at [email protected] or follow @medtech_ma or @EPVantage on Twitter

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