Pulmonary and Critical Care Regional Symposium April 25, 2015

Pulmonary and Critical Care Regional Symposium April 25, 2015 2015: Molecular Medicine, Resistance Mutations and Immunotherapy. Keeping Up With The Latest in NSCLC Barbara J. Gitlitz MD Associate Professor USC Keck School of Medicine

EVOLUTION Histology Based Rx 2

3.49 yrs Driver + T therapy 2.38 ys Driver no T therapy 2.08 yrs No Driver

What s Driving Your Patients Cancer?

Distinct Groups Of Biomarker + NSCLC EGFR Mutation: Sensitizing and Resistance EML4 ALK Mutation: Sensitizing and Resistance KRAS Mutation Rare Mutations

Treatment Naïve EGFR mut Patients: EGFR TKIs vs Chemotherapy Study Treatment N RR Median PFS, mo Median OS, mo Maemondo 1 Gefitinib vs Carboplatin / Paclitaxel 230 73.7% vs 30.7% 10.8 vs 5.4 (P <.001) 30.5 vs 23.6 (P =.31) Mitsudomi 2,3 Gefitinib vs Cisplatin / Docetaxel 177 62.1% vs 32.2% 9.2 vs 6.3 (P <.0001) 36 vs 39 (HR: 1.19) OPTIMAL 4,5 Erlotinib vs Carboplatin / Gemcitabine 165 83% vs 36% 13.1 vs 4.6 (P <.0001) HR: 1.065 (P =.65) EURTAC 6 Erlotinib vs plat-based 174 58% vs 15% 9.7 vs 5.2 (P <.0001) 19.3 vs 19.5 (P =.87) LUX-Lung 3 7 Afatanib vs CDDP/Pemetrexed 345 56% vs 23% 11.1 vs 6.9 (P =.001) 28.2 vs 28.2 (P =.38) LUX-Lung 6 8 Afatanib vs CDDP/Gemcitabine 364 68% vs 23% 11.0 vs 5.6 (P < 0.0001 23.1 vs 24.5 (P =.61) Interesting clinical/scientific challenge: Long lived Patients With Acquired Resistance to EGFR TKI! Maemondo M, et al. N Engl J Med. 2010;362:2380 2388. 2. Mitsudomi T, et al. Lancet Oncol. 2010;11:121 128. 3. Mitsudomi T, et al. ASCO 2012. Abstract 7521. 4. Zhou C, et al. Lancet Oncol. 2011;12:735 742. 5. Zhang C, et al. ASCO 2012. Abstract 7520. 6. Rosell R, et al. Lancet Oncol. 2012;13:239 246. 7. Sequist LV, et al. J Clin Oncol. 2013. 8. Wu YL, et al. Lancet Oncol, 2014;15(2) 231 22.

Evolutionary Biology and Driving Tumor Resistance EGFR TKi Naïve Tumor Population Selective Pressure Tumor Darwinism EGFR TKi EGFR Sensitizing Mutation T790M Mutation Bypass Track

Acquired Resistance/Adaptation to First Generation EGFR-TKI 1. Emergence of Tumor Clone Carrying the Gatekeeper T790M Resistance Mutation (~50% 60%) 2. Activation of Alternative Signaling Pathways: MET Amplification, PIK3CA (~20%) 3. Histologic Transformation! (NSCLC to SCLC) 5/37(14%) 4. EGFR Amplification 5. unknown Sequist L, Sci Transl Med 2011

Things to Ponder at Resistance Clinical Nature of PD?: Rapid - Global Progression Slow Growth Globally OLIGO-Metastatic Systemic PHARMACOLOGIC FAILURE-Brain Molecular: T790M Gatekeeper mutation Bypass Track MET PIK3CA SCLC Unknown (other pathways)

EGFR Mut+ on TKI Develops Oligometastatic PD Continue EGFR TKI Utilize radiation therapy or surgical resection LOCALIZED ABLATIVE THERAPY (LAT) Several studies demonstrate additional PFS benefit (6.2 10 months) and possibly OS (41 months) benefit with this strategy (LAT) Weickhardt AJ, et al. J Thorac Oncol. 2012;7:1807 1814. Yu A, et al. J Clin Oncol. 2012;30(suppl). Abstract 7517.

How About 2 nd or 3 rd Generation Inhibitors?

Designer Drugs Janne, PA et al. Novel mutant selective EGFR kinase inhibitors against EGFR T790M. Nature 2009

T790M Blocks Erlotinib Binding and Leads to Resistance to Inhibitor The Gatekeeper A Great Reason To Consider Re Biopsy at PD! Cells developing EGFR TKI acquired resistance via T790M remain addicted to EGFR signaling!!

Clinical activity of the mutant selective EGFR inhibitor AZD9291 in patients with EGFR inhibitor resistant non-small cell lung cancer 40 20 # # D D Best percentage change from baseline in target lesion: T790M+ evaluable patients, expansion cohorts only (N=107) Best percentage change from baseline in target lesion: all evaluable T790M+ patients, Part B 0-20 D D D D D D D DD -40-60 -80 20 mg QD 40 mg QD 80 mg QD 160 mg QD 240 mg QD D D D D D D D D D D D D -100 ORR* = 64% (69/107; 95% Cl 55%, 73%) in patients with EGFR T790M+ NSCLC Overall disease control rate (CR+PR+SD) = 94% (101/107; 95% CI 88%, 98%) 20 mg 40 mg 80 mg 160 mg 240 mg N (107) 10 29 34 28 6 ORR 50% 62% 68% 64% 83% *Includes confirmed responses and responses awaiting confirmation; # represents imputed values. Population: all dosed central T790M+ patients with a baseline RECIST assessment and an evaluable response (CR/PR, SD or PD), N=107 (from 120 T790M+ patients, 13 patients with a current non-evaluable response are not included). QD, once daily; central T790M+, T790M positive by central laboratory testing Presented by: Pasi A. Jänne ASCO 2014

Future clinical development AURA (NCT01802632; recruiting) Phase II extension further assessment of efficacy and tolerability of AZD9291 80 mg QD in patients with T790M+ NSCLC AURA 2 (NCT02094261; recruiting) Confirmatory global Phase II assessment of efficacy and tolerability of AZD9291 80 mg QD in patients with T790M+ NSCLC AURA 3 (NCTxxxxxxxx) Phase III efficacy and safety of AZD9291 vs platinumbased doublet chemotherapy in second-line patients with T790M+, advanced/metastatic NSCLC who have progressed following prior therapy with an EGFR-TKI

First in Human Evaluation of CO 1686 Heavily Pretreated Subjects CNS Responses observed Median PFS Very Encouraging: NR (est >12 months) No WT EGFR related toxicity observed Presented By Lecia Sequist, ASCO 2014

Current Options in Patients with EGFR mut at Progression/Resistance Continue Plus LAT Biopsy to rule out SCLC and to assess resistance mechanism Clinical trial to address MOR T790M or other Discontinue TKI and begin chemotherapy Continue TKI and add chemotherapy

Distinct Groups Of Biomarker + NSCLC EGFR Mutation: Sensitizing and Resistance EML4 ALK Mutation: Sensitizing and Resistance KRAS Mutation Rare Mutations

EML4 ALK Re arrangement Chr 2p Inversion ALK Fusion protein Cell survival PI3K AKT MTOR S6K BAD STAT3/5 ALK EML Proliferation RAS MEK ERK PLCγ PIP 2 IP 3 Shaw Clin Cancer Res:17:2081 86, 2011

PROFILE 1014: Phase III Chemo vs Crizotinib in ALK+ Treatment Naïve NSCLC pt Primary Endpoint Met: Crizotinib Superior to Pemetrexed-based Chemotherapy in Prolonging PFSa SECONDARY ENDPOINTS ORR 74% vs 45% Time to Response: 6.1 vs 12.1 weeks Mok T et al ASCO 2014

Profile 1007/Phase III Trial 2nd Line Crizotinib vs Chemotherapy in ALK+ NSCLC Primary Endpoint: PFS by Independent Radiologic Review (ITT Population) Probability of survival without progression (%) No. at risk Crizotinib Chemotherapy 100 80 60 40 20 Crizotinib (n=173) Chemotherapy (n=174) Events, n (%) 100 (58) 127 (73) Median, mo 7.7 3.0 HR (95% CI) 0.49 (0.37 to 0.64) P <0.0001 0 0 5 10 15 20 25 Time (months) 173 93 38 11 2 0 174 49 15 4 1 0 PFS of Crizotinib vs Pemetrexed or Docetaxel Probability of survival without progression (%) No. at risk Crizotinib Pemetrexed Docetaxel 100 80 60 40 20 Crizotinib (n=172 a ) Pemetrexed (n=99 a ) Docetaxel (n=72 a ) Events, n (%) 100 (58) 72 (73) 54 (75) Median, mo 7.7 4.2 2.6 HR b (95% CI) 0.59 (0.43 to 0.80) 0.30 (0.21 to 0.43) P 0.0004 <0.0001 0 0 5 10 15 20 25 Time (months) 172 93 38 11 2 0 99 36 12 3 1 0 72 13 3 1 0 Shaw AT, et al. N Engl J Med. 2013;368(25):2385 2394.

Acquired Resistance in ALK+ NSCLC Unknown Resistance to crizotinib Usually within 1-2 yrs CNS relapses are common (>30%) Mechanisms of resistance are diverse Pharmacologic Failure (Brain) ALK resistance mutations ALK Amplification Alternative signaling pathways ALK amp ALK+ No ALK amp or mut Bypass tracks EGFR MT KRAS MT ALK mut 1. Camidge DR, et al. Lancet Oncol. 2012. 2. Doebele RC, et al. Clin Cancer Res. 2012. 3. Takayama R et al. Sci Transl Med. 2012.

Other Drugs That Target ALK 2nd generation ALK Inhibitors: LDK378 (ceritinib) Attention to their Spectrum of CH5424802 (Alectinib) Activity and CNS penetration AP26113 (ALK, ROS1, EGFR) ASP3026 X 396 RXDX101 (Pan TRK, ROS and ALK inhibitor) TSR011 (ALK and TRK inhibitor) HSP90 Inhibitors:

Change from baseline in sum of longest diameters (%) Ceritinib in Advanced ALK-rearranged NSCLC Results of the ASCEND-1 Trial # # # ## # # # PFS event # # # ## # # # # ## # # # # ## # # # ## # # ## # # # # # # # # NSCLC with prior ALKi (n=163) ORR 54.6% NSCLC ALKi naïve (n=83) ORR 66.3% ##### # # # # ## ## # # ## ## # ## # # # ## # # # # # # # # # N=228* *Patients with measurable disease at baseline and at least 1 post baseline assessment without unknown response for target lesion or overall response # ### # ## # # # # # ###### # # # ## ## ## # ## # # # # # # # # ###### Presented by: Dong-Wan Kim

Progression-Free Survival in Patients with ALK+ NSCLC Probability (%) 100 90 80 70 60 50 40 30 20 10 0 0 3 6 9 Time (Months) Number of patients still at risk Time (Months) NSCLC with prior ALKi NSCLC ALKi naïve All NSCLC 0 163 83 246 3 103 63 166 6 58 38 96 9 29 22 51 12 15 18 12 10 11 21 NSCLC with prior ALKi (N=163) NSCLC ALKi naïve (N=83) All NSCLC (N=246) 15 2 5 7 Median: non-estimable (95% CI 8.31, non-estimable) PFS rate at 12 months: 61.3% Median: 8.21 months (95% CI 6.70, 10.12) PFS rate at 12 months: 39.1% Median: 6.90 months (95% CI 5.39, 8.41) PFS rate at 12 months: 28.4% 18 0 0 0 Presented by: Dong-Wan Kim

ALECTINIB IN CRIZOTINIB-RESISTANT ALK-REARRANGED NSCLC

CNS ACTIVITY OF ALECTINIB

Alectinib Approved in Japan 07/07/14 Phase I trial (n=24) RP2D 300mg BID Phase II trial ORR 43/46 pts 93.5% 83% PFS at 12 months Of 70 pts; 14 with brain metastases and 9:14 remained without CNS or systemic PD for >12 months Seto, T et al. Lancet Oncology 2013

AT13387 Inhibits Tumor Growth of a Crizotinib-Resistant Xenograft H2228 tumor xenografts treated with crizotinib H2228R tumor xenografts treated with AT13387 1400 500 Crizotinib 50 mg/kg po qd + cyclodextrin ip 1qw Crizotinib 50 mg/kg po qd + AT13387 55 mg/kg ip 1qw Tumor volume (mm 3 ) 1200 1000 800 600 400 200 1 2 3 4 5 6 7 Tumor #6 transplanted Tumor volume (mm 3 ) 400 300 200 100 0 1 29 57 85 113 141 169 197 Day Continuous daily crizotinib treatment 0 1 8 15 22 29 Day AT13387 treatment inhibits the growth of an ALK-dependent tumor xenograft with acquired resistance to crizotinib 31

AT13387-05: Phase 2 in ALK-positive NSCLC Part A Up to 30 subjects ALK+ NSCLC under treatment for 8 weeks Safety lead in dose escalation for the combination: AT13387:150, 180, and 220 mg/m 2 ; Crizotinib: 250 mg PO twice daily Selected dose for the combination (MTD, ALK knockdown in tumor tissue) ALK+ NSCLC under treatment for 8 weeks SD or PR PD Continue crizotinib Crizotinib+ AT13387 AT13387 AT13387 + crizotinib Part B Part C N = 128 subjects N = 36 70 subjects 32

Best Treatment for ALK-Rearranged NSCLC? NCCN Guidelines suggest evaluation for ALK at diagnosis and treatment with crizotinib if positive Ceritinib is now approved for crizotinib resistant pts Is crizotinib the best first line treatment? Planned Phase III Alectinib vs Crizotinib in ALK+ naïve pts. What about CNS metastases? What Niches will we find for various inhibitors? What about pemetrexed and HSP 90 inhibitors?

Distinct Groups Of Biomarker + NSCLC EGFR Mutation: Sensitizing and Resistance EML4 ALK Mutation: Sensitizing and Resistance KRAS Mutation Rare Mutations

ROS1+ NSCLC and ALK Homology ROS1 present in ~1% of NSCLC cases Enriched in younger, never, or light smokers with adenocarcinoma histology No overlap with other oncogenic drivers 35

Crizotinib in Advanced ROS1+ NSCLC Best change from baseline (%) 100 80 60 40 20 0-20 -40-60 -80 7 43+ 24 44 33+ 8+ 15+ Best overall response PD SD PR CR Overall response rate = 72% n = 50 evaluable patients; 3 CR and 33 PRs Median PFS NR! 19.2 months 28+ 10+ 36+ 12 45+ 18 44 16+ 7+ -100 44+ 53+ 80+ N = 23 Age, yrs Median (range) 47 (31, 72) Sex, n M / F 11/12 Smoking history, n (%) Never 18 (78) Former 5 (22) Shaw et al. NEJM 2015

GENOMICS OF YOUNG LUNG CANCER If No Known Actionable Mutation Referral Sources Clinical Genomics Targeted NGS (Influence on Rx?) Lung Cancer age of Diagnosis <40 Tumor Blood Questionnaire Known Actionable Mutation -Addario Lung Cancer Medical Institute -Foundation Medicine Research Genomics Whole Exome NGS Germ-line and Somatic (Genomic Discovery)

Preliminary Results Results of 33 Subjects with Adequate Data Average Age at Diagnosis: 33 years; Range 22-39 Years Histology: Adenocarcinoma: 29 Squamous: 4 Stage at Diagnosis Stage 4 n=26 (79%); Stage 1-3 n=7 (21%) Those with Stage 4 Adenocarcinoma n=24 (73%) (table below) Genomic Alteration Stage 4 AdenoCa ALK+ EGFR+ ROS1+ TP53+ Other Total (Alk; ROS1; EGFR) N (%) 10 (42) 5 (21) 3 (13) 3 (12) 3 (12) 18 (75) Thus far in our prospective series; those diagnosed with primary NSCLC < age 40 tend to have stage 4 adenocarcinoma with the vast majority having an actionable mutation for which they are on targeted therapy (75%).

Know Whatʹs Driving Your Patients NSCLC Different Species Bypass Mut Baseline Mut(t) Similar Species Gatekeeper Mut

Nivolumab in 2 nd line Squamous NSCLC

Immunologic Toxicity

PD-1/PD-L1 Drugs Nivolumab Pembrolizumab MPDL3280A MEDI 3745 MSB0010718C BMS Merck Genentech/Roche Astra Zeneca Pfizer (Merck kga)

Epigenetic Priming Trial Study population Epigenetic priming Immunotherapy 2 Azacitidine 40 mg/m2 SC d 1-6, 8-10 Entinostat 7mg PO days 3 + 10 28 day cycle 2 Nivolumab 3 mg/kg IV q 2 weeks Until progression Metastatic NSCLC 1 2 prior therapies ECOG PS 0-1 R CC-486 300 mg PO d1-21 2 28 day cycle 2 Nivolumab 3 mg/kg IV q 2 weeks Until progression Biopsy 1 Nivolumab 3 mg/kg IV q 2 weeks Until progression Control arm Biopsy

NCIC BR.31 trial