Beyond BRAFi/MEKi: Combination and Sequencing Approaches for in Patients with Metastatic BRAF V600 Mutant Melanoma:

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1 Beyond BRAFi/MEKi: Combination and Sequencing Approaches for in Patients with Metastatic BRAF V600 Mutant Melanoma: Michael B. Atkins, M.D. Deputy Director Georgetown-Lombardi Comprehensive Cancer Center

2 Disclosures Consultant Amgen BMS Genentech GSK Merck Neostem Novartis

3 BRAF/MEK Inhibitor Therapy Dabraf/Tramet produces superior efficacy to Dabraf alone without significant extra toxicity Similar results seen with Co-Brim and Combi-V trials (ESMO 2014) Ongoing/Future studies Adjuvant Dabraf/Tramet vs placebo or vemu vs placebo Sequence with immunotherapy Triple drug combinations Bev (MRFBC), PI3Ki, CDK4i, immunotherapy

4 Treatment for BRAF Mutant Melanoma Proportion Surviving Which is preferred? Ipilimumab BRAFi Years after stage IV diagnosis PRESENTED BY: Michael B. Atkins

5 The case for immunotherapy--- Immunotherapy produces durable treatment free tumor responses while BRAF inhibitors do not Benefit relative to other therapies largely confined to pts with M1C disease Immunotherapy works as well against BRAFV600 mutant melanoma as WT tumors BRAF inhibitors work as well in pts with prior immune therapy; the converse may not be so Immunotherapy is getting better Better drugs? Better patient selection

6 High Dose IL-2 Therapy* RR: 16% (43 / 270) Some large volume and visceral Most soft tissue and lung Durable responses Median 8.9 mos CR: not reached *Atkins et al JCO, 1999 (N=270) Survival Median 12 mos 11% >@ 5yrs

7 Primary Analysis of Pooled OS Data: 1861 Pts Median OS (95% CI): 11.4 ( ) Proportion Alive year OS Rate (95% CI): 22% (20 24%) Ipilimumab CENSORED Patients at Risk Months Ipilimumab Hodi et al ECCO 2013

8 BRAF inhibitor Therapy - Limitations Median PFS of only 6-7 months of single agent Median OS months Forrest plot suggests most of the benefit confined to patients with M1c disease Sosman et al NEJM 2012, Chapman et al ASCO 2012

9 BRIM 3 - Overall survival by baseline characteristic (February 01, 2012 cut-off) censored at crossover Factor Number of patients Favors vemurafenib Favors dacarbazine All patients 675 Age: <65 years years 161 Sex: ECOG status: 0 1 Female Male Disease stage: IIIc M1a M1b M1c LDH: Normal Elevated Chapman et al NEJM Hazard ratio and 95% confidence interval 20

10 BRAF inhibitor Therapy - Limitations Median PFS of only 6-7 months Median OS months Forest plot suggests most of the benefit confined to patients with M1c disease Combination BRAF-MEK inhibition may offer some advantages, but median PFS still only 7-10 months

11 COMBI-d: PFS by Baseline Characteristics* Factor Number of patients Favours dabrafenib + trametinib Favours dabrafenib All patients 423 Age: <65 yrs yrs 118 BRAF mut: V600E V600K Stage: IIIc/M1a/M1b* M1c LDH : N o Disease Sites 2* 3 Normal* Elevated *Low n o of events data immature Hazard ratio and 95% Confidence Interval Presented by: Georgina V. Long

12 The case for immunotherapy--- Immunotherapy produces durable treatment free tumor responses while BRAF inhibitors do not Immunotherapy works as well against BRAFV600 mutant melanoma as WT tumors BRAF inhibitors work as well in patients with prior immune therapy; the converse is not so Immunotherapy is getting better Better drugs? Better patient selection

13 Relationship of MAPKinase pathway mutations and response to HD IL-2 Mutation All CR/PR SD/PD P-value BRAF 60 14(23%) 46 (77%) NRAS 15 7 (47%) 8 (53%) 0.05 WT 26 3 (12%) 23 (88%) A significantly larger proportion of patients with BRAF or NRAS mutant tumors achieved CR/PR compared to those with WT tumors. Joseph, Sullivan et al- JIT 2011

14 No Association Between BRAF or NRAS Mutation Status and Response to Ipilimumab 14 Expanded Access Program: Patient Response vs BRAF Genotype 2 BRAFV600 mutation status NRAS mutation status Response according to Positive irrc, n (%) Negative Positive Negative a (n=20) (n=59) (n=4) (n=75) CR 2 (10) 3 (5) 1 (25) 4 (5) PR 6 (30) 14 (24) 1 (25) 19 (25) SD 3 (15) 19 (32) 1 (25) 21 (28) PD 9 (45) 23 (39) 1 (25) 31 (41) BORR (CR + PR) 8 (40) 17 (29) P= (50) 23 (31) P=0.42 DCR (CR + PR + SD) 11 (61) 36 (55) P= (75) 44 (49) P= year overall survival 58% 48% P= % 49% P=0.66 a Data missing from 1 patient. BORR=best overall response rate; CR=complete response; DCR=disease control status; irrc=immune-related response criteria; PR=partial response; SD=stable disease; PD=progressive disease; WT=wild type Simone et al. Presented at: ASCO Annual Meeting; June 1-5, 2012; Chicago, IL.

15 Ipi/Nivo Study: ORR and Tumor Burden Change by BRAF Mutation Status Cohort(s) [N * ] Evaluable Sample, N ORR, n/n (%) BRAF WT BRAF MT 1 3 [53] 51 18/39 (46) 3/12 (25) 8 [41] 39 10/27 (37) 6/12 (50) * Number of patients treated. MT=mutant (BRAFT V600 mutation positive); WT=wild type (BRAF V600 mutation negative). Maximum Response From Baseline in Target Lesion (%) Cohorts 1 3 Cohort JUNE 2014 data analysis. BRAF MT BRAF WT BRAF Unknown Kluger et al presented at SMR 11/14 15

16 The case for immunotherapy--- Immunotherapy produces durable treatment free tumor responses while BRAF inhibitors do not Immunotherapy works as well against BRAFV600 mutant melanoma as WT tumors BRAF inhibitors work as well in patients with prior immune therapy; the converse is not so Immunotherapy is getting better Better drugs? Better patient selection

17 BRIM2- ORR by pre-defined subgroups 80 Overall response rate (%) All treated patients Overall ORR of 53% (IRC) RR (size proportional to the number of patients in the subgroup) 95% Confidence intervals <65 65 Age Ribas et al ASCO 2011 F M Sex 0 1 ECOG PS M1a/ M1b M1c Stage 1 >1 # prior therapies Baseline characteristics Yes No Previous IL-2 Normal x ULN >1.5x ULN LDH at enrollment

18 BRAF inhibition Equally Effective in Patients with prior immunotherapy MAPKi PFS IT initially PFS 6.7 mo (CI mo) MAPKi initially PFS 5.6 mo (CI mo) p-value 0.43, log rank MAPKi OS IT initially OS 19.6 mo (CI mo) MAPKi initially OS 13.4 mo (CI mo) OS (probability) p-value 0.40, log rank Time (mo) Ackerman/Sullivan-BIDMC/MGH-Cancer 2014

19 Immunotherapy following MAPKI: DFHCC/MIA Retrospective Data 193 patients discontinued MAPKi therapy (176 with disease progression) Median OS 2.9 mos (CI mos) from last dose of MAPKi Single agent ipilimumab treatment (n=34 pts) No tumor responses (2 SD) Median PFS 2.7 mos, median OS 5 mos 50% of patients received < 4 doses All Pts alive > 1 year- are back on MAPK inhibitors inhibitors Summary: Patients progressing on BRAFi appear unlikely to respond to ipilimumab Those alive either had slow growing disease and short period of RAFi treatment due to toxicity or are back on a RAFi Ackerman/Sullivan-BIDMC/MGH-Cancer 2014

20 Ipilimumab following BRAF inhibitor Therapy PFS 2.7 mo (CI mo) OS 5.0 mo (CI mo) OS (probability) long term survivors all treated with additional MAPKi Time (mo) Ackerman/Sullivan-BIDMC/MGH-Cancer 2014

21 Overall survival for patients who received a BRAFi followed by ipilimumab or ipilimumab followed by a BRAFi Median follow-up of 11 months (range: 1 34) PFS (%) Median OS BRAF inhibitor then lpilimumab: 9.9 months (95% CI: ) lpilimumab then BRAF inhibitor: 14.5 months (95% CI: ) lpilimumab then BRAF inhibitor (n=48) 20 BRAF inhibitor then ipilimumab (n=45) Time (months) Median OS in patient subgroups unbalanced at baseline (Ipi-BRAFi vs BRAFi-Ipi) Elevated LDH: 14 months (95% CI: ) vs 7.5 months (95% CI ) respectively Brain metastasis: 12.3 months (95% CI: ) vs 7.5 months (95% CI ) respectively Ascierto et al JCO

22 Treatment Selection in Patients with BRAF Mutant Melanoma: Conclusions BRAFi therapy may not be the best initial option for all patients with BRAF V600E melanoma. Current data suggests that for many patients with BRAFV 600E melanoma starting with immunotherapy offers them a chance for longterm benefit without compromising their benefit from subsequent BRAFi therapy

23 Two shots on goal are better than one

24 The case for immunotherapy--- Immunotherapy produces durable treatment free tumor responses while BRAF inhibitors do not Immunotherapy works as well against BRAFV600 mutant melanoma as WT tumors BRAF inhibitors work as well in patients with prior immune therapy; the converse is not so Immunotherapy is getting better Better drugs? Better patient selection

25 Vemurafenib vs. Nivolumab/Ipilimumab Vemurafenib Nivolumab and Ipilimumab Chapman et al NEJM Wolchok, Sznol et al NEJM 2013 Presented by: Walter J. Urba, MD, PhD

26 Responses May Be Durable Overall Survival for Concurrent Therapy by Dose Cohort Yr OS 85% 1 Yr OS 94% 2 Yr OS 88% 2 Yr OS 79% Survival (%) Censored 1 Yr OS 57% Nivo 0.3 mg/kg + IPI 3 mg/kg (n=14) Nivo 1 mg/kg + IPI 3 mg/kg (n=17) Nivo 3 mg/kg + IPI 1 mg/kg (n=16) Nivo 3 mg/kg + IPI 3 mg/kg (n=6) Concurrent Cohorts 1-3 (n=53) 2 Yr OS 50% Months Presented by: Mario Sznol

27 Response Based on Tumor PD-L1 Expression (Central Review, RECIST v1.1) PD-L P = a PD-L1 + Rate, % a 1-sided P values calculated by logistic regression, adjusting for dose/schedule. PD-L1 positivity defined as staining in 1% of tumor cells. 125 patients were evaluable for PD-L1 expression. Analysis cut-off date: October 18, Daud A et al. Presented at: 2014 Annual AACR Meeting; April 5-9, 2014; San Diego, CA. 0 Unselected PD-L1 + PD-L1 Overall Response Rate Presented by: Antoni Ribas

28 ORR by PD L1 Status (5% cutoff) Cohort [n] Evaluable Samples ORR, n (%) PD L1 Status PD L1+ PD L1 Concurrent Cohorts 1 3 [53] 36 8/14 (57) 9/22 (35) Cohort 8 [41; Nivo1 + IPI3 ] 20 0/0 8/20 (40) Sequenced [33] 23 5/8 (63) 3/15 (20) Maximum % Response in Baseline Target Lesions Concurrent Cohorts 1-3 Patient PD-L1 Status Positive Negative Presented by: Sznol et al ASCO 2014

29 Treatment Selection in Patients with BRAF Mutant Melanoma: Conclusions (2) Newer immunotherapies are approaching the efficacy (RR and PFS) of BRAFi with more durability

30 Immunotherapy may even be the better of the two shots

31 The case for molecularly targeted therapy--- Activity of BRAF/MEKi therapy may be better than advertised produces tumor responses in the majority of patients Responses and median OS are best in patients with M1a/b disease with normal LDH Durable CRs are being observed Responses being reported with PD1 pathway blockers in patients resistant to BRAF/MEKi Toxicity of BRAF/MEK may be worse after immunotherapy

32 Dabraf/Trametinib Phase I Trial Part C 150/2 Arm: Overall Survival in Subgroups M1c Number of patients M1a/M1b Died 28 (74%) 4 (25%) Overall survival at 12 months (95% CI) 76% (59%-87%) 88% (59%-97%) Overall survival at 24 months (95% CI) 42% (26%-57%) 74% (45%-90%) LDH > ULN Number of patients LDH </= ULN Died 20 (91%) 12 (38%) Overall survival at 12 months (95% CI) 68% (45%-83%) 88% (70%-95%) Overall survival at 24 months (95% CI) 18% (6%-36%) 75% (56%-86%) Johnson, D. et al 2014

33 The case for molecular targeted therapy--- Activity of BRAF/MEKi therapy may be better than advertises Produces tumor responses in the majority of patients Responses and median OS are best in patients with M1a/b disease with normal LDH. Durable CRs are being observed Responses being reported with PD1 pathway blockers in patients resistant to BRAF/MEKi Toxicity of BRAF/MEK may be worse after immunotherapy

34 Ipilimumab + nivolumab response at 12 weeks Prior therapy with HD-IL2, multiple resections, Vemurafenib, and RT; LDH > 2000 at baseline; LDH nearly normal within 3 weeks Presented by Sznol et al ASCO 2014

35 Nivo 037 Study: ORR in Patient Subgroups By Central Review per RECIST 1.1 N ORR, n/n (%) Nivolumab ICC Favors ICC OVERALL /120 (32) 5/47 (11) BRAF Status Mutant 37 6/26 (23) 1/11 (9) Wild-type /94 (34) 4/36 (11) Prior ipilimumab benefit Yes 55 12/40 (30) 2/15 (13) No /80 (33) 3/32 (9) PD-L1 status Positive a 77 24/55 (44) 2/22 (9) Negative 87 13/64 (20) 3/23 (13) Favors nivolumab Weber et al ESMO Unweighted ORR difference, % (95% CI) Consistently higher clinical activity was observed for nivolumab versus ICC regardless of pre-treatment PD-L1 expression status, BRAF mutation status and prior ipilimumab benefit a PD-L1 positivity was defined as a tumor specimen with 5% tumor cell membrane staining measured by BMS/Dako immunohistochemistry assay. Three patients had indeterminate PD-L1 status by immunohistochemical staining. 35

36 Pembrolizumab Activity by BRAF Status and BRAF/MEK Inhibitor Treatment BRAF Status N RR (%) 95% CI BRAF WT BRAF Mutant* * All patients with BRAF mutant melanoma had received BRAF +/- MEK inhibitor therapy Robert C, Ribas A, Wolchok J et al Lancet

37 The case for molecular targeted therapy--- Activity of BRAF/MEKi therapy may be better than advertises produces tumor responses in the majority of patients Responses and median OS are best in patients with M1a/b disease with normal LDH. Durable CRs are being observed Responses being reported with PD1 pathway blockers in patients resistant to BRAF/MEKi Toxicity of BRAF/MEK may be worse after immunotherapy

38 Toxicity to BRAF inhibitors after Immunotherapy Other toxicities observed Acute renal failure due to interstitial nephritis Transaminitis and liver failure (bili > 5) Pt with vemurafenib 1 month after PD on ipi/nivo to nivolumab monotherapy

39 Treatment Selection in Patients with BRAF Mutant Melanoma: Conclusions Case can be made for initial Rx with either immunorx or molecularly targeted Rx Feasibility issues may exist for either approach Answer may be different for particular patient populations Retrospective data is likely very biased Prospective trial data is needed to address this issue

40 EA6134: Ipi/Nivo to D/T vs D/T to Ipi/Nivo Arm 1: PD ECOG PS LDH 1. Normal 2. Elevated R A N D O M I Z E Ipi 3/Nivo 1 mg/kg/ q 3wks x 4 Arm 2: D 150 BID / T 2 mg Qd PD D 150 BID / T 2 mg Qd Ipi 3/Nivo 1 mg/kg q 3wks x 4 ECOG and SWOG protocol Atkins, Chmielowski Anticipated opening 1/2015

41 EA6134 Objectives: Primary: 2 year landmark OS (70 vs 50%) 300 patients Secondary 3 year landmark OS HR for death at various time points RRs and PFS and safety in BRAF mutant population Activity of DT after ipi/nivo vs DT upfront Activity of ipi/nivo after DT vs ipi/nivo upfront Feasibility of crossover Platform for correlative studies

42 EA6134: Correlatives GWAS for immunotherapy response and autoimmune toxicity Kate Nathanson Penn SPORE Project Circulating BRAFV600 as a surrogate biomarker for response and resistance to each treatment Ryan Sullivan MRF Consortium Grant Difference between therapies? Difference between settings of same therapy, etc QOL studies Roxanne Jensen G-LCCC PROs

43 Building on BRAF inhibition CTLA 4 blockade PI3K/Akt CDK4 IL 2 BRAF/ MEK MITF/ apoptosis VEGF inhibition Epigenetic/ neural crest MDM2

44 Building on BRAF inhibition CTLA 4/PD1 blockade PI3K/Akt CDK4 IL 2 BRAF/ MEK MITF/ apoptosis VEGF inhibition Epigenetic/ neural crest MDM2

45 Multi institution Phase 1 study of BRAF (vemurafenib) and PI3K inhibition (PX 866) in advanced BRAF mutant solid tumors and melanoma T. C. Gangadhar 1, X. Xu 1, G. Karakousis 1, R. K. Amaravadi 1, N. Haas 1, R. Kudchadkar 2, A. Pavlick 3, J. A. Sosman 4, H. Tawbi 5, L. Walker 6, L. M. Schuchter 1 1 Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA, USA 2 H. Lee Moffitt Cancer Center, Tampa, FL, USA 3 New York University Medical Center, New York, NY, USA 4 Vanderbilt Ingram Cancer Center, Nashville, TN, USA 5 The University of Pittsburgh, Pittsburgh, PA, USA 6 Oncothyreon Inc., Seattle, WA, USA

46 Synergy with BRAFi in vivo 1205Lu xenograft model SMR 2013 poster #38 Batool Shannan et al. Wistar Institute/Penn Abramson Cancer Center, Philadelphia PA Shannan SMR 2013

47 Study schema: 3+3 dose escalation C1D1 PX 866 alone C1D8 PX vemurafenib Continue treatment until progression or unacceptable toxicity Biopsy + Collection of Archived tissue Biopsy Cohort 1: Vem 720 mg bid + PX mg daily Cohort 2: Vem 960 mg bid + PX mg daily Cohort 3: Vem 960 mg bid + PX mg daily (Cohort 4: Vem 720 mg bid + PX mg)

48 Summary of AEs and DLTs Cohort 1 (720/6) Cohort 2 (960/6) Cohort 3 (960/8) Cohort 4 (720/8) Dose Limiting Toxicity None Grade 3 rash (1) Grade 3 pancreatitis (1) None Grade 3 4 Adverse Events Rash Rash, nausea, vomiting, diarrhea Rash, diarrhea, nausea, arthralgia, hypokalemia None

49 Best response by prior treatment Cohort 1 (N=4) (720/6) Cohort 2 (N=10) (960/6) Cohort 3 (N=5) (960/8) All subjects (N=19) 2 PD 2 PR 1 CR 5 PR 2 SD 1 PD 4 SD 1 PD BRAF/MEK inhibitor naïve (N=13) Prior BRAF/MEK inhibitor (N=6) 2 PR 2 PD 1 CR 4 PR 1 SD 1 SD (C3) 1 PR (C10) 1 PD 4 SD 1 PD Cohort 4 (N=1) (720/8) 1 PR 1 PR NA Melanoma (N=19) CR+PR (9) 47% (8) 62% (1) 17%

50 PX 866 activity in tumor: Decrease in pakt GIST Melanoma Melanoma On PX 866 Baseline Staining for Ser473 pakt residue

51 Summary Combination therapy with PI3K inhibition appears to be tolerable at a modified dose of vemurafenib PI3K inhibition with PX 866 results in a pharmacodynamic decrease in tumor pakt in the majority of patients Durable ongoing responses were observed (both treatment naïve patients and prior BRAF or MEK inhibitor treated patients) Longer follow up and additional studies including IHC, RPPA and mutation analysis will further evaluate whether a subset of patients may gain increased benefit from PI3K inhibition with PX 866 in addition to BRAF inhibition Need to consider combination with BRAFi/MEKi

52 Building on BRAF inhibition CTLA 4/PD1 blockade PI3K/Akt CDK4 IL 2 BRAF/ MEK MITF/ apoptosis VEGF inhibition Epigenetic/ neural crest MDM2

53 BRAFi + Bev: Rationale (1) BRAFV600 mutation is associated with increased VEGF expression Resistance to BRAFi appears to involve restoration of VEGF expression (Martin et al-ca Discov 2012, Wargo et al)

54 Immune Effects of BRAF Inhibitors The use of BRAF inhibitors in patients with metastatic melanoma results in decreased immunosuppressive cytokines & VEGF IL-1 alpha VEGF VEGF Frederick et al CCR 2013, Khalili et al CCR 2012, Liu et al CCR 2012

55 Wargo et al MGH/MDACC

56 BRAFi + Bev: Rationale (2) Bevacizumab has role in melanoma, particularly in patients with M1c disease and elevated LDH (O Day et al- BEAM Trial) Thus, BRAFi + bevacizumab might increase RR (particularly in patients with high LDH) and prolong median PFS

57 MRFBC Trial: Vemu + Cobi +/- Bev Arm 1: Stratify: 1. LDH < NL 2. LDH > NL ECOG Performance Status > 1 Prior therapy 1. No prior therapy 2. Prior therapy R A N D O M I Z E Vemurafenib 960mg BID Cobimentiib 60 mg QD days 1-21 Bevacizumab 10 mg/kg IV on Day 1 and 15 of each 28 day cycle) Arm 2: Vemufafenib 960mg BID Cobmetinib 60 mg QD days 1-21 All drugs provided by Genentech, Tumor measurements every 8 weeks

58 Building on BRAF inhibition Immunotherapy CTLA 4/PD1 blockade PI3K/Akt CDK4 IL 2 BRAF (+MEK) MITF/ apoptosis VEGF inhibition Epigenetic/ neural crest MDM2

59 Overall Survival for Patients with Stage IV BRAF V600 Mutant Melanoma: The Future 1.0??? Comb Proportion Surviving Optimal immuno to optimal BRAF Nivoi + Ipi? Ipilimumab BRAFi Years after stage IV diagnosis PRESENTED BY: Michael B. Atkins

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