Amerikanischer Krebskongress 2018

Transcription

1 Congress-Lightning Amerikanischer Krebskongress 218 Dermatoonkologie Prof. Dr. Ralf Gutzmer, Hannover

2 Melanom adjuvant Melanom palliativ Nicht-melanozytäre Hauttumore

3 Adjuvant Therapy With Nivolumab Versus Ipilimumab After Complete Resection of Stage III/IV Melanoma: Updated Results From a Phase 3 Trial (CheckMate 238) Weber JS et al. Oral Abstract Session - Melanoma/Skin Cancers Abstract No. 952

4 CheckMate 238: Study Design Patients with: High-risk, completely resected stage IIIB/IIIC or stage IV (AJCC 7 th edition) melanoma No prior systemic therapy ECOG -1 R 1:1 Stratified by: Disease stage: IIIB/C vs. IV M1a-M1b vs. IV M1c PD-L1 status at a 5% cutoff in tumor cells n=453 n=453 NIVO 3 mg/kg IV Q2W and IPI Placebo IV Q3W for 4 doses then Q12W from week 24 IPI 1 mg/kg IV Q3W for 4 doses then Q12W from week 24 and NIVO placebo IV Q2W Follow-up Maximum treatment duration of 1 year Enrollment period: March 3, 215 to November 3, 215 Mod. Weber JS et al. ASCO 218, Oral Abstract Session - Melanoma/Skin Cancers, Abstract No. 952

5 Baseline Patient Characteristics and Treatment Summary NIVO (n=453) IPI (n=453) Median age, years Male, % Stage IIIB+IIIC, % Macroscopic lymph node involvement (% of stage IIIB+IIIC) 6 58 Ulceration (% of stage IIIB+IIIC) Stage IV, % M1c without brain metastases (% stage IV) PD-L1 expression 5%, % BRAF mutation, % LDH ULN, % Melanoma subtype, % Cutaneous Mucosal 4 3 Acral 4 4 Median doses were 24 (1-26) in the NIVO group and 4 (1-7) in the IPI group. 61% of patients in the NIVO group and 27% in the IPI group completed 1 year of treatment Mod. Weber JS et al. ASCO 218, Oral Abstract Session - Melanoma/Skin Cancers, Abstract No. 952

6 Study Overview Primary endpoint Recurrence-free survival (RFS): time from randomization until first recurrence (local, regional, or distant metastasis), new primary melanoma, or death Secondary endpoints Overall survival (OS), safety and tolerability, RFS by PD-L1 tumor expression, health-related quality of life Exploratory endpoint Distant metastasis-free survival (DMFS) Current analysis Updated RFS with subgroup analyses; updated DMFS Duration of follow-up: minimum 24 months; 392 events Per protocol, safety analysis was not updated given that all patients had been off study treatment >1 days at the time of the 18 month analysis Mod. Weber JS et al. ASCO 218, Oral Abstract Session - Melanoma/Skin Cancers, Abstract No. 952

7 Primary Endpoint: RFS in All Patients NIVO IPI Events/patients 171/ /453 7% 66% 63% Median (95% CI) 3.8 (3.8, NR a ) 24.1 (16.6, NR) HR (95% CI).66 (.54,.81) RFS (%) 6% 53% 5% Log-rank p-value <.1 NIVO IPI Months Number of Patients at Risk NIVO IPI a Median estimate not reliable or stable due to few patients at risk. Mod. Weber JS et al. ASCO 218, Oral Abstract Session - Melanoma/Skin Cancers, Abstract No. 952

8 Subgroup Analysis of RFS: Disease Stage III and IV Stage III NIVO IPI Stage IV NIVO IPI Events/patients 135/ /366 Events/patients 35/82 47/87 Median (95% CI) NR 25.5 (16.6, NR) Median (95% CI) 3.8 (15.9, NR a ) 15.4 (8.5, NR) HR (95% CI).68 (.54,.85) HR (95% CI).68 (.44, 1.6) 72% 67% 64% 63% 61% 58% RFS (%) 61% 55% 52% RFS (%) 56% 47% 44% NIVO IPI NIVO IPI Number of Patients at Risk NIVO IPI Months Number of Patients at Risk NIVO IPI Months a Median estimate not reliable or stable due to few patients at risk. Mod. Weber JS et al. ASCO 218, Oral Abstract Session - Melanoma/Skin Cancers, Abstract No. 952

9 Subgroup Analysis of RFS: Disease Stage IIIB and IIIC Stage IIIB NIVO IPI Stage IIIC NIVO IPI Events/patients 48/165 6/148 Events/patients 87/23 114/218 Median (95% CI) NR NR (24.2, NR) Median (95% CI) NR (24.9, NR) 16.6 (9.4, 27.2) HR (95% CI).68 (.47,1.) HR (95% CI).68 (.52,.91) RFS (%) 76% 74% 71% 7% 63% 61% RFS (%) 69% 55% 62% 49% 58% 45% NIVO IPI NIVO IPI Months Months Number of Patients at Risk NIVO IPI Number of Patients at Risk NIVO IPI Mod. Weber JS et al. ASCO 218, Oral Abstract Session - Melanoma/Skin Cancers, Abstract No. 952

10 Exploratory Endpoint: DMFS for Stage III Patients NIVO IPI Events/patients 17/37 126/366 8% 75% 71% Median (95% CI) NR NR HR (95% CI).76 (.59,.98) DMFS (%) 73% 67% 64% Log-rank p-value.34 NIVO IPI Number of Patients at Risk NIVO IPI Months a Median estimate not reliable or stable due to few patients at risk. Mod. Weber JS et al. ASCO 218, Oral Abstract Session - Melanoma/Skin Cancers, Abstract No. 952

11 External validation of the 8th Edition Melanoma Staging System of the American Joint Committee on Cancer (AJCC): Effect of adding EORTC sentinel node (SN) tumor burden criteria on prognostic accuracy in stage III Madu MF et al. Oral Abstract Session - Melanoma/Skin Cancers Abstract No. 95

12 Major changes for stage III in AJCC 8 th edition New N subcategories 3 4 stage III subgroups New TNM combinations T1a T1b T2a T2b T3a T3b T4a T4b AJCC 7 th N1a N1b N2a N2b N2c N3 Stage III T1a T1b T2a T2b T3a T3b T4a T4b AJCC 8 th N1a N1b N1c N2a N2b N2c N3a N3b N3c IIIA IIIB IIIC IIID New pathologic categories Change in pathologic definition New stage Grob et al. Eur J Cancer 217 Mod. Madu MF et al. ASCO 218, Oral Abstract Session - Melanoma/Skin Cancers, Abstract No. 95

13 Patients Prospective institutional (NKI) database of 64 AJCC stage III melanoma patients (2-216) Inclusion Regional lymph node metastasis, with or without concurrent local, satellite or intransit metastasis Exclusion Multiple positive regional nodal basins, metastasized second primary melanoma, unresectable disease, distant metastasis, non-standard surgery, (neo-)adjuvant therapy with recently available (from 21) targeted therapies or immunotherapies, <3 months of follow-up Mod. Madu MF et al. ASCO 218, Oral Abstract Session - Melanoma/Skin Cancers, Abstract No. 95

14 MSS comparison 8 th edition Melanoma-specific survival Number at Risk stage IIIA 77 stage IIIB 173 stage IIIC 259 stage IIID 28 IIIA 86% 5-YR IIIB 78% 5-YR IIIC 57% 5-YR IIID 19% 5-YR Follow-up time stage IIIA stage IIIB stage IIIC stage IIID p< Melanoma-specific survival probability IIIA IIIB IIIC IIID n 5-YR 1-YR IIIA 16 93% 88% IIIB % 77% IIIC % 6% IIID 25 32% 24% Years since Diagnosis NKI cohort Gershenwald et al. Ca cancer J Clin 217 Mod. Madu MF et al. ASCO 218, Oral Abstract Session - Melanoma/Skin Cancers, Abstract No. 95

15 Survival differentiation in stage IIIA 7 th edition 8 th edition Melanoma-specific survival 1. mm 89% 5-YR >1. mm 65% 5-YR p<.1 1. mm >1. mm Melanoma-specific survival 1. mm 91% 5-YR >1. mm 72% 5-YR p=.2 1. mm >1. mm Number at Risk 1. mm 93 >1. mm Follow-up time Number at Risk 1. mm 5 >1. mm Follow-up time Mod. Madu MF et al. ASCO 218, Oral Abstract Session - Melanoma/Skin Cancers, Abstract No. 95

16 Melanom adjuvant Die neuen Substanzen (Ipilimumab, PD1-Inhibitoren, BRAF + MEK Inhibitoren) wirken auch in der Adjuvanz. Etwa die Hälfte der Rezidive werden verhindert. Prognostische Abschätzung von Patienten im Stadium III wichtig, dazu Verbesserungen der aktuellen AJCC Klassifikation notwendig (Einbeziehung Tumorlast im Sentinel)

17 Melanom adjuvant Melanom palliativ Nicht-melanozytäre Hauttumore

18 4-Year Survival and Outcomes After Cessation of Pembrolizumab After 2 Years in Patients With Ipilimumab- Naive Advanced Melanoma in KEYNOTE-6 Long GV et al. Oral Abstract Session Melanoma/Skin Cancers Abstract No. 953

19 KEYNOTE-6 Study Design Patients: Unresectable, stage III or IV melanoma 1 previous therapy, excluding anti-ctla-4, PD-1, or PD-L1 agents Known BRAF statusa ECOG PS /1 No active CNS metastases No serious autoimmune disease R 1:1:1 n=834 n=279 n=277 n=278 Pembrolizumab 1 mg/kg IV Q2W for 2 years Pembrolizumab 1 mg/kg IV Q3W for 2 years Ipilimumab 3 mg/kg IV Q3W x 4 doses Stratification factors: ECOG PS ( vs. 1) Line of therapy (first vs. second) PD-L1 status (positiveb vs. negative Primary end points: PFS and OS Secondary end points: ORR and safety NCT a Prior anti-braf therapy was not required for patients with normal LDH levels and clinical significant tumor-related symptoms or evidence of rapidly progressing disease. b Defined as 1% staining in tumor and adjacent immune cells as assessed by IHC using 22C3 antibody. Mod. Long GV et al. ASCO 218, Oral Abstract Session Melanoma/Skin Cancers, Abstract No. 953

20 Baseline Characteristics Pembrolizumab n=556 Ipilimumab n=278 Age, median (range), y 62 (18-89) 62 (18-88) Males, n (%) 335 (6) 162 (58) ECOG PS, n (%) 384 (69) 188 (68) Elevated LDH, n (%) 179 (32) 91 (33) BRAF v6 mutant, n (%) 195 (35) 17 (38) PD-L1 positive a,n(%) 446 (8) 225 (81) M1c disease, n (%) 368 (66) 178 (64) 1 prior therapy b,n(%) 187 (34) C 97 (35) a Defined as 1% staining tumor and adjacent immune cells as assessed by IHC (22C3 antibody). b Per protocol, patients were previously treated with BRAF/MEK inhibitor, if indicated. c 1 additional patient had 2 lines of previous therapy. Data cutoff, Dec 4, 217 Mod. Long GV et al. ASCO 218, Oral Abstract Session Melanoma/Skin Cancers, Abstract No. 953

21 Poststudy Drug Therapy a Therapy, n (%) Pembrolizumab N=555 Ipilimumab n=256 1 new systemic therapy 259 (47) 144 (56) Immunotherapy b 186 (34) 13 (4) Anti-CTLA (26) 2 (8) Anti-PD-1 63 (11) 97 (38) Anti-PD-L1 3 (1) 1 (<1) BRAF inhibitor ±ME57K inhibitor 81 (15) 55 (21) MEK inhibitor 57 (1) 32 (13) Chemotherapy c 67 (12) 34 (13) Other d 1 (2) 12 (5) a Summary of new oncologic therapies after discontinuation from study treatment. b Immunotherapy + other, 1 patient in the Pemtrolizumab combined arm and 1 patient in Ipilimumab arm. c Chemotherapy + other, 1 patient in Pembrolizumab combined arm and patients in the Ipilimumab arm. d Includes Ckit inhibitor, EGFR inhibitor, VEGF/VEGFR inhibitor, and unspecified investigational drug. Mod. Long GV et al. ASCO 218, Oral Abstract Session Melanoma/Skin Cancers, Abstract No. 953

22 Overall Survival Median Follow-up 45.9 (.3-5.) Months All Patients 55.2% 42.4% Pembro Ipi Events, n All Patients.73 HR a (95% CI) ( ) - Median, b mo (95% CI) 32.7 ( ) 15.9 ( ) 48.1% 37.8% 41.7% 34.1% Treatment-Naive Patients 58.% 44.7% Pembro Ipi Events, n All Patients.73 HR a (95% CI) ( ) - Median, b mo (95% CI) 38.7 (27.3-NR) 17.1 ( ) 51.2% 4.8% 44.3% 36.4% Overall Survival (%) Pembro Ipi Overall Survival (%) Pembro Ipi No. at risk Pembro IPI Time, months No. at risk Pembro IPI Time, months a Based on Cox regression model with treatment as covariate stratified by line of therapy (1 st vs. 2 nd ), PD-L1 status (positive vs. negative), and ECOG ( vs. 1); if no patients are in one of the treatment groups involved in a comparison for a particular stratum, then that stratum was excluded from treatment comparison. b Derived by the product-limit (Kaplan-Meier) method for censored data. Data cutoff: Dec 4, 217 Mod. Long GV et al. ASCO 218, Oral Abstract Session Melanoma/Skin Cancers, Abstract No. 953

23 Progression-Free Survival a Median Follow-up 45.9 (.3-5.) Months All Patients Pembro Ipi Events, n All Patients.56 HR b (95% CI) ( ) - Median, c mo (95% CI) 8.3 ( ) 3.3 ( ) Treatment-Naive Patients Pembro Ipi Events, n All Patients.54 HR b (95% CI) ( ) - Median, c mo (95% CI) 11.2 ( ) 3.7 ( ) Progression-Free Survival (%) Pembro Ipi 33.6% 14.8% 31.1% 13.3% Progression-Free Survival (%) Pembro Ipi 38.7% 18.4% 36.2% 15.9% No. at risk Pembro IPI Time, months No. at risk Pembro IPI Time, months a Per immune-related response criteria by investigator review. b Based on Cox regression model with treatment as covariate stratified by line of therapy (1 st vs. 2 nd ), PD-L1 status (positive vs. negative), and ECOG ( vs. 1); if no patients are in one of the treatment groups involved in a comparison for a particular stratum, then that stratum was excluded from treatment comparison. c Derived by the product-limit (Kaplan-Meier) method for censored data; Data cutoff: Dec 4, 217 Mod. Long GV et al. ASCO 218, Oral Abstract Session Melanoma/Skin Cancers, Abstract No. 953

24 Duration of Response (irrc, investigator) All Patients Pembro Ipi Responder, a n Response 42 mo, n (%) 28 (62) 2 (59) Median, b NR NR mo (range) ( ) ( ) Treatment-Naive Patients Pembro Ipi Responder, a n Response 42 mo, n (%) 2 (65) 1 (68) Median, b NR NR mo (range) ( ) ( ) 69.6% 65.8% 65.6% 58.7% 71.6% 79.3% 68.9% 68.3% Response (%) Response (%) Pembro Ipi Pembro Ipi No. at risk Pembro IPI Time, months No. at risk Pembro IPI Time, months a Analyses on time to response and response duration are based on patients with a best overall response confirmed complete or partial response; b Derived by the product-limit (Kaplan-Meier) method for censored data; + indicates response duration is censored. Data cutoff: Dec 4, 217 Mod. Long GV et al. ASCO 218, Oral Abstract Session Melanoma/Skin Cancers, Abstract No. 953

25 Disposition of Patients Completing 94 Weeks of Pembrolizumab Treatment 556 patients received Pembrolizumab 13 (18.5%) completed 2 year Pembrolizumab treatment Median follow-up after 94 weeks pembro: 2.3 ( ) mo 28 (27.2%) CR 65 (63.1%) PR 1 (9.7%) SD 26 patients had an ongoing response 2 (7.1%) confirmed PD a 3 received 2 nd course of Pembrolizumab b 56 patients had an ongoing response 9 (13.8%) confirmed PD a 4 received 2nd course of Pembrolizumab 7 patients had an ongoing SD 3 (3%) confirmed PD a 1 received 2nd course of Pembrolizumab a Confirmed PD by investigator per irrc (confirmatory scan or no subsequent scan or not evaluable). An additional 5 pts with unconfirmed progressive disease were observed. b Includes 1 patient who discontinued early with CR and then progressed. Data cutoff: Dec 4, 217 Mod. Long GV et al. ASCO 218, Oral Abstract Session Melanoma/Skin Cancers, Abstract No. 953

26 PFS a in Patients Who Completed Protocol-Specified Time on Pembrolizumab (n=13) 95.8% Progression-Free Survival,% 91.3% 66.7% CR PR SD No. at risk CR PR SD Time, months a Per immune-related response criteria by investigator review; time is measured from last dose of Pembrolizumab. Data cutoff: Dec 4, 217 Mod. Long GV et al. ASCO 218, Oral Abstract Session Melanoma/Skin Cancers, Abstract No. 953

27 Outcome of 19 Progressors After 94 Weeks of Pembrolizumab (n=13) 19 (18%) patients had PD a post ~2 years of Pembrolizumab 11 off-study 8 2nd course Pembrolizumab 1 died (progressive disease) 7 (7%) received immunotherapy 4 Pembro 1 Ipi+Nivo 2 Ipi 2 died (progressive disease) a For 5 patients, PD was not confirmed with second scan. Data cutoff: Dec 4, 217. Mod. Long GV et al. ASCO 218, Oral Abstract Session Melanoma/Skin Cancers, Abstract No. 953

28 Pattern of Recurrence and Response in Patients on 2nd Course of Pembrolizumab Patient Site(s) of Recurrence After 1st Course 1st Course BOR 2nd Course BOR 2 nd Course DOR, mo Reason for 2 nd Course Discontinuation 1 Progression in iliac LNs CR PR b 2.8+ Treatment ongoing 2 Progression in skin CR CR 7.63 Completed 17 cycles 3 New and progression a of lung mets PR PR b + Treatment ongoing 4 Progression a in skin PR SD NA Pneumonia 5 Progression in pancreatic tail met PR PR 3.8+ Protracted respiratory infection 6 Progression in LNs SD SD NA Completed 17 cycles 7 New LN metastases CR SD c NA Completed 17 cycles 8 Progression a in LN PR PD NA PD a Confirmed PD by investigator per irrc (confirmatory scan or no subsequent scan or not evaluable), b Patients response was updated from the SD to PR by the site after LPLV date. c Reported as a CR, but had a recurrence, patient was free of disease by surgery before second course. Data cutoff: Dec 4, 217 Mod. Long GV et al. ASCO 218, Oral Abstract Session Melanoma/Skin Cancers, Abstract No. 953

29 Summary and Conclusions With 4 years of follow-up, Pembrolizumab continues to provide durable antitumor activity in treatment-naive and treatment-experienced patients with advanced melanoma. 86% of patients progression-free at 2 months after completing 2 years of Pembrolizumab. Retreatment with Pembrolizumab upon disease progression can provide additional antitumor activity with acceptable safety. Mod. Long GV et al. ASCO 218, Oral Abstract Session Melanoma/Skin Cancers, Abstract No. 953

30 Effektivität Immuntherapie Ansprechen [%] Medianes Progressions -freies ÜL [Monate] Medianes Gesamtüberleben [Monate] 1-Jahres Überleben 2-Jahres Überleben 3-Jahres Überleben 4-Jahres Überleben Dauer Ansprechen [Median, Monate] Ipilimumab (anti-ctla4) 11%⁶-19%³ 2.8¹-2.9³ 16.¹ 59%¹ 45%¹ 41%¹ 36%¹ >42¹ Pembrolizumab (anti-pd1) 42%¹ 4.9⁵ ¹ 24.4⁵ 66%⁵-68%¹ 5%⁵-58%¹ 51%¹ 44%¹ >42¹ Nivolumab (anti-pd1) 43.7%³ 6.9³ >24⁴ 63%²-71%⁴ 48%²-58%⁴ 52%³ ESMO 218 Nivolumab + Ipilimumab 57.6%³-59%⁶ 11.5³ NR 73%⁶ 64%⁶ 58%³ ESMO 218 ¹Keynote 6; ²CA29-3; ³Checkmate 67; ⁴Checkmate 66; ⁵Keynote 1; ⁶Checkmate 69 NR: Medianes Überleben noch nicht erreicht/berichtet

31 Overall Survival in COLUMBUS: A Phase 3 Trial of Encorafenib (ENCO) Plus Binimetinib (BINI) vs. Vemurafenib (VEM) or ENCO in BRAF-Mutant Melanoma Dummer R et al. Oral Abstract Session Melanoma/Skin Cancers Abstract No. 954

32 Study Design and Objectives COLUMBUS Part 1 Untreated or progressed on/after prior first-line immunotherapy R BRAF V6E and/or BRAF V6K ECOG PS -1 1:1:1 (N=577) COMBO45 Encorafenib 45 mg QD + Binimetinib 45 mg BID (n=192) VEM Vemurafenib 96 mg BID (n=191) ENCO3 Encorafenib 3 mg QD (194) Progression-Free Survival ()%) Median PFS in months (95% CI) COMBO ( ) VEM 7.3( ) HR (95% CI),.54 ( ) p<.1 Efficacy update with additional follow-up of 18 months: OS: Secondary Endpoint Planned after 232 events in the COMBO45 and VEM groups combined Median duration of follow-up : 36.8 months Time (mo) PFS: Dummer, R et al. Lancer Oncol. 218;13(5) Primary Endpoint Median duration of follow-up : 32.1 months COMBO45,Encorafenib 45 mg QD + Binimetinib 45 mg BID; ECOG PS, Eastern Cooperative Oncology Group performance status; OS=overall survival; PFS=progression-free survival; R=randomization; VEM=Vemurafenig 96 mg BID. included in hierarchical testing approach; Median follow-up of patients assessed using reverse Kaplan-Meier approach (i.e. median potential follow-up). Mod. Dummer R et al. ASCO 218, Oral Abstract Session Melanoma/Skin Cancers, Abstract No. 954

33 Baseline Characteristics Characteristic COMBO45 n=192 ENCO3 n=194 Median age (range), years 57 (2-89) 54 (23-88) 56 (21-82) Male sex 6% 56% 58% ECOG performance status 71% 72% 73% LDH > ULN 29% 24% 27% LDH ULN 71% 76% 73% BRAF mutation status ( BRAF V6E /BRAF V6K ) 89%/12% 89%/1% 88%/12% Tumor stage at study entry IIIB/IIIC 5% 3% 6% IVM1a 14% 15% 13% IVM1b 18% 2% 16% IVM1c 64% 62% 65% Number of organs involved 1 25% 29% 24% 2 3% 27% 31% 3 45% 44% 46% VEM n=191 COMBO45, Encorafenib 45 mg QD + Binimetinib 45 mg BID; ECOG=Eastern Cooperative Oncology Group; ENCO3, Encorafenib 3 mg QD; LDH=lactate dehydrogenase; ULN=upper limit of normal; VEM=Vemurafenib 96 mg BID. Mod. Dummer R et al. ASCO 218, Oral Abstract Session Melanoma/Skin Cancers, Abstract No. 954

34 Systemic Treatment Following Study Drug Discontinuation Treatment received after study drug* COMBO45 n=192 ENCO3 n=194 VEM n=191 Any treatment 42% 56% 62% Anti PD-1/anti PD-L1 2% 21% 25% Anti CTLA-4 17% 16% 19% Anti CTLA-4 + Anti PD-1/anti PD-L1 3% 2% 2% BRAFi+MEKi 5% 14% 2% BRAFi 6% 8% 13% Chemotherapy 7% 12% 12% Other 3% 2% 7% BRAFi=BRAF inhibitor; COMBO45=Encorafenib 45 mg QD + Binimetinib 45 mg BID; CTLA-4=Cytotoxic T-lymphocyte-associated protein 4; ENCO3=Encorafenib 3 mg QD; MEKi=MEK inhibitor; PD-1=programmed death 1; PD-L1, programmed death ligand 1; VEM=Vemurafenib 96 mg BID. *Multiple uses of a therapy in a single patient were only counted once in the frequency for that category of therapy; patients who received multiple categories of therapy are counted in each respective row. Mod. Dummer R et al. ASCO 218, Oral Abstract Session Melanoma/Skin Cancers, Abstract No. 954

35 Overall Survival: COMBO45 vs. VEM COMBO45 VEM Overall Survival % COMBO45 mos, months (95% CI) 33.6 ( ) HR (95% CI),.61 ( ) Nominal 2-sided p< ( ) VEM ++ Censored patients Patients at risk COMBO45 VEM Time (months) COMBO45-Encorafenib 45 mg QD + Binimetinib 45 mg BID, HR=hazard ratio; OS=overall survival; VEM=Vemurafenib 95mg BID Mod. Dummer R et al. ASCO 218, Oral Abstract Session Melanoma/Skin Cancers, Abstract No. 954

36 Overall Survival in Subgroups: COMBO45 vs. VEM Subgroup No. of Events/Patients Hazard Ratio (95% CI) All patients 232/ ( ) Sex Age BRAF mutation LDH ECOG Tumor stage No. of organs involved at baseline Male 144/226.7 ( Female 88/ ( ) <65 164/ ( ) 65 68/ ( ) V6E 28/338.7 ( ) V6K 24/45.31 ( ) ULN 14/ ( ) >ULN 92/17.95 ( ) PS= 158/ (.5-.93) PS=1 74/14.53 ( ) IIIb, IIIc, IVM1a,or IVM1b 88/168.7 ( ) IVM1c 144/ ( ) 1 42/92.65 ( ) 2 67/ ( ) 3 57/87.5 ( ) >3 66/87.85 ( ) COMBO45 Better VEM Better COMBO45 = Encorafenib 45 mg QD + Binimetinib 45 mg BID; ECOG = Eastern Cooperative Oncology Group; LDH = lactate dehydrogenase; PS = performance status; ULN = upper limit of normal; VEM = vemurafenib 96 mg BID. Mod. Dummer R et al. ASCO 218, Oral Abstract Session Melanoma/Skin Cancers, Abstract No. 954

37 Overall Survival: COMBO45 vs. ENCO3 COMBO45 ENCO3 Overall Survival, % COMBO45 mos, months (95% CI) 33.6 ( ) HR (95% CI),.81 ( ) Nominal 2-sided p= ( ) ENCO3 ++ Censored patients Patients at risk COMBO45 ENCO Time (months) COMBO45 = Encorafenib 45 mg QD + Binimetinib 45 mg BID; ENCO3 = Encorafenib 3 mg QD; HR = hazard ratio; OS = overall survival. Mod. Dummer R et al. ASCO 218, Oral Abstract Session Melanoma/Skin Cancers, Abstract No. 954

38 Overall Survival: ENCO3 vs. VEM ENCO3 VEM Overall Survival, % ENCO3 mos, months (95% CI) 23.5 ( ) HR (95% CI),.76 ( ) Nominal 2-sided p= ( ) VEM ++ Censored patients Patients at risk ENCO3 VEM Time (months) ENCO3 = Encorafenib 3 mg QD; HR = hazard ratio; OS = overall survival; VEM = Vemurafenib 96 mg BID. Mod. Dummer R et al. ASCO 218, Oral Abstract Session Melanoma/Skin Cancers, Abstract No. 954

39 Updated Progression-Free Survival: COMBO45 vs. VEM COMBO45 VEM Progression-Free Survival % COMBO45 VEM mpfs, months (95% CI) 14.9 ( ) HR (95% CI),.51 ( ) Nominal 2-sided p< ( ) ++ Censored patients Patients at risk COMBO45 VEM Time (months) COMBO45 = Encorafenib 45 mg QD + Binimetinib 45 mg BID; HR = hazard ratio; PFS = progression-free survival; VEM = Vemurafenib 96 mg BID. Mod. Dummer R et al. ASCO 218, Oral Abstract Session Melanoma/Skin Cancers, Abstract No. 954

40 Confirmed Response Rates Confirmed Response Central Review COMBO45 n=192 Local Review Central Review ENCO3 n=194 Local Review Central Review VEM n=191 Local Review ORR (95% CI)* 64% (57-7) 76% (69-81) 52% (44-59) 58% (5-65) 41% (34-48) 49% (42-57) CR 11% 19% 7% 1% 8% 8% PR 52% 56% 44% 48% 32% 41% Median DOR (95% CI), mo 18.6 ( ) 16.2 ( ) 15.2 ( ) 14.8 ( ) 12.3 ( ) 7.7 ( ) SD 29% 17% 32% 29% 4% 35% PD 8% 7% 16% 13% 19% 16% DCR (95% CI) 92% (87-96) 93% (88-96) 84% (78-89) 87% (81-91) 81% (75-86) 84% (78-89) COMBO45 = Encorafenib 45 mg QD + Binimetinib 45 mg BI; CR = complete response; DCR = disease control rate; DOR = duration of response; ENCO3 = Encorafenib 3 mg QD; ORR = overall response rate; PD = progressive disease; PR = partial response; SD = stable disease; VEM = Vermurafenib 96 mg BID; *ORR = CR + PR; Includes patients with only non-target lesions with best response of non-cr/non-pd; Includes patients with best response of unknown or no assessment; DCR = CR + PR + SD. Mod. Dummer R et al. ASCO 218, Oral Abstract Session Melanoma/Skin Cancers, Abstract No. 954

41 Conclusions COMBO45 showed improved OS vs. VEM: 33.6 mo vs mo (HR.61; nominal 2-sided p>.1) Updated PFS results remained the same as previously reported: median PFS 14.9 mo 1 Performance of VEM in COLUMBUS as consistent with historical data for ORR, PFS and OS 2,3 Use of subsequent systemic therapies in COLUMBUS was similar to phase 3 studies of established BRAFi/MEKi therapies 2,4 COMBO45 showed a favorable tolerability profile and no new safety concerns Encorafenib plus Binimetinib combination therapy provides a new efficacy benchmark for targeted therapy and it is a promising treatment option for patients with BRAF V6 -mutant melanoma BRAFi = BRAF inhibitor; COMBO45 = Encorafenib 45 mg QD + Binimetinib 45 mg BID; HR = hazard ratio; MEKi = MEK inhibitor; OS = overall survival; PFS = progression-free survival; VEM = Vemurafenib 96 mg BID. 1 Dummer R. et al. Lancet Oncol K 218;19:63-615; ²Ascierto PA, et al. Lancet Oncol 216;1: ; ³Robert C, et al. Eur J Cancer 215;51:S663-S664; 4 Long GV, et al. Ann Oncol 217;28: Mod. Dummer R et al. ASCO 218, Oral Abstract Session Melanoma/Skin Cancers, Abstract No. 954

42 Efficacy and safety of Cobimetinib combined with Vemurafenib in patients with BRAF v6 mutation-positive metastatic melanoma: analysis from the 4-year extended follow-up of the phase 3 cobrim study Dreno B et al. Poster Session Melanoma/Skin Cancers Abstract No. 9522

43 cobrim study design Unresectable locally advanced or metastatic melanoma (N=495) BRAF V6 mutation (cobas 48) No prior systemic therapy for advanced disease R 1:1 Cobimetinib 6 mg QD x 21 days (days 1-21) + Vemurafenib 96 mg BID x 28 days (days 1-28) Stratification: Geographic region Extent of disease (M1c vs. other) Disease progression, unacceptable toxicity or withdrawal of consent ECOG PS /1 Placebo + Vemurafenib 96 mg BID x 28 days (days 1-28) BID, twice daily; ECOG PS, Eastern Cooperative Oncology Group performance status; QD, once daily; R, randomization. Mod. Dreno B et al. ASCO 218, Poster Session Melanoma/Skin Cancers, Abstract No. 9522

44 Patient characteristics P + V n=248 C+ V n=247 Age Median (range), y 55 (25-85) 56 (23-88) Sex ECOG PS, n (%) Male 14 (57) 146 (59) Female 18 (44) 11 (41) 164 (67) 184 (76) 1 8 (33) 58 (24) 2 1 (<1)ª Previously treated brain metastasis, n (%) 2 (1) 1 (<1) Unresectable stage IIIc 13 (5) 21 (9) Disease stage, n (%) Stage IV, M1a 4 (16) 4 (16) Stage IV, M1b 42 (17) 4 (16) Stage IV, M1c 153 (62) 146 (59) Elevated LDH level, n (%) 14 (43) 112 (46) Follow-up Median (IQR), months 16.8 ( ) 21.2 ( ) C; Cobimetinib; ECOG PS, Eastern Cooperative Oncology Group performance status; IQR, interquartile range; LDH, lactate dehydrogenase; P, Placebo; V, Vemurafenib. ªOne patient was ECOG PS 1 at enrollment and ECOG PS 2 before first first administration of combination. Mod. Dreno B et al. ASCO 218, Poster Session Melanoma/Skin Cancers, Abstract No. 9522

45 Overall survival Kaplan-Meier plot of OS at the October 13, 217, data cut-off of cobrim Survival, % + Cobimetinib + Vemurafenib Placebo + Vemurafenib Censored Patients at Risk, n Cobimetinib + Vemurafenib Placebo + Vemurafenib Time, months OS, overall survival. Mod. Dreno B et al. ASCO 218, Poster Session Melanoma/Skin Cancers, Abstract No. 9522

46 Landmark OS rates in cobrim at 4 years P + V n=248 C+ V n=247 OS events, n year OS, % (95% CI) 63.8 ( ) 74.5 ( ) 2-year OS, % (95% CI) 39. ( ) 49. ( ) 3-year OS, % (95% CI) 31.1 ( ) 38.5 ( ) 4-year OS, % (95% CI) 29.2 ( ) 34.7 ( ) Subgroup analyses of OS showed that a significant OS benefit from Cobimetinib combined with Vemurafenib could be observed in many patient subgroups, including those with M1c disease, ECOG PS of 1, age 65 years, male sex, normal LDH levels, absence of brain metastases, and those who did not receive prior adjuvant therapy Lack of an observable OS benefit in other patient subgroups may be due to low sample number C, Cobimetinib; OS, overall survival; P, Placebo; V, Vemurafenib. Mod. Dreno B et al. ASCO 218, Poster Session Melanoma/Skin Cancers, Abstract No. 9522

47 Overall survival subgroup analyses Forest plot for hazard ratios of overall survival subgroup analyses intent-to-treat patients Total n P + V n=248 Median, months C + V n=247 Median, months Hazard Ratio 95% Wald CI C + V better P + V better All patients ( ) Disease stage (IIIc,/M1a/M1b, or M1c) Age group, y M1c ( ) Unresectable stage IIIc/M1c/M1b ( ) < ( ) (.4-.94) ( ) ECOG PS ( ) NE NE (NE-NE) C, Cobimetinib; CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group performance status; LDH, lactate dehydrogenase; NE, not estimable; P, Placebo; V, Vemurafenib. Mod. Dreno B et al. ASCO 218, Poster Session Melanoma/Skin Cancers, Abstract No. 9522

48 Overall survival subgroup analyses Forest plot for hazard ratios of overall survival subgroup analyses intent-to-treat patients Total n P + V n=248 Median, months C + V n=247 Median, months Hazard Ratio 95% Wald CI C + V better P + V better Screening serum, LDH Previously treated brain metastases Prior adjuvant therapy BRAF V6 mutation status Elevated Normal Yes 3 NE NE <.1.-NE No Yes No V6E V6K C, Cobimetinib; CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group performance status; LDH, lactate dehydrogenase; NE, not estimable; P, Placebo; V, Vemurafenib. Mod. Dreno B et al. ASCO 218, Poster Session Melanoma/Skin Cancers, Abstract No. 9522

49 Effektivität der BRAF-gerichteten Therapie Ansprechen (%) Medianes Progressionsfreies ÜL (Monate) Medianes Gesamtüberleben (Monate) 1-Jahres Überleben 2-Jahres Überleben 3-Jahres Überleben 4-Jahres Überleben Mediane Dauer Ansprechen (Monate) Dabrafenib + Trametinib¹ 69% % 53% 44% 12.9 Vemurafenib + Cobimetinib² 7% % 49% 39% 35% 13. Encorafenib + Binimetinib³ 64-76% % 58% 47% ¹COMBI-D/COMBI-V (Schadendorf et al. EJC 217); ²coBRIM (McArthur et al., SMR 216, Ascierto Lancet Oncol 216, Dreno ASCO 218); ³Columbus (Dummer R et al., SMR 216, ASCO 218).

50 Melanom palliativ Sequenzen? Welche Erstlinientherapie? Reinduktionen? Kombinationen?

51 Activity of Targeted Therapy After Failure of First-Line Immunotherapy in BRAF-Mutant Metastatic Melanoma Xia CY et al. Poster Session Melanoma/Skin Cancers Abstract No. 9532

52 Methods Patients with BRAF V6 mutant metastatic melanoma who progressed on 1 or more lines of immunotherapy and were then treated with BRAF/MEKi were identified from 6 centres. Disease characteristics, treatment details, RECIST response and survival data were retrospectively examined. Where patients ceased BRAF/MEKi for toxicity prior to first response assessment, best response was deemed as progressive disease (PD). Mod. Xia CY et al. ASCO 218, Poster Session Melanoma/Skin Cancers, Abstract No. 9532

53 Results Patient characteristics at start of first line IT Total 79 Age at diagnosis (years) Mean (SD) 57. (14.4) Median range 59. (2., 86.) Gender Female 29 (37%) Male 5 (63%) Primary melanoma type Cutaneous non-acral 68 (86%) Acral 1 (1%) Mucosal 1 (1%) Occult 9 (12%) BRAF mutation V6E 67 (85%) V6K 1 (13%) V6M 1 (1%) V6R 1 (1%) Mod. Xia CY et al. ASCO 218, Poster Session Melanoma/Skin Cancers, Abstract No. 9532

54 Results 1 st line Immunotherapy Best Response with 1 st line IT PD1 Monotherapy PD1 + Ipilimumab Blinded PD1 vs. PD1 + Ipilimumab Ipilimumab Monotherapy PD1 +/-TVEC CR PR SD PD % pts (44%) received prior PD-1 based therapy 11% 17% % Median duration of treatment 9 weeks (1, 94) Mod. Xia CY et al. ASCO 218, Poster Session Melanoma/Skin Cancers, Abstract No. 9532

55 Results BRAF/MEKi treatment Best Response with BRAF/MEKi after IT failure Trametinib Dabrafenib + Trametinib Vemurafenib + Cobimetinib Dabrafenib Vemurafenib CR PR SD PD pts (68%) received combination BRAF + MEKi 29% 5% 52 11% 55% Median duration of treatment 21 weeks (1, 299) Mod. Xia CY et al. ASCO 218, Poster Session Melanoma/Skin Cancers, Abstract No. 9532

56 Results BRAF/MEKi treatment 2 18 Trametinib Dabrafenib Dabrafenib + Trametinib Vemurafenib Vemurafenib + Cobimetinib 52 Best Response with 1 st Line IT CR PR SD PD 5% 29% 11% 55% pts (68%) received Combination BRAF + MEKi Median duration of treatment 21 weeks (1, 299) In the 35 (44%) pts that had received prior PD1 antibodies: Overall Response Rate was 66% Median PFS was 4.1 months ( ) Median OS was 13.6 months (1.2 NA) ORR in pts treated with 1 st line PD1 based therapy (N=35) PR 22 (63%) CR 1 (3%) SD 2 (6%) PD 1 (28%) ORR in pts treated with 1 st line Ipilimumab monotherapy (N=44) PR 21 (48%) CR 3 (7%) SD 7 (16%) PD 13 (29%) Mod. Xia CY et al. ASCO 218, Poster Session Melanoma/Skin Cancers, Abstract No. 9532

57 Results PFS from BRAF/MEKi treatment Progression-free survival Median (95% CI): 4.4 (3.5, 6.2) months 12 month PFS 17% OS from BRAF/MEKi treatment 67% Follow-up time (months) Median (95% CI): 18. (14.6, 4.3) months 39% Alive at 3 years Overall survival 45% 39% 65% pts had subsequent treatment, including PD1 antibodies in 5% Follow-up time (months) Numbers at risk Mod. Xia CY et al. ASCO 218, Poster Session Melanoma/Skin Cancers, Abstract No. 9532

58 Conclusions This is the first study to examine efficacy of BRAF/MEKi after immunotherapy failure in metastatic melanoma. BRAF/MEKi have efficacy in BRAF V6+ patients previously treated with immunotherapy. 1,2 Despite having more adverse characteristics than seen in first-line trials, the response rate appears similar. 1,3,4,5,7 Results suggest that BRAF/MEKi is effective after failure of immunotherapy, supporting the use of first-line immunotherapy in selected BRAF-mutant melanoma patients. 4,6 1. Ackermann A et al. Cancer 214;12: ; 2.Wolchok et al. ASCO 216; 3. Long GV et al. Ann Oncol 217 Jul 1;28(7): ; 4. Robert C et al. N Engl J Med 215; 372:3-39; 5. Larkin et al. N Engl J Med 215;373:23-34; 6. Jang S et al. Lancet Oncol 213; 14: e6-e69; 7. Robert C et al. 215 Abstract 331 Mod. Xia CY et al. ASCO 218, Poster Session Melanoma/Skin Cancers, Abstract No. 9532

59 Epacadostat Plus Pembrolizumab Versus Pembrolizumab Alone in Patients With Unresectable or Metastatic Melanoma: Results of the Phase 3 ECHO-31/KEYNOTE- 252 Study Long GV et al. Clinical Science Symposium - Compelling Combinations: Raising the Bar With Immunotherapy Abstract No. 18

60 Background: Rationale for Combination and Dosing Treatment-Naive Melanoma Phase 1/2 (n=54) Best Change From Baseline, % ORR=55% Epacadostat 1 mg BID + Pembrolizumab 2 mg Q3W Other Epacadostat doses + Pembrolizumab 2 mg Q3W ECHO-22/KEYNOTE-37 Phase 1: Epacadostat 5, 1, or 3 mg PO BID + Pembrolizumab 2 mg IV Q3W MTD of Epacadostat not reached Phase 2: Epacadostat 1 mg PO BID Phase 1/2 efficacy in treatmentnaive melanoma: ORR=55% Median PFS=22.8 mo (12.4 mo all melanoma) Patients BID, twice daily; MTD, maximally tolerated dose; PD-L1, programmed death ligand-1; Q3W, every 3 weeks. Hamid O, et al. Ann Oncol. 217;28(suppl 5):1214O. Mod. Long GV et al. ASCO 218, Clinical Science Symposium - Compelling Combinations: Raising the Bar With Immunotherapy, Abstract No. 18

61 Study Design: Phase III Randomized Controlled Trial Key Eligibility Criteria Unresectable stage III or IV melanoma, advanced/metastatic disease Patients with BRAF mutation could have received prior BRAF/MEK therapy Prior anti-ctla-4 or interferon in adjuvant setting permitted ECOG performance status -1 No active CNS metastases Stratification PD-L1 status (positive a vs. negative) BRAF mutation status Wild type Mutant with prior BRAF-directed therapy Mutant without prior BRAF-directed therapy N=76 R 1:1 Epacadostat 1 mg PO BID + Pembrolizumab 2 mg IV Q3W n=354 Placebo + Pembrolizumab 2 mg IV Q3W n=352 Primary endpoints: PFS (RECIST v1.1) and OS Secondary endpoints: ORR (RECIST v1.1), DOR, safety BID, twice daily; DOR, duration of response; ECOG, Eastern Cooperative Oncology Group; ORR, objective response rate; OS, overall survival; PD-L1, programmed death ligand 1; PFS, progression free survival; Q3W, every 3 weeks; RECIST, Response Evaluation Criteria In Solid Tumors. a 1% staining in tumor and adjacent immune cells as assessed by IHC (22C3 antibody). Mod. Long GV et al. ASCO 218, Clinical Science Symposium - Compelling Combinations: Raising the Bar With Immunotherapy, Abstract No. 18

62 Treatment Disposition 76 patients randomized 72.5% PD-L % BRAF mutant 12.2% prior BRAF/MEK therapy Epacadostat + Pembrolizumab Placebo + Pembrolizumab 354 randomized a 352 randomized 226 Discontinued 151 progressive disease 47 adverse events 19 clinical progression 4 withdrawal by patient 2 complete response 2 non-study anti-cancer therapy 1 physician decision Median follow-up (range):12.4 ( ) months 219 Discontinued b 153 progressive disease 31 adverse events 24 clinical progression 3 complete response 3 physician decision 3 withdrawal by patient 2 non-study anti-cancer therapy PD-L1, programmed death ligand 1; a One patient randomized to the Epacadostat + Pembrolizumab group did not receive treatment; b 2 additional patients discontinued Placebo but continued receiving Pembrolizumab. Mod. Long GV et al. ASCO 218, Clinical Science Symposium - Compelling Combinations: Raising the Bar With Immunotherapy, Abstract No. 18

63 Progression-Free Survival (Recist v1.1, BICR) Events, n (%) Median PFS, months (95% CI) E + P 218 (61.6) 4.7 ( ) Progression-Free Survival (%) E + P Placebo + P 45.8% 45.8% 36.9% 36.6% Placebo + P 219 (62.2) 4.9 ( ) HR (95% CI): 1. ( ) p=.517 Number at risk E + P Placebo + P Time (months) BICR, blinded independent review; CI, confidence interval; E, Epacadostat; HR, hazard ratio; P, Pembrolizumab; PFS, progression-free survival; RECIST, Response Evaluation Criteria In Solid Tumors. PFS defined as time from randomization to disease progression or death, whichever occurred first. Mod. Long GV et al. ASCO 218, Clinical Science Symposium - Compelling Combinations: Raising the Bar With Immunotherapy, Abstract No. 18

64 Progression-Free Survival by Subgroups # Events/N HR (95% CI) Overall 437/76 1. ( ) Sex Female Male Age <65 65 Race White Non-white Disease Stage III IVM1a IVM1b IVM1c 182/ /423 24/ /33 372/626 65/79 18/26 44/82 82/ / ( ) 1.1 ( ).96 ( ) 1.1 ( ) 1.2 ( ).87 ( ).47 ( ).79 ( ).94 ( ) 1.11 ( # Events/N HR (95% CI) Overall 437/76 1. ( ) Baseline ECOG PS 1 BRAF Mutation Status BRAF wild type BRAF mutant, prior BRAF trt BRAF mutant, no prior BRAF trt Baseline LDH ULN >ULN but <2X ULN 2X ULN PD-L1 Status PD-L1+ PD-L1-318/ /178 24/392 59/86 138/ / /192 39/44 36/ / ( ) 1.18 ( ) 1.2 ( ) 1.31 ( ).88 ( ).89 ( ) 1.16 ( ) 1.21 ( ).97 ( ) 1.1 ( ) HR HR CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; LDH, lactate dehydrogenase; PD-L1, programmed death ligand 1; trt, treatment; ULN, upper limit of normal. Mod. Long GV et al. ASCO 218, Clinical Science Symposium - Compelling Combinations: Raising the Bar With Immunotherapy, Abstract No. 18

65 Overall Survival Overall Survival (%) E + P Placebo + P 84.1% 87.2% 74.4% 74.1% Events, Median OS, months n (%) (95% CI) E + P 16 (29.9) NR (NR, NR) Placebo + P 98 (27.8) NR (NR, NR) HR (95% CI): 1.13 ( ) p=.87 Number at risk E + P Placebo + P Time (months) CI, confidence interval; E, Epacadostat; HR, hazard ratio; NR, not reached; OS, overall survival; P, Pembrolizumab. Mod. Long GV et al. ASCO 218, Clinical Science Symposium - Compelling Combinations: Raising the Bar With Immunotherapy, Abstract No. 18

66 Overall Survival by Subgroups # Events/N HR (95% CI) Overall 24/ ( ) Sex Female Male Age <65 65 Race White Non-white Disease Stage IVM1a IVM1b IVM1c 84/283 12/ /376 92/33 171/626 33/79 14/82 33/ / ( ) 1.16 ( ) 1.13 ( ) 1.16 ( ) 1.19 ( ).7 ( ) 1.3 ( ) 1.9 ( ) 1.15 ( ) # Events/N HR (95% CI) Overall 24/ ( ) Baseline ECOG PS 1 BRAF Mutation Status BRAF wild type BRAF mutant, prior BRAF trt BRAF mutant, no prior BRAF trt Baseline LDH ULN >ULN but <2X ULN 2X ULN PD-L1 Status PD-L1+ PD-L1-131/528 73/ /392 23/86 58/228 14/463 65/192 33/44 149/512 55/ (.7-1.4) 1.41 ( ) 1.29 ( ) 1.39 ( ).78 ( ) 1.5 ( ) 1.2 ( ) 1.38 ( ) 1.4 ( ) 1.41 ( ) 1 HR HR 5 1 CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; LDH, lactate dehydrogenase; PD-L1, programmed death ligand 1; trt, treatment; ULN, upper limit of normal. Mod. Long GV et al. ASCO 218, Clinical Science Symposium - Compelling Combinations: Raising the Bar With Immunotherapy, Abstract No. 18

67 Best Objective Response (RECIST v1.1, BICR) Response, n (%) ORR CR PR Epacadostat + Pembrolizumab (n=354) 121 (34.2) 14 (4.) 17 (3.2) Placebo + Pembrolizumab (n=352) 111 (31.5) 15 (4.3) 96 (27.3) SD 59 (16.7) 68 (19.3) DCR (CR + PR + SD) 18 (5.8) 179 (5.9) PD 151 (42.7) 15 (42.6) Non-CR/Non-PD 1 (2.8) 9 (2.6) Not available or evaluable a 13 (3.7) 14 (4.) Median DOR (range), months NR (.+ to 14.7+) NR (.+ to 15.+) BICR, blinded independent central review; CR, complete response; DCR, disease control rate; DOR, duration of response; NR, not reached; ORR, objective response rate; PD, progressive disease; PR, partial response; RECIST, Response Evaluation Criteria In Solid Tumors; SD, stable disease. a Patient had no post-baseline imaging or had post-baseline imaging and the best objective response was determined to be non-evaluable per RECIST 1.1. Mod. Long GV et al. ASCO 218, Clinical Science Symposium - Compelling Combinations: Raising the Bar With Immunotherapy, Abstract No. 18

68 Summary of Adverse Events Patients, n (%) Epacadostat + Pembrolizumab (n=353) Placebo + Pembrolizumab (n=352) Treatment-related AEs a 28 (79.3) 285 (81.) Grade 3 treatment-related AEs 77 (21.8) 6 (17.) Serious treatment-related AEs 37 (1.5) 32 (9.1) Discontinued drug due to a treatment-related AE 39 (11.) 34 (9.7) Dose reductions Epacadostat/Placebo due to AE 12 (3.4) 6 (1.7) Dose interruptions (any treatment) due to AE 121 (34.3) 98 (27.8) AE, adverse event. a No patient died due to a treatment-related AE. Mod. Long GV et al. ASCO 218, Clinical Science Symposium - Compelling Combinations: Raising the Bar With Immunotherapy, Abstract No. 18

69 Conclusions The efficacy and safety of Pembrolizumab in this study are consistent with KEYNOTE-6 (Pembrolizumab vs. Ipilimumab for advanced melanoma) In patients with unresectable or metastatic melanoma, the addition of Epacadostat to Pembrolizumab did not result in greater clinical benefit than Pembrolizumab alone External Data Monitoring Committee recommendation Stop trial as study did not meet primary endpoint of PFS, and OS was not expected to reach statistical significance Additional analyses are underway to better understand these findings IDO1 expression by RNAscope Tumor mutation burden RNAseq Baseline Kyn and other blood-based markers IDO1, indoleamine 2,3 dioxygenase 1; Kyn, kynurenine. Mod. Long GV et al. ASCO 218, Clinical Science Symposium - Compelling Combinations: Raising the Bar With Immunotherapy, Abstract No. 18

70 Melanom palliativ - Kombinationen Pembrolizumab + Epacadostat: kein Vorteil Weitere vielversprechende Studienansätze PD1 + niedrig dosiertes Ipilimumab: Checkmate 511 PD1 + T-VEC intratumoral: Masterkey 265 PD1 + zielgerichtete Therapie: Trilogy, COMBI-i PD1 + TLR9 Liganden intratumoral PD1 + HDAC-Inhibitoren PD1 + andere Checkpoint-Inhibitoren (LAG3) PD1 + NKTR-214

71 Melanom adjuvant Melanom palliativ Nicht-melanozytäre Hauttumore

72 Kutanes Plattenepithelkarzinom PD-1 Blockade with Cemiplimab in Advanced Cutaneous Squamous-Cell Carcinoma Migden MR et al. N Engl J Med. 218 Jun 4. [Epub ahead of print]

73 Kutanes Plattenepithelkarzinom Baseline Characteristics of the Patients Characteristic Expansion Cohorts Metastatic-Disease of the Phase 1 StudyCohort of the Phase (N=26) 2 Study (N=59) Age Median (range) yr 73 (55-88) 71 (38-93) 65 yr no. (%) 21 (81) 43 (73) Male sex no. (%) 21 (81) 54 (92) ECOG performance status score 1 (38) 23 (39) no. (%) 1 16 (62) 36 (61) Primary site of cutaneous squamous-cell carcinoma no. (%) Previous systemic therapy for cutaneous squamous-cell carcinoma no. of patients (%) Previous radiotherapy for cutaneous squamous-cell carcinoma no (%) Extent of cutaneous squamouscell carcinoma no. (%) Head or neck 18 (69) 38 (64) Arm or leg 5 (19) 12 (2) Trunk 2 (8) 9 (15) Penis 1 (4) No regimens 8 (31) 26 (44) Any regimen 15 (58) 33 (56) 1 regimen 15 (58) 22 (37) 2 regimens 11 (19) 2 (77) 5 (85) Distant metastasis 8 (31) 45 (76) Regional metastasis only 8 (31) 14 (24) Locally advanced progression only 1 (38) Complete response Stable disease Target lesion could not be evaluated after the initiation of therapy Partial response Progressive disease Nontargeted lesion only Surgical removal of target lesion Ongoing treatment Ongoing participation in the study Tumor Response to Cemiplimab, as Assesd by Independent Central Review Outcome Expansion Cohorts of the Phase 1 Study (N=26) Metastatic-Disease Cohort of the Phase 2 Study (N=59) Complete response 4 (7) Best Partial response 13 (5) 24 (41) overall Stable disease 6 (23) 9 (15) response Progressive disease 3 (12) 11 (19) no. (%) Could not be evaluated 3 (12) 7 (12) Nontarget lesion onlyʃ 1 (4) 4 (7) Objective response - % (95% CI) 5 (3-7) 47 (34-61) Durable disease control - % (95% CI) 65 (44-83) 61 (47-74) Median observed time to response (range) mo 2.3 ( ) 1.9 (1.7-6.) Tumor Response over Time for 28 Patients in the Phase 2 Study Patients Who Had a Response Months Mod. Migden MR et al. N Engl J Med. 218 Jun 4. [Epub ahead of print]

74 Merkelzellkarzinom Update der Studien zu Pembrolizumab (PD-1) und Avelumab (PD-L1) In der Erstlinie deutlich wirksamer (ORR ca. 6%) als nach Chemotherapie (ORR ca. 3%) Ansprechen dauerhaft