Revolution in der adjuvanten Therapie des Melanoms? Was bleibt? Was wird sich verändern?

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1 Revolution in der adjuvanten Therapie des Melanoms? Was bleibt? Was wird sich verändern? Dr. Peter Mohr, Elbeklinikum Buxtehude Hautkrebszentrum Oktober 217

2 Approved treatments for melanoma in the adjuvant setting 1-4 Interferon alfa-2b Dec 1995 Peginterferon alfa-2b Mar 211 Ipilimumab Oct Interferon alfa-2b Jun 1997 Interferon alfa-2a Jun 1999 Compared with rapid advancements in the treatment of metastatic melanoma, few therapies have been approved for melanoma in the adjuvant setting in the last decade 1. Available at: Accessed 11 September 217; 2. Available at: Accessed 11 September Accessed 3 Oct Accessed 3 Oct

3 Adjuvant trials leading to regulatory approval in the U.S. Study Stage N Treatment Regimen E1684 T4, N+ 287 HD-IFN vs observation E169 T4, N+ 642 E1694 T4, N+ 88 EORTC EORTC 1871 N1, N1,2,3 951 HD-IFN or LD-IFN vs observation HD-IFN vs GMK vaccine Pegylated IFN vs observation Ipilimumab 1 mg/kg vs placebo Follow-up Median, yr RFS (HR) OS (HR) HD-IFN: IFN-a2b 2 MU/m 2 /day IV for 1 month then 1 MU/m 2 SC TIW for 11 months. Pegylated IFN-a: pifn-a2b 6 mg/kg/week SC for 8 weeks then 3 mg/kg/week for 5 years. EORTC 1871: Ipilimumab 1 mg/kg IV every 21 days 4 then every 12 weeks for 3 years. Tarhini AA, et al. J Clin Oncol. 217;35:(suppl; abstr 95). 3

4 Use of Adjuvant Interferon Therapy in the USA (22-1) Treatment Stage IIB (n=125) % Stage IIC (n=68) % Stage III (n=196) % Stage IV- NED (n=28) % No treatment Other treatment IFN treatment Micheal Atkins ASCO 216 Micheal Atkins ASCO 216

5 Use of Adjuvant Interferon Therapy in the USA (22-1) Treatment Stage IIB (n=125) % Stage IIC (n=68) % Stage III (n=196) % Stage IV- NED (n=28) % No treatment New unpublished data suggest: Other treatment IFN treatment Only 3% of patients in stage III get adjuvant therapy Micheal Atkins ASCO 216 Micheal Atkins ASCO 216; personal communication Peter Mohr, MD

6 Treatment patterns Stage IIIB/IIIC melanoma in France, Germany and the United Kingdom (MELABIS) (29-11) Treatment France (n=199) % Germany (n=146) % United Kingdom (n=195) % Overall (n=588) % No treatment Other Treatment High-dose IFN Intermediate IFN Low-dose IFN Pegylated-IFN Harries M, Mohr P, Grange F, et al. Int J Clin Pract. 217 May 71(5)

7 Benefits of Adjuvant Interferon in Meta Analysis Overall Risk Dose Event Free Survival Overall Survival High (N=1196).83 ( ).93 (.8-1.8) Peg-IFN (N=1256).83 (.76-1.).96 ( ) Intermediate (N=2243).84 ( ).91 ( ) Low (N=2732).85 ( ).86 ( ) Very low (N=484).99 ( ).96 ( ) Overall (95%CI).86 ( ).9 ( ) Natalie et al. European Journal of Cancer 82 (217) 171e183

8 Immunotherapies Small Molecule Therapies Key melanoma data highlighting recent developments in the adjuvant setting COMBI-AD (phase 3) adjuvant dabrafenib + trametinib vs placebo Primary analysis BRIM8 (phase 3) adjuvant vemurafenib vs placebo Primary analysis OCT ESMO 216 JUN ASCO 217 OCT ESMO 217 EORTC 1871 (phase 3) adjuvant ipilimumab vs placebo Intergroup E169 (phase 3) adjuvant ipilimumab (3 or 1 mg/kg) vs. high-dose IFN α-2b CheckMate 238 (phase 3) adjuvant nivolumab vs ipilimumab Final OS Preliminary safety and efficacy Primary analysis Clinicaltrials.gov EORTC 1871: NCT636168; Intergroup E169: NCT ; COMBI-AD: NCT168283; BRIM8: NCT ; CheckMate 238: NCT

9 Agenda 1. EORTC 1871: Adjuvant ipilimumab vs placebo 2. COMBI-AD:)Adjuvant dabrafenib + trametinib vs placebo 3. BRIM8: Adjuvant vemurafenib vs placebo 4. CheckMate 238: Adjuvant nivolumab vs ipilimumab 1

10 EORTC 1871: Adjuvant ipilimumab vs placebo

11 EORTC 1871: phase 3 study design 1,2 N = 951 Randomized, double-blind, phase 3 study Key eligibility criteria Stage IIIA, IIIB, or IIIC melanoma metastatic to lymph node Complete and adequate resection of stage III melanoma No prior systemic therapy Stratified by: Stage (IIIA vs IIB vs IIIC 1-3 positive lymph nodes vs IIIC 4 positive lymph nodes) Region of the world R A N D O M I Z A T I O N 1:1 INDUCTION Ipilimumab 1 mg/kg Q3W 4 (n = 475) Q3W 4 (n = 476) Wk 1 Wk 12 Wk 24 MAINTENANCE Ipilimumab 1 mg/kg Q12W up to 3 years Q12W up to 3 years Treat up to a maximum of 3 years or until disease progression, intolerable toxicity, or withdrawal Primary endpoint RFS Secondary endpoints OS, DMFS, safety, HRQOL DMFS, distant metastasis-free survival; HRQOL, health-related quality of life; OS, overall survival; PFS, progression-free survival; Q3W, every 3 weeks; Q12W, every 12 weeks; RFS, relapse-free survival. 1. Eggermont AM, et al. J Clin Oncol 214;32:5s(suppl; abstr LBA98); 2. Eggermont A, et al. ESMO. 216;[abstr LBA2_PR]. 12

12 Patients Alive and Without Recurrence, % EORTC 1871: RFS 1,2 Ipilimumab Events/patients 264/ /476 HR (95%CI) a.76 (.64,.89) Log-rank P value a.8 Median RFS, months (95% CI) 27.6 (19.3, 37.2) 17.1 (13.6, 21.6) % 2 35% 2 41% 3% O N Number of patients at Risk Years Ipilimumab a Stratified by stage provided at randomization. CI, confidence interval. 1. Eggermont A, et al. ESMO. 216;[abstr LBA2_PR]; 2. Eggermont AM, et al. Lancet Oncol. 215;16:

13 Patients Alive and without Distant Metastasis, % EORTC 1871: DMFS Ipilimumab Events/patients 227/ /476 HR (95%CI) a.76 (.64,.92) Log-rank P value a.2 Median RFS, months (95% CI) 48% 39% 48.3 (35.5, 71.6) 27.5 (21.9, 34.8) O N Number of patients at Risk Years Ipilimumab a Stratified by stage provided at randomization. Eggermont A, et al. ESMO. 216;[abstr LBA2_PR]. 14

14 Patients Alive, % EORTC 1871: OS Ipilimumab Deaths/patients 162/ /476 HR (95%CI) a.72 (.58,.88) Log-rank P value a.1 65% 54% O N Number of patients at Risk Years Ipilimumab a Stratified by stage provided at randomization. Eggermont A, et al. ESMO. 216;[abstr LBA2_PR]. 15

15 EORTC 1871: Post-relapse therapies Patients With an RFS Event Post-relapse Therapy, % a Ipilimumab (n = 264) (n = 323) Any antitumoral therapy Chemotherapy Radiotherapy Surgery Chemoradiotherapy Other Ipilimumab Anti PD-1 agent BRAF inhibitor a Patients could receive more than 1 subsequent antitumoral therapy. Eggermont A, et al. ESMO. 216;[abstr LBA2_PR]. 16

16 EORTC 1871: safety summary Ipilimumab (n = 471) (n = 474) Any grade Grade 3/4 Any grade Grade 3/4 Any AE, % Treatment-related AE, % Treatment-related AE leading to discontinuation, % Any immune-related AE, % No new deaths due to drug-related AEs compared with the primary analysis 5 patients (1.1%) in the ipilimumab group 3 patients with colitis (2 with gastrointestinal perforations) 1 patient with myocarditis 1 patient had multiorgan failure with Guillain-Barré syndrome No deaths related to study drug in the placebo group Eggermont A, et al. ESMO. 216;[abstr LBA2_PR]. 17

17 COMBI-AD:) Adjuvant dabrafenib + trametinib vs placebo

18 COMBI-AD: phase 3 study design N = 87 Treatment: 12 months a Key eligibility criteria Completely resected, high-risk stage IIIA (lymph node metastasis > 1 mm), IIIB, or IIIC cutaneous melanoma BRAF V6E/K mutation Surgically free of disease 12 weeks before randomization ECOG performance status or 1 No prior radiotherapy or systemic therapy R A N D O M I Z A T I O N 1:1 Dabrafenib 15 mg BID + trametinib 2 mg QD (n = 438) 2 matched placebos (n = 432) Follow-up b until end of study c Stratification BRAF mutation status (V6E, V6K) Disease stage (IIIA, IIIB, IIIC) Primary endpoint: RFS d Secondary endpoints: OS, DMFS, FFR, safety BID, twice daily; DMFS, distant metastasis-free survival; ECOG, Eastern Cooperative Oncology Group; FFR, freedom from relapse; OS, overall survival; QD, once daily; RFS, relapse-free survival. a Or until disease recurrence, death, unacceptable toxicity, or withdrawal of consent; b Patients were followed for disease recurrence until the first recurrence and thereafter for survival; c The study will be considered complete and final OS analysis will occur when 7% of randomized patients have died or are lost to follow-up; d New primary melanoma. considered as an event. Hauschild A, ESMO. 217;[abstr LBA6_PR]. 19

19 COMBI-AD: study analyses and endpoints Efficacy analyses included all patients (intent-to-treat population), and safety analyses included all patients who received 1 dose of randomized treatment (safety population) OS was to be tested only if the primary endpoint (RFS) significantly favored the combination arm OS statistical significance boundary (O Brien-Fleming) for first interim analysis, P =.19 All recurrence analyses were based on investigator assessment and defined as follows: RFS: time from randomization to disease recurrence or death from any cause Study was designed to provide > 9% power (assuming 41 RFS events observed) to detect an HR of.71 with an overall 2-sided type I error rate of 5% DMFS: time from randomization to date of first distant metastasis or death, whichever occurred first FFR: time from randomization to recurrence, with censoring of patients dying from causes other than melanoma or treatment-related toxicity HR, hazard ratio. Hauschild A, ESMO. 217;[abstr LBA6_PR]. 2

20 COMBI-AD: baseline characteristics and demographics Category a Dabrafenib Plus Trametinib (n = 438) (n = 432) Total (N = 87) Median age (range), years 5 (18-89) 51 (2-85) 5 (18-89) Male, n (%) 195 (45) 193 (45) 388 (45) BRAF mutation status, n (%) V6E 397 (91) V6K b 41 (9) 395 (91) 37 (9) 792 (91) 78 (9) ECOG performance status of, n (%) 42 (92) 39 (9) 792 (91) Disease stage, n (%) IIIA IIIB IIIC III (unspecified) 83 (19) 169 (39) 181 (41) 5 (1) 71 (16) 187 (43) 166 (38) 8 (2) 154 (18) 356 (41) 347 (4) 13 (1) a Reported for patients with available data. b One patient had both BRAF V6E and BRAF V6K mutations and was included in the V6K subset. Hauschild A, ESMO. 217;[abstr LBA6_PR]. 21

21 COMBI-AD: baseline characteristics and demographics (cont) Category a Dabrafenib Plus Trametinib (n = 438) (n = 432) Total (N = 87) Number of positive lymph nodes, n (%) 1 2 or (4) 158 (36) 73 (17) 183 (42) 15 (35) 72 (17) 36 (41) 38 (35) 145 (17) Type of lymph node involvement, n (%) Microscopic Macroscopic Not reported 152 (35) 158 (36) 128 (29) 157 (36) 161 (37) 114 (26) 39 (36) 319 (37) 242 (28) Primary tumour ulceration, n (%) Yes No 179 (41) 253 (58) 177 (41) 249 (58) 356 (41) 52 (58) In-transit disease, n (%) Yes No 51 (12) 387 (88) 36 (8) 395 (91) 87 (1) 782 (9) a Reported for patients with available data. Hauschild A, ESMO. 217;[abstr LBA6_PR]. 22

22 Proportion Alive and Relapse Free COMBI-AD: RFS y, 88% y, 67% P = y, 56% 3 y, 58% y, 44% 3 y, 39%.2.1. Group Events, n (%) Median (95% CI), mo Dabrafenib 166 (38) plus trametinib NR (44.5-NR) 248 (57) 16.6 ( ) HR (95% CI).47 ( ); P <.1 No. at Risk Dabrafenib plus trametinib Months From Randomization Hauschild A, ESMO. 217;[abstr LBA6_PR]. 24

23 COMBI-AD: RFS by subgroup V6K (n = 78) V6E (n = 792) Male (n = 482) Female (n = 388) < 65 years (n = 712) 65 years (n = 158) Disease stage IIIA (n = 154) Disease stage IIIB (n = 356) Disease stage IIIC (n = 347) Micrometastasis (n = 39) Macrometastasis (n = 319) Micrometastasis and ulceration (n = 143) Micrometastasis and no ulceration (n = 165) Macrometastasis and ulceration (n = 116) Macrometastasis and no ulceration (n = 21) 1 Nodal metastatic mass (n = 36) 2 3 Nodal metastatic masses (n = 38) 4 Nodal metastatic masses (n = 145) HR Hauschild A, ESMO. 217;[abstr LBA6_PR]. Favors Dabrafenib Plus Trametinib Favors 25

24 Proportion Alive and Distant Metastasis Free COMBI-AD: DMFS y, 91% y, 7% 2 y, 77% 2 y, 6% 3 y, 71% 3 y, 57% Events, Group n (%) Dabrafenib plus 11 (25) trametinib 152 (35) Median (95% CI), mo NR (NR-NR) NR (41.2-NR) HR (95% CI).51 (.4-.65); nominal P <.1 No. at Risk Dabrafenib plus trametinib Months From Randomization Hauschild A, ESMO. 217;[abstr LBA6_PR]. 27

25 Proportion Alive COMBI-AD: OS (first interim analysis) y, 97% 1 y, 94% 2 y, 91% 3 y, 86% y, 83% 3 y, 77% Events, Group n (%) Dabrafenib plus 6 (14) trametinib 93 (22) Median (95% CI), mo NR (NR-NR) NR (NR-NR) HR (95% CI).57 ( ); P =.6 No. at Risk Dabrafenib plus trametinib Months From Randomization Hauschild A, ESMO. 217;[abstr LBA6_PR]. 28

26 COMBI-AD: post-recurrence therapy among patients with relapse Post-recurrence Therapy (relapsed patients) Dabrafenib Plus Trametinib (n = 163) (n = 247) Any post-recurrence anticancer therapy, n (%) 148 (91) 217 (88) Surgery 78 (48) 131 (53) Radiotherapy 6 (37) 72 (29) Any systemic post-recurrence anticancer therapy, n (%) 12 (74) 183 (74) Small molecule targeted therapy Any BRAF inhibitor a Any MEK inhibitor b Immunotherapy Anti PD-1/PD-L1 Anti CTLA-4 Interferon T-VEC 63 (39) 63 (39) 47 (29) 89 (55) 71 (44) 53 (33) 6 (4) 137 (55) 137 (55) 77 (31) 13 (42) 68 (28) 68 (28) 11 (4) 1 (< 1) Biologic therapy 1 (1) 1 (< 1) Chemotherapy 2 (12) 23 (9) Investigational treatment 6 (4) 19 (8) Other therapy 2 (1) Median time from disease recurrence to start of systemic postrecurrence therapy, excluding radiotherapy and surgery (range), weeks 7.1 (-136) 7.3 (-78) CTLA-4, cytotoxic T-lymphocyte associated 4; PD-1, programmed cell death 1; PD-L1 programmed cell death ligand 1; T-VEC, talimogene laherparepvec. a Included dabrafenib, vemurafenib, and encorafenib; b Included trametinib, cobimetinib, and binimetinib. Hauschild A, ESMO. 217;[abstr LBA6_PR]. 29

27 COMBI-AD: safety summary AE Category, n (%) Dabrafenib Plus Trametinib (n = 435) (n = 432) Any AE 422 (97) 38 (88) AEs related to study treatment 398 (91) 272 (63) Any grade 3/4 AE 18 (41) 61 (14) Any SAE 155 (36) 44 (1) SAEs related to study treatment 117 (27) 17 (4) Fatal AEs related to study drug AEs leading to dose interruption 289 (66) 65 (15) AEs leading to dose reduction 167 (38) 11 (3) AEs leading to treatment discontinuation 114 (26) 12 (3) AE, adverse event; SAE, serious adverse event. Hauschild A, ESMO. 217;[abstr LBA6_PR]. 3

28 COMBI-AD: common AEs Dabrafenib Plus Trametinib (n = 435) (n = 432) AEs, n (%) All Grades Grade 3/4 All Grades Grade 3/4 Any AE (> 2% with dabrafenib plus trametinib) a 422 (97) 18 (41) 38 (88) 61 (14) Pyrexia 273 (63) 23 (5) 47 (11) 2 (< 1) Fatigue 24 (47) 19 (4) 122 (28) 1 (< 1) Nausea 172 (4) 4 (< 1) 88 (2) Headache 17 (39) 6 (1) 12 (24) Chills 161 (37) 6 (1) 19 (4) Diarrhea 144 (33) 4 (< 1) 65 (15) 1 (< 1) Vomiting 122 (28) 4 (< 1) 43 (1) Arthralgia 12 (28) 4 (< 1) 61 (14) Rash 16 (24) 47 (11) 1 (< 1) a Eleven patients (3%) in the treatment arm and 1 patients (2%) in the placebo arm had new primary melanomas; 8 (2%) and 7 (2%), respectively, had cutaneous squamous cell carcinoma/keratoacanthoma; 19 (4%) and 14 (3%), respectively, had basal cell carcinoma; and 1 (2%) and 4 (1%), respectively, had noncutaneous malignancies. Hauschild A, ESMO. 217;[abstr LBA6_PR]. 31

29 BRIM8: Adjuvant vemurafenib vs placebo

30 BRIM8: phase 3 study design Cohort 1 Fully resected, high-risk stage IIC, IIIA (lymph node metastasis > 1 mm), or IIIB melanoma BRAF V6 mutation N = 314 R 1:1 Vemurafenib 96 mg BID 52 wk (n = 157) 52 wk (n = 157) Cohort 2 Fully resected, high-risk stage IIIC melanoma BRAF V6 mutation Stratification Cohort 1: Disease stage and geographic region Cohort 2: Geographic region DFS, disease-free survival. Lewis K, et al. ESMO. 217;[abstr LBA7_PR]. N = 184 Primary endpoint: DFS Secondary endpoints: DMFS, OS, safety, HRQoL Current analysis: median follow-up of 31 months ( 2.6 y) for cohort 1 and 34 months ( 2.8 y) for cohort 2 R 1:1 Vemurafenib 96 mg BID 52 wk (n = 93) 52 wk (n = 91) 33

31 BRIM8: Statistical assumptions Median DFS assumptions Target HR DFS events needed Cohort 1 = 314 (Stage IIC, IIIA a, IIIB) = 24. months Vemurafenib = 4. months HR =.6 12 events Cohort 2 = 184 = 7.7 months (Stage IIIC) Vemurafenib = 13.3 months HR = events Hierarchical testing of DFS in C2 before C1 was prespecified to maintain an overall Type I error rate <.5 (two-sided) Only a p-value for C2 of.5, would provide the opportunity for the analysis of C1 to be considered statistically significant. DFS, disease-free survival; HR, hazard ratio. 34 a Patients with stage IIIA melanoma were eligible if they had one or more nodal metastasis >1 mm in diameter. Lewis K et al. Presented at: ESMO 217. Madrid, Spain. Abstract LB7_PR.

32 BRIM8: baseline characteristics Cohort 2 (N = 184) Cohort 1 (N = 314) Vemurafenib (n = 93) (n = 91) Vemurafenib (n = 157) (n = 157) Age, median years (range) 55. (21-8) 5. (19-77) 51. (18-77) 49. (26-79) Male, n (%) 52 (56) 59 (65) 84 (54) 88 (56) Pathologic stage, n (%) IIC IIIA IIIB IIIC (1) (1) 15 (1) 36 (23) 16 (68) - 12 (8) 39 (25) 16 (68) - Presence of tumor ulceration status, n/n (%) 57/85 (67) 49/78 (63) 63/144 (14) 49/143 (34) Presence of first metachronous nodal recurrence, n/n (%) Lymph node type at baseline, n/n (%) Micrometastasis Macrometastasis N3 29/93 (31) 32/9 (36) 26/157 (17) 36/157 (23) 3/93 (32) 63/93 (68) 27/91 (3) 64/91 (7) 84/142 (59) 58/142 (41) 76/145 (52) 69/145 (48) ECOG PS, n/n (%) 1 81/92 (88) 11/92 (12) 78/91 (86) 13/91 (14) 143/155 (92) 12/155 (8) 136/157 (87) 21/157 (13) 35 Lewis K et al. Presented at: ESMO 217. Madrid, Spain. Abstract LB7_PR.

33 Patients Alive and Disease Free, % Patients Alive and Disease Free, % BRIM8: DFS (primary endpoint) Cohort 1 (stage IIC-IIIB) Cohort 2 (stage IIIC) Vemurafenib (n = 157) (n = 157) Vemurafenib (n = 93) (n = 91) 1 Events, n (%) 45 (29) 72 (46) Median DFS, months (95% CI) NE 36.9 (21.4-NE) 1 Events, n (%) 52 (56) 53 (58) Median DFS, months (95% CI) 23.1 ( ) 15.4 ( ) % HR (95% CI).54 ( ) Log-rank P value.1 a 8 HR (95% CI).8 ( ) Log-rank P value % 72.3% 56.5% % 58.% 46.3% 47.5% Vemurafenib Time, months No. at risk Vemurafenib Vemurafenib Time, months No. at risk Vemurafenib a Cannot be considered significant because primary endpoint was not met in cohort 2. Lewis K, et al. ESMO. 217 [abstract LBA7_PR]. 36

34 Patients Alive and Disease Free, % BRIM8: prespecified exploratory DFS analysis in the pooled ITT population Vemurafenib (n = 25) 82.2% HR (95% CI).65 (.5-.85) Log-rank P value.13 a 63.1% 62.2% (n = 248) Events, n (%) 97 (39) 125 (5) Median DFS, months (95% CI) NE (29.8-NE) 25.8 (2.5-NE) % 2 No. at risk Vemurafenib Vemurafenib Time, months ITT, intention-to-treat. a Not significant because the primary endpoint was not met in cohort 2. Lewis K, et al. ESMO. 217 [abstract LBA7_PR]. 37

35 Patients Alive and Without Distant Metastasis, % Patients Alive and Without Distant Metastasis, % BRIM8: DMFS Cohort 1 (stage IIC-IIIB) Cohort 2 (stage IIIC) % 79.5% 81.% 66.9% % 77.% 62.4% 57.5% 2 Vemurafenib Time, months 2 Vemurafenib Time, months No. at risk Vemurafenib Cohort 1 (IIC IIIB) Vemurafenib (n = 157) (n = 157) Events, n (%) 34 (22) 52 (33) Median DMFS, months (95% CI) HR (95% CI).58 (.37-.9) Log-rank P value NE.133 a NE (36.9-NE) No. at risk Vemurafenib Cohort 2 (IIIC) Vemurafenib (n = 93) (n = 91) Events, n (%) 38 (41) 37 (41) Median DMFS, months (95% CI) 37.2 (22.1-NE) HR (95% CI).91 ( ) Log-rank P value.6815 a 3.7 (24.5-NE) a Cannot be considered significant because the primary endpoint was not met in cohort 2. Lewis K, et al. ESMO. 217 [abstract LBA7_PR]. 38

36 BRIM8: safety summary Vemurafenib (n = 247) (n = 247) Dose intensity, median % Treatment duration, median days Any grade AEs, n (%) 246 (1) 219 (89) Grade 3-4 AEs, n (%) 141 (57) 37 (15) Grade 5 AEs, n (%) 1 (<1) a Treatment discontinuation for AEs, n (%) 49 (2) b 5 (2.) b a Refers to a case of a patient who died 2 months after hospitalization for hypertension; brain imaging revealed hemorrhage in a cerebral lesion consistent with metastasis. The patient had surgery for the cerebral hemorrhage and was subsequently discharged. The death was not considered to be related to the study drug. b Treatment discontinuation for AEs by cohort: cohort 1 13 (14%) for vemurafenib vs for placebo; cohort 2 34 (22%) for vemurafenib vs 5 (3%) for placebo. 39 Lewis K et al. Presented at: ESMO 217. Madrid, Spain. Abstract LB7_PR.

37 BRIM8: common any-cause AEs ( 15% any grade, any arm) a All events were grade 3.. Vemurafenib (n = 247) (n = 247) Any grade, % Grade 3/4, % Any grade, % Grade 3/4, % Any Arthralgia 61 7 a 22 Alopecia 38 < 1 a 6 Rash Hyperkeratosis 35 1 a 2 Nausea 35 < 1 a 18 Photosensitivity reaction 34 2 a 4 Fatigue 32 3 a 28 < 1 a Pruritus 29 < 1 a 12 Diarrhoea 26 2 a 17 < 1 a Headache 2 17 Dry skin 19 7 Pain in extremity 19 < 1 a 8 Pyrexia Lewis K et al. Presented at: ESMO 217. Madrid, Spain. Abstract LB7_PR.

38 CheckMate 238 (phase 3) Adjuvant nivolumab vs ipilimumab

39 CheckMate 238: phase 3 study design N = 96 Key eligibility criteria Completely resected, high-risk stage IIIB/IIIC or stage IV melanoma Surgically free of disease 12 weeks before randomization ECOG performance status or 1 No prior radiotherapy or systemic therapy for melanoma Patients with ocular/uveal, acral, or mucosal melanoma per permitted R A N D O M I Z A T I O N 1:1 NIVO 3 mg/kg IV Q2W and IPI placebo IV Q3W 4 then Q12W from wk 24 (n = 453) IPI 1 mg/kg IV Q3W 4 then Q12W from wk 24 and NIVO placebo IV Q2W (n = 453) Follow-up Maximum treatment duration of 1 year Stratification Disease stage (IIIB/C vs IV M1a-M1b vs IV M1c) PD-L1 status at a 5% cutoff in tumor cells Primary endpoint: RFS Secondary endpoints: OS, safety, RFS by PD-L1 tumor expression, HRQoL Current analysis: interim analysis; median follow-up, 1.5 years (36 events) HRQoL, health-related quality of life; IPI, ipilimumab; NIVO, nivolumab. Weber J, et al. ESMO. 217;[abstr LBA8_PR]. 43

40 CheckMate 238: baseline patient characteristics NIVO (n = 453) IPI (n = 453) Median age, years Male, % Stage, IIIB + IIIC, % Macroscopic lymph node involvement (% of stage IIIB + IIIC) Ulceration (% of stage IIIB + IIIC) Stage IV, % M1c without brain metastasis (% stage IV) PD-L1 expression 5%, % BRAF mutation, % LDH ULN, % Most patients had cutaneous melanoma (85%); 4% had acral and 3% had mucosal melanoma All 95 patients were off treatment at the data cutoff; number of median doses were 24 (range, 1-26) for NIVO and 4 (range, 1-7) for IPI 397 patients completed 1 year of treatment (NIVO, 61%; IPI, 27%) LDH, lactate dehydrogenase; ULN, upper limit of normal. Weber J, et al. ESMO. 217 [abstract LBA8_PR]. 44

41 CheckMate 238: RFS primary endpoint NIVO IPI Events/patients 154/453 26/453 Median (95% CI) NR NR (16.6, NR) HR (97.56% CI).65 (.51,.83) Log-rank P value <.1 Weber J et al. Presented at: ESMO 217. Madrid, Spain. Abstract LBA8_PR. 8

42 CheckMate 238: RFS by prespecified Subgroups Subgroup No. of events/no. of patients NIVO 3 mg/kg IPI 1 mg/kg Unstratified HR (95% CI) Overall Overall 154/453 26/ (.53,.81) Age <65 years 16/ / (.51,.84) 65 years 48/12 59/ (.45,.97) Sex Male 99/ / (.53,.88) Female 55/195 73/ (.44,.89) Stage (CRF) Stage IIIb 41/163 54/ (.44, 1.) Stage IIIc 79/24 19/ (.49,.87) Stage IV M1a-M1b 25/62 35/66.63 (.38, 1.5) Stage IV M1c 8/2 8/21 1. (.37, 2.66) Not reported 1/2 / Stage III: Ulceration Absent 58/21 94/ (.42,.82) Stage III: Lymph node involvement Present 6/153 64/ (.51, 1.4) Not reported 2/15 5/15.39 (.7, 2.) Microscopic 41/125 55/ (.47, 1.7) Macroscopic 72/219 11/ (.46,.84) Not reported 7/25 7/18.6 (.21, 1.72) PD-L1 status <5%/indeterminate 123/3 149/ (.56,.9) 5% 31/152 57/154.5 (.32,.78) BRAF mutation status Mutant 63/187 84/ (.52, 1.) Wild-type 67/197 15/ (.43,.79) Not reported 24/69 17/45.83 (.45, 1.54) Unstratified HR (95% CI) 1 2 NIVO IPI Weber J et al. Presented at: ESMO 217. Madrid, Spain. Abstract LBA8_PR.

43 RFS (%) RFS (%) CheckMate 238: RFS by BRAF mutation status BRAF Mutant BRAF Wild type NIVO IPI Events/patients 63/187 84/194 Median (95% CI) NR NR (16.1, NR) HR (95% CI).72 (.52, 1.) NIVO IPI Number of patients at risk NIVO IPI 68% 63% Months NIVO IPI NIVO IPI Events/patients 67/197 15/214 Median (95% CI) NR 16.6 (12.3, NR) HR (95% CI).58 (.43,.79) NIVO IPI Number of patients at risk 72% 57% Months Weber J et al. Presented at: ESMO 217. Madrid, Spain. Abstract LBA8_PR.

44 RFS (%) RFS (%) CheckMate 238: RFS by disease stage Stage III Stage IV NIVO IPI NIVO IPI Events/patients 12/ /366 Median (95% CI) NR NR (16.6, NR) Events/patients 33/82 43/87 Median (95% CI) NR (15.9, NR) 16.8 (8.5, NR) 1 NIVO IPI NIVO IPI HR (95% CI).65 (.52,.83) Number of patients at risk 72% 62% Months NIVO IPI HR (95% CI).7 (.45, 1.1) NIVO IPI Number of patients at risk 63% 58% Months Weber J et al. Presented at: ESMO 217. Madrid, Spain. Abstract LBA8_PR.

45 DMFS (%) CheckMate 238: DMFS for stage III patients % 73% NIVO IPI NIVO IPI Events/patients 93/ /366 Median (95% CI) NR NR HR (95% CI).73 (.55,.95) Log-rank P value.24 Number of patients at risk Months NIVO IPI Weber J et al. Presented at: ESMO 217. Madrid, Spain. Abstract LBA8_PR.

46 % Recurrence-free Survival RFS: CA and CheckMate 238 (Stage III only) % 62% 52% 44% CheckMate 238 CA NIVO IPI 1 mg/kg IPI 1 mg/kg 2 1 Number of patients at risk Months NIVO IPI 1 mg/kg IPI 1 mg/kg R. Dummer Discussant LBA8_PR ESMO. 217

47 CheckMate 238: post-protocol treatment NIVO IPI Treatment, n (%) a (n = 453) (n = 453) Any 129 (28.5) 171 (37.7) Systemic therapy 9 (19.9) 136 (3.) Chemotherapy 25 (5.5) 24 (5.3) Immunotherapy Anti PD-1 agent Nivolumab b Pembrolizumab Other CTLA-4 inhibitor Ipilimumab Ipilimumab/nivolumab combination a Patients may have received 1 type of post-protocol therapy, and 1 agent within each type. All percentages are based on the total number of patients in each group; b May include patients treated in combination with IPI; c Indicates tumor resection for diagnostic purposes and biopsies. Weber J, et al. ESMO. 217;[abstr LBA8_PR]. 5 (11.) 1 (.2) 17 (3.8) 1 (2.2) 1 (.2) 35 (7.7) 3 (.7) 14 (23.) 2 (.4) 43 (9.5) 63 (13.9) 1 (.2) 15 (3.3) 1 (.2) BRAF inhibitor 41 (9.1) 4 (8.8) MEK inhibitor 31 (6.8) 4 (8.8) BRAF/MEK combination 3 (.7) 1 (.2) Surgery c 69 (15.2) 64 (14.1) Radiotherapy 24 (5.3) 26 (5.7) 51

48 CheckMate 238: safety summary NIVO (n = 452) IPI (n = 453) AE, n (%) Any grade Grade 3/4 Any grade Grade 3/4 Any AE 438 (97) 115 (25) 446 (98) 25 (55) Treatment-related AE 385 (85) 65 (14) 434 (96) 28 (46) Any AE leading to discontinuation Treatment-related AE leading to discontinuation 44 (1) 21 (5) 193 (43) 14 (31) 35 (8) 16 (4) 189 (42) 136 (3) There were no treatment-related deaths in the NIVO group There were 2 (.4%) treatment-related deaths in the IPI group (marrow aplasia and colitis), both > 1 days after the last dose Weber J, et al. ESMO. 217;[abstr LBA8_PR]. 52

49 CheckMate 238: treatment-related select AEs NIVO (n = 452) IPI (n = 453) AE, n (%) Any grade Grade 3/4 Any grade Grade 3/4 Skin 21 (44.5) 5 (1.1) 271 (59.8) 27 (6.) Gastrointestinal 114 (25.2) 9 (2.) 219 (48.3) 76 (16.8) Hepatic 41 (9.1) 8 (1.8) 96 (21.2) 49 (1.8) Pulmonary 6 (1.3) 11 (2.4) 4 (.9) Renal 6 (1.3) 7 (1.5) Hypersensitivity/infusion reaction 11 (2.4) 1 (.2) 9 (2.) Endocrine Adrenal disorder Diabetes Pituitary disorder Thyroid disorder 6 (1.3) 2 (.4) 8 (1.8) 92 (2.4) 2 (.4) 1 (.2) 2 (.4) 3 (.7) 13 (2.9) 1 (.2) 56 (12.4) 57 (12.6) 4 (.9) 13 (2.9) 4 (.9) Median time to onset to treatment-related select AEs was generally shorter for patients receiving IPI (range wk) than for those receiving NIVO (range, wk) Weber J, et al. ESMO. 217;[abstr LBA8_PR]. 53

50 Immunotherapy Targeted therapy Ongoing Adjuvant Trials a Study KEYNOTE 54 (Ph 3) ECOG 169 (Ph 3) CheckMate 238 (Ph 3) EORTC 1881 (Ph 3) SWOG S144 (Ph 3) CheckMate 915 (Ph 3) IMMUNED (Ph 2) BRIM8 (Ph 3) COMBI-AD (Ph 3) Design PEMBRO vs PBO HD IPI or LD IPI vs HD IFN-α NIVO vs IPI PEG-IFN 2 years vs obs PEMBRO vs IPI or HD IFN-α NIVO+IPI vs NIVO NIVO+IPI or NIVO vs PBO Vem vs PBO Dab + Tram vs PBO Patient pop Compl. resected, stage IIIA (if N1a, at least 1 mets > 1mm); stage IIIB or IIIC; no in-transit mets Compl. resected stage IIIB/C or stage IV (M1a/M1b) Compl. resected, high-risk stage IIIB/C or IV Compl. resected, ulcerated primary melanoma > 1mm Compl. resected, high-risk stage IIIA (N2a), IIIB, IIIC, or IV Compl. resected, high-risk stage IIIB/C/D or IV NED b Compl. resected, stage IV NED Surgically resected, stage IIC- IIIC, BRAF mutant melanoma at high risk for recurrence Compl. resected, BRAF+, high-risk stage IIIA (LN mets > 1 mm), IIIB, or C. Stage I/II with initial resect. LN recurrence Accrual goal Primary endpoint RFS/RFS in PD-L1+ OS/RFS RFS RFS OS/RFS/ PD-L1+ RFS PFS DFS RFS Status (primary compl) Ongoing (Aug 217) Ongoing (May 218) Ongoing (Nov 218) Closed Recruiting (Jun 22) Recruiting (Dec 22) Recruiting (Jun 221) Ongoing (Jun 217) Ongoing (Dec 217) a Select trials in cutaneous melanoma are shown. b Note staging based on AJCC Staging 8th Edition. Accessed September 217.; PEMBRO: pembrolizumab; IPI: ipilimumab; IFN: interferon; NIVO: nivolumab, Vem: vemurafenib; Dab + Tram: Dabrafenib + Trametinib Clinicaltrials.gov Keynote54: NCT ; EORTC 1871: NCT636168; Intergroup E169: NCT ; EORTC 1881: NCT152696; SWOG S144 : NCT256153; CheckMate 915: NCT368455; IMMUNED: NCT ; COMBI-AD: NCT168283; BRIM8: NCT ; CheckMate 238: NCT238896

51 Zusammenfassung Adjuvante Therapie (Peter Mohr, MD) Verlängertes OS ist das wichtigste Ziel der adjuvanten Therapie, aber schwer zu erreichen! Safety/benefit ratio wird von FDA/EMA berücksichtigt Interferon: Meta-Analyse zeigen ein verbessertes rezidivfreies Überleben 1% und ges. Überleben 3-5 % Keine adjuvanten Studien im Stadium IIa,b des Melanoms: Interferon for ever? Ipilimumab zeigt Vorteile im RFS und OS; Toxizität, keine Zulassung in Europa!

52 Adjuvante Therapie Zukunft (Peter Mohr, MD) Vemurafenib verbessert das RFS Im Stadium IIC-IIIB aber nicht IIIC; Zulassung? Dabrafenib und Trametinib werden neuer Standard im Stadium III bei BRAF mutierten Patienten! Nivolumab wird neuer Standard in der adjuvanten Therapie im Stadium III und IV Wann wird bei BRAF pos. Patienten ein BRAF + MEK Inhibitor und wann anti-pd-1 verwendet werden? Werden die Therapien bei progredienten Patienten erneut im Stadium IV wirken? Weitere Studienergebnisse werden 218 kommen

53 Danke!