Title of the presentation Subtitle of the presentation

Interim analysis of prospective observational study on the efficacy of nivolumab for Japanese advanced melanoma patients (CREATIVE study)

Naoya Yamazaki¹, Akira Takahashi¹, Kenjiro Namikawa¹, Tatsuya Takenouchi², Yasuhiro Nakamura³, Shigehisa Kitano⁴, Tomonobu Fujita⁵, Kazumi Kubota⁶, Takeharu Yamanaka⁶, Yutaka Kawakami⁵;

¹Department of Dermatologic Oncology, National Cancer Center Hospital, Tokyo, JP,² Department of Dermatology, Niigata Cancer Center, Niigata, JP, ³Department of Skin Oncology/Dermatology, Saitama Medical University International Medical Center, Saitama, JP, ⁴Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, JP, ⁵Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, JP, ⁶Department of Biostatistics and Epidemiology, Yokohama City University School of Medicine, Yokohama, JP

24/November/2019

DISCLOSURE INFORMATION

Naoya Yamazaki

Speaker’s bureau : ONO, BMS, MSD, Novartis

• Recent progress and better understanding of cancer immunity led to the development of anti-PD-1 antibody, which is directed against the negative immunoregulatory cell surface receptor PD-1.

• Anti-PD-1 antibody nivolumab has been approved for advanced melanoma in Japan.

• The incidence rate of each clinical subtype and the status of BRAF mutation are different between Caucasians and Asians.

• Although there have been clinical trial reports on nivolumab treatment for advanced melanoma, the real-world data for nivolumab efficacy and immune-related adverse effects in Asian patients are still lacking.

BACKGROUND

Interim analysis of prospective observational study on the efficacy of

nivolumab for Japanese advanced melanoma patients (CREATIVE study) The aim of this study is to obtain post-marketing data for the efficacy of nivolumab in Japanese advanced melanoma patients.

OBJECTIVE

METHODS

• This prospective observational study was performed on unresectable or metastatic melanoma patients.

• The patients were treated with nivolumab at a dose of 2mg/kg every 3weeks or 3mg/kg were 2weeks.

• Primary endpoints are response rate (RR) and overall survival (OS).

• Secondary endpoints are progression-free survival (PFS) and selection of factors predictive of treatment response after administration of nivolumab.

Interim analysis of prospective observational study on the efficacy of

nivolumab for Japanese advanced melanoma patients (CREATIVE study) No. of Patients 124

Sex

Male 72 (58.4%)

Female 52 (41.6%)

Age (year)

Mean 65.9

Range 35-88

Clinical subtype

NM 19 (15.2%)

SSM 16 (12.8%)

LMM 3 (2.4%)

ALM 25 (20.0%)

Mucosal 42 (33.9%)

Unclassified・Others 19 (15.3%)

Stage (AJCC-TNM 7th)

III 12 (9.7%)

IV 110 (88.7%)

Others 2 (1.6%)

Radiation

No 85 (68.9%)

Yes 39 (31.5%)

PATIENT CHARACTERISTICS

Best response RECIST

(N=124) irRECIST (N=121)

CR 3 (2.4%) 2 (1.7%)

PR 19 (15.3%) 20 (16.5%)

SD 29 (23.4%) 27 (21.8%)

PD 58 (46.8%) 50 (41.3%)

NE 165(12.1%) 12 (9.9%)

CR+PR (ORR) 22 (17.6%) 22 (18.2%)

DCR 571(41.1%) 49 (40.5%)

BEST RESPONSE （RECIST and irRECIST)IN ALL PATIENTS

BEST RESPONSE(WITH irAE)

Group N

CR N (%)

PR N (%)

SD N (%)

PD N (%)

NE N (%)

N[%(95%CI)]

All 124

3(2.4%)

19(15.3%)

29(23.4%)

58(46.8%)

15(12.1%)

22[17.7%(11.5-25.6)]

Immune-related Adverse Effect

N 67 0(0.0%) 3(4.5%) 14(20.9%) 35(52.2%) 15(22.4%) 3[4.5%(0.9-12.5)]

(irAE） Y 57 3(5.3%) 16(28.1%) 15(26.3%) 23(40.4%) 0(0.0%) 19[33.3%(21.4-47.1)]

Hyperthyroidism 8 2(25.0%) 0(0.0%) 2(25.0%) 4(50.0%) 0(0.0%) 2[25.0%(3.2-65.1)]

Hypothyroidism 13 1(7.7%) 5(38.5%) 5(38.5%) 2(15.4%) 0(0.0%) 6[46.2%(19.2-74.9)]

Hypophysitis 3 0(0.0%) 1(33.3%) 1(33.3%) 1(33.3%) 0(0.0%) 1[33.3%(0.8-90.6)]

Leukoplakia 14 1(7.1%) 7(50.0%) 4(28.6%) 2(14.3%) 0(0.0%) 8[57.1%(28.9-82.3)]

Skin lesion 22 1(4.5%) 10(45.5%) 3(13.6%) 8(36.4%) 0(0.0%) 11[50.0%(28.2-71.8)]

OVERALL SURVIVAL IN ALL PATIENTS

Group N 1yearOS (95%CI)

Median survival (95%CI)

Logrank

p-value All 124 0.66(0.56 - 0.73) 15.93(14.82-20.04)

Sex M 72 0.60(0.48 - 0.71) 15.34(8.77-22.24) 0.469

F 52 0.73(0.58 - 0.84) 17.45(13.70-20.67)

Age 65≦ 79 0.64(0.52 - 0.74) 15.64(14.82-22.24) 0.911

＜65 45 0.69(0.53 - 0.80) 15.93(13.01-20.67)

PS 0 79 0.82(0.71 - 0.89) 18.89(15.34-24.34) <0.001

1, 2 45 0.36(0.21 - 0.50) 6.64(2.73-15.28)

BRAF(PRE) Wild 93 0.67(0.56 - 0.75) 15.64(13.70-18.89) 0.352

Mut 20 0.47(0.24 - 0.68) 9.53(2.66-31.11)

logrank p-value

SSM LMN ALM Mucosal

Clinical subtype NM 19 0.56(0.31 - 0.75) 13.70(5.82-27.73) 0.072 1.911 1.360 0.085

SSM 16 0.48(0.22 - 0.70) 9.53(2.99-20.34) - 3.255 2.053 0.006

LMN 3 1.00(1.00 - 1.00) miss(miss-miss) - - 0.067 2.304

ALM 25 0.76(0.54 - 0.88) 17.45(13.11-25.76) - - - 1.525

Mucosal 42 0.67(0.50 - 0.79) 15.64(11.89-18.50)

Brain meta N 110 0.69(0.59 - 0.77) 15.93(14.82-20.04) 0.272

Y 14 0.43(0.18 - 0.66) 8.30(2.10-27.73)

OVER ALL SURVIVAL

median survival 1year OS

N (95%CI) (95%CI) 124 15.93(14.82-20.04) 0.66(0.56-0.73)

OS ratio PFS ratio

Progression-Free SURVIVAL

Progression Free Survival : CLINICAL SUBTYPE

PFS ratio

ENDOCRINE RELATED irAE AND PFS (HYPERTHYROIDISM, HYPOTHYROIDISM, AND HYPOPHYSITIS)

PFS ratio N 1year PFS(95%CI) Median survival(95%CI)

NO 67 0.04(0.01 - 0.11) 2.14(1.87-2.50)

YES 24 0.33(0.16 - 0.52) 6.75(3.19-28.78)

Logrank p= <0.001

RESULTS

• This interim analysis for the real-world use of nivolumab showed lower RR(18%)and PFS(2.6months)than that in the phase III randomized trials (RR:40-44%, median PFS: 5.1 months) reported from Western counties.

• Subgroup analysis according to the clinical subtype indicated that the

best response was 19% in mucosal melanoma patients and 16% in acral melanoma patients.

The best response was low, regardless of clinical type of melanoma, and there are no differences in PFS among these subgroup of patients divided by clinical subtype of melanoma. • Patients with irAE showed higher response rate(33.4% vs 4.5%) and

Patients with endocrine-related AE had significantly higher PFS than those without.(median survival 6.75m vs 2.14m)

CONCLUSIONS

• The difference from Western countries in proportion of clinical subtypes will lead to lower anti-tumor efficacy to nivolumab in Japan.

• Response rate and PFS in patients with immune-lerated adverse effects were significantly higher than that of non-irAE patients.

• In consideration of side effects of nivolumab monotherapy, it will be necessary to evaluate the combination of molecular target therapy with single dose of nivolumab.

ACKNOWLEGMENTS

This study was coordinated by Public Health Research Foundation with funding from Ono Pharmaceutical Co., Ltd. and Bristol-Myers Squibb.