1 / 54

BEST OF ASCO LUNG CANCER 2012

BEST OF ASCO LUNG CANCER 2012. David R. Gandara, MD University of California Davis Comprehensive Cancer Center. Disclosures. Research Grants: Abbott, BMS/ ImClone , Genentech, GSK, Lilly , Merck, Novartis

kail
Download Presentation

BEST OF ASCO LUNG CANCER 2012

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

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 • 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: • Small Cell Lung Cancer (SCLC): • Limited & Extensive Stage • Non Small Cell Lung Cancer(NSCLC): • Genomics: The “Big Bang” effect • Advanced Stage NSCLC • Targeted Therapies: “Coming of Age” • ALK • ROS1 • MEK • Emerging Role of Immunotherapy

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

  5. Demographic, Biologic, Clinical & Therapeutic Differences between SCLC & NSCLC

  6. #7004: 1st versus 3rd Cycle TRT + Cisplatin-Etoposidein L-SCLC (Park et al) 1st Cycle arm (n=111) E P E P E P E P PCI for patients with PR or CR TRT LD-SCLC Treatment-naïve N=219 EP: Etoposide 100mg/m2 D1-3 Cisplatin 70mg/m2 D1, q3 w TRT: 52.5 Gy/25 fxs (2.1 Gy/fx, once daily) R 1:1 3rd Cycle Delayed arm (n=108) E P E P E P E P TRT • Primary end point: Complete response rate (WHO criteria) • Secondary end point: ORR, OS, PFS, and toxicity (NCI-CTC ver. 2.0) • Enrollment between 2003 and 2010 (7 years) • Median Follow Up is 59.4 months (about 5 years)

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

  8. Perspective on this Abstract: Therapy of Limited Stage SCLC • Platinum/Etoposide (PE) + 1st 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 • 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 • A great deal of attention has already been paid to optimizing • the timing of TRT in L-SCLC. Why Revisit It Now? • In reality, 1st cycle concurrent TRT is not feasible in a substantial subset of patients with L-SCLC • Radiation volume considerations (V20 or other parameters) • Delays in radiation planning in some settings/countries • Need for systemic therapy on an urgent basis in some cases

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

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

  11. Summary: #7004 Timing of TRT • The results add to literature concluding that earlyTRT 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 • 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

  12. #7003: JCOG 0509 (Kotani et al) R A N D O M I Z E ED-SCLC 20-70 yrs PS 0-1 Stratification ●PS ●institution ●sex Sample size n= 282 (n= 141 per Arm) IP Irinotecan 60 mg/m2 D1,8,15 Cisplatin 60 mg/m2 D1 Q4 weeks x 4 cycles PCI if CR (2.5Gy/10 Fx) Amrubicin* 40 mg/m2 D1-3 Cisplatin 60 mg/m2 D1 Q3 weeks x 4 cycles AP • Primary Endpoint= OS • IP dose schedule was identical to J9511 & SWOG 0124 • Amrubicin dose amended to 35 mg/m2 due to FN • Trial 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

  15. Comparative Efficacy of JCOG 9511 versus SWOG 0124 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 • Lara et al: JCO, 2009

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

  17. #7005: Topotecan +/- AVE0005 (Aflibercept) in 2nd Line Therapy of E-SCLC (S0802- Allen et al) R A N D O M I Z E Topotecan IV 4 mg/m2 Days 1, 8, and 15 AVE0005 IV 6 mg/kg on Day 1 Platinum Sensitive Response to 1st Line Chemotherapy and Progression > 90 days (ES) or 180 days (LS) S T R A T I F Y Topotecan IV 4 mg/m2 Days 1, 8, and 15 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 R A N D O M I Z E Topotecan IV 4 mg/m2 Days 1, 8, and 15 AVE0005 IV 6 mg/kg on Day 1 Platinum Refractory Progression ≤ 90 days (ES) or < 180 days (LS) after 1st Line Chemotherapy Topotecan IV 4 mg/m2 Days 1, 8, and 15 * Topotecan is omitted on Day 15 for all patients starting on Cycle 5.

  18. #7005: Efficacy of Topotecan +/- AVE0005

  19. Perspective on this Abstract: 2nd Line Therapy of Extensive SCLC • In 2nd 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 • 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

  20. Investigation of “Targeted Therapies” in Extensive SCLC • Biologic Activity of some Targeted Agents may occur without RECIST response • Manifest as improved DCR (CR/PR + SD), PFS/OS or Biomarker/Imaging effects • “Four Dimensional Model”

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

  22. Biologic Activity without RECIST Response

  23. Phase II Study of Aflibercept in Refractory NSCLC 40 Best response vs baseline 20 Best % Tumor Shrinkage 0 -20 -40 Patients Leighl et al: J ThoracOncol , 2010

  24. SHARP Trial: Sorafenibvs 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 • RECIST response was low & there was no impact on OS • These data remain hypothesis-generating & require confirmation (Predictive Biomarker development is essential) • How to best combine VE0005 & Chemotherapy remains unclear

  26. Advances in Sequencing Technologies and Human Genomics Sequencing Technology (kilobases/day/machine) Massively parallel sequencing Single molecule? Capillary sequencing (109) Short-read sequencers 2nd generation capillary sequencer Gel-based Systems (107) Microwellpyrosequencing 1st generation capillary sequencer Automated slab gel (103) (105) Manual slab gel (50) (102) (10) I I I I I I I I Future 1990 2005 2010 1980 1985 1995 2000 1975 I I I I I I I I Human Genomics & Lung Cancer (year) EGFR mutations (2004-2009) ALK gene rearrangement (2007-2011) Ras mutations as 1st oncogenes (1982) Human Genome Project (2001-2006) 1000 Human Genome (2007- ) The Cancer Genome Atlas (2010- ) lung adenocarcinoma genome (2008) Somatic mutations in lung adenocarcinoma (2008) Small cell lung cancer genome (2009) Li, Gandara et al: JCO 2012 (in press) Squamous cell lung cancer genome (2012)

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

  28. #7006: Characterization of Genomic Alterations in Cancer (TCGA) Wild type AGTGA Mutant AGAGA • This presentation: Squamous Cell Cancer • Goal 500 • Accrued so far 300 • Analysis completed 178 reported here From Govindan et al: ASCO 20`2

  29. #7006: NSCLC (including SCCA) has a very high rate of somatic mutations n=109 81 64 38 316 100 17 82 28 119 21 40 20 Carcinogen- Induced Cancers 100 / Mb Hematologic & Childhood Cancers Ovarian, Breast & Prostate Cancers 10 / Mb “Smart Cancers” 1 / Mb “Stupid Cancers” 0.1 / Mb ?? Courtesy: Gaddy Getz and Mike Lawrence, Broad Institute, MIT

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

  31. 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 • Proposed a molecular sub-classification (yet to be clinically validated) • 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/ERBB2and Cyclin/CDK complexes

  33. “Targeted Therapies Coming of Age” (from Li, Gandara et al: JCO 2012, in press) Squamous Cell Cancer FGFR1 Amp EGFRvIII Unknown PI3KCA EGFR DDR2 NSCLC as one disease Adenocarcinoma 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) R A N D O M I Z A T I ON Stage IIIB-IV Adenocarcinoma with EGFR mutation Afatinib 2:1 Pemetrexed + cisplatin • Primary endpoint: PFS • Secondary endpoints: ORR, DCR, OS

  35. #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 2007-2012 2012 2010 2008 2007 Crizotinib FDA approval in 2011

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

  38. First-in-human Phase I trial of ALK inhibitor LDK378 in ALK+ solid tumors Ranee Mehra,1 D. Ross Camidge,2 Sunil Sharma,3Enriqueta Felip,4 Daniel Tan,5 Johan Vansteenkiste,6Tommaso De Pas,7 Dong-Wan Kim,8Armando Santoro,9 Geoffrey Liu,10 Meredith Goldwasser,11 David Dai,12 Anthony L. Boral,11 Alice Shaw13 • Potent activity in enzymatic and cell based assays • LDK378 treatment results in tumor regression in EML4-ALK expressing xenografts Mehra R, et al. ASCO. 2012; #3007

  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 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. Shaw1, D. Ross Camidge2, Jeffrey A. Engelman1, Benjamin J. Solomon3,Eunice L. Kwak1, Jeffrey W. Clark1, Ravi Salgia4, Geoffrey I. Shapiro5, Yung-Jue Bang6, Weiwei Tan7, Lesley Tye7, Keith D. Wilner7, Patricia Stephenson8, Marileila Varella-Garcia2, Kristen Bergethon1, A. John Iafrate1, and Sai-Hong I. Ou9 1Massachusetts General Hospital Cancer Center, Boston, MA, USA; 2University of Colorado Cancer Center, Aurora, CO, USA; 3Peter MacCallum Cancer Centre, East Melbourne, Australia; 4University of Chicago Cancer Center, Chicago, IL, USA; 5Dana Farber Cancer Institute, Boston, MA, USA; 6Seoul National University, Seoul, Korea; 7Pfizer Inc, La Jolla, CA, USA; 8Rho, Inc, Chapel Hill, NC;9Chao Family Comprehensive Cancer Center, Orange, CA, USA Shaw et al: ASCO Annual Meeting 2012, June 1–5, Chicago, IL

  42. #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) ROS-1 fusion partners TPM3-ROS1 SDC4-ROS1 SLC34A2-ROS1 CD74-ROS1 EZR-ROS1 Break-Apart FISH Assay LRIG3-ROS1 Abstract: 7508 Bergethon et al., JCO 30(8): 863-70, 2012; Takeuchi et al., Nat Med 18(3): 378-81, 2012

  43. Background on ROS1 Signaling Pathways

  44. #7508: Clinical activity of crizotinib in ROS1-positive NSCLC (Shaw A et al) (N=14) Abstract: 7508 Bergethon et al., JCO 30(8): 863-70, 2012; Takeuchi et al., Nat Med 18(3): 378-81, 2012

  45. Chemotherapy +/- MEK inhibition (Selumetinib or AZ6244) in KRAS mutant NSCLC (Janne et al: ASCO 2012, #7503) R A N D O M I Z A T I ON Stage IIIB-IV NSCLC with KRAS mutation Docetaxel + AZD6244 Docetaxel • Primary endpoint: PFS • Secondary endpoints: ORR, DCR, OS

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

  47. 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. Gettinger8 #7509: Clinical Activity and Safety of Anti-PD1 (BMS-936558, MDX-1106) in Advanced Non-Small-Cell Lung Cancer

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

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

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

More Related