Earlier this week, Bristol-Myers Squibb an­nounced that it had filed an appli­ca­tion to have elotuzumab approved in Europe as a new treat­ment for mul­ti­ple mye­lo­ma patients who have re­ceived one or more prior ther­a­pies (see re­lated Bristol-Myers press re­lease ^[1]).

An im­por­tant part of elotuzumab ^[2]’s Euro­pean ap­prov­al appli­ca­tion will be ef­fi­cacy and safety data from a Phase 3 clin­i­cal trial known as ELOQUENT-2. These re­sults drew sig­nif­i­cant attention when they were pre­sented at this summer’s Amer­i­can Society of Clinical Oncology (ASCO) and Euro­pean Hema­tology Associ­a­tion (EHA) annual meetings. The trial re­­sults also were pub­lished in a lead­ing med­i­cal journal.

Given the attention the ELOQUENT-2 trial re­­sults have re­ceived and the role they will play in the drug’s recent ap­prov­al appli­ca­tion, now seems a good time to take a closer look at the trial re­­sults.

The re­­sults show that adding elotuzumab to Revlimid ^[3] (lena­lido­mide) and dex­a­meth­a­sone ^[4] (Decadron) in­creases treat­ment re­sponse rates and pro­longs pro­gres­sion-free sur­vival in patients with re­lapsed / re­frac­tory mul­ti­ple myeloma.

Patients in the trial who re­ceived elotuzumab in com­bi­na­tion with Revlimid and dex­a­meth­a­sone had a medi­an pro­gres­sion-free sur­vival of 19.4 months, com­pared to 14.5 months for patients who re­ceived treat­ment with just Revlimid and dex­a­meth­a­sone alone.

Moreover, dif­fer­ences in pro­gres­sion-free sur­vival seemed to persist over time in the trial. This is un­usual. Often in trials com­par­ing one myeloma treat­ment regi­men to another, dif­fer­ences in sur­vival rates de­crease as one looks at longer and longer times from the start of treat­ment. There might be, for example, a 15 per­cent dif­fer­ence in sur­vival rates at one year after the start of treat­ment, but only a 10 per­cent dif­fer­ence at two years, and then a 5 per­cent dif­fer­ence at three years.

This was not the case in the ELOQUENT-2 trial. Differences in pro­gres­sion-free sur­vival were actually greater two years after the start of treat­ment than after one year.

It is possible that the persistence in elotuzumab’s sur­vival ben­e­fit may be a peculiarity of this par­tic­u­lar trial – a point explored later in this article. Nevertheless, it raises the possibility that some re­lapsed myeloma pa­tients may achieve par­tic­u­larly long remissions when treated with elotuzumab.

“Based on this ran­dom­ized Phase 3 trial, we hope that we will soon have a new treat­ment op­tion for patients with re­lapsed or re­frac­tory myeloma where an im­mune ther­apy-based ap­proach can be added with lena­lido­mide and dex­a­meth­a­sone for the man­age­ment of these patients,” said the lead in­ves­ti­ga­tor of the trial, Dr. Sagar Lonial from the Winship Cancer In­sti­tute of Emory Uni­ver­sity, during the press briefing prior to the ASCO meeting.

Background

Elotuzumab is being devel­oped jointly by the pharma­ceu­tical com­pa­nies Bristol-Myers Squibb (NYSE: BMY) and AbbVie (NYSE:ABBV).  The drug, which the com­pa­nies in­tend to mar­ket under the brand name “Empliciti,” belongs to a class of ther­a­pies known as mono­clonal anti­bodies. These drugs identify cancer cells through spe­cif­ic pro­teins on the surface of those cells. Once they have identified the cancer cells, mono­clonal anti­bodies either signal the im­mune sys­tem to attack the cancer cells, or they attack the cells themselves, or they do both (signal and attack on their own).

In the case of elotuzumab, a pro­tein known as SLAMF7 is targeted by the drug.  SLAMF7, also known as CS1, is commonly found on the surface of myeloma cells.

Elotuzumab has shown en­cour­ag­ing ac­­tiv­ity in com­bi­na­tion with Revlimid and dex­a­meth­a­sone in a Phase 1b/2 study in re­lapsed / refractory mul­ti­ple myeloma patients (see re­lated Beacon ^[5] news).

The agent re­ceived a break­­through ther­apy desig­na­tion from the U.S. Food and Drug Admin­istra­tion (FDA) in May 2014 for use in com­bi­na­tion with Revlimid and dex­a­meth­a­sone for patients with mul­ti­ple myeloma fol­low­ing one or more prior ther­a­pies (see re­lated Beacon ^[6] news).

There are cur­rently no FDA-approved mono­clonal anti­bodies for the treat­ment of mul­ti­ple myeloma, although there are sev­er­al such agents being in­ves­ti­gated for the treat­ment of the dis­ease, in­clud­ing dara­tu­mu­mab ^[7], SAR650984 ^[8], and MOR202 ^[9].

Design of the ELOQUENT-2 Study

The open-label Phase 3 ELOQUENT-2 trial in­cluded 646 patients with re­lapsed / refractory mul­ti­ple myeloma with a median age of 66 years.

Patients had re­ceived a median of two prior ther­a­pies, in­clud­ing Velcade ^[10] (bor­tez­o­mib) (70 per­cent), tha­lid­o­mide (48 per­cent), and Revlimid (6 per­cent). Over­all, 35 per­cent of patients were resistant (refractory) to their most recent ther­apy. No patients, how­ever, were re­frac­tory to Revlimid, and only 6 per­cent of the patients in the study were pre­vi­ously treated with Revlimid.

Overall, 32 per­cent of patients had a 17p deletion and 9 per­cent had a t(4;14) translocation, which are con­sidered high-risk chromosomal ab­nor­mal­i­ties.

Patients were ran­dom­ized to re­ceive either Revlimid and dex­a­meth­a­sone alone, or Revlimid and dex­a­meth­a­sone in com­bi­na­tion with elotuzumab.

Elotuzumab was admin­istered in­tra­venously at 10 mg/kg weekly for the first two cycles and then biweekly there­after. In addi­tion, patients re­ceived 25 mg of Revlimid on days 1 to 21 of each 28-day treat­ment cycle plus 40 mg of oral dex­a­meth­a­sone weekly. For patients who re­ceived elotuzumab, dex­a­meth­a­sone was dosed at 28 mg orally plus 8 mg in­tra­venously in weeks that elotuzumab was admin­istered, and 40 mg per week other­wise. Treatment in both groups of patients was admin­istered until dis­ease pro­gres­sion or unacceptable toxicity.

The pri­mary out­come measures for the study were over­all re­sponse rate and pro­gres­sion-free sur­vival. Over­all sur­vival was a sec­ond­ary end­point.

The median follow-up time was two years.

Study Results

Efficacy: Re­sponse Rates and Survival

The re­­sults show that 79 per­cent of patients responded to the elotuzumab-Revlimid-dex­a­meth­a­sone com­bi­na­tion, com­pared to 66 per­cent of patients who re­ceived Revlimid and dex­a­meth­a­sone alone.

The median pro­gres­sion-free sur­vival was 19.4 months for patients who re­ceived the elotuzumab regi­men versus 14.9 months for patients who re­ceived Revlimid and dex­a­meth­a­sone alone.

The dif­fer­ence in pro­gres­sion-free sur­vival rates be­tween the two groups of patients in­creased with time after the start of treat­ment.

At one year after the start of treat­ment, the dif­fer­ence in the pro­gres­sion-free sur­vival rate was 11 per­cent (68 per­cent for patients re­ceiv­ing the elotuzumab com­bi­na­tion, com­pared to 57 per­cent for patients re­ceiv­ing Revlimid and dex­a­meth­a­sone alone).

At two years after the start of treat­ment, the dif­fer­ence in sur­vival rates was 14 per­cent (41 per­cent for patients re­ceiv­ing the elotuzumab com­bi­na­tion, com­pared to 27 per­cent for patients on Revlimid and dex­a­meth­a­sone alone).

The pro­gres­sion-free sur­vival ben­e­fit observed with elotuzumab in the over­all study pop­u­la­tion was also observed for patients with high-risk chromosomal ab­nor­mal­i­ties.

The trial has not yet been on­go­ing long enough to permit an accurate analysis of over­all sur­vival re­­sults. At this time, how­ever, 70 per­cent of the patients in the elotuzumab group are still alive, and 63 per­cent of the patients treated with Revlimid and dex­a­meth­a­sone are still alive.

Safety and Tolerability

According to trial in­ves­ti­ga­tors, the elotuzumab treat­ment regi­men was well tol­er­ated.

The most common severe side effects were blood cell count-related. They in­cluded neu­tro­penia (25 per­cent of patients re­ceiv­ing elotuzumab-Revlimid-dex­a­meth­a­sone versus 33 per­cent of patients re­ceiv­ing Revlimid-dex­a­meth­a­sone alone) and anemia (15 per­cent versus 16 per­cent).

Ten per­cent of patients re­ceiv­ing elotuzumab had in­fusion site reac­tions, the majority of which were mild in nature.

Five patients treated with the elotuzumab com­bi­na­tion, and six patients treated with Revlimid and dex­a­meth­a­sone, died during the study for reasons that could be the re­­sult of the treat­ment they re­ceived.

Among the patients treated with elotuzumab, Revlimid, and dex­a­meth­a­sone, the five deaths were due to in­fec­tions (2 patients) and single-patient instances of pul­mo­nary embolism, gastro­in­tes­ti­nal cancer, and myelo­dys­plastic syn­dromes. Among the patients treated with Revlimid and dex­a­meth­a­sone alone, the six deaths were due to in­fec­tion (5 patients) and pul­mo­nary embolism.

At the time the re­­sults were analyzed, 35 per­cent of patients re­ceiv­ing the elotuzumab com­bi­na­tion and 21 per­cent of patients re­ceiv­ing Revlimid and dex­a­meth­a­sone alone remained on ther­apy.

Disease pro­gres­sion was the pri­mary cause of treat­ment dis­con­tinu­a­tion. There was no sig­nif­i­cant dif­fer­ence be­tween the two groups of patients in the share of patients who halted treat­ment due to side effects or patient pref­er­ence.

Persistence of Survival Benefit: A Comparison

As mentioned earlier, a key as­pect of the ELOQUENT-2 trial re­­sults that has attracted attention is the persistence of elotuzumab’s sur­vival ben­e­fit over time.

This raises the question: Is the persistence “real,” in the sense that it is likely to be seen again and again whenever elotuzumab is used to treat patients like those in the ELOQUENT-2 trial?

Or is the persistence some­thing of a fluke – some­thing that is spe­cif­ic to the sample of patients in this trial, and not really rep­re­sentative of how elotuzumab is likely to per­form in widespread clin­i­cal prac­tice?

Addressing these questions re­quires some analyses that may be overly tech­ni­cal for some Beacon readers, who may wish to skip the rest of this article. Readers, on the other hand, who are par­tic­u­larly interested in the persistence issue, and are comfortable with the finer details of trial re­­sults, will probably wish to forge ahead.

To shed some light on the po­ten­tial persistence of an elotuzumab sur­vival ben­e­fit, The Beacon con­structed a comparison be­tween the re­­sults of the ELOQUENT-2 trial and those of a very similar trial – the ASPIRE study, which com­pared treat­ment of re­lapsed myeloma with Kyprolis ^[11] (car­filz­o­mib), Revlimid, and dex­a­meth­a­sone to treat­ment with Revlimid and dex­a­meth­a­sone alone.

Both the ELOQUENT-2 and ASPIRE trials were large Phase 3 inter­na­tional trials. There were nearly 800 patients, for example, en­rolled in the ASPIRE trial. Both trials in­cluded re­lapsed myeloma patients who had re­ceived one to three prior treat­ments, and the median num­ber of prior ther­a­pies – in both patient groups in both trials – was two.

In addi­tion, the dosing of Revlimid in both trials was the same, and the dosing of dex­a­meth­a­sone was nearly identical.

Thus, although tre­men­dous caution is always in order when com­par­ing re­­sults from dif­fer­en­t clin­i­cal trials, the ELOQUENT-2 and ASPIRE trials were de­signed so similarly that cer­tain high-level comparisons can be justified.

Figure 1 com­bines the pro­gres­sion-free sur­vival re­­sults from the ELOQUENT-2 trial with those from the ASPIRE trial.  The figure was con­structed by re-scaling graphs of the pro­gres­sion-free sur­vival re­­sults from both trials so that they have the same time and sur­vival scales.

In Figure 1, the sur­vival ben­e­fit of adding elotuzumab to Revlimid and dex­a­meth­a­sone is reflected in the gap at each point in time be­tween the “EloRd” curve and the “Rd” (ELOQUENT-2) curve.  The gap is larger at 24 months, for example, than it is at 12 months.

More spe­cif­i­cally, the gap initially grows until about 8 months after the start of treat­ment, is then con­stant until about 18 months, and after 18 months begins to widen fur­ther over time.

A comparison of the ELOQUENT-2 re­­sults with those from the ASPIRE trial sug­gests, how­ever, that the widening of the sur­vival gap in the elotuzumab trial may not be due to elotuzumab’s im­pact on patient pro­gres­sion-free sur­vival. Instead, it may be due to some­thing un­usual having hap­pened among the patients in the trial who were treated with just Revlimid and dex­a­meth­a­sone.

Note how the Rd curves from the two dif­fer­en­t trials move over time. The two curves either overlap or closely parallel one another up until about 18 months. After 18 months, the sur­vival curve for the Rd patients in the ELOQUENT-2 trial dips down in comparison to the Rd curve from the ASPIRE trial. The curves then grow fur­ther and fur­ther apart, almost until each curve ends.

If the Rd curve from the ELOQUENT trial had looked more like the Rd curve from the ASPIRE trial, there would have been less of a persistent gap be­tween the EloRd and Rd curves from the ELOQUENT-2 trial.

In other words, elotuzumab would have much less of a persistent pro­gres­sion-free sur­vival ben­e­fit com­pared to what one sees in the pub­lished ELOQUENT-2 re­­sults.

The kind of exercise just described is worth carrying out not just because the ASPIRE trial is very similar to the ELOQUENT-2 trial. It is also useful because the ASPIRE re­­sults are based on data from a larger num­ber of patients, and were calculated after a longer median follow-up time. Larger num­bers of trial par­tic­i­pants, and longer follow-up times, both lead to more precise sur­vival esti­mates.  (The median follow-up for the ASPIRE data was about 32 months, versus 24 months for the ELOQUENT-2 re­­sults).

Still, the comparison sketched in Figure 1 is just a first step to better under­stand­ing how much one can gen­er­al­ize from the ELOQUENT-2 re­­sults to what will hap­pen if elotuzumab is used reg­u­larly in clin­i­cal prac­tice. Myeloma re­searchers will have to analyze and compare the trial re­­sults more thoroughly to reach more definitive conclusions on that issue.

Additional In­for­ma­tion

The re­­sults of the ELOQUENT-2 trial were pub­lished in Lonial, S. et al., “Elotuzumab Therapy for Re­lapsed or Re­frac­tory Multiple Myeloma,” The New England Journal of Medicine, June 2, 2015 (full text of article and supple­ments ^[13]). Slides from the ASCO pre­sen­ta­tion summarizing the ELOQUENT-2 re­­sults can be viewed here ^[14] (PDF, courtesy of Dr. Lonial).

The re­­sults of the ASPIRE trial were pub­lished in Stewart, A.K. et al., “Carfilzomib, Lena­lido­mide, and Dexa­meth­a­sone for Re­lapsed Multiple Myeloma,” The New England Journal of Medicine, Jan­u­ary 8, 2015 (full text of article and supple­ments ^[15]). Slides from a pre­sen­ta­tion summarizing the ASPIRE re­­sults, given by Dr. A. Keith Stewart of the Mayo Clinic at the 2014 American Society of He­ma­tol­ogy annual meeting, can be viewed here ^[16] (PDF, courtesy of Dr. Stewart).