Randomized phase 3 study of elotuzumab for relapsed or refractory multiple myeloma: ELOQUENT-2 Japanese patient subanalysis

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Citation: Blood Cancer Journal (2017) 7, e540; doi:http://dx.doi.org/10.1038/bcj.2017.18

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LETTER TO THE EDITOR

Randomized phase 3 study of elotuzumab for relapsed or refractory multiple myeloma: ELOQUENT-2 Japanese patient subanalysis

Blood Cancer Journal (2017) 7, e540; doi:http://dx.doi.org/10.1038/bcj.2017.18

Web End =10.1038/bcj.2017.18 ; published online 10 March 2017

Elotuzumab is a humanized immunoglobulin G1 immunostimulatory monoclonal antibody targeted against signaling lymphocytic activation molecule F7 (SLAMF7).1 A phase 1 clinical study (NCT01241292) of elotuzumab in combination with lenalidomide and dexamethasone (ELd) in six patients with relapsed/refractory multiple myeloma (RRMM) was conducted in Japan. The study reported an acceptable safety and tolerability prole and an overall response rate of 83% (5/6).2 ELOQUENT-2 (NCT01239797) is a phase 3, international, randomized clinical trial that investigated the efcacy and safety of ELd compared with lenalidomide/dexamethasone (Ld) in patients with RRMM who had received one to three previous therapies.3 Patients were randomized 1:1 to ELd (n = 321) or Ld (n = 325). Asian patients comprised 10% (64/646) of the overall population, of which 94% (60/64) were enrolled from Japan.

We performed a subanalysis to assess the efcacy and safety of ELd in the Japanese population from ELOQUENT-2, to determine whether results are aligned with those from the global study population. Coprimary endpoints were progression-free survival and overall response rate, assessed by an independent review committee. Further details of the study design can be found in the Supplementary Methods. Sixty patients from Japan were enrolled between October 2011 and September 2012: 31 randomized to the ELd group and 29 to the Ld group (Supplementary Table S1). At the time of data cutoff (October 2014) with follow-up of 2 years, 17 patients were still on treatment (ELd, n = 12; Ld, n = 5). The most common reason for discontinuation was disease progression. Eighty-four percent (26/31) of ELd patients tolerated 90% of the planned elotuzumab dose. The median (95% condence interval (CI)) progression-free survival was 22.2 (17.5not estimated (NE)) months in the ELd group and 18.5 (11.121.2) months in the Ld group. The hazard ratio (HR) was 0.51 (95% CI: 0.251.06), representing a 49% reduction in the risk of disease progression or death in patients treated with ELd. The rate (95% CI) of progression-free survival in the ELd and Ld groups, respectively, was 74% (5586%) and 66% (4580%) at 1 year, and 48% (29 65%) and 18% (734%) at 2 years (Figure 1). There was no signicant difference in overall response rate (95% CI) between treatment groups: 84% (6695%) in the ELd group versus 86% (6896%) in the Ld group (stratied common odds ratio 0.68(0.162.90); Supplementary Table S2). A complete response or better was observed in four patients in the Ld group, but the rate of complete response or better in the ELd group may have been underestimated due to the interference of elotuzumab on serum protein electrophoresis and immunoxation assays.4

At the interim analysis of overall survival (October 2015), with follow-up of 3 years, 40% (24/60) of patients had died: 39% (12/31) in the ELd group and 41% (12/29) in the Ld group. Median overall survival was not reached. The interim HR (95% CI) for overall survival was 0.81 (0.351.87). One-year survival rates (95% CI) among ELd and Ld patients, respectively, were 100% (NENE) and 97% (78100%), 2-year survival rates were 90% (7397%) and 86%

(6794%), and 3-year survival rates were 68% (4881%) and 64% (4479%).

Although there are some limitations to this subpopulation analysisthe small sample and patient demographics, including the greater number of patients with high-risk cytogenetic proles del(17p) and t(4;14) in the Ld groupELd demonstrated efcacy in the Japanese cohort of ELOQUENT-2, similar to the high response rates and durable responses observed in the Japanese phase 1 study.2 Drug-related adverse events (AEs) of any grade were reported in 97% (30/31) of patients in the ELd group and 97% (28/29) in the Ld group (Supplementary Table S3). There were more non-hematological grade 3 or 4 AEs in the ELd group (94%) than in the Ld group (76%); the most common (15%) included cataract (ELd 19% and Ld 14%) and pneumonia (ELd 19% and Ld 3%). Hematological AEs were similar between the ELd and Ld groups, except for grade 3 or 4 lymphopenia, which was more frequent in the ELd group (Supplementary Table S3). Serious AEs, regardless of relationship to treatment, were reported for 81% of patients in the ELd group and 62% in the Ld group. The most common serious AEs (10% in any arm) were pneumonia and cataract (Supplementary Table S4). AEs leading to discontinuation of 1 study drug occurred in 16% of patients in the ELd group versus 14% in the Ld group. Grade 3 or 4 AEs led to discontinuation of elotuzumab in 16% of ELd patients, whereas grade 3 or 4 AEs led to discontinuation in 7% of Ld patients. The most frequently reported cause of death was disease progression; one death in the ELd group was caused by myelodysplastic syndrome. Second primary malignancies were reported in three patients in the ELd group, and included basal cell carcinoma, myelodysplastic syndrome and squamous cell carcinoma of skin. There were no second primary malignancies in the Ld group. The occurrence of second primary malignancies was generally consistent with previous studies with lenalidomide.57 Four

patients (13%) in the ELd group reported infusion reactions, which were pyrexia (four patients), asthenia (one patient), chills

0.0

1.0

0.9

0.8

1 year 2 years

74%

66%

48%

Probability Progression Free

0.7

0.6

0.5

0.4

0.3

0.1

18%

ELd (events: 16/31)

Ld (events: 23/29)

0.2

0 4

2 6 8 10 12 14

PFS (Months)

16 18 20 22 36

24 26 28 30 32 34

No. of patients at risk:ELd 31 31 29 27 27 25 21 21 20 17 15 14 12 10 5 5 1 1 0 Ld 29 28 26 24 22 21 19 16 16 14 12 8 5 5 4 3 2 0 0

Figure 1. PFS. Abbreviations: ELd, elotuzumab plus lenalidomide and dexamethasone; Ld, lenalidomide and dexamethasone; PFS, progression-free survival.

Letter to the Editor

2

Table 1. Summary of infections

Parameter ELd (n = 31) Ld (n = 29)

Infection-associated deaths 0 0 Infection (any grade) 25 (81) 23 (79) Infection (grades 34) 12 (39) 5 (17) Exposure-adjusted infections, per 100person-years

172.6 183.4

Discontinuation due to infection 2 (6) 0 Serious infections (any grade) 14 (45) 6 (21) Median time to onset of rst infection,months

3.4 3.7

Median duration of rst infection, days 15.0 9.0 Pneumonia 9 (29) 2 (7) Exposure-adjusted pneumonia, per 100person-years

16.7 4.5

Abbreviations: ELd, elotuzumab plus lenalidomide and dexamethasone; Ld, lenalidomide and dexamethasone. Data reported as n (%) unless indicated otherwise.

(one patient) and headache (one patient). All were grade 1 and none led to discontinuation of study medication.

Infections occurred in 81% (25/31) of the ELd group and 79% (23/29) of the Ld group (Table 1). There were no infection-related deaths. Pneumonia was reported in 29% (9/31) of the ELd group compared with 7% (2/29) of the Ld group. Patients with pneumonia in the ELd group were 5779 years old and experienced grade 2 or 3 pneumonia with onset ranging from study days 10 to 870, 427 days from the last dose of elotuzumab, with a duration of 731 days. The two patients with pneumonia in the Ld group were 47 and 78 years old, respectively, and experienced grades 2 and 3 pneumonia with onset on study days 155 and 173, with a duration of 22 and 6 days. Although the limited numbers in this analysis make interpretation of this nding difcult, there were no specic factors (for example, patient age, study day or persistence of the infection) associated with pneumonia in patients enrolled from Japan. All cases of pneumonia were reported as serious AEs, but were manageable and resolved by elotuzumab omission or treatment with antibiotics. No patients discontinued elotuzumab due to pneumonia.

In conclusion, Japanese patients treated with ELd experienced prolonged progression-free survival, consistent with the international ELOQUENT-2 population, with a similar overall response rate to the international ELd treatment group.3 AEs were manageable and the safety prole was similar to the global study. Although median overall survival has not been reached, preliminary evaluation suggests a benet with elotuzumab. These results suggest that elotuzumab is a feasible new treatment option in Japanese patients with RRMM, with potential to provide durable responses.

CONFLICT OF INTEREST

KSuz has received personal fees from Celgene, Janssen Pharmaceutical, Takeda and Novartis. KSun has received research funding from Ono Pharmaceutical Co. Ltd., Takeda, Celgene K.K., Novartis Pharma K.K., Bristol-Myers Squibb K.K., Daiichi Sankyo Co. Ltd., Sano K.K. and Janssen Pharmaceutical K.K., and lecture honoraria from Celgene K.K. KO has nothing to declare. SI has received research funding from Kyowa Hakko Kirin, Chugai, Takeda, Celgene, Ono Pharmaceutical Co. Ltd., Eli Lilly, Sano, Novartis, Teijin, Astellas, Toyama Chemical, Janssen Pharmaceutical and Bristol-Myers Squibb KK, and Bristol-Myers Squibb K.K. and honoraria from Celgene, Janssen, Ono Pharmaceutical Co. Ltd., Takeda and Bristol-Myers Squibb K.K. TM has received honoraria for lectures from Janssen Pharmaceutical, Celgene, Kyowa Hakko Kirin, Astellas and Chugai Pharmaceuticals, and research funding from Novartis. HH has received research funding from Bristol-Myers Squibb K.K., Kyowa Hakko Kirin, Nihon Shinyaku and Toyama Kagaku. KM has received honoraria from Celgene. MMiy is an employee of Bristol-Myers Squibb K.K. EB is an employee of Bristol-Myers Squibb. MMat has received honoraria from Janssen Pharmaceutical and Celgene. MMat has

received research funding from Celgene, Bristol-Myers Squibb K.K. Kyowa Hakko Kirin, Chugai Pharma and Janssen Pharmaceutical.

ACKNOWLEDGEMENTS

This study was funded by Bristol-Myers Squibb. Professional medical writing assistance was provided by Kate Rees, PhD, at Caudex and funded by Bristol-Myers Squibb K.K.

K Suzuki1, K Sunami2, K Ohashi3, S Iida4, T Mori5, H Handa6, K Matsue7, M Miyoshi8, E Bleickardt9, M Matsumoto10 and

M Taniwaki11

1Department of Hematology, Japanese Red Cross Medical Center, Tokyo, Japan;

2Department of Hematology, National Hospital Organization Okayama Medical Center, Okayama, Japan;

3Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan;

4Department of Hematology and Oncology, Nagoya City University Hospital, Nagoya, Japan;

5Division of Hematology, Department of Medicine, Keio University School of Medicine, Tokyo, Japan;

6Integrative Center of Internal Medicine, Division of Hematology, Gunma University Hospital, Gunma, Japan;

7Department of Internal Medicine, Kameda Medical Center, Kamogawa, Japan;

8Bristol-Myers Squibb K.K, Tokyo, Japan;

9Oncology Clinical Development, Bristol-Myers Squibb, Princeton, NJ, USA;

10Department of Hematology, National Hospital Organisation, Shibukawa Medical Center, Shibukawa, Japan and

11Department of Hematology, University Hospital, Kyoto Prefectural University of Medicine, Kyoto, Japan E-mail: mailto:[email protected]

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