Once-weekly high-dose Kyprolis led to higher response rates and longer remissions in re­lapsed / refractory myeloma patients than twice-weekly, lower-dose Kyprolis (car­filz­o­mib), interim results of the Phase 3 "ARROW" clinical trial show.

Dr. Maria-Victoria Mateos presented the trial results earlier this month at the 2018 American Society of Clinical Oncology (ASCO) annual meeting in Chicago, and also last weekend at the 2018 congress of the European Hematology Association, held in Stockholm. In addi­tion, the trial results were recently published in a medical journal (reference).

The over­all response rate to the two-drug, Kyprolis-dexamethasone regi­men tested during the ARROW trial was 63 per­cent in patients who received high-dose Kyprolis once per week versus 41 per­cent in patients who received lower-dose Kyprolis twice each week.

Similarly, median pro­gres­sion-free survival was 11.2 months in once-weekly patients compared to 7.6 months in twice-weekly patients.

Participants in the trial who received Kyprolis once each week were admin­istered a dose of 70 mg/m² per infusion, compared to 27 mg/m² per infusion (54 mg/m² per week) for those who received Kyprolis twice per week.

Given that the once-weekly patients in the trial received 30 per­cent more Kyprolis each week than the twice-weekly patients, it is not entirely surprising that response rates and pro­gres­sion-free survival were higher in the once-weekly group.

What was noteworthy, however, was that the incidence of side effects and adverse events was similar in the two groups of trial participants. This result drew the attention of many myeloma specialists. In the Beacon's recent review of the myeloma-related presentations at the ASCO meeting, for example, both Dr. Heather Landau of Memorial Sloan-Kettering Cancer Center in New York and Dr. Prashant Kapoor of the Mayo Clinic in Minnesota noted the safety results when they char­ac­ter­ized the ARROW results as potentially "practice changing."

That said, there still is reason for pause in the ARROW side effect and safety results. There were, for example, five treat­ment-related deaths in the once-weekly, high-dose group of patients in the trial, versus one treat­ment-related death in the twice-weekly, lower-dose group.

Amgen, the com­pany that markets Kyprolis, hopes the ARROW results will persuade physicians that once-weekly, high-dose Kyprolis is both effective and safe. Doing so would reduce two key barriers to the drug's wider use: the inconvenience of twice-weekly infusions, and concerns about the drug's safety.

These barriers, coupled with competitive pressure, caused Kyprolis sales in the United States to be flat from the first quarter of 2017 to the first quarter of this year, at a time when U.S. sales of com­peting myeloma ther­a­pies, such as Pomalyst (poma­lido­mide, Imnovid) and Darzalex (dara­tu­mu­mab), con­tinued to rise. (U.S. sales of Kyprolis account for almost two-thirds of the drug's global sales.)

Background

When Kyprolis originally was approved by the U.S. Food and Drug Administration (FDA) as a new treat­ment for multiple myeloma, the recommended dosing of the drug was twice per week at a dose of 20 mg/m² for the first cycle of ther­apy, and then twice per week at a dose of 27 mg/m², if tolerated, for all sub­se­quent cycles.

Since the drug's initial approval, addi­tional dosing regi­mens have been tested and eventually approved by the FDA. However, all approved dosing regi­mens con­tinue to involve twice-weekly dosing of the drug.

In an effort to develop a more convenient Kyprolis treat­ment regi­men, once-weekly Kyprolis plus dexa­meth­a­sone was pre­vi­ously assessed in the Phase 1/2 "CHAMPION-1" trial (reference). In that study, the maximum tolerated weekly dose of Kyprolis was established as 70 mg/m².

To further explore the once-weekly treat­ment option, Amgen initiatied the Phase 3 ARROW trial to compare once-weekly Kyprolis at the pre­vi­ously established maximum tolerated dose of 70 mg/m² to twice-weekly Kyprolis at the drug's initially approved dose of 27 mg/m². Kyprolis would be com­bined with dexa­meth­a­sone in both the once-weekly and twice-weekly dosing regi­mens, and the trial would enroll re­lapsed and refractory multiple myeloma (as did the CHAMPION-1 trial).

Study Design

The ARROW trial included 478 patients who had pre­vi­ously received two or three prior lines of ther­apy, and whose prior treat­ments had included both

1. A proteasome inhibitor other than Kyprolis (so Velcade (bor­tez­o­mib) in almost all cases), and
2. An immuno­modu­la­tory agent, meaning either Revlimid (lena­lido­mide), Pomalyst, or thalido­mide.

The treat­ment cycle for all patients in the trial was 28 days, and treat­ment con­tinued until disease pro­gres­sion or unacceptable toxicity.

The once-weekly treat­ment group received Kyprolis intravenously over 30 minutes on days 1, 8, and 15 of all treat­ment cycles (20 mg/m² on day 1 of cycle 1 and 70 mg/m²thereafter). The twice-weekly treat­ment group received Kyprolis intravenously over 10 minutes on days 1, 2, 8, 9, 15, and 16 (20 mg/m² on days 1 and 2 of cycle 1 and 27 mg/m² thereafter). In addi­tion, all patients received 40 mg of dexa­meth­a­sone on days 1, 8, 15 of all treat­ment cycles plus on day 22 of treat­ment cycles 1 through 9.

The ARROW trial was conducted at 140 different sites primarily in Europe, although there were about 10 sites in the United States,

Study Results

The results of the trial show that the over­all response rate was higher in the treat­ment group that received once-weekly high-dose Kyprolis than in the one that received twice-weekly lower-dose Kyprolis (63 per­cent versus 41 per­cent).

More patients in the once-weekly treat­ment arm of the trial reached a com­plete response (7.1 per­cent) than in the twice-weekly treat­ment arm (1.7 per­cent). Similarly, more patients in the once-weekly arm reached at least a very good partial response (34 per­cent) than in the twice-weekly arm (13 per­cent).

The once-weekly dosing also resulted in longer remissions. Median pro­gres­sion-free survival was 11.2 months in the once-weekly group compared to 7.6 months in in the twice-weekly group.

There also is a trend to im­proved over­all survival in the patients who received the once-weekly dosing. However, patients in the trial have been followed for a median of only one year thus far. So the over­all survival results are still limited in scope.

Many aspects of the side effect profile were similar for the two arms of the trial. The most common side effects in both treat­ment arms included anemia, fever, high blood pressure, and fatigue, and there was no significant difference in how often these side effects occurred in the once-weekly and twice-weekly groups of patients.

For example, high blood pressure was observed in 21 per­cent of the patients in the once-weekly arm of the trial, compared to 20 per­cent of the patients in the twice-weekly arm.

That said, five treat­ment-related deaths occurred in the once-weekly treat­ment arm (due to sepsis, acute lung injury, acute res­pira­tory distress syn­drome, and tumor lysis syn­drome) compared to one treat­ment-related death in the twice-weekly treat­ment arm (due to congestive heart failure).

Potential Impact Of The ARROW Results

Kyprolis sales in the United States were flat from the first quarter of 2017 to the first quarter of 2018, and they actually declined from the fourth quarter of 2017 to the first quarter of 2018.

The flattening of Kyprolis's U.S. sales trajectory is unusual for such a comparatively young drug (Kyprolis was first approved in the United States in 2012). In the period where U.S. sales of Kyprolis were flat, for example, sales of Pomalyst increased almost 40 per­cent, and Pomalyst was approved in the United States not long after Kyprolis. Pomalyst also outsells Kyprolis by a ratio of about two-to-one in both the U.S. and inter­na­tional markets.

The rapid growth of Darzalex as a myeloma treat­ment option is often cited as a reason for the slowing of Kyprolis sales, with Darzalex increasingly being used in re­lapsed myeloma patients who in the past might have been prescribed Kyprolis.

Competitive pressure from Darzalex, however, is not the only explanation for what has happened with the U.S. sales of Kyprolis. Pomalyst, for example, also has been used in the past almost exclusively in re­lapsed patients, yet the growth in Darzalex pre­scrib­ing has not hindered con­tinued use of Pomalyst.

Instead, it seems likely that both convenience and safety perceptions have played a role in what has happened with Kyprolis pre­scrib­ing.

Kyprolis is an infused drug which, up until now, has had to be admin­istered twice a week. Pomalyst, in contrast, is an oral drug, as is, for that matter, Ninlaro (ixazomib), a proteasome inhibitor like Kyprolis that is seeing wider use in re­lapsed patients.

As for safety, concerns on that front date back at a minimum to when the U.S. FDA was first con­sidering approving the drug. They have been highlighted more recently, however, by studies noting the risks asso­ci­ated with Kyprolis in comparison, for example, to Velcade (see related press release).

The current U.S. pre­scrib­ing in­­for­ma­tion for Kyprolis underscores such concerns by noting that in a large trial com­par­ing Kyprolis, mel­phalan, and pred­ni­sone (KMP) to Velcade, mel­phalan, and pred­ni­sone (VMP) in newly diagnosed myeloma patients, the trial participants who were treated with Kyprolis were almost twice as likely to ex­peri­ence fatal adverse events than those treated with Velcade. Kyprolis-treated patients in the trial also were about three times as likely to ex­peri­ence cardiac failure or high blood pressure than their Velcade-treated counterparts (related press release).

The results of the ARROW trial are therefore important in that they address the convenience and safety concerns which may have been hindering broader use of Kyprolis in both re­lapsed and newly diagnosed myeloma patients.

For more in­­for­ma­tion about the results of the ARROW trial, please see the related ASCO abstract #8000, EHA abstract S849, ASCO presentation slides (courtesy of Dr. Mateos), or the recent journal article summarizing the results.