ASCO 2014: The Future is Here. What I Will Talk About. George W. Sledge MD Stanford University School of Medicine

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1 ASCO 214: The Future is Here George W. Sledge MD Stanford University School of Medicine What I Will Talk About Two paths to a Cure Slicing the pie MelMng the snowflake The Past Isn t Dead Improving PaMent s Lives 1

2 Slicing the Pie IdenMfy the molecular lesion Measure it Target it Bruton s Tyrosine Kinase in CLL 2

3 PFS (%) EvaluaMon of IbruMnib Monotherapy 3 Yrs PosMniMaMon in CLL/SLL: PFS and OS TN R/R + Censored PFS Mos TN R/R 3- mo PFS, % (95% CI) ( ) ( ) Median PFS Not reached Not reached O Brien S, et al. ASCO 214. Abstract 714. OS (%) TN R/R + Censored OS Mos TN R/R 3- mo OS, % (95% CI) ( ) ( ) Median OS Not reached Not reached SomaMc mutamon frequencies observed in exomes from 3,83 tumour normal pairs. MS Lawrence et al. Nature, 1-5 (213) doi:1.138/nature

4 Melanoma: MutaMonal Complexity Affects Drug SensiMvity Baseline 15 weeks 22 weeks Wagle, N et al. JCO 211 epub ahead of print Vemurafenib in Melanoma 4

5 Rationale for BRAFi + MEKi Combination Slicing the Pie RAS BRAFi (dabrafenib) PFS 5.1 mo; RR 53% 1 Hyperproliferative skin AEs MEKi (trametinib) OS HR.54 v chemo PFS 4.8 mo; RR 22% 2 Rash AE mutbraf MEK perk Preclinical BRAFi +MEKi Delays BRAFi resistance Hyperproliferative skin AE Proliferation Survival Invasion Metastasis 1. Hauschild A, Lancet 212; 2. Flaherty K, NEJM 212 COMBI-d: Overall Survival<br />Data cut August 213 Presented By Georgina Long at 214 ASCO Annual Meeting 5

6 Part C BRAFi and MEKi Associated AEs Monotherapy D (n=53) Combination D+T 15/1 (n=54) Combination D+T 15/2 (n=55) Skin papilloma 8 (15) 4 (7) 2 (4) Hyperkeratosis 16 (3) 3 (6) 5 (9) Squamous cell carcinoma/ keratoacanthoma 1 (19) 1 (2) p=.4 4 (7) p=.9 Acneiform rash 2 (4) 6 (11) 9 (16) Ejection Fraction 2 (4) 5 (9) Chorioretinopathy 1 (2) No cases of RVO Long et al., ESMO 212, Flaherty, K. et al 212 The Orphan Disease Era A myriad of rare diseases Many genomic drivers Complex biology Uncertain therapeumcs Phase III trials difficult 6

7 All Snowflakes are Different But they all Melt PD-1: Role in T Cell Activation What is PD-1? Member of CD28 family involved in T cell regulation Expressed by activated T cells, memory T cells and regulatory T cells Down regulates T cell activity upon binding to PD-L1/L2 Tumor PD-L1 expression may correlate with negative prognosis potential mechanism of tumor self defense 7

8 Pembrolizumab (MK-3475) in Advanced Melanoma: Response by PD-L1 Expression PD-L P =.7* PD-L1+ ORR (%) PD-L1 positivity: staining in 1% of tumor cells 125 patients evaluable for PD-L1 expression Kefford R, et al. ASCO 214. Abstract 35. Unselected (n = 113) PD- L1+ (n = 83) PD- L1 (n = 3) *1-sided P values calculated by logistic regression, adjusting for dose/schedule. 1 8 Pembrolizumab (MK-3475) in Advanced Melanoma: Survival by PD-L1 Expression Progression-Free Survival 1 8 Overall Survival PFS (%) PD-L1 positive PD-L1 negative 2 4 Wks 6 P =.51 8 OS (%) PD-L1 positive PD-L1 negative 2 4 Wks 6 P = PD-L1 positivity: staining in 1% of tumor cells Kefford R, et al. ASCO 214. Abstract 35. 8

9 Pembrolizumab in Advanced Melanoma: Expert Perspective Excellent toxicity profile Response rates of up to 4% in ipilimumabnaive patients Lower response rates in patients who progressed after ipilimumab, BRAF inhibitor, or LDH > ULN 2 mg/kg and 1 mg/kg every 3 wks equally effective Estimated median OS is over 24 mos Approval in the US expected by late fall 214 Phase I Study: Nivolumab + Ipilimumab in Stage III/IV Melanoma Concurrent therapy study design Patients with stage III/IV melanoma with 3 previous therapies Cohort 1, 2, 2a, 3 (n = 53) Cohort 8 (n = 41) InducMon Ipilimumab q3w x 4 cycles + Nivolumab q3w x 8 cycles InducMon Ipilimumab 1 mg/kg q3w x 4 cycles + Nivolumab 3 mg/kg q3w x 4 cycles Maintenance Ipilimumab + Nivolumab q12w x 8 cycles Maintenance Nivolumab 3 mg/kg q2w (max 48 doses) Sequenced therapy study design Patients with stage III/IV melanoma with 3 previous doses of ipilimumab (n = 33) Cohorts 6, 7 Nivolumab (1 or 3 mg/kg) q2w unml progression Wolchok JD, et al. N Engl J Med. 213;369: Sznol M, et al. ASCO 214. LBA93. 9

10 Phase I Study of Nivolumab + Ipilimumab in Melanoma: OS for Concurrent Tx Survival (%) Censored Pts at Risk, n Nivo.3/IPI Nivo 1/IPI Nivo 3/IPI Nivo 3/IPI Concurrent Sznol M, et al. ASCO 214. LBA Nivo.3 mg/kg + IPI 3 mg/kg Nivo 1 mg/kg + IPI 3 mg/kg Nivo 3 mg/kg + IPI 1 mg/kg Nivo 3 mg/kg + IPI 3 mg/kg Concurrent cohort Mos yr OS: 5% yr OS: 88% 2-yr OS: 79% Phase I Study of Nivolumab + Ipilimumab in Advanced Melanoma: Safety AE, % Concurrent Cohorts 1-3 (n = 53) Any Gr Sznol M, et al. ASCO 214. LBA93. Gr 3/4 Cohort 8 (n = 41) Any Gr Gr 3/4 Any Gr All Concurrent (n = 94) All related AEs Select AEs GastrointesMnal HepaMc Skin Endocrine Renal Other UveiMs PneumoniMs Lipase increased Amylase increased Gr 3/4 No new safety signals with 22 mos of follow-up for the initial concurrent cohorts 22/94 (23%) patients discontinued treatment due to treatment-related adverse events 1/94 drug-related death in trial; fatal multiorgan failure (as a result of colitis) in cohort 8 1

11 EORTC 1871: Adjuvant Ipilimumab vs Placebo for Resected Stage III Disease Stratified by stage (IIIa vs IIIb vs IIIc with 1-3 positive LN vs IIIc with 4 positive LN), region (North America, Europe, Australia) Patients with high-risk, completely resected stage III melanoma and ECOG PS /1 (N = 951) Ipilimumab 1 mg/kg q3w x 4 then q12w for up to 3 yrs (n = 475) Placebo q3w x 4 then q12w for up to 3 yrs (n = 476) Primary endpoint: RFS per IRC (Mme to local, regional, distant metastasis, or death) Secondary endpoints: OS, DMFS, AE profile, health- related QoL Eggermont A, et al. ASCO 214. LBA98. Adjuvant Ipilimumab vs Placebo for Resected Stage III Disease: RFS Patients Alive Without Relapse (%) Median: 26.1 mos Median: 17.1 mos Ipilimumab Placebo Events/patients 234/ /476 HR (95% CI)*.75 (.64-.9) Log-rank P value*.13 2-yr RFS rate, % yr RFS rate, % Ipilimumab 1 mg/kg Placebo Mos Patients at Risk, n O N Ipilimumab Placebo Eggermont A, et al. ASCO 214. LBA *Stratified by stage. Data are not yet mature. 6 11

12 Antitumor Activity of MK-3475 in PD-L1+ NSCLC RECIST v1.1, Central Review a irrc, InvesPgator Review ORR b DCR b ORR b DCR b MK Dose n n (% ) [95% CI] n (%) [95% CI] n n (%) [95% CI] n (%) [95% CI] 2 mg/kg Q 3W 6 2 (33) [4-78] 3 (5%) [12%, 88%] 6 4 (67) [22-96] 5 (83) [36-1] 1 mg/kg Q 3W 2 4 (2) [6-44] 14 (7%) [46%, 88%] 22 1 (46) [24-68] 18 (82) [6-95] 1 mg/kg Q 2W 16 5 (31) [11-59] 1 (63) [35-85] 17 7 (41) [18-67] 12 (71) [44-9] Total (26) [14-42] 27 (64) [48 78] (47) [32-62] 35 (78) [63-89] Interim median PFS c : 27. weeks (95% CI, ) by RECIST v1.1 per central review 37. weeks (95% CI, 27.-NR) by irrc per investigator review Analysis cut-off date: March 3, 214. DCR = Disease Control Rate (complete response + partial response + stable disease) a 3 patients did not have measurable disease by RECIST v1.1 per indepdendent central review at baseline and were not evaluated for response by RECIST v1.1/ b Includes confirmed and unconfirmed responses. c From product-limit (Kaplan-Meier) method for censored data. Presented by: Naiyer A. Rizvi abstr 87 12

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14 Some Odds and Ends The past isn t dead, it isn t even past Making our paments lives beoer The Past Isn t Dead: Taxanes in Prostate Cancer 14

15 The Past Isn t Dead: Taxanes in Prostate Cancer Phase III POEMS Trial: LHRH Analogue Treatment During Chemotherapy Stratified by age, chemotherapy regimen Premenopausal paments < 5 yrs of age with stage I, II, or IIIA ER/PgR- breast cancer (N = 257) Cyclophosphamide- containing adjuvant or neoadjuvant chemotherapy (n = 131) Cyclophosphamide- containing adjuvant or neoadjuvant chemotherapy + Goserelin* 3.6 mg SC every 4 wks (n = 126) 2-yr follow-up Primary endpoint: ovarian failure at 2 yrs Secondary endpoint: ovarian dysfunction, pregnancy outcomes, DFS (exploratory), OS (exploratory) *Goserelin initiated at least 1 wk prior to chemotherapy and continued until within 2 wks (before or after) of chemotherapy completion. Moore H, et al. ASCO 214. Abstract LBA55. 15

16 POEMS: Ovarian Outcomes With Goserelin Treatment During Chemotherapy Regimen Ovarian failure rate at 2 yrs decreased with goserelin (8%; 5 of 66 pts) compared with no LHRH analogue (22%; 15 of 69 pts) LogisPc Regression Analysis OR 95% CI P Value Secondary ovarian outcomes 1 Sided 2 Sided Univariate StraMfied* MulMvariate* Outcome, % (n/n) 2- yr ovarian failure sensimvity analysis Standard Chemotherapy Chemotherapy + Goserelin *Accounting for age and regimen. Moore H, et al. ASCO 214. Abstract LBA55. Reprinted with permission. MulPvariate Regression* OR 95% CI P Value 45 (31/69) 2 (13/66) yr dysfuncmon 37 (28/75) 23 (18/78) yr dysfuncmon 33 (22/67) 14 (9/63) Conclusions We are seeing two divergent paths to a cure Slicing the pie : A genomics- based approach MelMng the snowflake : Immune- based approach The past isn t dead, it isn t even past We can make our pament s lives beoer even as we allow them to live longer 16

17 Thank You 33 CTLA-4 and PD-1/L1 Checkpoint Blockade Priming phase (lymph node) Effector phase (peripheral tissue) Dendritic cell T cell T-cell migration T cell Cancer cell MHC TCR TCR MHC Dendritic cell B7 CD28 CTLA-4 T cell T cell PD-1 PD-L1 Cancer cell Ribas A. N Engl J Med. 212;366: