Kyprolis Fails To Provide Overall Survival Benefit In FOCUS Phase 3 Trial
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.
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.
- Kyprolis Succeeds In Phase 3 Relapsed Multiple Myeloma Trial – Approval Filings Planned For Europe And Other Countries
- Broad Range Of Kyprolis Studies Presented At ASH 2013
- Kyprolis - Questions And Answers About The FDA Approval
- Kyprolis In Multiple Myeloma Patients With Kidney Damage
- Researchers Publish Final Results Of Kyprolis Study That Led To FDA Approval