Initial results of a large, head-to-head clinical trial show that re­lapsed myeloma patients treated with high-dose Kyprolis and dex­a­meth­a­sone had twice the pro­gres­sion-free survival of re­lapsed patients treated with Velcade and dex­a­meth­a­sone.

Median pro­gres­sion-free survival in the Phase 3 trial was 18.7 months in trial participants treated with high-dose Kyprolis ^[1] (car­filz­o­mib) and dex­a­meth­a­sone ^[2] (Decadron), compared to 9.4 months in patients treated with Velcade ^[3] (bor­tez­o­mib) and dex­a­meth­a­sone.

The results of the so-called “ENDEAVOR” trial were announced this past Sunday evening in a press release ^[4] issued by Amgen (NASDAQ:AMGN). The com­pany’s Onyx Pharmaceuticals sub­sid­i­ary developed and markets Kyprolis in the U.S.

The ENDEAVOR results are being released on the heels of publication earlier this year ^[5] of positive results from another important Kyprolis trial, known as the ASPIRE study. In the ASPIRE study, the com­bi­na­tion of Kyprolis, Revlimid ^[6] (lena­lido­mide), and dex­a­meth­a­sone noticeably improved pro­gres­sion-free survival in re­lapsed myeloma patients versus Revlimid and dex­a­meth­a­sone alone.

The ENDEAVOR results announced on Sunday, com­bined with the results of the ASPIRE trial, “tilt the balance in favor of Kyprolis” in comparisons between the Amgen drug and Velcade, myeloma specialist Dr. Prashant Kapoor of the Mayo Clinic told The Beacon.  Other myeloma specialists The Beacon consulted about the ENDEAVOR results also were impressed with Kyprolis’s performance in the trial.

Caveats When Interpreting The Trial Results

There are, however, at least two issues related to the ENDEAVOR study that hamper conclusions about the relative effectiveness of Kyprolis and Velcade in day-to-day use.

First, patients could par­tic­i­pate in the ENDEAVOR trial if they had been treated pre­vi­ously with either Vel­cade or Kyprolis.

In practice, this eligibility require­ment is likely to mean that many more patients in the study had been pre­vi­ous­ly treated with Velcade than with Kyprolis. Velcade is readily available in most, if not all, the countries where the ENDEAVOR trial was conducted, and the drug is frequently used as first-line ther­apy. Kyprolis, on the other hand, is only available through par­tic­i­pa­tion in a clinical trial in most countries other than the U.S.

Patients who have been pre­vi­ously treated with any myeloma ther­apy – whether it be Velcade, Kyprolis, or some other drug – tend not to respond as well to re-treatment with the same drug than patients who have never been treated with the drug.

Thus, because the ENDEAVOR trial is likely to have enrolled many more Velcade pre-treated patients than Kyprolis pre-treated patients, it was inclined from the start to find more benefit from Kyprolis treat­ment than Velcade treat­ment.

The second issue with the study design is that the Kyprolis dose in the trial was twice the FDA-approved dose. Myeloma specialists are increasingly experimenting with higher-than-approved Kyprolis doses. How­ever, in day-to-day practice, dosing closer to the approved dose is likely to be more common.

Because treat­ment response tends to be dose-related, the higher Kyprolis dose used in the ENDEAVOR trial also made it more likely that the Kyprolis-treated patients would see a better response to treat­ment than the Velcade-treated patients.

Safety Results From The Trial

It seems unlikely that either of the two issues just described, alone or in com­bi­na­tion with one another, would completely negate the Kyprolis pro­gres­sion-free survival advantage observed in the ENDEAVOR trial. None­the­less, the issues do make assessing the “true” survival advantage more challenging.

This is important, in part, because Kyprolis-treated patients in the ENDEAVOR study were more likely to experience several potentially serious side effects than the Velcade-treated patients.

In particular, patients who received Kyprolis during the study were more likely to experience heart failure, kidney failure, high blood pressure, and breathlessness than the Velcade-treated patients.

Amgen noted in its announcement of the trial results, though, that the rates of heart failure and kidney failure observed among the Kyprolis-treated patients in the ENDEAVOR trial were similar to those seen in the ASPIRE trial. Myeloma specialists generally have reacted positively to the Kyprolis safety results from the ASPIRE trial.

Amgen also reported, however, that the rates of high blood pressure and breathlessness among Kyprolis-treated patients were higher in the ENDEAVOR trial than in the ASPIRE trial.

At the same time, periph­eral neu­rop­athy occurred less frequently in the Kyprolis-treated patients in the EN­DEAV­OR trial than the Velcade-treated patients.

Also, despite the difference in how often some side effects occurred in the two arms of the ENDEAVOR trial, there was no statistically significant difference in how often the Kyprolis- and Velcade-treated patients dis­con­tinued treat­ment due to side effects. In addi­tion, there was no statistically significant difference in the number of deaths while on treat­ment between the two groups of patients.

More On The Efficacy Results From The Trial

The ENDEAVOR trial was designed with a focus on measuring the pro­gres­sion-free survival of the two groups of patients in the study – those treated with Kyprolis, and those treated with Velcade.  Progression-free survival was measured from the start of treat­ment until either disease pro­gres­sion or death.

As noted earlier, patients in the trial who were treated with high-dose Kyprolis and dex­a­meth­a­sone had a median pro­gres­sion-free survival of 18.7 months versus 9.4 months for the patients treated with Velcade and dex­a­meth­a­sone.

Amgen also has reported that more patients in the Kyprolis arm of the trial responded to treat­ment than in the Velcade arm of the trial, although no response rates from the trial have yet been published.

As for the over­all survival results from the study, Amgen said that they “are not yet mature and con­tinue to be monitored.”

Looking Ahead

Amgen announced in late January ^[7] that it has filed for the approval of Kyprolis in Europe based on the results of the ASPIRE trial, and it also has requested a broadening of the drug’s approval in the U.S.  In addi­tion, the com­pany reported last week ^[8] that its application for Kyprolis approval in Europe has been accepted for review by the European Medicines Agency.

The ENDEAVOR study is one of three ongoing head-to-head clinical trials comparing Kyprolis and Velcade as myeloma ther­a­pies. The two other studies, which also are Phase 3 trials, are comparing the two drugs in newly diagnosed patients.

1. The “CLARION” trial ^[9] is comparing the combination of Kyprolis, melphalan ^[10] (Alkeran), and prednisone ^[11] to Velcade, melphalan, and prednisone in newly diagnosed myeloma patients.  The global trial, like the ENDEAVOR study, is sponsored by Amgen.
2. The “ENDURANCE” trial ^[12] is comparing Kyprolis, Revlimid, and dex­a­meth­a­sone to Velcade, Revlimid, and dex­a­meth­a­sone in newly diagnosed patients. The trial, which is being run by the Eastern Coop­erative Oncology Group (ECOG) in the U.S., also will compare fixed-duration Revlimid main­te­nance therapy versus Revlimid maintenance until progression.

Head-to-head trials are not yet commonplace among studies testing myeloma ther­a­pies. Such comparative trials are, however, being organized more frequently as the number of myeloma ther­a­pies approved by reg­u­la­tory agencies increases, and pharma­ceu­tical com­pa­nies seek an advantage for their prod­ucts vis-à-vis the growing num­ber of competitors.

Design of the ENDEAVOR Study

The ENDEAVOR study enrolled 929 re­lapsed myeloma patients in 235 different locations across the globe.

Patients in the trial had 1 to 3 prior myeloma ther­a­pies.  Those ther­a­pies could include either Velcade or Kyprolis, provided the patient achieved at least a partial response to treat­ment involving those drugs, and provided it had been at least six months since the patient was last treated with either drug.

Once enrolled in the study, participants were randomly assigned to be treated with either high-dose Kyprolis plus dex­a­meth­a­sone, or Velcade plus dex­a­meth­a­sone.

Kyprolis treat­ment was twice a week during the first three weeks of a 28-day cycle: Days 1, 2, 8, 9, 15, and 16 of the cycle.

The initial Kyprolis dose during the first week of treat­ment was 20 mg/m². In sub­se­quent weeks of Cycle 1 – and in all later cycles – the Kyprolis dose was increased to 56 mg/m².  This dose is more than twice the FDA-approved dose of Kyprolis, which is 20 mg/m² in the first cycle and – if tolerated – 27 mg/m² in later cycles.

Kyprolis-treated patients also received 20 mg of dex­a­meth­a­sone twice a week in each week of the 28-day treat­ment cycle: Days 1, 2, 8, 9, 15, 16, 22, and 23.

Velcade treat­ment was twice a week during the first two weeks of a 21-day cycle: Days 1, 4, 8, and 11 of the cycle. The drug’s dose was the FDA-approved dose of 1.3 mg/m².  Patients treated with Velcade also received 20 mg of dex­a­meth­a­sone four days per week during the first two weeks of the 21-day cycle: Days 1, 2, 4, 5, 8, 9, 11, and 12 of the cycle.

Patients could be given Velcade either sub­cu­tane­ously or by infusion, and about 75 per­cent of the Velcade-treated patients were given the drug sub­cu­tane­ously.

Both groups of patients in the trial received their assigned treat­ment regi­men until either they could no longer tolerate treat­ment, disease pro­gres­sion, or death.

Additional in­­for­ma­tion about the design of the trial, including patient eligibility criteria, can be found in the trial in­­for­ma­tion at clinicaltrials.gov ^[13].