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Posts tagged ‘Multiple Myeloma Market’

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.

This week Amgen announced that their second generation proteasome inhibitor, carfilzomib (Kyprolis), had met the primary endpoint of progression free survival (PFS) in the phase III ASPIRE trial. This study compared the triple combination of Kyprolis plus Revlimid and low dose dexamethasone (KRd) to the doublet of Revlimid plus low dose dexamethasone (Rd) in relapsed/refractory multiple myeloma. The overall survival (OS) is not yet mature and statistical significance was not been reached at the interim analysis. We will have to see how that data is looking in a few months time at the American Society of Hematology (ASH) meeting in December.

This is an important trial because the data will enable Amgen to file for approval of carfilzomib in Europe with the survival data. The PFS for the two groups (26.3 vs. 17.6 months) showed a clear benefit in favour of adding carfilzomib to standard therapy by 8.7 months:

“Results from the ASPIRE study will form the basis for regulatory submissions through­out the world beginning in the first half of 2015.”

Allowing time for CHMP approval and country reimbursement, this means that carfilzomib will possibly be available in 1H16 in Europe.

What impact will this data have on the multiple myeloma landscape?

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New Orleans – Novartis announced this morning that their novel pan-HDAC inhibitor, panobinostat (LBH589) in combination with bortezomib (Velcade) and dexamethasone significantly prolonged progression-free survival (PFS) of patients with Multiple Myeloma in the phase III PANORAMA-1 trial.

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I’m not a great fan of Twitter lists, especially those that imply you are a “Top Cat,” because they can end up being divisive and generate resentment in those not included.

ASH Logo picture credit: Pieter DroppertThat said, without wishing to offend anyone, here’s my initial starting point of those I will be following at the 2012 annual meeting of the American Society of Hematology in Atlanta from December 8 – 11 (#ASH12):

American Society of Hematology

Publications

Patient Advocacy

Companies /Industry Execs

Physicians/Researchers & Institutions

This is not intended to be a definitive list, so I encourage you to watch the #ASH12 Twitter stream for additional people to follow depending on your interests. I have intentionally not included PR folks, investors, journalists who are usually too busy writing their own stuff and exhibitors who just want to tweet their own news. However, if I have missed anyone who has a burning desire to be included, please contact me.

Wifi permitting (always a big IF since many conference venues have not invested sufficiently in infrastructure to cope with demand) I’m hoping there will be a good Twitter conversation in Atlanta.

One of the hot topics this year is Multiple Myeloma, for which there are four “Super Friday” satellite symposia and over 700+ abstracts.

Earlier this year, the FDA approved Onyx’s carfilzomib (Kyprolis) and approval for Celgene’s pomalidomide (Actimid) is expected by year-end.  Several other new agents are on the horizon including Millennium’s new proteasome inhibitor ixazomib/MLN9708 that Dr Sundar Jagannath discussed at the recent Chemotherapy Foundation Symposium in New York. The availability of new treatment options is certainly good news for patients.

I am looking forward to attending the ASH education session on Keeping Pace with Advances in Myeloma. Hope to see you there if you have plans to be in Atlanta next week.

2 Comments

New treatments for multiple myeloma (MM) are changing the treatment landscape and that is set to continue over the next few years as several new products come to market.

This year we have seen the FDA approval of subcutaneous bortezomib (Velcade®) and carfilzomib (Kyprolis®). Approval for pomalidomide is anticipated soon.

Earlier this week at the 2012 Chemotherapy Foundation Symposium in New York, Sundar Jagannath, M.D., Professor of Medicine at Mt. Sinai School of Medicine presented on “New IMiD and Proteasome Inhibitors.”

Dr Jagannath told a large audience at the Symposium (also known as the Greenspan Meeting) that he hoped “pomalidomide will get accelerated approval and be in your hands by New Year”

In his presentation, Jagannath discussed some of the new products in development. One that he mentioned in detail was MLN9708/ixazomib (Millennium), a new reversible, oral proteasome inhibitor currently in early clinical trials.

He noted that is not just being developed as a single agent in advanced disease, but is already being tested in combination with lenalidomide and dexamethasone therapy in earlier settings.

Companies with MM drugs in the pipeline will need to look closely as to how the treatment landscape may change in the next few years if new products such as ixazomib are approved and replace existing products such as bortezomib.

Although Dr Jagannath’s talk was very informative from a new product development perspective, I did wonder whether some of the community medical oncologists in the audience, who only see a few myeloma patients, might have benefitted from a more practice orientated perspective.

I sat next to a community oncologist from Florida, for example, who told me he found the MM treatment regimens difficult to understand for the few patients that he saw.

Dr Jagannath concluded his presentation with the thought that “rapid strides in genomics promises new drugs and personalized medicine in the near future.”

I look forward to hearing more about the latest research in Multiple Myeloma at the annual meeting of the American Society of Hematology (ASH 2012) in Atlanta next month.

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