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Kyprolis Fails To Provide Overall Survival Benefit In FOCUS Phase 3 Trial

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Published: Aug 17, 2014 4:10 pm

Amgen has given a first glimpse of key results from its FOCUS Phase 3 clinical trial testing Kyprolis in relapsed and refractory multiple myeloma patients.

The company reported this past Wednesday that Kyprolis did not provide an overall survival advantage in the trial, which is being con­ducted out­side the United States.

In addition, the company noted that patients treated with Kyprolis during the trial experienced more kidney-related side effects than patients who were not treated with the drug.

Up until recently, the primary significance of the FOCUS trial would have been its impact on Amgen’s plans to seek regulatory approval for Kyprolis in Europe and other parts of the world besides the United States.

The U.S. is currently the only country where the drug is approved for use outside of clinical trials.

However, earlier this month, Amgen announced initial results of another Kyprolis Phase 3 trial, known as the ASPIRE study, and at the same time said that it would use the results of that study as the basis for its Kyprolis approval submissions in Europe and elsewhere (see related Beacon news).

Thus, oddly enough, the key question in regard to this week’s FOCUS results is whether or not they will im­pact Kyprolis in the United States.

For the immediate term, the answer to that question seems to be no. The trial has no bearing on the drug's existing approval from the U.S. Food and Drug Administration, and the trial's survival outcome was not un­ex­pected.

There could be, however, a longer-term impact of the trial on Kyprolis in the U.S. as a result of the kidney-related side effects seen in the trial. Whether or not this occurs will depend on what is learned when more data about those side effects are made public.

Study Design

The FOCUS trial enrolled 315 relapsed and refractory patients at treatment centers across Europe, Israel, and Australia. Trial participants were heavily pretreated, having received a median of five previous treatment regimens.

Patients in the Phase 3 trial were randomly selected to receive one of two treatment regimens.

The first regimen consisted of single-agent Kyprolis (carfilzomib).

The second regimen consisted of a steroid, such as pred­ni­sone or dexa­meth­a­sone (Decadron), optionally combined with oral cyclo­phos­pha­mide (Cytoxan). Most of the patients receiving the second treatment reg­i­men did in fact receive cyclo­phos­pha­mide.

The dosing of Kyprolis in the trial was similar to what is recommended in the official U.S. prescribing in­for­ma­tion for the drug, with an upward adjustment in the trial to dosing in the first cycle, and a downward ad­just­ment in cycles 10 and beyond.

All patients in the trial continued on their assigned treatment regimen until disease progression or until they could no longer tolerate the treatment.

Top-Line Study Results

In Wednesday’s announcement, Amgen (NASDAQ:AMGN) reported that there was no statistically significant difference in overall survival between the two treatment regimens. The company did not report actual overall survival times for the two regimens, nor did it report any progression-free survival or response rate results.

Amgen also reported that there was no significant difference between the two treatment regimens in terms of the percent of patients who discontinued treatment due to severe side effects or death.

In addition, the rate of heart-related severe side effects in FOCUS trial participants treated with Kyprolis was similar to what is reported in the drug's U.S. prescribing information.

There were, however, a higher number of kidney-related side effects seen among Kyprolis-treated patients in the FOCUS trial than in patients in the trial who were not treated with the drug, and as compared to what is in the drug's U.S. prescribing information.

Amgen intends to provide additional details about the FOCUS trial results at an upcoming scientific meeting.

Financial Market Reaction To The FOCUS Results

The stock market initially reacted negatively to Wednesday’s news of the FOCUS trial results. Amgen re­ported the results immediately after the close of U.S. financial markets that day, and the company’s stock declined by up to 2 percent in after hours trading that evening.

Since Wednesday, however, financial markets appear to have reassessed the implications of the trial re­sults. Amgen’s stock closed Friday afternoon up more than 4 percent from its Wednesday close. The stock market as a whole was up about half a percent over that same period of time.

Impact Of The Study Results On Perceptions Of Kyprolis’s Effectiveness

One potential way the results of the FOCUS trial could affect the use of Kyprolis in the United States is by changing physician perceptions of how effective the drug is.

Myeloma specialists contacted by The Beacon, however, were not concerned by the FOCUS trial's survival outcome and do not believe the results will negatively affect impressions of the drug's effectiveness.

"I am not surprised" by the trial's survival outcome, said Dr. Jatin Shah of the MD Anderson Cancer Center in Houston, "and most doctors in the multiple myeloma community are not surprised."  He added that the trial "does not change the view that Kyprolis is very active."

The key factor to bear in mind when interpreting the survival outcome, The Beacon was told several times, is that patients in the trial who were not treated with Kyprolis typically received a two-drug regimen – a steroid combined with cyclo­phos­pha­mide – that can be active even in heavily pretreated patients.

Dr. Prashant Kapoor of the Mayo Clinic, for example, noted that previous research has shown that pred­ni­sone combined with cyclo­phos­pha­mide can be quite active in advanced myeloma. In addition, pred­ni­sone is often the steroid that myeloma specialists prefer to combine with cyclo­phos­pha­mide in patients such as those in the FOCUS trial.

Impact Of The Study Results On Perceptions Of Kyprolis’s Safety

Another potential way the FOCUS trial could affect the use of Kyprolis in the U.S. is by changing physician perceptions of how safe the drug is.

The good news for Kyprolis in this regard is that patients in the FOCUS trial who were treated with the drug did not experience heart-related side effects to a greater degree than was seen in other key Kyprolis trials. Some U.S. physicians have had concerns about Kyprolis’s potential for heart-related side effects.

The not-so-good news on the safety front, however, is that Kyprolis-treated patients in the FOCUS trial ex­per­i­enced more kidney-related side effects than the other patients in the trial.

Some industry analysts have downplayed the significance of this result by noting (correctly) that patients admitted to the FOCUS trial were allowed to have much more kidney damage than was permitted in other key Kyprolis trials, such as the ASPIRE trial and the Phase 2 trial for U.S. approval.

This difference in trial design may explain why the Kyprolis-treated patients were more likely in the FOCUS trial to have kidney-related side effects than was the case in the other two trials.

It does not explain, however, why the Kyprolis-treated patients in the FOCUS trial had kidney-related side effects more often than patients in the same trial who were not treated with Kyprolis. All patients in the FOCUS trial, regardless of the treatment regimen they received, were admitted to the trial using exactly the same screening criteria.

That said, it is also true that, in its announcement of the ASPIRE trial results earlier this month, Amgen did not indicate that the Kyprolis-treated patients in that trial experienced higher kidney-related side effects than the patients in the trial who were not treated with Kyprolis.

Thus, the FOCUS trial is the only Kyprolis trial thus far in which a kidney-related safety issue has been flagged. This will likely limit the impact of that issue in the immediate term.

The Relevance Of Kidney-Related Side Effects To Kyprolis

Yet, if more detailed data from the trial indicate that the side effects were not just a sta­tis­ti­cal fluke, the potential longer-term significance of the kidney-related side effects in the FOCUS trial should not be overlooked.

Many physicians and myeloma patients today consider Kyprolis to be primarily a treatment option for re­lapsed myeloma patients, with Pomalyst (pomalidomide, Imnovid) being perhaps the key alternative to Kyprolis.

However, in the longer term, it is likely that Kyprolis will compete more and more with Velcade (bortezomib) for use in newly diagnosed as well as relapsed myeloma patients. Kyprolis and Velcade are both in the same class of drugs, and Amgen has conducted – and is conducting – numerous clinical trials testing Kyprolis in newly diagnosed myeloma patients.

One key reason physicians turn to Velcade when treating myeloma patients, however, is that it is considered safe to use in patients with damaged kidneys. Moreover, kidney damage is quite common in myeloma patients.

Thus, any credible finding that Kyprolis may have kidney-related safety issues, while it may not have an im­me­di­ate effect on the drug’s use, could have longer-term implications for how often the drug is pre­scribed.

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

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  • Jan Stafl MD said:

    As disappointing as this news is, it is reassuring to see negative data from clinical trials get publicized, which has often not occurred in the past. Both positive and negative data availability is important to balance the benefit/risk ratio. It is also true that Kyprolis compared to Cytoxan, with added steroids, appear to have similar PFS and OS rates, superior to other alternatives.

    The adverse renal effects of Kyprolis may be detected early with frequent monitoring of renal functions, especially the GFR (glomerular filtration rate). Discontinuation or reduction of the drug should lead to recovery of kidney function. Kyprolis does have less neuropathy associated with it than Velcade, and it is more effective in refractory MM. Thus it remains an important option for treatment of advanced MM. However, this news does caution against the use of Kyprolis as front line therapy.

  • Maro said:

    Sad to hear. Yet as Jan Stafl MD stated it is good to see that studies and clinical trials are objective and publicize the results even when they are not in favor of a cure.

    Keeping fingers crossed in the hope that some day (very soon!) some miracle drug will be found ;-)

  • Pat Killingsworth said:

    Maybe we're looking at this all wrong. Isn't it good news: that Cytoxan and prednisone was so effective!

  • Nels Hollo said:

    I have been through stem cell removal and replacement. Afterward I used a Velcade maintenance. Tylenol eased the pain in my right inside shoulder, under my arm pit and into my elbow. Now they put me on a Phase 1/2 study of weekly carfilzomib and dexamethasone. Now Tylenol doesn't ease the pain but hydrocodone helps a little. I am discouraged.

  • Myeloma Beacon Staff said:

    Sorry to hear that you're a bit discouraged with the weekly Kyprolis treatment you've been receiving, Nels. One thing to keep in mind, though, is that Kyprolis can typically be given for many cycles, allowing time for the medication to work. So it may be too early to draw any conclusions from how you have reacted so far.

    Good luck!