1、May 31 - June 4, 2013Chicago, Illinois,Lung Cancer CCO Independent Conference Coverageof the 2013 American Society of Clinical Oncology Annual Meeting*,*CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference c

2、overage and other educational programs.,This program is supported by an educational grant from,This program is supported by educational grants from,About These Slides,Users are encouraged to use these slides in their own noncommercial presentations, but we ask that content and attribution not be cha

3、nged. Users are asked to honor this intent These slides may not be published or posted online without permission from Clinical Care Options (email ),DisclaimerThe materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Car

4、e Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using an

5、y therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.,Faculty,David R. Gandara, MDProfessor of Clinical Medicine UC Davis Comprehensive Cancer CenterSacramento, California Heather Wakelee, MDAssoc

6、iate Professor of Medicine, OncologyDepartment of Medicine/OncologyStanford University Stanford, California,Disclosures,David R. Gandara, MD, has disclosed that he has received funds for research support from Abbott, Bristol-Myers Squibb, Eli Lilly and Company, Genentech, ImClone, Merck, Novartis, a

7、nd Pfizer; and has received consulting fees from Amgen, AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Genentech, ImClone, Merck, Novartis, Pfizer, Response Genetics, Sanofi-Aventis, and Syntia. Heather Wakelee, MD, has disclosed that she has received consulting f

8、ees from Gilead Sciences and funds for research support from Agennix, Arqule, AstraZeneca, Celgene, Clovis, Eli Lilly and Company, Exelixis, Genentech, Merck, Novartis, Pfizer, and Regeneron.,Overview,Local-Regional NSCLC Phase III RTOG 0617: 74 Gy vs 60 Gy RT Phase III START: tecemotide (L-BLP25) v

9、s placebo EGFR TKIs in Advanced NSCLC Phase III PRONOUNCE: Pem/Carbo Pem vs Pac/Carbo Bev Phase III PROSE: serum protein test in predicting survival for patients on second-line erlotinib vs chemotherapy Extensive-Stage Small-Cell Lung Cancer Phase II CALGB 30504: chemo maintenance sunitinib,Targeted

10、 Therapy Phase III LUME Lung 1: docetaxel nintedatinib in advanced/metastatic NSCLC Phase II GALAXY-1: docetaxel ganetespib in adenocarcinoma Phase I study of nivolumab (antiPD-L1 antibody) monotherapy in NSCLC Phase IA study of MPDL3280A (antiPD-L1 antibody) in solid tumors Phase I study of LDK378

11、in advanced ALK+ NSCLC Phase II study of dabrafenib (BRAF V600E kinase inhibitor) in stage IV NSCLC,Local-Regional NSCLC,RTOG 0617: Phase III Trial of 74 Gy vs 60 Gy RT in Unresectable Stage III NSCLC,Primary endpoint: OS,Bradley JD, et al. ASCO 2013. Abstract 7501. Used with permission.,*CT consist

12、ed of carboplatin/paclitaxel.400 mg/m2 loading dose on Day 1, followed by weekly dose of 250 mg/m2,Patients with newly diagnosed, unresectable stage IIIA/IIIB NSCLC (N = 464),Stratified by RT technique, Zubrod status, PET staging, histology,Concurrent Treatment,Consolidation Treatment,Standard-Dose

13、RT +concurrent CT*(n = 125),Consolidation CT*,High-Dose RT +concurrent CT*(n = 121),Consolidation CT*,Standard-Dose RT +concurrent CT* +Cetuximab (n = 108),Consolidation CT* + Cetuximab,High-Dose RT+concurrent CT* +Cetuximab (n = 110),Consolidation CT* + Cetuximab,RTOG 0617: Survival,Bradley JD, et

14、al. ASCO 2013. Abstract 7501. Used with permission.,RTOG 0617: Safety,Grade 3 esophagitis occurred significantly more often with high-dose vs standard-dose RT (20.9% vs 7.0%; P = .0003),Bradley JD, et al. ASCO 2013. Abstract 7501. Used with permission.,Summary,High-dose RT (74 Gy) associated with hi

15、gher risk of death, locoregional recurrence, and incidence of fatal AEs vs low-dose RT (60 Gy) when administered with concurrent CT in patients with newly diagnosed, unresectable stage III NSCLC Analysis of the addition of cetuximab to high- and low-dose RT with concurrent CT is ongoing,Bradley JD,

16、et al. ASCO 2013. Abstract 7501. Used with permission.,Tecemotide (L-BLP25): Novel Lipopeptide Cancer Vaccine,Adjuvant = Monophosphoryl lipid AThe adjuvant supports T-cell response by inducing pro-inflammatory cytokines (via TLR4 stimulation),Antigen = BLP25 lipopeptideThe amino acids of the lipopep

17、tide provide antigenic epitopes for T cells,MUC1 mucin,Structural lipids = cholesterol, DPPC, and DMPGFurther enhancement of antigen delivery/uptake into APCs and immune reaction,G S T A P P A H G V T S A P D T R P A P,S T A P P A H G V T S A P D T R P A P G S T A P P - Lys (PAL) G,Butts CA, et al.

18、ASCO 2013. Abstract 7500. Used with permission.,START: Study Design,Patients with unresectable stage IIIA/B NSCLC without disease progression following chemoradiotherapy (N = 1239),Tecemotide 806 g SC weekly for 8 wks, then every 6 wks thereafter + Best Supportive Care (n = 829),Placebo + Best Suppo

19、rtive Care (n = 410),Randomized 2:1; stratified by disease stage, response to chemoradiotherapy, concurrent vs sequential chemoradiotherapy, geographic region,Treated until PD,1 dose of cyclophosphamide 300 mg/m2 or saline given 3 days prior to first tecemotide or placebo dose, respectively.,Butts C

20、A, et al. ASCO 2013. Abstract 7500. Used with permission.,START: Overall Survival,Survival (%),*2-sided, strata and multiplicity adjusted,Mos,L-BLP25Placebo,100,90,80,70,60,50,40,30,20,10,0,0,6,12,18,24,30,36,42,48,54,60,66,Region,0.86 (0.67-1.11),0.90 (0.74-1.09),0.79 (0.58-1.09),0.91 (0.71-1.17),0

21、.95 (0.73-1.22),0.85 (0.65-1.11),0.91 (0.75-1.10),0.78 (0.64-0.96),1.11 (0.86-1.43),Favors L-BLP25,Stage IIIA (n = 487),Stage IIIB (n = 752),NA and Aus. (n = 321),W. Europe (n = 475),Rest of world (n = 443),SD (n = 396),Obj. response (n = 843),Concurrent (n = 806),Sequential (n = 433),Stage,Response

22、to chemo/RT,Chemo/ RT type,Median OS, Mos L-BLP25 vs Placebo,HR* (95% CI),Favors Placebo,*Not adjusted for strata.,Butts CA, et al. ASCO 2013. Abstract 7500. Used with permission.,START: OS Analyses by Randomization Strata,27.6 vs 23.1,23.7 vs 20.9,34.1 vs 21.7,24.2 vs 22.3,21.8 vs 22.7,20.4 vs 17.8

23、,27.8 vs 23.9,30.8 vs 20.6,19.4 vs 24.6,0.5,1.0,2.0,START: OS in Patients With Concurrent Chemo/RT,Survival (%),*2-sided, adjusted for strata,Mos,L-BLP25Placebo,100,90,80,70,60,50,40,30,20,10,0,0,6,12,18,24,30,36,42,48,54,60,66,Butts CA, et al. ASCO 2013. Abstract 7500. Used with permission.,START:

24、Safety,Patients (%),Butts CA, et al. ASCO 2013. Abstract 7500. Used with permission.,100,90,80,70,60,50,40,30,20,10,0,91.6,90.6,33.4,35.8,29.6,31.7,4.5,7.3,Any AE,Any Grade3/4 AE,Any SeriousAE,Any AELeading to Death,Tecemotide (n = 1024)Placebo (n = 477),Summary,Study did not meet primary endpoint o

25、f significant improvement in OS with use of tecemotide maintenance Prespecified subgroup analysis identified significant 10.2-mo OS benefit with tecemotide in patients who received concurrent initial chemotherapy and radiotherapy Tecemotide therapy was well tolerated AE incidence similar to placebo,

26、Defining the Continuing Role of Chemotherapy and EGFR TKIsin Advanced NSCLC,Primary objective: PFS without grade 4 AE Composite endpoint considers the first occurrence of either: Grade 4 AE (lower grade AEs are not considered) or disease progression or death (PFS),PRONOUNCE: Phase III Superiority Tr

27、ial of Pem/Carbo Pem vs Pac/Carbo Bev,Induction (q21d, 4 cycles),Maintenance (q21d until PD),Pemetrexed (folic acid log-rank P = .615),0,3,6,9,12,15,18,21,24,42,0,20,40,60,80,100,Mos,Patients, %,182179,156151,125121,10296,7273,4859,3338,50,50,50,27,30,33,36,39,2028,1110,113,51,51,Zinner R, et al. AS

28、CO 2013. Abstract LBA8003. Used with permission.,Pts at Risk, nPem + CbPac + Cb + Bev,Possibly Drug-Related Grade 3/4 CTCAE,Zinner R, et al. ASCO 2013. Abstract LBA8003. Used with permission.,Summary,Study failed to establish that first-line pemetrexed/ carboplatin superior to paclitaxel/carboplatin

29、/bevacizumab for PFS without grade 4 AEs PFS, OS, and ORR similar between arms AE profiles of each arm differed, but both tolerable Pem + Cb arm with more anemia and thrombocytopenia Pac + Cb + Bev arm with more neutropenia No unexpected AEs in either arm,Zinner R, et al. ASCO 2013. Abstract LBA8003

30、.,PROSE: Validation of Multivariate Serum Protein Test,Background: EGFR-activating mutations associated with improved PFS on erlotinib, but: Most pts with NSCLC have wild-type or unknown EGFR status Additional predictive biomarkers needed to guide treatment choice Multivariate protein-based serum te

31、st developed for NSCLC Test classifies patients according to protein signature: “good” or “poor” Study aim: prospectively validate ability of test to predict survival outcomes in setting of second-line NSCLC (erlotinib vs chemotherapy),Lazzari C, et al. ASCO 2013. Abstract LBA8005.,EGFR inhibitornai

32、ve patients with stage IIIB-IV NSCLC who received 1 previous line of platinum-based therapy,Erlotinib 150 mg/day (n = 134),Pemetrexed 500 mg/m2 or Docetaxel 75 mg/m2 (n = 129),Stratified by multivariate serum protein test status (patients and investigators blinded to results), ECOG PS, smoking statu

33、s,Crossover permitted at progression,PROSE: Multicenter Randomized Phase III Trial of Second-line Erlotinib vs CT,Lazzari C, et al. ASCO 2013. Abstract LBA8005.,PROSE: OS by Treatment Arm,Third-line treatment at progression: CT arm: 41% overall (48% Good and 27% Poor) ERL arm: 52% overall (56% Good

34、and 39% Poor),1.0,0.8,0.6,0.4,0.2,0,Survival,Mos From Randomization,0,6,12,18,24,134120,7887,4251,2224,1412,Lazzari C, et al. ASCO 2013. Abstract LBA8005. Used with permission,Pts at Risk, n,PROSE: OS by Multivariate Serum Protein Test Classification,Good Classification,Poor Classification,1.0,0.8,0

35、.6,0.4,0.2,0.0,Survival,Mos From Randomization,0,6,12,18,24,9688,68 66,4042,2119,1411,0.8,0.6,0.4,0.2,0.0,Mos From Randomization,0,6,12,18,24,3841,10 21,29,15,01,Survival,1.0,Lazzari C, et al. ASCO 2013. Abstract LBA8005. Used with permission.,Pts at Risk, n,Pts at Risk, n,Treatment Adjusted Interac

36、tion Analysis for OS,ECOG PS and multivariate serum protein test classification are prognostic for outcome independent of treatment Multivariate serum protein test predictive of significant differential treatment benefit between CT and erlotinib when adjusted for potential confounding factors,Lazzar

37、i C, et al. ASCO 2013. Abstract LBA8005. Used with permission,Summary,Classification of patients with a novel multivariate serum protein test validated as providing useful information for guiding treatment decisions in second-line NSCLC Patients classified as poor (30% to 35%) attained better surviv

38、al with single-agent chemotherapy vs erlotinib Patients classified as good (65% to 70%) attained similar survival outcomes with either single-agent chemotherapy or erlotinib,Lazzari C, et al. ASCO 2013. Abstract LBA8005.,Extensive-Stage Small-Cell Lung Cancer,CALGB 30504 (ALLIANCE): Chemo Maintenanc

39、e Sunitinib in ES SCLC,Randomized, placebo controlled phase II study Primary endpoint: PFS from randomization,Untreated ES SCLC; 4-6 cycles of chemo; SD, PR, CR; PCI allowed (n = 85),Sunitinib 37.5 mg/day, until progression (n = 44),Placebo until progression (crossover allowed) (n = 41),Ready NE, et

40、 al. ASCO 2013. Abstract 7506.,CALGB 30504: Progression-Free Survival,Median PFS, Mos Sunitinib: 3.77 Placebo: 2.30 HR: 1.53 (90% CI: 1.03-2.27; stratified 1-sided log-rank P = .037),Mos From Randomization,PFS Probability,0,3,6,9,12,15,0,0.2,0.4,0.6,0.8,1.0,Placebo,Sunitinib,Ready NE, et al. ASCO 20

41、13. Abstract 7506. Used with permission.,CALGB 30504: Overall Survival,Median OS, Mos Sunitinib: 8.95 Placebo: 6.89 HR: 1.17 (90% CI: 0.77-1.78; stratified log-rank 1-sided P = .27),Mos From Randomization,OS Probability,0,5,10,15,20,25,30,35,40,0,0.2,0.4,0.6,0.8,1.0,Placebo,Sunitinib,Ready NE, et al

42、. ASCO 2013. Abstract 7506. Used with permission.,%,Grade 4 toxicities: sunitinib, 1 case GI hemorrhage and 1 case pancreatitis; placebo, 1 case platelets,CALGB 30504: Maintenance Toxicity Grade 3/4 5%,All,Fatigue,19.5,7,5,2,2,0,46.5,19,14,7,7,5,0,10,20,30,40,50,60,70,80,90,100,Placebo,Sunitinib,Pat

43、ients (%),Neutrophils,Leukocytes,Platelets,Hyponatremia,Ready NE, et al. ASCO 2013. Abstract 7506. Used with permission.,Summary,Trial met its primary endpoint of PFS, with an OS trend Only 59% received maintenance Maintenance sunitinib was safe and feasible? 46% grade 3/4 toxicity, 19% grade 3 fati

44、gue Biomarker analysis of blood samples is being planned ALLIANCE will propose a phase III trial to confirm,Targeted Therapies,Characteristics of Nintedanib,Oral angiokinase inhibitor targeting VEGFR 1-3, FGFR 1-3, and PDGFR / as well as RET1,2 Manageable safety profile in combination with Docetaxel

45、3 Pemetrexed4 Paclitaxel/carboplatin5 Gemcitabine/cisplatin6 Afatinib7 Single-agent nintedanib active in a phase II trial in recurrent NSCLC8,1. Hilberg F, et al. Cancer Res. 2008;68:4774-4778. 2. Data on file. 3. Stopfer P, et al. Xenobiotica. 2011;41:297-311. 4. Bousquet G, et al. Br J Cancer. 201

46、1;105:1640-1645. 5. Ellis PM, et al. Clin Cancer Res. 2010;16:2881-2889. 6. Doebele RC, et al. Ann Oncol. 2012;23:2094-2102. 7. Soria JC, et al. Ann Oncol. 2012;23(suppl 9): Abstract 979. 8.Reck M, et al. Ann Oncol. 2011;22:1374-1381. Used with permission.,Patients with stage IIIB/IV or recurrent NS

47、CLC and 1 previous line of chemotherapy (N = 1314),Nintedanib 200 mg BID on Days 2-21 + Docetaxel 75 mg/m2 on Day 1 of a 21-day cycle* (n = 655),Placebo BID on Days 2-21 + Docetaxel 75 mg/m2 on Day 1 of a 21-day cycle* (n = 659),Stratified by ECOG PS, previous bevacizumab, histology, brain metastase

48、s,Treatment until PD,LUME Lung 1: Randomized, Double-Blind, Placebo-Controlled Phase III Trial,*Docetaxel monotherapy allowed after 4 cycles of combination therapy.,Reck M, et al. ASCO 2013. Abstract LBA 8011. Used with permission.,LUME Lung 1: Primary Endpoint, PFS Independent Central Review in All

49、 Patients,100,80,60,40,20,0,Probability of PFS (%),Mos,Nintedanib + docetaxel Placebo + docetaxel,0,2,4,6,8,10,12,14,16,18,1,3,7,5,9,11,13,15,17,Reck M, et al. ASCO 2013. Abstract LBA 8011. Used with permission.,LUME Lung 1: OS in All Patients,100,80,60,40,20,0,Probability of OS (%),Mos,Nintedanib +

50、 docetaxel Placebo + docetaxel,655659,3428,374344,271250,200162,147120,6758,516511,10691,607600,444411,316290,130100,Pts at Risk, nNintedanibPlacebo,0,4,8,12,16,20,24,28,32,36,2,6,14,10,18,22,26,30,34,1413,234207,171144,8874,5151,2725,Reck M, et al. ASCO 2013. Abstract LBA 8011. Used with permission

51、.,LUME Lung 1: OS in Patients With Adenocarcinoma Histology,100,80,60,40,20,0,Probability of OS (%),Mos,Nintedanib + docetaxel Placebo + docetaxel,322336,2515,203184,163139,131101,9673,4633,263269,7255,302312,230219,180159,8762,Pts at Risk, n NintedanibPlacebo,0,4,8,12,16,20,24,28,32,36,2,6,14,10,18

52、,22,26,30,34,107,149119,11388,5946,3629,2213,52.7%,44.7%,25.7%,19.1%,Reck M, et al. ASCO 2013. Abstract LBA 8011. Used with permission.,LUME Lung 1: Summary of AEs,Common Terminology Criteria for Adverse Events version 3.0 was used,Reck M, et al. ASCO 2013. Abstract LBA 8011. Used with permission.,S

53、ummary,Second-line combination therapy with nintedanib and docetaxel significantly improved PFS vs docetaxel alone in patients with NSCLC independent of disease histology Addition of nintedanib to docetaxel also significantly improved OS vs docetaxel in patients with adenocarcinoma Safety profile of

54、 nintedanib in combination with docetaxel was manageable, with no unexpected safety signals,Ganetespib,Biologic effects of several oncoproteins rely on chaperone function of HSP-90 Ganetespib: highly potent second-generation inhibitor of HSP-90 Demonstrates activity in ALK-positive and/or BRAF-mutan

55、t NSCLC Associated with lower rates of visual AEs ( 50%) Combination therapy with ganetespib and docetaxel may yield synergistic effects in NSCLC based on single-agent activity profiles Manageable safety profile as monotherapy and in combination with docetaxel,Proia DA, et al. Invest New Drugs. 2012

56、;30:2201-2209.,GALAXY-1: Randomized, Open-Label Phase II Investigation of Ganetespib,Ramalingam SS, et al. ASCO 2013. Abstract CRA8007. Used with permission.,Patients with advanced adenocarcinoma who received 1 previous regimen (N = 252),Ganetespib 150 mg/m2 on Days 1, 15 + Docetaxel 75 mg/m2 on Day

57、 1 of a 21-day treatment cycle* (n = 125),Docetaxel 75 mg/m2 on Day 1 of a 21-day treatment cycle (n = 127),Stratified by ECOG PS, time since diagnosis of advanced disease, baseline serum LDH, smoking status,*Combination arm could continue ganetespib monotherapy following completion of docetaxel tre

58、atment.,GALAXY-1: PFS in All Adenocarcinoma,Mos,D G+D,Pts at Risk, n,Survival Probability,HR: 0.84 (90% CI: 0.65-1.07; P = .038) Cox regression: HR: 0.83 (90% CI: 0.64-1.06; P = .108),1.0,0.8,0.6,0.4,0.2,0,0,2.5,5.0,7.5,10.0,12.5,127125,104104,8188,5873,5267,3651,2024,1319,1113,59,35,25,23,10,0,Ramalingam SS, et al. ASCO 2013. Abstract CRA8007. Used with permission.,GALAXY-1: OS in All Adenocarcinoma,HR: 0.82 (90% CI: 0.62-1.09; P = .082) Cox regression: HR: 0.73 (90% CI: 0.55-0.98; P = .041),Mos,D G+D,Survival Probability,1.0,0.8,0.