The big news yesterday evening was that Amgen’s phase III FOCUS trial in relapsed/refractory multiple myeloma failed to meet its primary endpoint of overall survival (HR=0.975).

Kyprolis logoSuch a marginal hazard ratio (HR) tells us that the risk of death was not reduced by taking carfilzomib over best supportive care.

According to the company:

“The 315-patient, open-label study evaluated single-agent Kyprolis® (carfilzomib) for Injection compared to an active control regimen of low-dose dexamethasone, or equivalent corticosteroids, plus optional cyclophosphamide in patients with relapsed and advanced refractory multiple myeloma. Nearly all patients in the control arm received cyclophosphamide. Patients were heavily pretreated and had received a median of five therapeutic regimens prior to study entry.”

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Recall the PANORAMA-1 trial for panobinostat with Velcade plus dex versus Velcade + dec alone was presented at ASCO and achieved positive PFS and OS. The patients in this study were refractory to 1-4 or 1-3 lines of prior therapy respectively, with nearly half (48.4%) receiving ≥ 2 prior therapeutic regimens. To put this in context, this was a much less heavily pretreated/refractory group overall than the FOCUS trial in comparison.

At ASCO, opinions from experts I spoke to regarding the likelihood of a successful result from FOCUS were evenly divided, while ASPIRE was widely expected to succeed. As one well respected European thought leader – who erred on the side of caution – pointed out to me:

“Low dose dex (with or without cyclophosphamide) is an active, but fairly low hurdle to beat, even for salvage therapy. In this situation, you do need a gentle, well tolerated regimen to stand a chance of a successful outcome. Carfilzomib is neither of those things, so no, I won’t be at all surprised if it fails.”

Add this latest finding to the results from the ASPIRE study last week, where the PFS was met and OS was not yet mature, makes for a very tricky time for Amgen should they wish to seek EU approval and reimbursement. It is likely that a solid positive result for OS from the ASPIRE study may well be necessary now for EU success.  If a therapy or regimen does not convincingly improve patient outcome, then it is unlikely to obtain reimbursement in Europe given the current economic environment.

The ASPIRE data alone may possibly be enough for confirmatory approval of carfilzomib in relapsed/refractory myeloma in the US because it was conducted under an SPA, but this is not a guarantee of success given other uncertainties surrounding the carfilzomib data and the secondary endpoint (OS).

What about adverse events?

Recall that with the ASPIRE data, the rate of cardiac events observed in the carfilzomib arm were consistent with the current label approved by FDA. Discussion on the rate of cardiac events have dogged the drug since accelerated approval by the FDA and the black box warning that accompanied the label.

However, in the FOCUS study an increase in the incidence of renal adverse events of all grades was observed in the carfilzomib arm compared to both the active control arm AND the label.

This is a new finding and of particular concern because myeloma patients do tend to experience more severe renal impairment with worsening disease, thus any therapy that hastens or worsens that situation is clearly not a good thing.

Overall

One thing is very clear from these recent data announcements – the mature ASPIRE data is now going to be very keenly watched at ASH this year. The Kaplan-Meier curves could well make or break the chances for Kyprolis in Europe and a miss on OS could possibly jeopardize the US confirmation, if the curves cross-over or do not have a compelling readout.

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