The above Phase I results were encouraging- and elotuzumab-based combination therapy proceeded into Phase II trials. In a Phase II study, 73 patients with RRMM were enrolled (median age 63 years; range 39–82) and treated with elotuzumab 10 mg/kg, n=36 or 20 mg/kg, n=27 plus lenalidomide and low-dose dexamethasone. The ORR was 84% (10 mg/kg group was 92% and 20 mg/kg group was 76%); the median PFS was 29 months (10 mg/kg group was 32 months and 20 mg/kg group was 25 months).37 Owing to the safety and excellent efficacy at a lower dose, 10 mg/kg of elotuzumab was selected as the dosage for the Phase III trials, ELOQUENT-1 and ELOQUENT-2.38
The ongoing Phase III ELOQUENT-1 trial is a randomized, open-label study comparing lenalidomide/low-dose dexamethasone alone or in combination with elotuzumab in newly diagnosed MM. The primary end point is PFS and secondary end points include ORR and OS. This trial started in May 2011, and the estimated enrollment is 750 patients and the estimated study completion date will be July 2019 (ClinicalTrials.gov Identifier: NCT01335399).
The ongoing Phase III ELOQUENT-2 trial is a randomized, open-label study to assess whether the addition of elotuzumab to lenalidomide/low-dose dexamethasone will increase the PFS in patients with RRMM. Patients with RRMM were randomized to the control arm (lenalidomide/dexamethasone alone) and the elotuzumab arm (elotuzumab-lenalidomide/dexamethassone) (ClinicalTrials.gov Identifier: NCT01239797). The interim analysis of ELOQUENT-2 published in 2015, noted a total of 646 patients, with median age of 66 years, 32% with high-risk 17p deletion, 9% with t(4;14), were randomized to the elotuzumab group (n=321) and the control group (n=325). Patients had previously received one to three lines of therapy involving bortezomib (70%), ASCT (55%), melphalan (65%), thalidomide (48%) and lenalidomide (6%).38
Patients received 28-day cycles of lenalidomide 25 mg orally (days 1–21) and dexamethasone 40 mg weekly with or without elotuzumab 10 mg/kg IV (days 1, 8, 15 and 22 in the first two cycles and days 1 and 15 from cycle 3). Therapy was administered until disease progression or unacceptable toxicity. The median PFS was 19.4 months in elotuzumab group and 14.9 months in control group (HR, 0.70; 95% CI=0.57–0.85; p=0.004). The 3-year PFS rate was 26% with elotuzumab group versus 18% with the control group (HR 0.73; 95% CI=0.60–0.89; p=0.0014).39 ORR in elotuzumab group (79%) was significantly higher than control group (66%), p=0.002.38
ELOQUENT-3 is an open-label, Phase II trial, in which patients with RRMM are randomized to the control arm (pomalidomide/dexamethasone) or the elotuzumab arm (elotuzumab/pomalidomide/dexamethasone). It is, currently, recruiting participants and the estimated enrollment is 121 patients and the estimated study completion date is March 2019 (ClinicalTrials.gov Identifier: NCT02654132).
Mateos et al conducted a Phase II study evaluating the safety and tolerability of elotuzumab 10 mg/kg combined with thalidomide 50–200 mg and dexamethasone 40 mg (with/without cyclophosphamide 50 mg) (ClinicalTrials.gov Identifier: NCT01632150). Forty patients were enrolled having received a median of three previous regimens, including bortezomib (98%) and lenalidomide (73%). Patients received 28-day cycles and continued until disease progression or unacceptable toxicity. Thalidomide was administered 50 mg orally for the first 2 weeks, escalated to 100 mg for the next 2 weeks and beginning with cycle 2–200 mg, once daily. Elotuzumab (10 mg/kg) was administered as an IV weekly for the first two cycles and beginning with cycle 3. Dexamethasone was administered 40 mg orally weekly on those weeks when elotuzumab was not administered and 28 mg orally plus 8 mg IV on elotuzumab dosing weeks. The patients who did not have a partial response or better by the end of cycle 4 also received cyclophosphamide (50 mg).
Those patients did not have a partial response or better by the end of cycle 4 also received cyclophosphamide, 50 mg. The ORR was 38%; the median PFS was 3.9 months; the median OS was 16.3 months and 1-year OS rate was 63%. The addition of elotuzumab to thalidomide and dexamethasone with or without cyclophosphamide resulted in minimal incremental toxicity; suggesting that elotuzumab is well tolerated in combination regimens used to treat RRMM.40
The proof-of-concept, randomized, open-label, Phase II study investigated the efficacy and safety of elotuzumab plus bortezomib/dexamethasone (EBd) and bortezomib/dexamethasone (Bd) in patients with RRMM. A total of 152 patients (median age 66 years) with RRMM who had received one to three prior therapies were randomized to either EBd (n=77) or Bd group (n=75). EBd and Bd were administered until disease progression or unacceptable toxicity occurred. The results of EBd group and Bd group are as follows, the ORR: 66% versus 63%; the 1-year PFS: 39% versus 33%; the 2-year PFS: 18% versus 11% and the median PFS: 9.7 months versus 6.9 months, the OS: 51% versus 47%, respectively. EBd-treated patients homozygous for the high-affinity FcγRIIIa V allele (13 patients) had higher PFS than EBd-treated patients homozygous for the low-affinity FcγRIIIa F allele (24 patients), 22.3 months versus 9.8 months, respectively. Comparing the EBd group and Bd group, elotuzumab improved clinical benefit with limited added toxicity in patients with RRMM (ClinicalTrials.gov Identifier: NCT021478048).41 Major clinical trials of elotuzumab are listed in Table 1. As shown in Table 1, the clinical development path of elotuzumab received a breakthrough therapy designation and quickly approved under FDA’s priority review process for therapeutic use in combination with lenalidomide and dexamethasone for patients with MM who have received from one to three prior therapies.
(To view a larger version of Table 1, click here.)