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Posts tagged ‘ASH 2014 Multiple Myeloma’

San Francisco – the 2014 annual meeting of the American Society of Hematology kicks off today. Yesterday was “Super Friday” –  a day when the non-profit and industry sponsored satellite symposia and other ancillary meetings, take center stage.

Each day (Sat – Mon) at the ASH meeting here in San Francisco, we we’ll be sharing information on which sessions we are in. For all those who have asked how do we get a photo with our antibuddies: @gene_antibody, we’ll mention where they are if we see them 🙂

By the way to get a photo you have to be able to identify which one is which – tip: there’s a monoclonal, bispecific, ADC and glycoengineered. Can you work out which is which from the picture? If not, it’s time to brush up on your antibody structures!

In addition, throughout the day (schedule and wifi permitting) we’ll be updating the rolling blog with short comments on the oral sessions and posters we’ve been in and what’s captured our attention. The hematology community has embraced Twitter, with many of the leading experts in the field sharing commentary and insights on their specialized area. ASH is also particularly welcoming to patient advocates who will be live-tweeting too. Expect the #ASH14 Twitter hashtag to generate a lot of information. If you’d like to share the ASH journey with us over the next 3 days, you can purchase access by clicking on the blue icon at the end of the post.

Existing subscribers already know how to login. Let the meeting commence!

Coit Tower San FranciscoThe 2014 American Society of Hematology (ASH) annual meeting starts later this week in San Francisco. #ASH14 is a “must attend” given the innovation that has taken place in recent years for new treatments of blood related cancers.

One of the highlights of last year’s ASH was the data for CTL019 Chimeric Antigen Receptor CAR-T in children with acute lymphoblastic leukemia (ALL) presented by Stephan Grupp (CHOP). The data, in the opinion of many, was worthy of presentation in the plenary session of the meeting.

CAR-T cell therapy remains in the news, with the recent announcement that Seattle based Juno Therapeutics have an initial public offering (IPO) planned, and last week Kite Pharmaceuticals announced a secondary offering to raise additional funds. Last month, Houston based Bellicum Pharmaceuticals also filed an IPO to raise funds for development of their GvHD and CAR-T therapies.

It already looks a highly competitive marketplace and nobody is yet in phase 3 development. In addition to Juno, Kite, Novartis/UPenn and Bellicum, the Chinese also have CAR-T therapies in development. Other companies in the field include Cellectis, who have partnerships with Servier and Pfizer. On top of all this activity, only a week ago Janssen announced they had partnered with Transposagen Biopharmaceuticals. Wow!

In addition to ALL, CLL, and NHL, new developments are starting to emerge in myeloma, not just with CAR T cell therapies, but also checkpoint inhibitors and modified measles virus therapy.

Investor interest in immuno-oncology is certainly very high, and one has to question whether it is beginning to border on “tulip mania”? As we’ve written about on the blog, there remain a number of challenges that have to be overcome with CAR-T therapy, particularly in adults, and at the moment it’s still very much an experimental therapy.

In this post, we offer some top line thoughts on what to expect and look out for at ASH14 in Multiple Myeloma. It is consistently an area that attracts a lot of interest at the meeting and this year promises not to disappoint.

If you have to plans to be in San Francisco, do say “hello.”

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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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