Kyprolis Succeeds In Phase 3 Relapsed Multiple Myeloma Trial – Approval Filings Planned For Europe And Other Countries
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.
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.
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.
- High-Dose Kyprolis Extends Progression-Free Survival Versus Velcade In Head-To-Head Relapsed Myeloma Trial
- Extended Use Of Revlimid Plus Dexamethasone Delays Progression Of Relapsed / Refractory Myeloma
- Kyprolis Fails To Provide Overall Survival Benefit In FOCUS Phase 3 Trial
- Continuous Revlimid-Dexamethasone Therapy Delays Progression And Improves Survival In Older Newly Diagnosed Myeloma Patients (ASH 2013)
- Additional Analyses Of Pomalyst Plus Low-Dose Dexamethasone Studies Presented At ASH 2013