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 ^[1] (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 ^[2] 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 ^[3] (lena­lido­mide), and dex­a­meth­a­sone ^[4] (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 ^[5] (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 ^[6] with Revlimid and dex­a­meth­a­sone in re­lapsed patients (see related Beacon ^[7] 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 ^[8] and, at the physician’s discretion, cyclophosphamide ^[9] (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 ^[10].  See the in­­for­ma­tion at clinicaltrials.gov for further details of the ASPIRE ^[11] and the FOCUS ^[12] trials.