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BEST OF ASCO LUNG CANCER 2012 David R. Gandara, MD University of California Davis Comprehensive Cancer Center.

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Presentation on theme: "BEST OF ASCO LUNG CANCER 2012 David R. Gandara, MD University of California Davis Comprehensive Cancer Center."— Presentation transcript:

1 BEST OF ASCO LUNG CANCER 2012 David R. Gandara, MD University of California Davis Comprehensive Cancer Center

2 Disclosures Research Grants: Abbott, BMS/ImClone, Genentech, GSK, Lilly, Merck, Novartis Research Grants: Abbott, BMS/ImClone, Genentech, GSK, Lilly, Merck, Novartis Consultant: Abbott Molecular, AstraZeneca, Biodesix, Boehringer-Ingelheim, BMS/ImClone, Caris, Celgene, GlaxoSmithKline, Genentech, Lilly, Merck, Novartis, Pfizer, Response Genetics, Sanofi-Aventis Consultant: Abbott Molecular, AstraZeneca, Biodesix, Boehringer-Ingelheim, BMS/ImClone, Caris, Celgene, GlaxoSmithKline, Genentech, Lilly, Merck, Novartis, Pfizer, Response Genetics, Sanofi-Aventis

3 BEST OF ASCO LUNG CANCER 2012 Abstracts for Discussion: Abstracts for Discussion: – Small Cell Lung Cancer (SCLC): Limited & Extensive Stage Limited & Extensive Stage – Non Small Cell Lung Cancer(NSCLC): Genomics: The “Big Bang” effect Genomics: The “Big Bang” effect Advanced Stage NSCLC Advanced Stage NSCLC – Targeted Therapies: “Coming of Age” » ALK » ROS1 » MEK – Emerging Role of Immunotherapy

4 SCLC Abstracts for Discussion #7004: Concurrent TRT-Chemotherapy: 1 st Cycle vs 3 rd Cycle. Phase III (Park et al) #7004: Concurrent TRT-Chemotherapy: 1 st Cycle vs 3 rd Cycle. Phase III (Park et al) #7003: Amrubicin-Cisplatin vs Irinotecan-Cisplatin in E-SCLC. Phase III JCOG 0509 (Kotani et al) #7003: Amrubicin-Cisplatin vs Irinotecan-Cisplatin in E-SCLC. Phase III JCOG 0509 (Kotani et al) #7005: Weekly Topotecan +/- AVE0005 (Aflibercept) in 2 nd line therapy of E-SCLC. Randomized Phase II S0802 (Allen et al) #7005: Weekly Topotecan +/- AVE0005 (Aflibercept) in 2 nd line therapy of E-SCLC. Randomized Phase II S0802 (Allen et al) #7004 Limited Stage: Timing of Chemo-Radiation#7003 Extensive Stage 1 st Line Chemotherapy: Amrubicin#7005 Extensive Stage 2 nd Line Therapy: AVE0005

5 Demographic, Biologic, Clinical & Therapeutic Differences between SCLC & NSCLC FeatureSCLCNSCLC IncidenceDecreasingIncreasing Association with Smoking Universal Highly Variable Growth Kinetics ~RapidVariable Biologic Diversity (Histologic & Molecular) ~Homogeneous Distinct Subtypes Early Metastases UniversalVariable Sensitivity to DNA-damaging chemotherapy (1 st line) HighVariable Sensitivity to Radiotherapy HighVariable Advances in Therapy ~15 years Few Advances Dramatic Advances

6 #7004: 1 st versus 3 rd Cycle TRT + Cisplatin-Etoposide in L-SCLC (Park et al) R 1 st Cycle arm(n=111) arm(n=111) EPEP TRTTRT EPEPEPEPEPEP LD-SCLC Treatment- naïve N=219 LD-SCLC Treatment- naïve N=219 1:1 PCI for patients with PR or CR  Primary end point: Complete response rate (WHO criteria)  Secondary end point: ORR, OS, PFS, and toxicity (NCI-CTC ver. 2.0) 3 rd Cycle Delayedarm(n=108) Delayedarm(n=108) EPEP TRTTRT EPEPEPEPEPEP EP: Etoposide 100mg/m 2 D1-3 Cisplatin 70mg/m 2 D1, q3 w TRT: 52.5 Gy/25 fxs (2.1 Gy/fx, once daily)  Enrollment between 2003 and 2010 (7 years)  Median Follow Up is 59.4 months (about 5 years)

7 Efficacy Comparisons: 1 st (initial) vs 3 rd (delayed) cycle TRT Favors Cycle 1 but not significantly different

8 Perspective on this Abstract: Therapy of Limited Stage SCLC Platinum/Etoposide (PE) + 1 st cycle concurrent thoracic radiotherapy (TRT) has been standard of care in the U.S. for ~20 years Platinum/Etoposide (PE) + 1 st cycle concurrent thoracic radiotherapy (TRT) has been standard of care in the U.S. for ~20 years Regimens adding new systemic agents or substituting agents have generally failed to show sufficient promise to replace PE Regimens adding new systemic agents or substituting agents have generally failed to show sufficient promise to replace PE Advance: Twice day hyperfractionated RT + PE was proven superior to once daily standard fraction RT (Turrisi et al: NEJM, 1999), but has not been widely adopted in practice Advance: Twice day hyperfractionated RT + PE was proven superior to once daily standard fraction RT (Turrisi et al: NEJM, 1999), but has not been widely adopted in practice In reality, 1 st cycle concurrent TRT is not feasible in a substantial subset of patients with L-SCLC In reality, 1 st cycle concurrent TRT is not feasible in a substantial subset of patients with L-SCLC Radiation volume considerations (V20 or other parameters) Radiation volume considerations (V20 or other parameters) Delays in radiation planning in some settings/countries Delays in radiation planning in some settings/countries Need for systemic therapy on an urgent basis in some cases Need for systemic therapy on an urgent basis in some cases A great deal of attention has already been paid to optimizing A great deal of attention has already been paid to optimizing the timing of TRT in L-SCLC. the timing of TRT in L-SCLC. Why Revisit It Now?

9 Meta-Analysis of TRT Timing: Overall Survival Pijls-Johannasma et al: Cancer Treat Rev, 2007 Meta-Analysis Favors Early TRT 2-3 Year OS 5 Year OS

10 Amended to allow Cycle 1 or Cycle 2 TRT Testing Cycle 2 TRT in both arms Testing Cycle 2 TRT in both arms Two Ongoing Phase III Trials in L-SCLC: Testing Radiation Dose Schedules Both are focused on TRT Dose Schedule Both are focused on TRT Dose Schedule Neither is investigating timing of TRT Neither is investigating timing of TRT

11 Summary: #7004 Timing of TRT The results add to literature concluding that early TRT is important (but not necessarily cycle 1) in optimizing efficacy of Chemo-Radiation in L-SCLC The results add to literature concluding that early TRT is important (but not necessarily cycle 1) in optimizing efficacy of Chemo-Radiation in L-SCLC Cycle 1 TRT leads to an increase in some toxicities Cycle 1 TRT leads to an increase in some toxicities Other ongoing Phase III trials are investigating alternative TRT dose schedules but not timing or radiation volume issues Other ongoing Phase III trials are investigating alternative TRT dose schedules but not timing or radiation volume issues New systemic agents for inclusion into chemo- radiation regimens for L-SCLC are needed New systemic agents for inclusion into chemo- radiation regimens for L-SCLC are needed

12 #7003: JCOG 0509 (Kotani et al) RANDOMIZERANDOMIZE Irinotecan 60 mg/m 2 D1,8,15 Cisplatin 60 mg/m 2 D1 Q4 weeks x 4 cycles Amrubicin* 40 mg/m 2 D1-3 Cisplatin 60 mg/m 2 D1 Q3 weeks x 4 cycles PCI if CR (2.5Gy/10 Fx) IP AP ED-SCLC yrs PS 0-1 Stratification ● PS ● institution ● sex Sample size n= 282 (n= 141 per Arm) Primary Endpoint= OS Primary Endpoint= OS IP dose schedule was identical to J9511 & SWOG 0124 IP dose schedule was identical to J9511 & SWOG 0124 Amrubicin dose amended to 35 mg/m 2 due to FN Amrubicin dose amended to 35 mg/m 2 due to FN Trial was closed early by the DSMCTrial was closed early by the DSMC

13 Efficacy Comparisons: AP versus IP (JCOG0509)

14 Phase III Investigation of “Newer” Chemotherapeutic Agents in E-SCLC from Gandara et al: NCI Early Drug Development Symposium, April 2012 Agent Response Rate in Phase II: 1 st line/2 nd line 1 st line/2 nd line Results (1 st line in combination with Platinum) Paclitaxel~35%/~25% Negative Phase III trial (Niell et al) Gemcitabine~25%/14% Phase II: not promising (Hesketh et al) Topotecan?/~18% “Positive” Phase III: but not adopted (Heigener et al) Irinotecan~35%/~25% Conflicting results of Phase III trials (Noda; Lara; Hanna) Pemetrexed? Negative Phase III trial (Socinski et al) Amrubicin~40% Negative Phase III trial as 2 nd line- single agent 2 nd line- single agent ( Jotte et al)

15 S0124 did not confirm results of J9511 Efficacy of Irinotecan greater in Japanese patients Toxicity was also greater in Japanese patients Population-related Pharmacogenomics may have influenced results Comparative Efficacy of JCOG 9511 versus SWOG 0124 Lara et al: JCO, 2009 Lara et al: JCO, 2009

16 Summary: #7003: AP vs IP in 1 st Line Therapy of E-SCLC Another promising drug in SCLC has failed to pass the Phase III test Another promising drug in SCLC has failed to pass the Phase III test Approaches exploiting the initial high sensitivity of SCLC to 1 st line DNA-damaging chemotherapy are worth pursuing (ECOG 2511: PARPi ABT888) Approaches exploiting the initial high sensitivity of SCLC to 1 st line DNA-damaging chemotherapy are worth pursuing (ECOG 2511: PARPi ABT888) Demonstrating new agent activity in the 2 nd line setting in platinum-refractory disease may be a logical prerequisite for testing in the 1 st line setting Demonstrating new agent activity in the 2 nd line setting in platinum-refractory disease may be a logical prerequisite for testing in the 1 st line setting

17 #7005: Topotecan +/- AVE0005 (Aflibercept) in 2 nd Line Therapy of E-SCLC (S0802- Allen et al) Eligibility Criteria Small cell lung cancer Extensive or limited stage 1 prior platinum-based chemotherapy regimen ECOG PS 0-1 Adequate organ function No “anti-angiogenic” risk factors Eligibility Criteria Small cell lung cancer Extensive or limited stage 1 prior platinum-based chemotherapy regimen ECOG PS 0-1 Adequate organ function No “anti-angiogenic” risk factors STRATIFYSTRATIFY STRATIFYSTRATIFY Platinum Sensitive Response to 1 st Line Chemotherapy and Progression > 90 days (ES) or 180 days (LS) Platinum Sensitive Response to 1 st Line Chemotherapy and Progression > 90 days (ES) or 180 days (LS) Platinum Refractory Progression ≤ 90 days (ES) or < 180 days (LS) after 1 st Line Chemotherapy Platinum Refractory Progression ≤ 90 days (ES) or < 180 days (LS) after 1 st Line Chemotherapy Topotecan IV 4 mg/m 2 Days 1, 8, and 15 AVE0005 IV 6 mg/kg on Day 1 Topotecan IV 4 mg/m 2 Days 1, 8, and 15 AVE0005 IV 6 mg/kg on Day 1 RANDOMIZERANDOMIZE RANDOMIZERANDOMIZE Topotecan IV 4 mg/m 2 Days 1, 8, and 15 Topotecan IV 4 mg/m 2 Days 1, 8, and 15 Topotecan IV 4 mg/m 2 Days 1, 8, and 15 AVE0005 IV 6 mg/kg on Day 1 Topotecan IV 4 mg/m 2 Days 1, 8, and 15 AVE0005 IV 6 mg/kg on Day 1 Topotecan IV 4 mg/m 2 Days 1, 8, and 15 Topotecan IV 4 mg/m 2 Days 1, 8, and 15 * Topotecan is omitted on Day 15 for all patients starting on Cycle 5. RANDOMIZERANDOMIZE RANDOMIZERANDOMIZE

18 #7005: Efficacy of Topotecan +/- AVE0005

19 Perspective on this Abstract: 2 nd Line Therapy of Extensive SCLC In 2 nd line therapy, a number of chemotherapeutic agents are active in “platinum-sensitive” patients, but the “platinum-refractory” subset fares poorly In 2 nd line therapy, a number of chemotherapeutic agents are active in “platinum-sensitive” patients, but the “platinum-refractory” subset fares poorly Example: Topotecan is primarily active only in “platinum- sensitive” patients Example: Topotecan is primarily active only in “platinum- sensitive” patients Identifying agents active in the “platinum-refractory” subset is therefore a high priority in clinical research in SCLC Identifying agents active in the “platinum-refractory” subset is therefore a high priority in clinical research in SCLC Additional studies evaluating novel targeted agents in SCLC are needed Additional studies evaluating novel targeted agents in SCLC are needed

20 Investigation of “Targeted Therapies” in Extensive SCLC Selected Agents Target(s) Results Results Imatinib (Johnson et al) KIT, SCF Inactive Bec2/BCG(Giaccone) GD3 ganglioside Negative Phase III trial Bortezomib (PS-341) (Lara et al) Proteasome Insufficient activity Sorafenib (Gitliz et al) VEGFR Insufficient activity PR: PlatSens: 5% PlatRef: 2% Vandetanib (ZD6474) (Arnold et al) EGFR/VEGFR HR 1.43 vs Placebo for OS ABT263 & Obatoclax (Rudin et al; Langer et al) Bcl-2 Insufficient activity PE + GDC0449 or IMC-A12: E1508 (Belani/Rudin) Hedgehog or IGF-1R Pending Completion ABT888 + PE vs PE: E2511 (Owonikoko/Belani) (Owonikoko/Belani)PARP Pending Activation Biologic Activity of some Targeted Agents may occur without RECIST response Biologic Activity of some Targeted Agents may occur without RECIST response Manifest as improved DCR (CR/PR + SD), PFS/OS or Biomarker/Imaging effects Manifest as improved DCR (CR/PR + SD), PFS/OS or Biomarker/Imaging effects “Four Dimensional Model” “Four Dimensional Model”

21 Classic Tumor Response (RECIST) (RECIST) Disease Control (CR + PR + SD) or Timed DCR Biologic Effects on Tumor Biologic Effects on Tumor (Biomarkers, Functional imaging) Survival Endpoints Survival Endpoints (OS, PFS) (OS, PFS) Measuring Effects of “Novel Therapeutic Agents”: A Four Dimensional Model adapted from Gandara et al, Clin Lung Cancer, 2007

22 Biologic Activity without RECIST Response

23 Phase II Study of Aflibercept in Refractory NSCLC Number of patients 98Treatment Aflibercept 4 mg/kg q 2 wks Prior treatment 69.4% pts ≥ 3 lines Primary Objective (RECIST) ORR 2 % 95% CI [ 0.2 – 7.2%] Best response vs baseline Best % Tumor Shrinkage Patients Leighl et al: J Thorac Oncol, 2010

24 SHARP Trial: Sorafenib vs Placebo in Hepatocellular Cancer Llovet et al: NEJM 2008

25 Summary: #7005: Topotecan +/-VE0005 The S0802 trial met the primary endpoint of improved 3- month PFS The S0802 trial met the primary endpoint of improved 3- month PFS RECIST response was low & there was no impact on OS RECIST response was low & there was no impact on OS These data remain hypothesis-generating & require confirmation (Predictive Biomarker development is essential) These data remain hypothesis-generating & require confirmation (Predictive Biomarker development is essential) How to best combine VE0005 & Chemotherapy remains unclear How to best combine VE0005 & Chemotherapy remains unclear

26 Advances in Sequencing Technologies and Human Genomics Automated slab gel Manual slab gel 1 st generation capillary sequencer Gel-based Systems Capillary sequencing 2 nd generation capillary sequencer Microwell pyrosequencing Short-read sequencers Single molecule? Massively parallel sequencing (10) (50) (10 3 ) (10 5 ) (10 7 ) (10 9 ) (10 2 ) Sequencing Technology (kilobases/day/machine) Future I I I I I I I I I I I I I I I I Ras mutations as 1 st oncogenes (1982) EGFR mutations ( ) ALK gene rearrangement ( ) Human Genome Project ( ) Human Genomics & Lung Cancer (year) Somatic mutations in lung adenocarcinoma (2008) The Cancer Genome Atlas (2010- ) Small cell lung cancer genome (2009) lung adenocarcinoma genome (2008) 1000 Human Genome (2007- ) Squamous cell lung cancer genome (2012) Li, Gandara et al: JCO 2012 (in press)

27 Comprehensive Characterization of Squamous Cell NSCLC (SCCA) #7006 Ramaswamy Govindan, Peter Hammerman, Neil Hayes, Matthew Wilkerson, Steve Baylin and Matthew Meyerson On Behalf of the Lung Cancer Working Group of The Cancer Genome Atlas (TCGA) Project

28 Structural variants TranslocationsTranslocations FusionsFusions InversionInversion Copy number alterations AmplificationsAmplifications DeletionsDeletions LOHLOH Point mutations & indels MissenseMissense NonsenseNonsense Splice siteSplice site FrameshiftFrameshift Gene expression Outlier expressionOutlier expression Isoform usageIsoform usage Pathways & signaturesPathways & signatures Wild type AGTGA Mutant AGAGA From Govindan et al: ASCO 20`2 This presentation: Squamous Cell Cancer Goal500Goal500 Accrued so far300Accrued so far300 Analysis completed178 reported hereAnalysis completed178 reported here #7006: Characterization of Genomic Alterations in Cancer (TCGA)

29 29 #7006: NSCLC (including SCCA) has a very high rate of somatic mutations 1 / Mb 10 / Mb 100 / Mb 0.1 / Mb n= Hematologic & Childhood Cancers Carcinogen- Induced Cancers ? Courtesy: Gaddy Getz and Mike Lawrence, Broad Institute, MIT Ovarian, Breast & Prostate Cancers “Stupid Cancers” “Smart Cancers”

30 30 mRNA Expression Analysis of SCCA 15% 36% 24% 25% PI3K alterations NF1 loss

31 Gene Event Type Frequency CDKN2A Deletion/Mutation- Methylation 72% PI3KCAMutation16% PTENMutation/Deletion15% FGFR1Amplification15% EGFRAmplification9% PDGFRAAmplification/Mutation9% CCND1Amplification8% DDR2Mutation4% BRAFMutation4% ERBB2Amplification4% FGFR2Mutation3% New Therapeutic Targets in squamous cell lung carcinoma (SCCA)

32 Summary: Characterization of Squamous Cell NSCLC (SCCA) SCCA characterized by: Complex genomes with frequent and unique rearrangements SCCA characterized by: Complex genomes with frequent and unique rearrangements Proposed a molecular sub-classification (yet to be clinically validated) Proposed a molecular sub-classification (yet to be clinically validated) Multiple mechanisms for alteration/inactivation of the same gene (e.g. CDKN2A) Multiple mechanisms for alteration/inactivation of the same gene (e.g. CDKN2A) Potentil therapeutic targets identified in 75% of patients, including FGFRs, PI3 kinase pathway, EGFR/ERBB2 and Cyclin/CDK complexes Potentil therapeutic targets identified in 75% of patients, including FGFRs, PI3 kinase pathway, EGFR/ERBB2 and Cyclin/CDK complexes

33 Unknown FGFR1Amp EGFRvIII PI3KCA EGFR DDR2 Squamous Cell Cancer Adenocarcinoma “Targeted Therapies Coming of Age” (from Li, Gandara et al: JCO 2012, in press) NSCLC as one disease Histology-based Subtyping

34 #7500: LUX-Lung 3: Phase III trial of afatinib versus pemetrexed and cisplatin as first-line treatment for EGFR mutation+ adenocarcinoma (Yang et al) Pemetrexed + cisplatin Stage IIIB-IV Adenocarcinoma with EGFR mutation ● Primary endpoint: PFS ● Secondary endpoints: ORR, DCR, OS RANDOMIZATIONRANDOMIZATION Afatinib 2:1

35 ResponseAfatinibCis/Pem Overall56%23% E19del/L858R69%44% #7500: LUX-Lung 3: Phase III trial of afatinib versus pemetrexed and cisplatin as first-line treatment for EGFR mutation+ adenocarcinoma (Yang et al)

36 The Story of “ALK” in NSCLC Crizotinib Crizotinib FDA approval in 2011

37 ALK-positive NSCLC & Impact of ALK inhibition by Crizotinib Therapy Activity of ALK inhibitor Crizotinib in patients with advanced ALK- positive NSCLC (Response Rate=61%) Camidge et al: ASCO 2011; Abs #2501 Previously treated advanced NSCLC N=116 59% male 72% never-smoker 56% ≥2 prior regimens

38 Potent activity in enzymatic and cell based assays LDK378 treatment results in tumor regression in EML4- ALK expressing xenografts Assay LDK378 IC 50 (μM) Crizotinib IC 50 (μM) Enzymatic ALK MET Cell-based ALK MET Mehra R, et al. ASCO. 2012; #3007 First-in-human Phase I trial of ALK inhibitor LDK378 in ALK+ solid tumors Ranee Mehra, 1 D. Ross Camidge, 2 Sunil Sharma, 3 Enriqueta Felip, 4 Daniel Tan, 5 Johan Vansteenkiste, 6 Tommaso De Pas, 7 Dong-Wan Kim, 8 Armando Santoro, 9 Geoffrey Liu, 10 Meredith Goldwasser, 11 David Dai, 12 Anthony L. Boral, 11 Alice Shaw 13

39 LDK378 has antitumor activity in ALK+ NSCLC Of the 24 responding patients, 11 responses were confirmed, and 7 are awaiting confirmatory scans Response rate was 81% (21/26) in patients with NSCLC treated at ≥ 400 mg who progressed following crizotinib Initial dose (mg) Evaluable Patients (n)Responses (PR) NSCLC < (25) ≥ (67) Other diseases 50 – Mehra R, et al. ASCO. 2012; #3007

40 Response to LDK378 After 6 weeks on LDK378 Baseline Mehra R, et al. ASCO. 2012; #3007

41 #7508: Clinical Activity of Crizotinib in Advanced Non-Small Cell Lung Cancer (NSCLC) Harboring ROS1 Rearrangement Alice T. Shaw 1, D. Ross Camidge 2, Jeffrey A. Engelman 1, Benjamin J. Solomon 3, Eunice L. Kwak 1, Jeffrey W. Clark 1, Ravi Salgia 4, Geoffrey I. Shapiro 5, Yung-Jue Bang 6, Weiwei Tan 7, Lesley Tye 7, Keith D. Wilner 7, Patricia Stephenson 8, Marileila Varella-Garcia 2, Kristen Bergethon 1, A. John Iafrate 1, and Sai-Hong I. Ou 9 Shaw et al: ASCO Annual Meeting 2012, June 1–5, Chicago, IL 1 Massachusetts General Hospital Cancer Center, Boston, MA, USA; 2 University of Colorado Cancer Center, Aurora, CO, USA; 3 Peter MacCallum Cancer Centre, East Melbourne, Australia; 4 University of Chicago Cancer Center, Chicago, IL, USA; 5 Dana Farber Cancer Institute, Boston, MA, USA; 6 Seoul National University, Seoul, Korea; 7 Pfizer Inc, La Jolla, CA, USA; 8 Rho, Inc, Chapel Hill, NC; 9 Chao Family Comprehensive Cancer Center, Orange, CA, USA

42 #7508: Clinical activity of crizotinib in ROS1-positive NSCLC (Shaw A et al) #7508: Clinical activity of crizotinib in ROS1-positive NSCLC (Shaw A et al) ●ROS1 rearrangement in ~1% of NSCLC cases ●More common in younger never or light smokers with adenocarcinoma ●Multiple ROS1 fusion partners ●Measured by “Break-Apart” FISH Assay ●No overlap with other oncogenic drivers (EGFR MT) Bergethon et al., JCO 30(8): , 2012; Takeuchi et al., Nat Med 18(3): , 2012 TPM3-ROS1 SDC4-ROS1 CD74-ROS1 EZR-ROS1 LRIG3-ROS1 SLC34A2-ROS1 ROS-1 fusion partners Abstract: 7508 Break-Apart FISH Assay

43 Background on ROS1 Signaling Pathways

44 #7508: Clinical activity of crizotinib in ROS1-positive NSCLC (Shaw A et al) #7508: Clinical activity of crizotinib in ROS1-positive NSCLC (Shaw A et al) Bergethon et al., JCO 30(8): , 2012; Takeuchi et al., Nat Med 18(3): , 2012 Abstract: 7508 (N=14)

45 Docetaxel Stage IIIB-IV NSCLC with KRAS mutation ● Primary endpoint: PFS ● Secondary endpoints: ORR, DCR, OS RANDOMIZATIONRANDOMIZATION Docetaxel + AZD6244 Chemotherapy +/- MEK inhibition (Selumetinib or AZ6244) in KRAS mutant NSCLC (Janne et al: ASCO 2012, #7503) Chemotherapy +/- MEK inhibition (Selumetinib or AZ6244) in KRAS mutant NSCLC (Janne et al: ASCO 2012, #7503) ParameterDocetaxelDocetaxel/AZD6244 mPFS (mos) Response0%37% OS5.39.4

46 Chemotherapy +/- MEK inhibition (Selumetinib or AZ6244) in KRAS mutant NSCLC (Janne et al: ASCO 2012, #7503) Chemotherapy +/- MEK inhibition (Selumetinib or AZ6244) in KRAS mutant NSCLC (Janne et al: ASCO 2012, #7503) PFSOS

47 #7509: Clinical Activity and Safety of Anti-PD1 (BMS , MDX-1106) in Advanced Non-Small-Cell Lung Cancer J.R. Brahmer, 1 L. Horn, 2 S.J. Antonia, 3 D. Spigel, 4 L. Gandhi, 5 L.V. Sequist, 6 J.M. Wigginton, 7 D. McDonald, 7 G. Kollia, 7 A. Gupta, 7 S. Gettinger 8

48 APCT cell (+) Signal 2 B7.1 CD28 TCR Signal 1 MHC-Ag Tumor Role of PD-1 in suppressing antitumor immunity (“Tumor Cell Defense”) From Keir ME et al, Annu Rev Immunol 2008; Pardoll DM, Nat Rev Cancer 2012 Activation (cytokines, proliferation, migration, lysis)

49 APCT cell (+) Signal 2 B7.1 CD28 TCR Signal 1 MHC-Ag Tumor PD-L1 PD-1 (-) Inhibition of Tumor Cell Defense From Keir ME et al, Annu Rev Immunol 2008; Pardoll DM, Nat Rev Cancer 2012 Activation (cytokines, proliferation, migration, lysis) Role of PD-1 in suppressing antitumor immunity (“Tumor Cell Defense”)

50 APCT cell (+) Signal 2 B7.1 CD28 TCR Signal 1 MHC-Ag Tumor PD-L1 PD-1 (-) Inhibition Blocked Anti- PD-1 From Keir ME et al, Annu Rev Immunol 2008; Pardoll DM, Nat Rev Cancer 2012 Activation (cytokines, proliferation, migration, lysis) Role of PD-1 in suppressing antitumor immunity (“Tumor Cell Defense”)

51 Pop Dose (mg/kg) Pts n ORR n (%) Duration of Response (mo) SD  24 wk n (%) PFSR at 24 wk (%) ALL NSCLC (18)1.9+ to (7)26 NSCLC 1181 (6)9.2+1 (6) (32)1.9+ to (11) (18)3.7 to (5)24 Clinical Activity in NSCLC Patients ORR was assessed using modified RECIST v1.0 3 NSCLC patients had a persistent reduction in baseline target lesions in the presence of new lesions but were not classified as responders for the ORR calculation #7509: Clinical Activity and Safety of Anti-PD1 (BMS , MDX- 1106) in Advanced NSCLC

52 Pre/Post Anti-PD1 Treatment - 58 y/o ex smoker with squam NSCLC - 4 prior regimens for Stage IV disease

53 Association of PD-1 Expression in Tumor and Response to Anti-PD1 Treatment

54 Incremental progress in being made in understanding the underlying biology & genomics of lung cancer These findings are leading directly to discovery of new therapeutic targets and new therapeutic agents The age of “personalized therapy” for lung cancer is rapidly emerging Considerable challenges remain In every challenge there are opportunities We must take full advance of these opportunities to advance the care & cure of lung cancer patients Best of ASCO 2012: Lung Cancer: Gandara Summary


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