Overall Survival in COLUMBUS: A Phase 3 Trial of Encorafenib (ENCO) Plus Binimetinib (BINI) vs Vemurafenib (VEM) or ENCO in BRAF-Mutant Melanoma

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1 Overall Survival in COLUMBUS: A Phase 3 Trial of Encorafenib (ENCO) Plus Binimetinib (BINI) vs Vemurafenib () or ENCO in BRAF-Mutant Melanoma, Paolo A. Ascierto, Helen J. Gogas, Ana Arance, Mario Mandala, Gabriella Liszkay, Claus Garbe, Dirk Schadendorf, Ivana Krajsova, Ralf Gutzmer, Vanna Chiarion-Sileni, Caroline Dutriaux, Jan Willem B. de Groot, Naoya Yamazaki, Carmen Loquai, Laure A. Moutouh-de Parseval, Michael D. Pickard, Victor Sandor, Caroline Robert, Keith T. Flaherty 1

2 Background BRAFi/MEKi combinations are established as a standard of care for the treatment of advanced BRAF V600 -mutant melanoma with median PFS ( 12 months) and OS ( 24 months) 1-3 Approved combinations have unique toxicities that may impact the ability to deliver optimal treatment Dabrafenib/trametinib is associated with pyrexia 2,3 Vemurafenib/cobimetinib is associated with photosensitivity 4 ENCO has a unique pharmacologic profile with an on-target dissociation half-life of >30 hours, leading to sustained target inhibition 5 BINI has a shorter half-life than other MEKi; dose modification may be easier 6 Promising clinical activity and tolerability were demonstrated with ENCO + BINI in a phase 1b/II study 5,7 BINI=binimetinib; BRAFi=BRAF inhibitor; ENCO=encorafenib; MEKi=MEK inhibitor; OS=overall survival; PFS=progression-free survival 1. Chapman PB, et al. N Engl J Med. 2011;364(26): Robert C, et al. N Engl J Med. 2015;372(1): Long GV, et al. Lancet. 2015;386(9992): Ascierto PA, et al. Lancet Oncol. 2016;17: Delord JP, et al. Clin Cancer Res. 2017;23: Data on File. Array BioPharma Inc. 7. Sullivan RJ, et al. J Clin Oncol. 2015;33:

3 Study Design and Objectives COLUMBUS Part 1 Untreated or progressed on/after prior first-line immunotherapy BRAF V600E and/or BRAF V600K ECOG PS 0 1 R 1:1:1 (N=577) Encorafenib 450 mg QD + Binimetinib 45 mg BID () Vemurafenib 960 mg BID (n=191) Encorafenib 300 mg QD (n=194) COLUMBUS Part 2* R 3:1 (N=344) COMBO300 Encorafenib 300 mg QD + Binimetinib 45 mg BID (n=258) Encorafenib 300 mg QD (n=86) Efficacy update with additional follow-up of 18 months: OS: Secondary endpoint Planned after 232 events in the and groups combined Median duration of follow-up : 36.8 months PFS: Primary endpoint Median duration of follow-up : 32.1 months =encorafenib 450 mg QD + binimetinib 45 mg BID; ECOG PS=Eastern Cooperative Oncology Group performance status; OS=overall survival; PFS=progression-free survival; R=randomization; =vemurafenib 960 mg BID. *Amendment requested by FDA. Included in hierarchical testing approach. Median follow-up of patients assessed using reverse Kaplan-Meier approach (i.e. median potential follow-up). 3

4 Progression-Free Survival (%) Study Design and Objectives COLUMBUS Part 1 Untreated or progressed on/after prior first-line immunotherapy BRAF V600E and/or BRAF V600K ECOG PS 0 1 R 1:1:1 (N=577) Encorafenib 450 mg QD + Binimetinib 45 mg BID () Vemurafenib 960 mg BID (n=191) Encorafenib 300 mg QD (n=194) Median PFS in months (95% CI) 14.9 ( ) 7.3 ( ) HR (95% CI), 0.54 ( ) P< Time (mo) Dummer, R et al. Lancet Oncol. 2018; 19(5): Efficacy update with additional follow-up of 18 months: OS: Secondary endpoint Planned after 232 events in the and groups combined Median duration of follow-up : 36.8 months PFS: Primary endpoint Median duration of follow-up : 32.1 months =encorafenib 450 mg QD + binimetinib 45 mg BID; ECOG PS=Eastern Cooperative Oncology Group performance status; OS=overall survival; PFS=progression-free survival; R=randomization; =vemurafenib 960 mg BID. *Amendment requested by FDA. Included in hierarchical testing approach. Median follow-up of patients assessed using reverse Kaplan-Meier approach (i.e. median potential follow-up). 3

5 Patient Disposition Variable, % n=194 n=191 Untreated 0 1% 3% Discontinued treatment 78% 87% 91% Progressive disease 52% 52% 57% Adverse event 10% 13% 13% Physician or patient decision* 10% 21% 18% Death 4% 1% 2% Other 1% 1% 1% Treatment ongoing 22% 12% 7% =encorafenib 450 mg QD + binimetinib 45 mg BID; =encorafenib 300 mg QD; =vemurafenib 960 mg BID. *Physician or patient/guardian decision. Includes protocol violation, lost to follow-up, and new therapy for study indication. As of the data cutoff date of November 7,

6 Baseline Characteristics Characteristic n=194 n=191 Median age (range), years 57 (20 89) 54 (23 88) 56 (21 82) Male sex 60% 56% 58% ECOG performance status 0 71% 72% 73% LDH > ULN 29% 24% 27% LDH ULN 71% 76% 73% BRAF mutation status (BRAF V600E /BRAF V600K ) 89%/12% 89%/10% 88%/12% Tumor stage at study entry IIIB/IIIC 5% 3% 6% IVM1a 14% 15% 13% IVM1b 18% 20% 16% IVM1c 64% 62% 65% Number of organs involved 1 25% 29% 24% 2 30% 27% 31% 3 45% 44% 46% =encorafenib 450 mg QD + binimetinib 45 mg BID; ECOG=Eastern Cooperative Oncology Group; =encorafenib 300 mg QD; LDH=lactate dehydrogenase; ULN=upper limit of normal; =vemurafenib 960 mg BID. 6

7 Previous Immunotherapy Adjuvant/neoadjuvant settings n=194 n=191 Ipilimumab* 1% 1% 1% Interferons/interleukins Adjuvant 24% 24% 24% Neoadjuvant 0 1% 1% Advanced/metastatic settings n=194 n=191 Ipilimumab* 3% 5% 3% Anti PD-1 or anti PD-L1*, 1% 1% 0 Interferons/interleukins 2% 2% 3% =encorafenib 450 mg QD plus binimetinib 45 mg BID; =encorafenib 300 mg QD; PD-1=programmed death 1; PD-L1=programmed death ligand 1; =vemurafenib 960 mg BID. *A patient may have received ipilimumab and anti PD1/PD-L1 in combination. Includes interferon, interferon α, interferon α-2a, interferon α-2b, and interferon β. Nivolumab. Includes interferon, interferon α-2b, and interleukin-2. 7

8 Systemic Treatment Following Study Drug Discontinuation Treatment received after study drug* n=194 n=191 Any treatment 42% 56% 62% Anti PD-1/anti PD-L1 20% 21% 25% Anti CTLA-4 17% 16% 19% Anti CTLA-4 + anti PD-1/anti PD-L1 3% 2% 2% BRAFi + MEKi 5% 14% 20% BRAFi 6% 8% 13% Chemotherapy 7% 12% 12% Other 3% 2% 7% BRAFi=BRAF inhibitor; =encorafenib 450 mg QD + binimetinib 45 mg BID; CTLA-4=cytotoxic T-lymphocyte-associated protein 4; =encorafenib 300 mg QD; MEKi=MEK inhibitor; PD-1=programmed death 1; PD-L1=programmed death ligand 1; =vemurafenib 960 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. 8

9 Use of Checkpoint Inhibitors as First Post-Study Treatment Treatment received after study drug* n=194 n=191 Anti PD-1/anti PD-L1 20% 21% 25% Used first after study drug 12% 14% 13% Anti CTLA-4 17% 16% 19% Used first after study drug 15% 13% 15% Anti CTLA-4 + anti PD-1/anti PD-L1 3% 2% 2% Used first after study drug 2% 0 1% =encorafenib 450 mg QD + binimetinib 45 mg BID; CTLA-4=cytotoxic T-lymphocyte-associated protein 4; =encorafenib 300 mg QD; PD-1=programmed death 1; PD-L1=programmed death ligand 1; =vemurafenib 960 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. 9

10 Overall Survival, % Overall Survival: vs Median OS in months (95% CI) 33.6 ( ) 16.9 ( ) HR (95% CI), 0.61 ( ) Nominal 2-sided P< Censored patients Patients at risk Time (months) =encorafenib 450 mg QD + binimetinib 45 mg BID; HR=hazard ratio; OS=overall survival; =vemurafenib 960 mg BID. 10

11 Overall Survival, % Overall Survival Landmark Data: vs : 76% : 63% : 58% : 43% : 47%* : 32% Censored patients Patients at risk Time (months) =encorafenib 450 mg QD + binimetinib 45 mg BID; =vemurafenib 960 mg BID. *3-year rates are not fully mature. 11

12 Overall Survival in Subgroups: vs Subgroup No. of Events/Patients Hazard Ratio (95%CI) All patients 232/ ( ) Sex Male Female 144/226 88/ ( ) 0.57 ( ) Age < /272 68/ ( ) 0.71 ( ) BRAF mutation V600E V600K 208/338 24/ ( ) 0.31 ( ) LDH ULN >ULN 140/276 92/ ( ) 0.95 ( ) ECOG PS=0 PS=1 158/279 74/ ( ) 0.53 ( ) Tumor stage IIIb, IIIc, IVM1a,or IVM1b IVM1c 88/ / ( ) 0.59 ( ) No. of organs involved at baseline >3 42/92 67/117 57/87 66/ ( ) 0.63 ( ) 0.50 ( ) 0.85 ( ) Better Better =encorafenib 450 mg QD + binimetinib 45 mg BID; ECOG=Eastern Cooperative Oncology Group; LDH=lactate dehydrogenase; PS=performance status; ULN=upper limit of normal; =vemurafenib 960 mg BID. 12

13 Overall Survival, % Overall Survival: vs Median OS in months (95% CI) 33.6 ( ) 23.5 ( ) HR (95% CI), 0.81 ( ) Nominal 2-sided P= Censored patients Patients at risk Time (months) =encorafenib 450 mg QD + binimetinib 45 mg BID; =encorafenib 300 mg QD; HR=hazard ratio; OS=overall survival. 13

14 Overall Survival, % Overall Survival: vs Median OS in months (95% CI) 23.5 ( ) 16.9 ( ) HR (95% CI), 0.76 ( ) Nominal 2-sided P=0.033 Patients at risk Censored patients Time (months) =encorafenib 300 mg QD; HR=hazard ratio; OS=overall survival; =vemurafenib 960 mg BID. 14

15 Progression-Free Survival, % Updated Progression-Free Survival: vs Median PFS in months (95% CI) 14.9 ( ) 7.3 ( ) HR (95% CI), 0.51 ( ) Nominal 2-sided P< Censored patients Patients at risk Time (months) =encorafenib 450 mg QD + binimetinib 45 mg BID; HR=hazard ratio; PFS=progression-free survival; =vemurafenib 960 mg BID. 15

16 Progression-Free Survival, % Updated Progression-Free Survival Landmark Data: vs : 56% : 33% : 37% : 20% : 28%* : 13%* Censored patients Patients at risk Time (months) =encorafenib 450 mg QD + binimetinib 45 mg BID; =vemurafenib 960 mg BID. *3-year rates are not fully mature and are based on small numbers of patients at risk. 16

17 Progression-Free Survival, % Progression-Free Survival, % Updated Progression-Free Survival Censored patients Patients at risk Time (months) vs Median PFS in months (95% CI) 9.6 ( ) 7.3 ( ) HR (95% CI), 0.68 ( ) Nominal 2-sided P= Median PFS in months (95% CI) 14.9 ( ) 9.6 ( ) HR (95% CI), 0.77 ( ) Nominal 2-sided P= =encorafenib 450 mg QD + binimetinib 45 mg BID; =encorafenib 300 mg QD; HR=hazard ratio; PFS=progression-free survival; =vemurafenib 960 mg BID vs Censored patients Time (months) Patients at risk

18 Confirmed Response Rates Confirmed Response n=194 n=191 Central Review Local Review Central Review Local Review Central Review Local Review ORR (95% CI)* 64% (57 70) 76% (69 81) 52% (44 59) 58% (50 65) 41% (34 48) 49% (42 57) CR 11% 19% 7% 10% 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% 40% 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) =encorafenib 450 mg QD + binimetinib 45 mg BID; CR=complete response; DCR=disease control rate; DOR=duration of response; =encorafenib 300 mg QD; ORR=overall response rate; PD=progressive disease; PR=partial response; SD=stable disease; =vemurafenib 960 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. 18

19 Confirmed Response Rates Confirmed Response n=194 n=191 Central Review Local Review Central Review Local Review Central Review Local Review ORR (95% CI)* 64% (57 70) 76% (69 81) 52% (44 59) 58% (50 65) 41% (34 48) 49% (42 57) CR 11% 19% 7% 10% 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% 40% 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) =encorafenib 450 mg QD + binimetinib 45 mg BID; CR=complete response; DCR=disease control rate; DOR=duration of response; =encorafenib 300 mg QD; ORR=overall response rate; PD=progressive disease; PR=partial response; SD=stable disease; =vemurafenib 960 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. 19

20 Confirmed Response Rates Confirmed Response n=194 n=191 Central Review Local Review Central Review Local Review Central Review Local Review ORR (95% CI)* 64% (57 70) 76% (69 81) 52% (44 59) 58% (50 65) 41% (34 48) 49% (42 57) CR 11% 19% 7% 10% 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% 40% 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) =encorafenib 450 mg QD + binimetinib 45 mg BID; CR=complete response; DCR=disease control rate; DOR=duration of response; =encorafenib 300 mg QD; ORR=overall response rate; PD=progressive disease; PR=partial response; SD=stable disease; =vemurafenib 960 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. 20

21 Confirmed Response Rates Confirmed Response n=194 n=191 Central Review Local Review Central Review Local Review Central Review Local Review ORR (95% CI)* 64% (57 70) 76% (69 81) 52% (44 59) 58% (50 65) 41% (34 48) 49% (42 57) CR 11% 19% 7% 10% 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% 40% 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) =encorafenib 450 mg QD + binimetinib 45 mg BID; CR=complete response; DCR=disease control rate; DOR=duration of response; =encorafenib 300 mg QD; ORR=overall response rate; PD=progressive disease; PR=partial response; SD=stable disease; =vemurafenib 960 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. 21

22 Confirmed Response Rates Confirmed Response n=194 n=191 Central Review Local Review Central Review Local Review Central Review Local Review ORR (95% CI)* 64% (57 70) 76% (69 81) 52% (44 59) 58% (50 65) 41% (34 48) 49% (42 57) CR 11% 19% 7% 10% 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% 40% 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) =encorafenib 450 mg QD + binimetinib 45 mg BID; CR=complete response; DCR=disease control rate; DOR=duration of response; =encorafenib 300 mg QD; ORR=overall response rate; PD=progressive disease; PR=partial response; SD=stable disease; =vemurafenib 960 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. 22

23 Confirmed Response Rates Confirmed Response n=194 n=191 Central Review Local Review Central Review Local Review Central Review Local Review ORR (95% CI)* 64% (57 70) 76% (69 81) 52% (44 59) 58% (50 65) 41% (34 48) 49% (42 57) CR 11% 19% 7% 10% 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% 40% 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) =encorafenib 450 mg QD + binimetinib 45 mg BID; CR=complete response; DCR=disease control rate; DOR=duration of response; =encorafenib 300 mg QD; ORR=overall response rate; PD=progressive disease; PR=partial response; SD=stable disease; =vemurafenib 960 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. 23

24 Overall Summary of Safety Event Median Duration of Exposure: 51 weeks Median Duration of Exposure: 31 weeks n=186 Median Duration of Exposure: 26 weeks Adverse events 98% 99% 100% Grade 3/4 adverse events 64% 67% 66% Adverse events leading to discontinuation Adverse events leading to dose reduction/interruption 15% 15% 17% 53% 71% 62% On-treatment deaths* 12% 8% 11% =encorafenib 450 mg QD + binimetinib 45 mg BID; =encorafenib 300 mg QD; =vemurafenib 960 mg BID. *Includes on-treatment deaths and deaths within 30 days of stopping study treatment. 24

25 Patient (%) Groupings of AEs Associated With BRAFi and MEKi Initial analysis Updated analysis Initial analysis Updated analysis Initial analysis Updated analysis Rash Serous retinopathy Pyrexia Transaminases increased Skin papilloma LVD Photosensitivity CuSCC Dermatitis acneiform BCC Increased bilirubin Terms represent groupings of similar or related adverse events. BCC=basal cell carcinoma; BRAFi=BRAF inhibitor; =encorafenib 450 mg QD + binimetinib 45 mg BID; CuSCC=cutaneous squamous cell carcinoma; =encorafenib 300 mg QD; LVD=left ventricular dysfunction; MEKi=MEK inhibitor; =vemurafenib 960 mg BID. 25

26 Conclusions showed improved OS vs : 33.6 mo vs 16.9 mo (HR 0.61; nominal 2-sided P<0.0001) Updated PFS results remained the same as previously reported: median PFS 14.9 mo 1 Performance of in COLUMBUS was 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 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 V600 -mutant melanoma BRAFi=BRAF inhibitor; =encorafenib 450 mg QD + binimetinib 45 mg BID; HR=hazard ratio; MEKi=MEK inhibitor; OS=overall survival; PFS=progression-free survival; =vemurafenib 960 mg BID. 1. Dummer R, et al. Lancet Oncol. 2018;19: Robert C, et al. Eur J Cancer. 2015;51:S663-S Ascierto PA, et al. Lancet Oncol. 2016;17: Long GV, et al. Ann Oncol. 2017;28:

27 Acknowledgments The authors thank the patients, their families, and the sites participating in this study. This study was sponsored by Array BioPharma Inc., with funding support from Novartis Pharmaceuticals Corporation. 27