Puma pulls within sight of FDA OK

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A small if significant benefit, frequent side effects and a circuitous clinical programme were no barrier to Puma Biotechnology’s neratinib receiving backing from a US FDA advisory committee, which today decided that the need for an extended adjuvant breast cancer treatment following one year of Herceptin outweighed its drawbacks.

With many panel members urging a narrower patient population than Puma’s application seeks, the FDA’s label will be closely watched should regulators follow the adcom advice. A 12-4 vote is a strong but not overwhelming endorsement of neratinib, and the California-based group will need to hope that the regulator does not toughen its recent accommodating stance towards applicants.

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The main criticisms of neratinib were largely waved away by FDA reviewers, who were open to Puma’s statistical case and its approach to managing the chief side effect, diarrhoea. The phase III Extenet study had been abandoned by neratinib’s previous owners, Wyeth and then Pfizer, and this saw the patient population shrink when Puma picked it up, followed by an inability to follow up with the majority of subjects.

Sensitivity and “tipping point” analyses conducted by FDA staff outlined at the adcom meeting suggested, however, that missing data would have minimal effect on the chief finding – namely, that 94.2% of neratinib patients were free of invasive disease at two years, compared with 91.9% of patients taking placebo. This was calculated to be statistically significant, with a 34% reduction in risk of progression.

That small absolute benefit was balanced against occurrence of severe diarrhoea and discontinuation because of diarrhoea. Pre-treatment with loperamide lowered the incidence of grade 3 diarrhoea from 40% in Extenet to 31% in trial 6201, which studied anti-diarrhoeal prophylaxis – and more recent data suggest that this can be reduced to 8% if neratinib is combined with colestipol.

In spite of the promising data from the prophylaxis studies, many adcom members who voted in favour of approval were worried about exposing too many patients to that risk to improve invasive disease-free survival by 2.3 percentage points.

They suggested tightening the label to those who might benefit more, such as hormone receptor-positive patients, where the hazard ratio was calculated to be 0.49. But the data supporting neratinib's use in this population is from an exploratory analysis, making it a difficult recommendation for the FDA to follow.

Shorter odds, but …

Approval by the FDA decision date of July 21 would be a coup for Puma, as the odds of this looked decidedly longer just a few short days ago. The relatively benign FDA briefing documents released on Monday resulted in a 39% share price jump. After being suspended during the adcom's deliberations, shares resumed trading Wednesday afternoon and closed another 30% higher.

The commercial outlook looks tough, however. The sector is only 12 days away from hearing full data at Asco on Roche’s Aphinity trial of Herceptin and Perjeta as a one-year adjuvant treatment, with Herceptin alone as a comparator. The Swiss group has announced a positive result, and all that awaits is learning the magnitude of the benefit (Aphinity all but confirms Puma’s worst nightmare, March 2, 2017).

This could be doubly troublesome for Puma. For one, neratinib’s data show a benefit only when used after Herceptin alone, and Aphinity appears likely to change the standard of care.

For another, Perjeta is already on the market, and oncologists could conceivably begin prescribing in this setting the minute full data are available – not to mention the fact that compendia could be updated before regulators are able to approve a label expansion, opening the door to wider reimbursement of Perjeta plus Herceptin regardless of the label.

The final act has not played out for neratinib – its label and the Aphinity data will define its promise. But Puma executives at least have to be breathing a sigh of relief today.

To contact the writer of this story email Jonathan Gardner in Virginia at jonathang-us@epvantage.com or follow @ByJonGardner on Twitter

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