Asco – Aphinity and Roche’s 1% solution

Advantage Puma? This is the question the sector will be asking itself today with publication of full results from the Aphinity trial of Roche’s Perjeta and Herceptin in adjuvant treatment of breast cancer. The data show a significant but less than impressive one percentage point absolute survival benefit over Herceptin alone, and could give Puma’s neratinib a chance to remain competitive in this setting.

With an already high survival rate for post-surgical breast cancer patients treated with Herceptin, proving a massive benefit is probably a big task, and specialists may be pleased with incremental improvements. However, Perjeta and neratinib are looking pretty similar, and in the market it could come down to how payers balance a costly combination of Roche’s two biologicals against management of neratinib’s well-known diarrhoea side effect.

Success, but…

Aphinity should probably be declared a clinical success. The Swiss group wanted to improve on Herceptin’s prowess in preventing cancer recurrence if taken for a year following chemotherapy. Herceptin set a high bar by reducing the risk of recurrence by up to 52% in Her2-positive cancer, although it did not improve overall survival. By adding Perjeta to Herceptin, the risk of recurrence was reduced another 18% over Herceptin alone, statistically significant with a p value of 0.045.

In absolute terms, however, the result is less impressive. At the end of three years, 94.1% of the Perjeta/Herceptin patients were free of recurrence, compared with 93.2% in the Herceptin-only arm. On that measure it does not look numerically different from neratinib’s primary analysis in the Extenet trial, which found 94.2% of its patients recurrence-free at 24 months – with the usual cautions about cross-trial comparisons. Patients in that trial took neratinib after a year of Herceptin.

Another number, from investigator Gunter von Minckwitz of the German Breast Group, put the Aphinity findings more starkly. He calculated that 112 patients would need to be treated to avert one recurrence.

The Herceptin/Perjeta combination looks even weaker in that it could show no benefit in node-negative patients. Survival in node-positive patients drove the topline number – Perjeta plus Herceptin had a two percentage point advantage over Herceptin alone (92% vs 90.2%), yielding a 23% reduction in the risk of recurrence at a more persuasive p value of 0.019; the number needed to treat in this population was 56.

Asco’s designated representative, Dana-Farber Cancer Institute oncologist Harold Burstein, suggested that the combination be used only in node-positive patients, saying: “It’s clear this approach may not be advantageous for women with a lower risk for recurrence.”

Here, too, neratinib, now trademarked Nerlynx, looks similar – an FDA analysis suggested a 4.1 percentage point advantage over placebo for patients with four or more positive nodes (91.4% vs 87.3% free of recurrence), a 38% relative risk reduction. 

Among those with three or fewer positive nodes, neratinib’s advantage shrinks to 1.5 percentage points and a 30% relative risk reduction.

Not a problem

Neratinib’s trial, of course, suffered from a high rate of patient dropouts, which cast some doubt on its approvability (Puma files, and the battle begins, July 22, 2016).

This did not worry the US FDA, which conducted “tipping point” analyses and determined that an implausibly high number of recurrence events would have needed to occur in missing patients in order for Extenet to lose statistical significance. That analysis was part of the data package that persuaded an FDA advisory committee to vote 12-4 in favour of neratinib’s approval (Puma pulls within sight of FDA OK, May 24, 2017). 

The competing data present a commercial outlook that is difficult to predict. With Aphinity data now publicly available, oncologists in theory could begin prescribing Herceptin and Perjeta off-label in this setting from today – although Roche’s sales representatives would be proscribed from talking about it until approval, unless doctors ask them. An FDA decision is months away.

Neratinib, meanwhile, can expect an FDA decision by July 21, and Puma will need to think very hard about pricing. Coming in as a small molecule agent neratinib has the potential to beat Roche’s antibodies on price – but the diarrhoea side-effect and its associated costs have to be taken into consideration.

Dr Burstein, who served on the neratinib adcom, said he believes that both neratinib and Perjeta will get adjuvant approvals, leaving it up to guideline-setters and payers to decide how they are used. With regard to the number needed to treat calculations in the broad Aphinity group and subgroups, Dr Burstein said 112 is probably too high, but "50 is more in the ballpark of what is acceptable."

In the Extenet trial, 40% of patients taking neratinib experienced grade 3 diarrhoea, which can entail IV fluid replacement and hospitalisation. Oncologists can successfully reduce diarrhoea rates with prophylactic loperamide and colestipol, but of course that adds to the costs of the treatment regimen.

Puma also has to be mindful of Roche’s marketing power. Herceptin is well-established in the adjuvant space, and it could be an easier case for oncologists and patients to seek comfort in a Herceptin and Perjeta one-year treatment regimen rather than sequential Herceptin and neratinib.

To counter this, Puma will need more money, a partner, or – as bullish investors believe – a buyer. The interval between the FDA adcom vote and full approval would seem to be a time to strike, especially now that Aphinity has proven a solid punch but no knockout blow to neratinib.

To contact the writer of this story email Jonathan Gardner in Chicago at [email protected] or follow @ByJonGardner on Twitter

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