Biotech Strategy Blog

Commentary on Science, Innovation & New Products with a focus on Oncology, Hematology & Cancer Immunotherapy

Posts tagged ‘carfilzomib’

After some relatively quiet summer months, we have been deluged with questions and requests this month for commentary on some hot topics of late. This seems like a good time to take stock and reflect on some of most frequent ones sent in.

west-acton-tubeThe original Journal Club post slated for today will appear next week instead.

Here, we address numerous queries on the following five topics readers are interested in:

  • APHINITY trial in HER2+ adjuvant breast cancer
  • Array’s BRAF plus MEK data in metastatic melanoma
  • Kite’s interim ZUMA–1 phase 2 announcement
  • Amgen’s Kyprolis in newly diagnosed multiple myeloma
  • BMS nivolumab data in 1L lung cancer (CheckMate-026)

The last two in particular seem to be causing a lot of hand-wringing!

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Multiple myeloma (MM) has been very much in the news this week after the American Society of Clinical Oncology (ASCO) abstracts were released to much anticipation.

Myeloma is largely thought to be an incurable disease despite the option of an autologous stem cell transplant for newly diagnosed patients. That said, I have actually met some people who have had two or 3 transplants over several decades, a testament to their strength and fortitude in enduring such a challenging procedure.

This year, the news media have focused on elotuzumab (BMS/AbbVie), a CS1/SLAMF7 inhibitor that has previously shown clinical activity in earlier trials, after it was showcased in the ASCO Presscast last week. This why you see many articles on the data reported from this particular abstract.

New Orleans American QueenIt’s not the most exciting new data in this disease for me though, that honour goes to two other therapeutics of an entirely different kind. They come completely out of left field and what we saw over the last two months really caught our attention and may surprise you too.

Indeed, we saw hints of some of this data at the American Society for Gene and Cell Therapy (ASGCT) meeting last week in New Orleans.

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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.

In today’s post, we discuss multiple myeloma and the proteasome inhibitors (bortezomib, carfilzomib and ixazomib), in particular. One of the ongoing debates concerns the toxicities and how the drugs in this class might differ. Whereas melphalan and the immunomodulatory drugs or IMiDs (lenalidomide, pomalidomide and thalidomide) have both been associated with secondary primary malignancies including AML and MDS, especially in combination, cardiotoxicity has been the main focus of debate for the proteasome inhibitors.

Is this a fair rap though?

We should remember that people with multiple myeloma typically tend to be around age 70. Think of Tom Brokaw, the famous newscaster, who was recently diagnosed with the condition aged 74 and is in the median age range, for example. In general, most people over 65 tend to have an increased incidence of cardiovascular disease and myeloma patients also tend to have a slightly higher risk due to disease factors, so there is a background effect that needs to be taken into account.

We should be mindful of the recent scare with cardiovascular events associated with ponatinib (Iclusig) in relapsed/refractory CML, which led to a temporary suspension from the US market and subsequent re-instation with a narrower license, appeared to unnerve both the FDA and investors alike.

At the American Society of Hematology (ASH) meeting in Decemeber, there were some interesting posters, presentations and debates on the proteasome inhibitors in myeloma that are worthy of further discussion. In addition, I sought some thought leader opinions and curated some of the interactions on this topic to add some colour commentary.

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As 2013 draws to a close, I though it would be a good time to add one last ASH post before finishing for the year. More to come in the form of the tumour summaries in January.

One of my favourite activities at conferences is finding interesting gems in the poster hall. In New Orleans this year there were not one, but two huge halls! That’s a lot of shoe leather involved in order to browse, chat with investigators or researchers and cover them all.

So what nuggets stood out to me this year?

Companies mentioned: KBIO, Gilead, Incyte, Seattle Genetics, Array, Amgen
Drugs covered: KB004, momelotinib, ruxolitinib, idelalisib, brentuximab (Adcetris), filanesib (ARRY-520), carfilzomib

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This year at the American Society of Hematology (ASH) there are over 800 abstracts on multiple myeloma alone. Obviously, one can’t possible do them all justice, but there are a number of important ones that are well worth highlighting, especially given the raft of new products in development, as well as some solid data from existing approved products.

Myeloma has long been dominated by proteasome inhibitors and immunomodulatory (IMiD) agents in combination with prednisone, dexamethasone, melphalan or as a triplet such as RVd, VMP etc. In Europe, melphalan still dominates as part of the base therapy, while in the US, dexamethasone (dex or simply d) is preferred partner since the tolerability is much improved along with a lower risk for secondary primary malignancies (SPMs).

In this detailed preview, the following companies and products are covered:

Companies: Millennium, Celgene, J&J, Amgen, Novartis, GSK, Array, Actelion, Biotest, KaloBio, Curis, Verastem, Karyopharm, Aeterna Zentaris.
Products: Ixazomib, lenalidomide, pomalidomide, carfilzomib, panobinostat, daratumumab, ibrutinib, CC-292, afuresertib, GSK2857916, ARRY-520, ACY-1215, indatuximab ravtansine, CUDC-907, VS-5584, selinexor, LCL161, BYL917, perifosine.

I also discuss some controversial topics such as lack of overall survival in the Revlimid trials and the risk of cardiovascular adverse events with Kyprolis. There are also an exciting raft of new compounds with new targets in various stages of development.

Obviously there will be more to come at the meeting, but for now, there’s plenty to discuss and review ahead of time.

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