Integrating Targeted Agents into Combined Modality Therapy in LA-NSCLC A 2012 Perspective

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1 Integrating Targeted Agents into Combined Modality Therapy in LA-NSCLC A 2012 Perspective Corey J. Langer, M.D. Vice Chair, RTOG Director Thoracic Oncology Abramson Cancer Center Professor of Medicine University of Pennsylvania Philadelphia, PA Corey.langer@uphs.upenn.edu

Disclosures: past 5 yrs Grant/Research Support: Bristol Myers Squibb, Pfizer, Imclone, Lilly, Schering-Plough Research Institute (SPRI), Sanofi-Aventis,

, OrthoBiotech, Celgene, Vertex, Genentech, OSI, AstraZeneca, Pfizer, Active Biothech, Scientific Advisor: Bristol Myers Squibb, Imclone, Sanofi-Aventis,

2 Disclosures: past 5 yrs Grant/Research Support: Bristol Myers Squibb, Pfizer, Imclone, Lilly, Schering-Plough Research Institute (SPRI), Sanofi-Aventis, Amgen, Cell Therapeutics Inc., OrthoBiotech, Celgene, Vertex, Genentech, OSI, AstraZeneca, Pfizer, Active Biothech, Scientific Advisor: Bristol Myers Squibb, Imclone, Sanofi-Aventis, Pfizer- Pharmacia, Intrabiotics, GlaxoSmithKline, AVEO, Pharmacyclics, Amgen, AstraZeneca, Novartis, Abbott Genentech, OSI, Savient, Bayer/Onyx, Abraxis, Clarient, Vertex Speakers Bureau: curtailed as of 12/10 Bristol Myers Squibb, Imclone, Sanofi- Aventis, Lilly, Genentech, OSI

3 Conclusions: LA-NSCLC Concurrent chemoradiation has emerged as the standard of comparison in good prognosis pts [PS 0-1; < 5% wt loss] Role of surgery after concurrent chemoradiation remains controversial; significant increase in PFS in phase III testing, but no improvement in OS [except possibly in lobectomy candidates] No proven benefit for consolidation or induction therapy in context of concurrent chemort 3 rd generation chemoradiation regimens are equivalent to or superior to 2 nd generation regimens Tumor size, location, and intrinsic biology may have a far bigger influence on outcome than choice of chemo; dose, mode, and schedule of RT, and sequence of treatment

4 Conclusions: LA-NSCLC Concurrent chemoradiation has emerged as the standard of comparison in good prognosis pts [PS 0-1; < 5% wt loss] Role of surgery after concurrent chemoradiation remains controversial; significant increase in PFS in phase III testing, but no improvement in OS [except possibly in lobectomy candidates] No proven benefit for consolidation or induction therapy in context of concurrent chemort 3 rd generation chemoradiation regimens are equivalent to or superior to 2 nd generation regimens Tumor size, location, and intrinsic biology may have a far bigger influence on outcome than choice of chemo; dose, mode, and schedule of RT, and sequence of treatment Role of targeted therapy remains unclear and is yet unproven

LA-NSCLC Chemoradiation: Positive Trials

5 LA-NSCLC Chemoradiation: Positive Trials INDUCTION: 4 (CALGB; RTOG, French, UK) CONCURRENT: 3 (EORTC; Jeremic [2]) CONCURRENT v SEQUENTIAL: 3 (Furuse; RTOG; Czech) ADJUVANT/CONSOLIDATION: 0 (HOG) TARGETED TX 0 (SWOG 0023) DOSE ESCALATION of RT 0 (RTOG 0617)

6 LA-NSCLC Chemoradiation: Positive Trials INDUCTION: 4 (CALGB; RTOG, French, UK) CONCURRENT: 3 (EORTC; Jeremic [2]) CONCURRENT v SEQUENTIAL: 3 (Furuse; RTOG; Czech) ADJUVANT/CONSOLIDATION: 0 (HOG) TARGETED TX 0 (SWOG 0023) DOSE ESCALATION of RT 0 (RTOG 0617)

7 LA-NSCLC: SEQ vs CON: RP3 Data LONGTERM SURVIVAL Study Outcome N F/U Exp Ctrl p value Furuse (+) 320 5y 16% 9% 0.04 RTOG (+) 597 5y 16% 10% GLOT (-) 212 2y 35% 24% 0.55 CZECH (+) 207 2y 42% 15% Pay-off: Survival benefits Pay-back: Increased toxicity (Esophagitis)

8 LA-NSCLC: SEQ vs CON: RP3 Data LONGTERM SURVIVAL Study Outcome N F/U Exp Ctrl p value Furuse (+) 320 5y 16% 9% 0.04 RTOG (+) 597 5y 16% 10% GLOT (-) 212 2y 35% 24% 0.55 CZECH (+) 207 2y 42% 15% Pay-off: Survival benefits Pay-back: Increased toxicity (Esophagitis)

9 Synopsis Angioinhibition Vaccine Strategy Targeting EGFR

10 Integrating Angiogenesis Inhibitors ECOG 3598 SWOG Trial Sarah Cannon

11 ECOG 3598 ASCO 2009 #7503 (Schiller et al) R A N D O M I Z E Induction CbP RT/Thalid* +/- CbP^ Induction CbP RT+/- CbP^ * Continue X 2 yrs Agent Ind (3wk) ^Con Q wk Carbo AUC 6 2 Paclitaxel mg/m Hoang T et al. JCO 2012;30:

12 ECOG 3598 (n=589; 39 ineligible) Study closed early 07 [n=589] Recommendation by DSMC in 5/07 to stop Tx with thalidomide because of Increased risk of thromboembolic events No significant increase in survival Hoang T et al. JCO 2012;30:

13 ECOG 3598 (n=589; 39 ineligible) Arm Standard Thalidomide Thrombotic events 8 32 Before amendment 5 14 After amendment (ASA) 3 18 Med Surv (mo) Hoang T et al. JCO 2012;30:

14 Progression-Free Survival RESULTS Survival Stopped early 2 futility Median survival 14.9 vs 16.1 mo (Thalidomide) 2-yr survival 34 vs 33% (30% > 5% wt loss) Thalidomide associated with increase in thrombotic events, unrelieved by addition of ASA Hoang T et al. JCO 2012;30:

15 Hazard ratios for survival in patient subgroups. Hoang T et al. JCO 2012;30: by American Society of Clinical Oncology

SWOG Rand Phase II: LA-NSCLC Platform Regimen CDDP 50 mg/2 d 1,8,29,36 VP-16 50 mg/m2 d1-5, 29-33 XRT 1.

16 SWOG Rand Phase II: LA-NSCLC Platform Regimen CDDP 50 mg/2 d 1,8,29,36 VP mg/m2 d1-5, XRT Gy/d 61 Gy DOCETAXEL 75 mg/m2 x 3 cycles Grafting Bevacizumab 1 st Cohort: During Docetaxel (after Chemoradiation) 2 nd Cohort: Midway through Chemoradiation cycles 3 rd Cohort: At initiation of Chemoradiation

17 SWOG Rand Phase II: LA-NSCLC Platform Regimen CDDP 50 mg/2 d 1,8,29,36 VP mg/m2 d1-5, XRT Gy/d 61 Gy DOCETAXEL 75 mg/m2 x 3 cycles Grafting Bevacizumab 1 st Cohort: During Docetaxel (after Chemoradiation) 2 nd Cohort: Midway through Chemoradiation cycles 3 rd Cohort: At initiation of Chemoradiation

18 Tracheoesophageal fistula after treatment of small cell lung cancer with chemoradiation and bevacizumab 29 patients Objective response rate of 88% with 4 complete and 11 partial responses. Grade 3/4 toxicity: Diarrhea (21%), esophagitis (14%), fatigue (17%), pain (14%), neutropenia (18%), leukopenia (10%), and thrombocytopenia (28%). 2 patients developed tracheoesophageal fistulae (1 fatal), prompting early study closure. One patient died from an aerodigestive hemorrhage. One patient died from a treatment-related bowel perforation. Spigel et al, JCO 28:43, 2010

19 Tracheoesophageal fistula after treatment of non-small cell lung cancer with chemoradiation and bevacizumab 2 of 5 patients developed tracheoesophageal fistulae, prompting early study closure. Both patients developed esophageal toxicity during treatment. Spigel et al, JCO 28:43, 2010

START Trial Stimulating Targeted Antigenic Responses to NSCLC A Multicenter phase III randomized, double-blind placebocontrolled study of

20 START Trial Stimulating Targeted Antigenic Responses to NSCLC A Multicenter phase III randomized, double-blind placebocontrolled study of the cancer vaccine (L- BLP25 or BLP25 liposome vaccine) in non-small cell lung cancer (NSCLC) subjects with unresectable stage III disease

In preclinical studies, vaccination produced a proliferative T-cell

21 BLP25 Vaccine Liposome based MUC1 vaccine MUC1 is a mucinous glycoprotein that is overexpressed and aberrantly glycosylated in NSCLC In preclinical studies, vaccination produced a proliferative T-cell response to the MUC1 antigen and production of IFN g, indicating a T-helper type 1 response

22 Cancer-Associated Mucins Normal MUC1 Mucin MUC1 Cancer Mucin

23 B25-LG-304 Schema Stage IIIB/IV NSCLC Response or SD to 1 st -line Therapy R A N D O M I Z E L-BLP25 + Best Supportive Care Best Supportive Care

24 B25-LG-304 Treatment and Evaluation Schematic

Health-related quality of life (HRQoL) Assessed by FACT-L 2.

25 B25-LG-304 Objectives Primary 1. Efficacy: Overall survival 2. Safety of L-BLP25 Secondary: 1. Health-related quality of life (HRQoL) Assessed by FACT-L 2. Immune response elicited by L-BLP25 Assessed by MUC1 proliferative T-cell response Note: Tumour responses were not expected and thus not measured.

26 B25-LG-304 Study Design Survival Assessments Cox proportional hazard regression model Hazard ratio; 95% CI; p-value Kaplan-Meier estimate Study Assumptions Median Survival BSC arm: 7 months L-BLP25 + BSC arm: 12 months 108 deaths required for 80% power 150 patients required

27 B25-LG-304 Overall Survival Arm Placebo BLP25 1 yr OS% yr OS% yr OS% Butts C, Murray N, et al. JCO 23;6674, 2005

28 Stage IIIB Overall Survival from End of Chemotherapy or Chemoradiotherapy

Study Design: START trial (1) Multi-center phase III randomized, double-blind placebo-controlled study in pts with unresectable stage III NSCLC with either stable disease or objective response

29 Study Design: START trial (1) Multi-center phase III randomized, double-blind placebo-controlled study in pts with unresectable stage III NSCLC with either stable disease or objective response following primary chemo-radiotherapy (concomitant or sequential) Randomized 2:1 to L-BLP25 (investigational arm) or to placebo respectively Stratified by: Disease stage (IIIA versus IIIB). Response to primary chemo-radiotherapy (stable disease versus objective response). Type of primary chemo-radiotherapy (concomitant versus sequential). Region 1: North America [Canada, United States] and Australia, 2: Western Europe, 3: Rest of World: Mexico, Central /South America, E. Eur and Asia DSMC Overview

IIIA/IIIB Stable or Responding after primary Chemoradiation S T R A T I F Y R A N D O M I Z E Week 4

30 B25-LG-306: RPIIII Treatment and Evaluation Schematic L - BLP25 + BSC Arm Cyclo 300 mg/m2 Day 3 x 1 L - BLP25 1,000 µ g SC qw x 8 L - BLP25 1,000 µ g SC q6w Until patient withdrawn Unresectable Stage IIIA/IIIB Stable or Responding after primary Chemoradiation S T R A T I F Y R A N D O M I Z E Week 4 Evaluation Week 8 Evaluation Q 12 W Evaluation Placebo + BSC Saline infusion Day 3 x 1 Placebo SC qw x 8 Placebo SC q6w

31 Objectives: START trial Primary objective: Survival duration of all randomized subjects Secondary objectives Time to symptomatic progression (TTSP) as measured by the Lung Cancer Symptom Scale (LCSS). Time to progression (TTP) as determined by the investigator. One-, two-and three-year survival Safety.

Cancer stage must be confirmed by CT, MRI, or PET Documented stable disease or objective response, according to RECIST, after

32 Eligibility Histologically or cytologically documented unresectable stage III NSCLC. All histological subtypes are acceptable, including BAC ECOG performance status of 0-1. >18 years of age. Cancer stage must be confirmed by CT, MRI, or PET Documented stable disease or objective response, according to RECIST, after primary chemoradiotherapy (either sequential or concomitant) within 4 weeks (28 days) prior to randomization* Minimum of two cycles of platinum-based chemotherapy Min radiation dose of 50 Gy.

Eligibility (2) Completion of primary thoracic chemo-radiotherapy at least four weeks (28 days) and no later than 12 weeks (84 days) prior to randomization.

33 Eligibility (2) Completion of primary thoracic chemo-radiotherapy at least four weeks (28 days) and no later than 12 weeks (84 days) prior to randomization. Prophylactic brain irradiation allowable Geographically accessible for ongoing follow-up and committed to comply with the designated visits. Platelet count >100K WBC > 2500 Hemoglobin >9 g/dl. Written informed consent

34 Accrual/Statistics Planned 1322 subjects 881 on the investigational arm 441 on the placebo arm) followed for a minimum of 24 months Hazard ratio = (MS of 20 mos in control group) Alpha = (1-sided). Power = 90%. To anticipate 705 events (deaths).

35 Accrual/Statistics Planned 1322 subjects 881 on the investigational arm 441 on the placebo arm) followed for a minimum of 24 months Hazard ratio = (MS of 20 mos in control group) Alpha = (1-sided). Power = 90%. To anticipate 705 events (deaths) accrued; enrollment completed 7/11

36 WSJ.BY NEETHA MAHADEVAN AND CORRIE DRIEBUSCH Late-stage trial results for Merck KGaA's lung-cancer drug BLP25 liposomal vaccine won't be available until 2013 as the trial needs to continue, the German pharmaceutical and chemical company said in a presentation to analysts Tuesday (03/06/12).

37 Targeting EGFR TKIs MAbs

38 Incidence of EGFR Expression in Solid Tumors Tumor type EGFR expression (%) SCCHN 95 NSCLC Colorectal Glioblastoma Breast Esophageal Pancreatic Gastric Bladder Prostate Ovarian Arteaga C. Semin Oncol. 2003;30(suppl 7):3-14.

39 Antibody vs. Small Molecule Small Molecule Antibody Target TK External receptor Specificity Binding Reversible Internalize receptor MOA (?) cell cycle cell cycle apoptosis angiogenesis apoptosis angiogenesis ADCC (?) Dosing oral daily IV weekly Toxicity rash, diarrhea rash, HSR Activity Single agent Combined with chemo or XRT

40 Trials of RT with EGFR TKI Trial N Chemotherapy TKI RT Dose Komaki et al CALGB U of C UNC 48 Carboplatin Paclitaxel 39 Carboplatin Paclitaxel Carboplatin Paclitaxel Cisplatin Etoposide Carboplatin Paclitaxel Erl 150 mg QD Gef 250 mg QD Erl 150 mg QD Gef 250 mg QD MS (mo) RR OS % 1 year 84% % 1 year 53% % 59% 3 year 20% 3 year 16% NS 2 year 20% Komaki et al, J Clin Oncol 29: 2011 (suppl; abstr 7020) CALGB 30106: Ready N et al, J Clin Oncol 2006 (suppl; abstr 7046) U of Chicago: Hoffman et al, J Clin Oncol 2005 (suppl; abstr 7113)

CALGB (30106) Trial with Gefitinib in LA-NSCLC Induction Paclitaxel Carboplatin Gefitinib* PS 0-1 PS 2 PS

PD * Amended to delete Gefitinib during induction Ready N, Jänne PA, Bogart J, Dipetrillo T, Garst J,

stage III non-small cell lung cancer with epidermal growth factor receptor and KRAS mutation analysis:

41 CALGB (30106) Trial with Gefitinib in LA-NSCLC Induction Paclitaxel Carboplatin Gefitinib* PS 0-1 PS 2 PS 0-1 > 5% wt Concurrent RT (66Gy) Paclitaxel Carboplatin Gefitinib Concurrent RT Gefitinib Gefitinib till PD * Amended to delete Gefitinib during induction Ready N, Jänne PA, Bogart J, Dipetrillo T, Garst J, Graziano S, Gu L, Wang X, Green MR, Vokes EE; Cancer, Leukemia Group B, Chemoradiotherapy and gefitinib in stage III non-small cell lung cancer with epidermal growth factor receptor and KRAS mutation analysis: cancer and leukemia group B (CALEB) 30106, a CALGB-stratified phase II trial. J Thorac Oncol Sep;5(9):

42 TREATMENT Induction: Paclitaxel 200 mg/m2 IV every 21 days times 2 cycles Carboplatin AUC6 IV every 21 days times 2 cycles Gefitinib 250 mg daily (removed May 2004) Chemoradiotherapy: Radiation 2 Gy times 33 fractions for 66 Gy total dose [Stratum 1] Gefitinib 250 mg daily [Stratum 2] Gefitinib plus Carbo AUC 2 and Pac 50 mg/m2 weekly Maintenance: Gefitinib 250 mg daily Ready N, Jänne PA, Bogart J, Dipetrillo T, Garst J, Graziano S, Gu L, Wang X, Green MR, Vokes EE; Cancer, Leukemia Group B, Chemoradiotherapy and gefitinib in stage III non-small cell lung cancer with epidermal growth factor receptor and KRAS mutation analysis: cancer and leukemia group B (CALEB) 30106, a CALGB-stratified phase II trial. J Thorac Oncol Sep;5(9):

43 Probability CALGB 30106: by Strata CALGB 20106: Overall Survival by Strata Stratum One Stratum Two # Pts Survival Time (Months) Median Months 1-year Survival (%) OS Strata Strata FFS Strata Strata

44 Lessons Learned If adding a targeted agent to chemotherapy in the advanced disease setting yields no benefit, adding the same targeted agent to chemotherapy and radiation is unlikely to overcome established therapeutic antagonism Outcomes are liable to be unpredictable in the absence of markers

45 Lessons Learned If adding a targeted agent to chemotherapy in the advanced disease setting yields no benefit, adding the same targeted agent to chemotherapy and radiation is unlikely to overcome established therapeutic antagonism Outcomes are liable to be unpredictable in the absence of markers Prepare to part with some sacred cows and vested truisms when investigating new agents with unique MOAs

SWOG 0023: Gefitinib vs Placebo After Chemoradiation Followed by Docetaxel Schema Definition TX Consolidation Maintenance R CDDP 50 mg/m 2 d 1,8,29,36 VP-16 50 mg/m 2 d 1-5, 29-33 XRT 1.

46 SWOG 0023: Gefitinib vs Placebo After Chemoradiation Followed by Docetaxel Schema Definition TX Consolidation Maintenance R CDDP 50 mg/m 2 d 1,8,29,36 VP mg/m 2 d 1-5, XRT Gy/d 61 Gy Docetaxel 70 mg/m 2 x 3 cycles 1 Endpoint: overall survival; 2 Endpoint: PFS, toxicity and correlative science. Maintenance therapy could continue for a maximum of 5 years. Stratification factors: IIIA vs IIIB; measurable vs non-measurable disease; squamous vs nonsquamous. Kelly K, et al. ASCO Abstract J Clin Oncol. 2008;26: A N D O M I Z E Placebo Gefitinib 500 mg/day 250 mg/day (5-1-03)

47 SWOG 0023: Overall Survival from Randomization 100% 80% 60% 40% 20% 0% Median FU time: 27 months Months After Randomization Kelly K, et al. ASCO Abstract J Clin Oncol. 2008;26:

48 SWOG 0023: Overall Survival from Randomization 100% Gefitinib N 118 Events 71 Median in Months 23 1 YR OS 2 YR OS 73% 46% 80% Placebo P = % 59% 60% 40% 20% 0% Median FU time: 27 months Months After Randomization Kelly K, et al. ASCO Abstract J Clin Oncol. 2008;26:

49 SWOG 0023: Causes of Death by Treatment Arm Parameter Getfitinib N=118 Placebo N=125 Alive Dead 71 (60%) 54 (43%) Cancer 61 (86%) 43 (80%) Toxicity 2 (3%) 0 (0%) Other causes 1 (1%) 3 (6%) Unknown 7 (10%) 8 (15%) Kelly K, et al. ASCO Abstract J Clin Oncol. 2008;26:

50 What Went Wrong? Therapeutic Empiricism Absence of identifiable markers

51 Cetuximab and Radiation Effects of Cetuximab and ionizing radiation on H226 xenografts 4 Tumor Volume (cm 3 ) Control Cetuximab RT Cetuximab+RT Treatment Days

52 A431 Xenografts Control 18 Gy C225 X 1 18 Gy + C225 X 1 C225 X 3 18 Gy + C225 X 3

53 Overall survival (%) Cetuximab + RT in Locoregionally Advanced SCCHN: Overall Survival RT (N=213) RT+E (N=211) Two-year* 55% 62% Three-year* 44% 57% Five-year 36% 46% Median survival* 29 mo 49 mo 95% CI mo mo Log-rank p-value 0.03 Hazard ratio (95% CI) 0.714( ) Radiotherapy plus cetuximab Overall Survival (%) Radiotherapy Months Bonner J, et al. N Engl J Med. 2006;354:

Concurrent Carboplatin, Paclitaxel, Cetuximab and

Cetuximab for patients with unresectable Stage III NSCLC

Paclitaxel 45/mg² qweek x 7 XRT 63 Gy over 7 weeks +

and 2 cycles of consolidation Cb/Paclitaxel Blumenschein

54 Concurrent Carboplatin, Paclitaxel, Cetuximab and Radiation Therapy followed by Carboplatin, Paclitaxel with Cetuximab for patients with unresectable Stage III NSCLC RTOG 0324 R E G I S T E R N=84 Carboplatin AUC qweek x 7 Paclitaxel 45/mg² qweek x 7 XRT 63 Gy over 7 weeks + Cetuximab 400mg/m² loading and 250mg/m² weekly during RT and 2 cycles of consolidation Cb/Paclitaxel Blumenschein et al ASCO 08, A 7516; J Clin Oncol Jun 10;29(17): Epub 2011 May 9

RTOG 0324 - Overall Survival Median survival 22.7 months 2 yr survival 49.

55 RTOG Overall Survival Median survival 22.7 months 2 yr survival 49.3% Blumenschein et al ASCO 08, A 7516; J Clin Oncol Jun 10;29(17): Epub 2011 May 9

56 Longterm Outcome in RTOG LA-NSCLC Trials Trial RT Chemo Sequence MST 5 yr OS Gy (SDFx) Pac-Carbo Con-Consol 22.7 m N/A Gy (BID Fx) Pac-Carbo/Amif Ind-Con % Gy (BID Fx) Pac-Carbo Ind-Con % Gy (SDFx) VBL-DDP Con % Gy (SDFx) VBL-DDP Ind % Gy (BID Fx) VP-16DDP Con % Blumenschein et al ASCO 08, A 7516; J Clin Oncol Jun 10;29(17): Epub 2011 May 9

57 Longterm Outcome in RTOG LA-NSCLC Trials Trial RT Chemo Sequence MST 5 yr OS Gy (SDFx) Pac-Carbo Con-Consol 22.7 m N/A Gy (BID Fx) Pac-Carbo/Amif Ind-Con % Gy (BID Fx) Pac-Carbo Ind-Con % Gy (SDFx) VBL-DDP Con % Gy (SDFx) VBL-DDP Ind % Gy (BID Fx) VP-16DDP Con % Potential Explanations True superiority (C225 enhances the efficacy of chemoradiation) Will Rogers Phenomenon (Routine PET imaging Stage Migration) Improved RT technique and supportive care Patient Selection Dumb luck

58 RTOG 0617: Conventional vs High Dose RT (3D Conformal) R A N D O M I Z E RT: 60 Gy Paclitaxel Carboplatin RT: 74 Gy Paclitaxel Carboplatin Paclitaxel Carboplatin X2

59 RTOG 0617: Conventional vs High Dose RT (3D Conformal) +/- C225 R A N D O M I Z E RT: 60 Gy Paclitaxel Carboplatin +/- Cetuximab RT: 74 Gy Paclitaxel Carboplatin +/- Cetuximab Paclitaxel Carboplatin X2

60 RTOG 0617: Conventional vs High Dose RT (3D Conformal) +/- C225 R A N D O M I Z E RT: 60 Gy Paclitaxel Carboplatin +/- Cetuximab RT: 74 Gy Paclitaxel Carboplatin +/- Cetuximab Paclitaxel Carboplatin X2 Stratifications: PS RT Technique Histology PET: Y vs N

61 But Beware: We cannot let enthusiasm preempt reason and logic

Progression-Free Survival (%) Overall Survival (%) RTOG 0522 100 Primary Endpoint 100 75 75 50 Hazard Ratio (95% CI) 1.05 (0.84, 1.29) P= 0.66 (log-rank, 1-sided) 50 Hazard Ratio (95% CI) 0.87 (0.

62 Progression-Free Survival (%) Overall Survival (%) RTOG Primary Endpoint Hazard Ratio (95% CI) 1.05 (0.84, 1.29) P= 0.66 (log-rank, 1-sided) 50 Hazard Ratio (95% CI) 0.87 (0.66, 1.15) P= 0.17 (log-rank, 1-sided) 25 2-Year Rate (95% CI) Cisplatin 64.3% (59.7, 68.8) Cisplatin+Cet 63.4% (58.7, 68.0) Years after Randomization # Patients at Risk Year Rate (95% CI) Cisplatin 79.7% (75.9, 83.6) Cisplatin+Cet 82.6% (78.9, 86.3) Years after Randomization # Patients at Risk

63 Concurrent Carboplatin, Pemetrexed, and Radiation Therapy followed by Carboplatin, Pemetrexed with or without Cetuximab for patients with unresectable Stage III NSCLC: Randomized Phase II Trial R A N D O M I Z E CALGB 3040 Arm A Arm B Carboplatin AUC 5 q3week x 4 Pemetrexed 500/mg² q3week x 8 XRT 70 Gy over 7 weeks Carboplatin AUC 5 q3week x 4 Pemetrexed 500/mg² q3week x 8 XRT 70 Gy over 7 weeks + Cetuximab 400mg/m² loading and 250mg/m² weekly during RT

64 CALGB 30407: RESULTS MS for Pem/Carbo/XRT: 21.2 vs Pem/Carbo/XRT/C225: 25.2 (p = NS) No significant difference between sq and non-sq histology Grades 3/4 AEs: Neutropenia 50-59%, Thrombocytopenia 34-36%, Dysphagia 24-32%, Pneumonitis 8-12% Pemetrexed can be given with platinum at full systemic dose No obvious benefit for the addition of cetuximab (unselected patients; small #) Maintenance Tx beyond 4 cycles generally not feasible Govindan, R et al J Clin Oncol 29:

RTOG 0324 Toxicity and AEs Myelosuppression Grade 3-4: 55%

Pneumonitis Grade 3-4: 7% Grade 5 adverse events: 5 6% Toxicity

Encephalopathy and hypoxia 99 Pneumonitis 46 Death NOS 95

65 RTOG 0324 Toxicity and AEs Myelosuppression Grade 3-4: 55% Non-hematoloigic AEs Gr > 3 63% Esophagitis Grade 3: 8% Pneumonitis Grade 3-4: 7% Grade 5 adverse events: 5 6% Toxicity Days post start of RT ARDS & hypoxia 87 Sepsis 165 Encephalopathy and hypoxia 99 Pneumonitis 46 Death NOS 95 Blumenschein et al ASCO 08, A 7516; J Clin Oncol Jun 10;29(17): Epub 2011 May 9

66 RTOG 0324 Toxicity and AEs Myelosuppression Grade 3-4: 55% Non-hematoloigic AEs Gr > 3 63% Esophagitis Grade 3: 8% Pneumonitis Grade 3-4: 7% Grade 5 adverse events: 5 6% Toxicity Days post start of RT V20 ARDS & hypoxia Sepsis 165 Encephalopathy and hypoxia Pneumonitis Death NOS 95 Blumenschein et al ASCO 08, A 7516; J Clin Oncol Jun 10;29(17): Epub 2011 May 9

67 Longterm Outcome in RTOG LA-NSCLC Trials Trial RT Chemo Sequence MST 5 y OS Gy (SDFx) S Pac-Carbo Con-Consol 26.7 m NA Gy (SDFx) Pac-Carbo Con-Consol 21.6 m NA Gy (SDFx) Pac-Carbo-C225 Con-Consol 22.7 m N/A Gy (SDFx) Pac-Carbo +/- C Gy (SD Fx) Pac-Carbo +/- C225 Con-Consol 20.7 m N/A Con Consol 21.7 m N/A

68 RTOG 0617: Conventional vs High Dose RT (3D Conformal) +/- C225 R A N D O M I Z E RT: 60 Gy Paclitaxel Carboplatin +/- Cetuximab RT: 74 Gy Paclitaxel Carboplatin +/- Cetuximab Paclitaxel Carboplatin X2

RTOG 0617: Radical Thoracic RT* +/- C225 R A N D O M I Z E RT: 60-74 Gy Paclitaxel Carboplatin + Cetuximab RT: 60-74 Gy

69 RTOG 0617: Radical Thoracic RT* +/- C225 R A N D O M I Z E RT: Gy Paclitaxel Carboplatin + Cetuximab RT: Gy Paclitaxel Carboplatin Paclitaxel Carboplatin X2 + Cetuximab Paclitaxel Carboplatin X2 * Study since amended to allow 60Gy only

Three Possible Scenarios Positive trial ( ) across the board, independent of molecular marker analysis [H score, etc] Trending trial, but subanalysis shows distinct

70 Three Possible Scenarios Positive trial ( ) across the board, independent of molecular marker analysis [H score, etc] Trending trial, but subanalysis shows distinct molecularly distinguished population which derives a significant benefit, and another population which is not helped Truly negative trial ( ) with no molecular subset showing a benefit

71 An Evolving View of Adenocarcinoma Emergence of Molecular Markers KRAS?? Pending MEK BRAF PIK3CA FGFR4 HER2 EML4-ALK EGFR

72 SELECTED PATIENT

73 Conclusions: Targeted Agents in Combined Modality Therapy Make sure the target is actionable Pre-clinical and xenograft data Verified safety and activity in the advanced disease setting Isolation of the population most likely to benefit Mandatory collection of tissue and blood for biocorrelative investigation Well vetted safety data [new context with RT] Pro-active measures to mitigate toxicity Conduct Randomized phase II trials to avoid the trap of shifting baselines and misleading historic controls

LA- NSCLC: Langer s Perspective Platinum-based chemoradiation regimens differ very little on therapeutic outcome, only on toxicity, and even then, esophagitis is similar and

the target and are able to enrich the population for that target Successful administration of optimized radiation or chemoradiation and new agents hinges on the following factors

74 LA- NSCLC: Langer s Perspective Platinum-based chemoradiation regimens differ very little on therapeutic outcome, only on toxicity, and even then, esophagitis is similar and likely to be dose-limiting in the short-run, while pulmonary fibrosis remains the main late toxicity Empiric use of targeted agents is unlikely to provide benefit unless we know the target and are able to enrich the population for that target Successful administration of optimized radiation or chemoradiation and new agents hinges on the following factors Clear preclinical evidence of synergy with XRT using standard xenografts Reasonable safety profile established in phase I/II trials Activity [ideally] in the advanced disease setting

75 Courtesy of Dr. Benjamin Movsas

76 Mr Debonnair strikes out

Stage III NSCLC: Overview

Locally Advanced NSCLC: New Concepts in Combined Modality Therapy NSCLC: Stage Distribution Randeep Sangha, MD Visiting Assistant Professor UC Davis Cancer Center Sacramento, CA Stage III NSCLC: Overview