Home » News

Kyprolis Succeeds In Phase 3 Relapsed Multiple Myeloma Trial – Approval Filings Planned For Europe And Other Countries

16 Comments By
Published: Aug 4, 2014 6:51 pm

Amgen this morning announced initial results of its Phase 3 “ASPIRE” trial com­par­ing Kyprolis-Revlimid-dex­a­meth­a­sone to Revlimid-dex­a­meth­a­sone in pa­tients with relapsed multiple myeloma.

Patients in the trial who received the Kyprolis-Revlimid-dex­a­meth­a­sone com­bi­na­tion (KRd) had significantly longer progression-free survival (26.3 months) than patients who received only Revlimid and dex­a­meth­a­sone (Rd) (17.6 months).

There was also a trend in the results toward improved overall survival among the patients who received KRd versus those who did not. How­ever, the difference is not yet statistically significant.

The results of the trial are important for two reasons.

First, they will enable Amgen to request regulatory approval of Kyprolis (carfilzomib) as a treat­ment for multiple myeloma in Europe and other parts of the world where the drug is not yet approved.  Progression-free survival is the key endpoint in the trial for approval purposes.

Amgen noted in a press release this morning that, “Results from the ASPIRE study will form the basis for regulatory submissions through­out the world beginning in the first half of 2015.” This submission timeline would enable the drug to be approved in Europe, for example, by late next year or early 2016.

Second, the initial ASPIRE trial results provide further evidence that the Kyprolis-Revlimid-dex­a­meth­a­sone regimen is a highly active therapy for relapsed myeloma. Initial indications of the regimen’s activity already have been seen in published results of the  Phase 2 part of a trial testing the regimen’s efficacy and safety in relapsed myeloma (see related Beacon news).

Dr. Ravi Vij, a myeloma specialist at the Washington University School of Medicine in St. Louis, noted that the ASPIRE results “certainly show a clinically meaningful improvement in progression-free survival.” He added, however, that it is difficult to fully assess the results of the trial without “a better understanding of the demo­graph­ics of the patients enrolled.” Although some patients who were previously treated with Revlimid could participate in the trial, he explained as an example, patients resistant to Revlimid could not.

In addition, Dr. Vij noted that “the issue of three- versus two-drug regimens as salvage therapy remains an open one, as patients have heterogeneous presentations at time of disease progression, and two-drug combinations may still be appropriate for a lot of patients.”

Dr. Vij’s comments were echoed in feedback provided to The Beacon by Dr. Sergio Giralt of the Memorial Sloan-Kettering Cancer Center in New York City. Dr. Giralt is impressed by the initial ASPIRE results, going so far as to wonder whether the regimen could become the standard of care for relapsed patients. Yet he also believes it will be important to understand more about what patients were included in the trial and which patients responded to KRd.  Likewise, he considers it an open question “whether the goal for first salvage therapy should be depth of response.”

Amgen (NASDAQ:AMGN) noted in its press release earlier today that further information about the trial and its results will be submitted for presentation at the American Society of Hematology annual meeting in early December.  Amgen’s stock was up 2.5 percent today on news of the ASPIRE trial.

Study Design

The ASPIRE trial has enrolled 792 patients at over 100 treat­ment centers in North America, Europe, and Israel. Patients in the trial were randomly selected to receive either Kyprolis, Revlimid (lenalidomide), and dex­a­meth­a­sone (Decadron) (KRd), or Revlimid and dex­a­meth­a­sone (Rd) without Kyprolis.

To participate in the trial, patients have to have had at least one, but not more than three, previous myeloma treat­ment regimens.  Previous treat­ment with either Velcade (bor­tez­o­mib) or Revlimid was permitted.  However, patients could not participate in the trial if they experienced progression while previously treated with Velcade

In addition, patients could not participate in the trial if they were previously treated with a Revlimid-dex­a­meth­a­sone combination and either experienced disease progression during the first three months of treat­ment, or experienced progression on the combination and it was their most recent line of therapy.

Patients in the KRd arm of the trial received Kyprolis dosed at 20 mg/m2 on days 1 and 2 of cycle 1 only, then 27 mg/m2 in subsequent cycles.

Patients in both arms of the trial received Revlimid at 25mg per day for 21 days on, 7 days off, and low-dose dex­a­meth­a­sone (40 mg per week in 4 week cycles).

Treatment with both regimens continued until disease progression or until patients could not tolerate treat­ment any further.

Study Results

Progression-free survival among patients in the KRd arm of the trial was 26.3 months, a statistically sig­nif­i­cant improvement versus the 17.6 months observed in patients re­ceiv­ing the Rd regimen.

There also was a trend to improved overall with KRd versus Rd, although the difference in overall survival is not statistically significant at this time.

As for the safety of the KRd regimen, Amgen noted in today’s press release that

The safety profile observed in this study is consistent with the current U.S. Kyprolis label, including the rate of cardiac events. Treatment discontinuation due to adverse events and on-study deaths were comparable between the two arms. No new safety signals were identified.

The survival outcomes of the ASPIRE trial suggest that the three-drug KRd regimen is highly active in re­lapsed myeloma patients.

The 26.3 month progression-free survival reported for KRd is not much less, for example, than the 33 months reported for the combination of the potential new myeloma therapy elotuzumab with Revlimid and dex­a­meth­a­sone in relapsed patients (see related Beacon news).  The elotuzumab combination is con­sidered by many myeloma specialists to be highly active.  However, the trial of the elotuzumab regimen excluded patients who had previously been treated with Revlimid.  This exclusion makes it more likely that patients in that trial would respond to – and benefit from – the Revlimid-containing elotuzumab regimen.

Regulatory Implications Of The ASPIRE Trial

Amgen is expected to request approval for Kyprolis in Europe and other countries, such as Canada, based on the results of the ASPIRE trial.  It expects to initiate such filings by the first half of next year, which could enable approval in Europe, for example, by late 2015 or early 2016.

Amgen is also conducting another Phase 3 trial of Kyprolis in relapsed myeloma patients known as the FOCUS trial. That trial is being conducted with patients who have had at least three prior treat­ments. It is comparing treat­ment with single-agent Kyprolis to best supportive care, which can include treat­ment with a steroid such as dex­a­meth­a­sone or prednisone and, at the physician’s discretion, cyclophosphamide (Cytoxan).

Results of the FOCUS trial are expected soon and also may be used by Amgen in its applications for approval of Kyprolis in Europe and other parts of the world.

For further information about the ASPIRE trial results announced today, see the Amgen press release.  See the information at clinicaltrials.gov for further details of the ASPIRE and the FOCUS trials.

Photo by Unhindered By Talent on Flickr - some rights reserved.
Tags: , , , , , , ,


Related Articles:

16 Comments »

  • R said:

    Will the Kyprolis side effect profile (untoward events, including PN) and tolerance, be released , as well ?

    Thanks.

  • Myeloma Beacon Staff said:

    Hi R,

    Good question. We would expect the ASH presentation about the ASPIRE trial to have relatively detailed information about the safety and tolerability results from the trial.

    If you look at the ASCO presentation that was made about the “PANORAMA 1″ Phase 3 trial for panobinostat, for example, you’ll find four pages devoted to safety-related results.

  • Ivan said:

    Dear Beacon,

    Could you please elaborate on this statement, “The elotuzumab combination is con­sidered by many myeloma specialists to be highly active. However, the trial of the elotuzumab regimen excluded patients who had previously been treated with Revlimid.”

    If I recall correctly, the elotuzumab studies in point are the ELOQUENT-I and ELOQUENT-II studies. I was not aware those excluded patients previously treated with Revlimid. Where did you obtain this information?

    This study design point is crucial when comparing treatments for relapsed patients. I for one have been operating under the presumption that nothing at this point can touch the 33 months shown by Elo. However, if indeed the studies excluded Revlimid, this is a major, major, flaw in my mind considering that Revlimid is frontline therapy pretty much for all patients these days.

    Thanks

  • Ivan said:

    Nevermind. I found it here:

    http://www.myelomabeacon.com/docs/asco2013/Lonial-ElotuzumabRevDexRRMM.pdf

    I was at a loss about this. This is a huge point and has slipped between the cracks for me. Thanks for pointing this out.

  • Myeloma Beacon Staff said:

    Hi Ivan,

    Glad you found the relevant poster presentation. The presentation, as you’ve probably noted, is about an earlier Phase 1/2 trial, not the ongoing ELOQUENT-2 Phase 3 trial of elotuzumab-Revlimid-dex in relapsed / refractory patients.

    Note that the inclusion and exclusion criteria for the ELOQUENT-2 study are not the same as the earlier Phase 1/2 trial, which, as we noted, excluded patients previously treated with Revlimid.

    In particular, patients who have previously been treated with Revlimid are able to participate in the ELOQUENT-2 trial. However, as with the ASPIRE trial, there are restrictions that mean that not just any patient previously treated with Revlimid will be able to participate in the trial.

    We’re not aware of any results having been released for the ELOQUENT-2 trial. If you come across any, please let us know.

  • Ivan said:

    Thanks Beacon Staff.

    The criteria for ELOQUENT-2 includes patients with prior treatment with lenalidomide [Revlimid] if best response achieved was ≥ partial response (PR); patient was not refractory; reason for discontinuation was not a related Grade 3 or 4 adverse event.

    I am not aware of any results as of now. I posted recently on the forum asking patients enrolled in the trial whether they have heard how things are going, but I didn’t really get much feedback. I have the sneaking suspicion that the results will not be as promising as the ones reported by BMS. To me, the fact that Revlimid was excluded in the BMS Phase 2 trial considerably skews the results in favorable light. At least that’s how I see it.

    Thanks again

  • Joe Courtney said:

    I would appreciate anyone who could expound on what was meant by the quote- that it was still an open question -”whether the goal from initial salvage therapy should be depth of response”.

    I tend to agree with that, but I would appreciate a discussion of what the context is for making that statement. This particular study seems remarkably cherry picked to insure good results. I am personally looking for a long stable response, but if a longer deep response were available I would gladly take it – if the side effects were acceptable.

    Joe

  • Ivan said:

    Joe, when you say cherry picked, not sure what you mean, but to me personally, the following element of the study design gives me significant discomfort.

    “However, patients could not participate in the trial if they experienced progression while previously treated with Velcade

    In addition, patients could not participate in the trial if they were previously treated with a Revlimid-dex­a­meth­a­sone combination and either experienced disease progression during the first three months of treat­ment, or experienced progression on the combination and it was their most recent line of therapy.”

    In all likelihood, the typical patient that will be relying on Kyprolis would be refractory to Velcade and progressing on Revlimid. I know that at least this is my game plan. I see absolutely no point in talking about Kyprolis if Velcade and Revlimid continue to work. The study imposes inclusion limitations on the 2 most prevalent and effective frontline (and maintenance) drugs out there right now. I see that for purposes of comparison (i.e. comparing Kyprolis versus no Kyprolis protocols) this is OK, but for me, in absolute PFS terms, the study is useless. The 26-month PFS is as meaningless to me as the 33-month elotuzumab PFS.

    We need studies that include patients refractory to Revlimid and Velcade. That would be the largest crop of patients using these new meds. Even the ELOQUENT-2 trial, which includes patients previously treated with Revlimid, excludes those patients that are refractory to Revlimid.

    In all likelihood such studies will come in the future, but at this point, these flashy numbers, i.e. 33 months, 26 months and so on, are rather useless (at least in my mind).

  • Myeloma Beacon Staff said:

    Thanks for the additional comments, Ivan and Joe.

    Joe – In regard to your question related to the feedback we quote in the article from Dr. Ravi Vij and Dr. Sergio Giralt, we asked Dr. Vij if he could elaborate a bit on the issue you inquired about. His response can be found in the next comment.

  • Ravi Vij, M.D. said:

    Thank you for your question, Joe. Allow me to elaborate a bit on the comments quoted in the Beacon’s article that you have asked about.

    Often at first progression, patients have only laboratory (M protein or sFLC) progression of disease while on maintenance therapy or during a period of observation off therapy. These patients have no worsening of the CRAB criteria, are asymptomatic, and are often working full time. In such situations, even a wait and watch strategy can be successful for several months or longer. Often the most appropriate first intervention involves increasing the dose, or frequency of the dose, of the maintenance therapy agent, or adding a second agent (often dexamethasone) before switching therapy.

    On the other hand, as one gets to later lines of progression, it is probably best to intervene early with a change in therapy as in this scenario progression is usually brisk and waiting for worsening of CRAB criteria, or for symptoms to develop, often leads to the patient getting sick and regrets about not having intervened earlier. Here three drug combinations have a more established role.

    Treating patients is as much art as it is science. Trials such as the ASPIRE study give us vital guidance, but each patient is unique and requires a personalized approach.

  • Mark said:

    Hi Ivan,

    I think you are showing a U.S. patient based bias with respect to your discussion of this trial. As was noted in the article, the study was designed to get the drug approved for relapsed patients in Europe and other countries. In other countries, the Velcade / Revlimid / dex combo is not commonly used for induction.

    I am going on 4 years since diagnosis and I have never had to use Revlimid and I have had 3 lines of prior therapy, so there are patients like me who are not relying only on never ending cycles of IMIDs and proteasome inhibitors. These study results are not useless to patients like me.

    Myeloma therapy should be viewed as a marathon and nothing shortens the race like getting patients resistant to IMIDs and proteasome inhibitors early in disease course does.

    Mark

  • Ivan said:

    Mark,

    I see your point and it is great that the study is encouraging to you. That said, I am not sure where you get this “As was noted in the article the study was designed to get the drug approved for relapsed patients in Europe and other countries.” Maybe I am missing something.

    My understanding is that Onyx/Amgen conducted the ASPIRE study under a Special Protocol Assessment (SPA) from the U.S. Food and Drug Administration. The study involved patients from all over but I would suspect mostly from the U.S. (if anyone has the breakdown of the 792 patients, please share). Amgen is going to use the trial results for approval in Europe, sure. Not sure, however, how that means that the trial’s goal was approval for European patients.

    The trial started in 2012 while the FDA was still reviewing the drug and contemplating an accelerated approval here in the US. Since the drug was already approved here on accelerated basis, the results obviously will be used for approvals in other jurisdictions. The approval here in the U.S. was based on a different study if I recall correctly (Phase 2b 003-A1) which studied Kyprolis as a single-agent. OS in that study was 15 months and included 80% patients refractory to Rev and Vel.

    The ASPIRE study is trying to answer the question of Kyprolis’ efficacy as a combination therapy with Revlimid for relapsed patients (i.e. whether Kyprolis + Revlimid is more effective than Revlimid). Again, to me personally (from a U.S. perspective) where most relapsed patients would likely be relapsing on Velcade and Revlimid, the 26-month number is not that meaningful.

    I do appreciate the point, though, that people outside of the US who take meds other than Revlimid and Velcade could see this differently. I also appreciate the point that since the combination therapy comparison included Revlimid, probably it does not make much sense to include people refractory to Revlimid, but still, why exclude refractory Velcade? Anyways, these are just my thoughts …

    Best of luck to all.

  • Joe Courtney said:

    Thank you Dr. Vij. Your explanation makes much sense and amazingly it was information I had not heard before. I agree that each patient is different. I am experiencing something that is somewhere in between a first progression and a second one. Won’t go into the details, but my doctor seems to be thinking the way you do.

    Ivan, you say you did not understand what I was referring to by the term “cherry picked”. Those two words were my way of simply expressing what you point out in your long post.

    Joe

  • Mark said:

    Hi Ivan,

    “That said, I am not sure where you get this “As was noted in the article the study was designed to get the drug approved for relapsed patients in Europe and other countries.” Maybe I am missing something.”

    “Results from the ASPIRE study will form the basis for regulatory submissions throughout the world beginning in the first half of 2015. In the U.S., the data may support the conversion of accelerated approval to full approval and expand the current indication.”

    http://www.myelomabeacon.com/pr/2014/08/04/kyprolis-aspire-trial-results-interim-analysis/

    It was also mentioned in the Beacon article above.

    In the US it is possible to use the drug off label so they can get sales from Kyprolis here in the US other than for what it is approved for. They cannot sell it in Europe, for example, currently which is a large market. Amgen does not make money by providing drugs free of charge for patients in clinical trials.

    “I also appreciate the point that since the combination therapy comparison included Revlimid, probably it does not make much sense to include people refractory to Revlimid, but still, why exclude refractory Velcade?”

    That should be obvious. Why provide your drug for a clinical trial that does not give your drug the best chance to succeed? Running clinical trials that include patients that are refractory to Velcade make it less likely Kyprolis will succeed in a given trial. Getting the drug approved so they can sell it in more countries and earlier in disease course can make them money. There are patients like me that were responding to Velcade when they stopped using it. Do you think Amgen would want me/my doctor thinking about using Kyprolis if I relapse as opposed to going back to Velcade until I become refractory to it?

    Do you think Amgen would like to change this kind of thinking with respect to newly diagnosed and future myeloma patients?:

    “In all likelihood, the typical patient that will be relying on Kyprolis would be refractory to Velcade and progressing on Revlimid. I know that at least this is my game plan. I see absolutely no point in talking about Kyprolis if Velcade and Revlimid continue to work.”

    I would be very hesitant to use Kyprolis due to the cardiac toxicity and I would only use it if I was refractory to Velcade. That being said, I see nothing wrong with the design of this Phase 3 clinical trial. Revlimid / dex is a common drug combo that is approved for relapsed myeloma patients in both the U.S. and Europe. It is common for Phase 3 trials to add the experimental drug to an existing standard of care. Amgen got a lot of good headlines in the “business press” the day this news was announced. IF the regulators in various countries approve the drug for the use this trial studied, then the trial was a success from Amgen’s perspective.

    Mark

  • Nancy Shamanna said:

    Hi! This is such an interesting discussion about Kyprolis.

    Ivan, you ask about the demographics of the study … Just click on the link to the ASPIRE study in the article and you can read that the four major investigators were from the U.S. (2), France and Italy. The study took place in 127 locations, of which 22 were in the US, 8 in Canada and most of the rest were in different countries in Europe. Also, Russia and Israel had locations. Very international in scope.

    My understanding is that Amgen has more of a worldwide network of offices than does Onyx. Amgen is trying to get Kyprolis marketed internationally, and they would be in favour of a phase 3 clinical trial that showed impressive results. Countries with universal health care do not necessarily approve a new drug if they think there is already a similar one that works as well. And also, they won’t approve drugs without having phase 3 data, usually.

    I hope that kyprolis IS approved in more countries, since it gives patients more choices upon relapse. Also, I think that in the US probably the results of phase 3 clinical trials would be useful for having more information available.

  • shay said:

    I’m on KRd for five cycles now with great results.

    I’m high risk and I started this treatment following very aggressive relapse (just after two D-PACE cycles). Though we can’t tell if its the Revlimid or the Kyprolis (or both) who did the wonder. But the bottom line is that I’m in deep remission now following this treatment.

Leave a comment

Comments and feedback are welcomed. If you would like to leave a comment, please fill out the form below. If you would like to ask a medical question not directly related to the content above, or which is specific to your case, please post your comment to the Myeloma Beacon forums.