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Early Stage NSCLC: Imprimatur of Adjuvant Therapy Corey J Langer MD, FACP Professor of Medicine Director of Thoracic Oncology Abramson Cancer Center University.

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Presentation on theme: "Early Stage NSCLC: Imprimatur of Adjuvant Therapy Corey J Langer MD, FACP Professor of Medicine Director of Thoracic Oncology Abramson Cancer Center University."— Presentation transcript:

1 Early Stage NSCLC: Imprimatur of Adjuvant Therapy Corey J Langer MD, FACP Professor of Medicine Director of Thoracic Oncology Abramson Cancer Center University of Pennsylvania Philadelphia, PA Overview of Recent Data

2 Disclosures: Past 10 yrs Grant/Research Support:Grant/Research Support: –Bristol Myers Squibb, Pfizer, Imclone, Lilly, Schering- Plough Research Institute, Sanofi-Aventis, Amgen, Cell Therapeutics, OrthoBiotech, Celgene, Vertex, Genentech, OSI, AstraZeneca, Pfizer, Medimmune, GSK Scientific Advisor: Scientific Advisor: –Bristol Myers Squibb, Imclone, Sanofi-Aventis, Pfizer, GlaxoSmithKline, Pharmacyclics, Amgen, AstraZeneca, Novartis, Genentech, OSI, Savient, Bayer/Onyx, Abraxis, Clarient, Morphotek, Biodesix, AVEO, Synta Speakers Bureau:curtailed as of 12/10 Speakers Bureau:curtailed as of 12/10 –Bristol Myers Squibb, Imclone, Sanofi-Aventis, Lilly, Genentech, OSI

3 3 Welcome to Winter in NJ 2-14

4 Stage is Destiny!

5 UICC6 T/M DescriptorProposed T/MN0N1N2N3 T1 (< 2 cm)T1aIAIIAIIIAIIIB T1 (> 2-3 cm)T1bIAIIAIIIAIIIB T2 ( 3 to < 5 cm)T2aIBIIAIIIAIIIB T2 (>5-7)T2bIIAIIBIIIAIIIB T2 (> 7 cm)T3IIBIIIA IIIB T3 invasionT3IIBIIIA IIIB T4 (same lobe nodules)T3IIBIIIA IIIB T4 (extension)T4IIIA IIIB M1 (ipsilateral Lung)T4IIIA IIIB T4 (pleural effusion)M1aIV M1 (contralateral lung)M1aIV M1 (distant)M1bIV New Staging System (IASLC ’07) to be instituted 2009

6 UICC6 T/M DescriptorProposed T/MN0N1N2N3 T1 (< 2 cm)T1aIAIIAIIIAIIIB T1 (> 2-3 cm)T1bIAIIAIIIAIIIB T2 ( 3 to < 5 cm)T2aIBIIAIIIAIIIB T2 (>5-7)T2bIIAIIBIIIAIIIB T2 (> 7 cm)T3IIBIIIA IIIB T3 invasionT3IIBIIIA IIIB T4 (same lobe nodules)T3IIBIIIA IIIB T4 (extension)T4IIIA IIIB M1 (ipsilateral Lung)T4IIIA IIIB T4 (pleural effusion)M1aIV M1 (contralateral lung)M1aIV M1 (distant)M1bIV New Staging System (IASLC ’07) Instituted 2009

7 Limitations of Earlier Adjuvant Trials Use of regimens with marginal activity in advanced NSCLCUse of regimens with marginal activity in advanced NSCLC Inclusion of patients with compromised PS and multiple co-morbiditiesInclusion of patients with compromised PS and multiple co-morbidities Difficulty administering systemic therapy in the post-op settingDifficulty administering systemic therapy in the post-op setting Inadequate power or overly ambitious survival endpointsInadequate power or overly ambitious survival endpoints

8 Surgery plus Chemotherapy Surgery Percentage Survival Time from Randomization (months) BMJ 31: , Meta-Analysis Adjuvant Cisplatin Trials n=1394 HR 0.87 p=0.08 5% absolute survival benefit at 5 years, NS

9 Plaitnum-Based Adjuvant Trials in Resected NSCLC TrialN. of PatientsHR (95%CI) BMJ meta ( ) IALT ( ) ALPI ( ) E ( ) BLT ( ) BR ( ) CALGB ( ) ANITA ( ) LACE meta ( ) NEJM 00; JNCI 03; EuroJTS 04, NEJM 04; NEJM 05; ASCO 04+06; Lancet Oncology 06

10 Plaitnum-Based Adjuvant Trials in Resected NSCLC: Longterm Results TrialN. of PatientsHR (95%CI) BMJ meta ( ) IALT ( ) ALPI ( ) E ( ) BLT ( ) BR ( ) CALGB ( ) ANITA ( ) LACE meta ( ) NEJM 00; JNCI 03; EuroJTS 04, NEJM 04; NEJM 05; ASCO 04+06; Lancet Oncology 06

11 Intl Adjuvant Lung Cancer Trial (IALT) 1867 pts, I-III Randomized to obs vs. 4 cycles post-op chemo*Randomized to obs vs. 4 cycles post-op chemo* Radiation therapy optional (~30%)Radiation therapy optional (~30%) 4.1% absolute benefit at 5 years, p<0.03†4.1% absolute benefit at 5 years, p<0.03† –Stage III > Stage I benefit Diminished at 7 yr follow-upDiminished at 7 yr follow-up HR 0.86 [ ]  0.91 [ ];HR 0.86 [ ]  0.91 [ ]; –p = 0.04  0.1 after 5 yrs due to non-cancer deaths ^ † Arriagado, NEJM 350:351, 2004, ^ Le Chevalier ASCO 2008 *cisplatin + etoposide or vinca alkaloid

12 Randomized International Adjuvant Lung Cancer Trial (IALT): Cisplatin-Based Chemotherapy vs No Chemotherapy for Resected NSCLC Stage I-III NSCLC Complete surgical resection within 60 days N=1867 Arm A* Cisplatin 80 mg/m 2  4 cycles OR Cisplatin 100 mg/m 2  3-4 cycles OR Cisplatin 120 mg/m 2  3 cycles PLUS Etoposide 100 mg/m 2  3 days/cycle OR Vinorelbine 30 mg/m 2 weekly OR Vinblastine 4 mg/m 2 weekly OR Vindesine 3 mg/m 2 weekly n=935 Arm B Observation ± thoracic radiotherapy  60 Gy † n=932 *Each center selected which chemotherapy it would use. † Optional, but predefined by N stage at each center. Le Chevalier et al. Proc Am Soc Clin Oncol. 2003;22:2. Abstract and oral presentation; Arriagada et al. N Engl J Med. 2004;350:351. R A N D O M IZ E

13 Adjuvant Chemotherapy IALT n=1867 cDDP was 80 q 3 weeks X 4cDDP was 80 q 3 weeks X q 4 weeks X q 4 weeks X q 4 weeks X q 4 weeks X 3 56% + Etoposide 10056% + Etoposide % + Vinorelbine 3027% + Vinorelbine 30 11% + Vinblastine 411% + Vinblastine 4 6% + Vindesine 36% + Vindesine 3 Le Chevalier, ASCO 2003 abstract 6, NEJM 2004

14 Adjuvant Chemotherapy IALT (International Adjuvant Lung Trial) n= countries, initial accrual goal was countries, initial accrual goal was /20 M/F80/20 M/F Mean age 59 (all < 75)Mean age 59 (all < 75) Squamous 47%, ACAs 40%Squamous 47%, ACAs 40% Chemo to start < 60 days after surgeryChemo to start < 60 days after surgery Median f/u: 56 monthsMedian f/u: 56 months Le Chevalier, ASCO 2003 abstract 6, NEJM 1/04

15 Observation ± RT Chemotherapy Months Le Chevalier et al. Proc Am Soc Clin Oncol. 2003;22:2. Abstract and oral presentation. NEJM 1/04 IALT: Cisplatin-Based Chemotherapy vs No Chemotherapy for Resected NSCLC: Overall Survival (Med F/U 56 mos) HR=0.86 ( ) P<0.03 % Survival

16 IALT Trial ARMAdjuvant chemoControl Number of enrollees Dead of disease progression Tx-related deaths (n) 14 2 Compliance with RT (%) Median DFS (mo) yr DFS (%) yr DFS (%) Median Survival Time (mo) yr OS (%) yr OS (%)

17 Benefit seen across all demographic variablesBenefit seen across all demographic variables –Gender –type of surgery –use of RT –geographical location Greatest benefit in stage III pts (~7.5%)Greatest benefit in stage III pts (~7.5%) In subgroup analyses, survival advantage for stage I and II was not statistically significantIn subgroup analyses, survival advantage for stage I and II was not statistically significant AdjControl Rel %↑ –Stage I –Stage II –Stage III IALT: Cisplatin-Based Chemotherapy vs No Chemotherapy for Resected NSCLC: Overall Survival

18 % 20% 40% 60% 80% 100% years chemotherapy: 578 deaths deaths before 5 years - 83 deaths after 5 years control 590 deaths deaths before 5 years - 56 deaths after 5 years HR: 0.91 ( , P = 0.10) Le Chevalier T, et al. J Clin Oncol. 2008(May 20 suppl). Abstract IALT: Cisplatin + a Vinca or Etoposide 2008 Update: 7.5-Year Median Follow-Up

19 Criticisms of IALT Heterogenous staging, chemo and application of RT (HR favored stage III, not stage I or II) Heterogenous staging, chemo and application of RT (HR favored stage III, not stage I or II) Study actually closed earlier than planned because of emerging interest in neoadjuvant Tx Study actually closed earlier than planned because of emerging interest in neoadjuvant Tx Potential Molecular Imbalances: Results of ERCC1 suggest that one can select a group more likely to benefit; other bio-correlatives still pending Potential Molecular Imbalances: Results of ERCC1 suggest that one can select a group more likely to benefit; other bio-correlatives still pending Elderly (> 75) excluded; how do we address this expanding cohort? Elderly (> 75) excluded; how do we address this expanding cohort? Dissipation of survival benefit after 5 years Dissipation of survival benefit after 5 years Why was this trial positive when so many similar trials proved negative? Why was this trial positive when so many similar trials proved negative?

20 Recent (-) Trials of Adjuvant CT in Completely Resected NSCLC StudyCountry CT Regimen # of Patients Outcome on OS INT 0115 ALPI/EORTC BLT USA Italy/Europe International VP16-P x 4 MVP x 3 V-P x Negative

21 2004: Paradigm Shift

22 Recently Completed (+) Randomized Adjuvant Trials in Early Stage NSCLC Stage No. Intervention Stage No. Intervention CALGB 9633IB 500 Carboplatin/Paclitaxel NCI-C* IB-II 480Cisplatin/Vinorelbine 2004: Paradigm Shift

23 Recently Completed (+) Randomized Adjuvant Trials in Early Stage NSCLC Stage No. Intervention Stage No. Intervention CALGB 9633IB 500 Carboplatin/Paclitaxel NCI-C* IB-II 480Cisplatin/Vinorelbine ANITA I-IIIA 840Cisplatin/Vinorelbine 2005: Paradigm Shift

24 CALGB pts, stage IB 4 cycles carboplatin/paclitaxel vs. observation4 cycles carboplatin/paclitaxel vs. observation Radiation therapy not allowedRadiation therapy not allowed HR 0.62; p = HR 0.62; p = HR 0.80; p = HR 0.80; p = 0.10 Strauss Proc ASCO 2004 abs 7019, 2006 abs 7007, JCO 2009

25 Strauss Proc ASCO 2004 abs 7019, 2006 abs 7007, JCO 2008 Years Probability Observation Paclitaxel + Carboplatin Observation Paclitaxel + Carboplatin n=97 n=99 n=74 HR = 0.66; 90% CI, ; P=0.04HR = 1.02; 90% CI, ; P=0.51 Tumor ≥4 cmTumor <4 cm CALGB 9633 Overall Survival by Tumor Size

26 RANDOMIZERANDOMIZE Vinorelbine 25 mg/m 2 weekly x 16 plus Cisplatin 50 mg/m 2 day 1 & 8 q4wk x 4 cycles ELIGIBLE: Resected IB and II T2N0, T1N1, or T2N1 No prior chemo No RT Observation JBR.10 Winton T, et al. N Engl J Med. 2005;352: Primary endpoint = overall survival Stratification: Nodal status – N0 vs N1 RAS status N = 240 N = 242

27 NCIC-CTG JBR pts, stage IB-II Stage IB-II onlyStage IB-II only 4 cycles of post-op cis/vin vs. observation4 cycles of post-op cis/vin vs. observation No radiation therapyNo radiation therapy 15% survival advantage at 5 years15% survival advantage at 5 years –54% vs 69% alive (NEJM paper) HR 0.69, p=.012 in 482 ptsHR 0.69, p=.012 in 482 pts Benefit only in stage II in subset analysisBenefit only in stage II in subset analysis –Although post-hoc analysis shows a benefit in IB > 4cm Winton, Proc ASCO 2004 Abs:7018, 2004, NEJM 2005

28 Overall Survival by Treatment Arm Absolute improvement in 5 yr OS = 11% (67% vs 56%); benefit persists at 9+ yrs Vincent, Butts et al, 2009, ASCO All Patients Absolute improvement in 5 yr OS = 15% (69% vs 54%) Winton et al. NEJM 2005 HR yr: 69% vs 54% MST 94 m vs 73 m Fig.1 5 yr: 67% vs 56% MST 94m vs 72m

29 Cumulative Incidence Plots for Disease and Non-disease Related Deaths

30 Stage IB Analysis T < 4 cmT ≥ 4 cm HR OSp p CALGB JBR No Chemo Benefit Potential Chemo Benefit Strauss JCO 2008

31 ANITA pts, stage IB-IIIA 1:1 Randomization post-resection1:1 Randomization post-resection – Vinorelbine (30 mg/m2) Q wk X 16 + Cisplatin 100 mg/m2 Q 4 wks X 4 vs Cisplatin 100 mg/m2 Q 4 wks X 4 vs – Observation Radiation therapy allowedRadiation therapy allowed 8.6% survival advantage at 5 years (persists at 7 yr)8.6% survival advantage at 5 years (persists at 7 yr) –42.6% vs 51.2% alive HR 0.7 [ ], p =.013HR 0.7 [ ], p =.013 Benefit only in stage II and IIIABenefit only in stage II and IIIA Douillard Lancet Oncol. 7:719, 2006

32 ANITA: Rand Phase III Trial of Vinorelbine and Cisplatin vs Obs in Resected stage I-III NSCLC: Demographics 840 pts accrued from 12/94 through 12/00840 pts accrued from 12/94 through 12/00 Median F/U > 70 mosMedian F/U > 70 mos Each arm well balancedEach arm well balanced Median age 59 (18 – 75)Median age 59 (18 – 75) 86% male86% male 95% PS 0-195% PS % Squamous ca59% Squamous ca 37% pneumonectomy37% pneumonectomy StageStage –I – 35% –II – 30% –III – 35% Douillard Lancet Oncol. 7:719, 2006

33 Overall survival - ITT population months Survival Distribution Function OBS.NVB + CDDP Median months P-value0.013 Hazard Ratio0.79 [ ] Obs NVB + CDDP Abstract #7013: ANITA Trial Douillard Lancet Oncol. 7:719, 2006

34 ANITA: Randomized Phase III Trial of Vinorelbine and Cisplatin vs Observation in resected stage I-III NSCLC ArmObservationAdjuvant No RFS (mo)2136 Median Surv (mo)* yr OS yr OS yr OS yr OS Stage I6263 Stage II3952 Stage III2642 * P =0.002, HR 0.76 Douillard Lancet Oncol. 7:719, 2006

35 ANITA: Randomized Phase III Trial of Vinorelbine and Cisplatin vs Observation in resected stage I-III NSCLC ArmObservationAdjuvant No RFS (mo)2136 Median Surv (mo)* yr OS yr OS yr OS yr OS Stage I6263 Stage II3952 Stage III2642 * P =0.002, HR 0.76 Douillard Lancet Oncol. 7:719, 2006

36 ANITA: Randomized Phase III Trial of Vinorelbine and Cisplatin vs Obs in resected stage I-III NSCLC Adjuvant Toxicities Douillard et al ASCO 2005, A-7013, p624 Neutropenia Gr 3+486% Febrile Neutropenia12.5% Nausea-Vomiting Gr 3+427% Aesthenia28% Constipation5% Peripheral Neuropathy3% Drug-Related Fatality1%

37 LACE:Trials and patients 5 trials including 4,584 patients5 trials including 4,584 patients Median follow-up: 5.1 years (3.1 – 5.9)Median follow-up: 5.1 years (3.1 – 5.9) 80% male80% male Median age 59 years, 9% > 70 years oldMedian age 59 years, 9% > 70 years old Pathological Stage:Pathological Stage: IA: 8%, IB: 30%, II: 35%, III: 27% IA: 8%, IB: 30%, II: 35%, III: 27% Surgery: 31% pneumonectomySurgery: 31% pneumonectomy Histology:Histology: 49% squamous cell, 49% squamous cell, 39% adenocarcinoma, 12% other 39% adenocarcinoma, 12% other Pignon Proc ASCO 2006 abs 7008

38 Survival curve

39 CT effect & stage CT may be detrimental for stage IA, but stage IA patients were generally not given the potentially best combination cisplatin+vinorelbine (13% of stage IA patients versus ~43% for other stages)

40 CT effect & stage CT may be detrimental for stage IA, but stage IA patients were generally not given the potentially best combination cisplatin+vinorelbine (13% of stage IA patients versus ~43% for other stages)

41 Stage-Specific Hazard Ratios Recent Adjuvant Trials Trial I < 4 cm I > 4 cm IIIIIA IALT BR N/A ANITA CALGB N/A LACE1.41*0.91*0.83 Negative Positive Indeterminate Not studied * 3 cm as cut point

42 Therapeutic Implications Short course adjuvant, platinum-based therapy has emerged as standard practice in resected stage Ib-IIIa NSCLCShort course adjuvant, platinum-based therapy has emerged as standard practice in resected stage Ib-IIIa NSCLC Ongoing controversies re:Ongoing controversies re: –Molecular Selection –Influence of Age on Outcome –Ideal platinating agent: carbo vs cisplatin –Choice of partner agent –Impact of Stage –Role of targeted agents –Utility of RT in IIIA (N2)

43 Potential Benefit from Adjuvant Systemic Therapy Disease Free Patients (%) Years Patients cured with local regional therapy Patients with residual micrometastases resistant to adjuvant therapy Patients with residual micrometastases sensitive to adjuvant therapy Prognostic Markers ? Predictive Markers ?

44 Influence of Age on Outcome

45 Elderly Specific Analyses: BR10 Pepe et al ASCO ’06, A : designated cut-off65: designated cut-off –327 younger pts (68 %) –155 older pts (32 %) Baseline demographics similar except for histology and PSBaseline demographics similar except for histology and PS CohortYoungerOlderP value Adenoca58%43%0.001 Squamous32%59%0.001 PS 053%42%0.01

46 JBR-10 Outcomes by Age Worse PS in older; fewer PS 0 >65 (53% vs 41%, = 0.01)Worse PS in older; fewer PS 0 >65 (53% vs 41%, = 0.01) adeno>squam in younger, squam>adeno in older pts.adeno>squam in younger, squam>adeno in older pts. Patients >65 received significantly less chemoPatients >65 received significantly less chemo –no significant diff. in toxicity, or growth factor support –more elderly patients refused treatment OS 46% vs. 66% for obs. vs. chemo in pts >65OS 46% vs. 66% for obs. vs. chemo in pts >65 –Overall Survival HR 0.61 [ ], p =.04 in elderly OS 58% vs. 70% for obs. vs. chemo in pts <65OS 58% vs. 70% for obs. vs. chemo in pts <65 –Overall Survival HR 0.77 [ ], p = 0.14 in young Older patients (>75)Older patients (>75) –Worse survival regardless of Rx, but same when corrected for disease-specific survival –Benefit from chemo not seen in pts >75 (?harmful) – However, patient numbers are too small to answer clearly Pepe C, et al.Pepe C, et al. Adjuvant vinorelbine and cisplatin in elderly patients: National Cancer Institute of Canada and Intergroup Study JBR.10. J Clin Oncol Apr 20;25(12):

47 BR10: Overall Survival by Age Group Time (Years) Probability >75 N = N = N = N = >75 N = 23  75 N = 459 Log-Rank, p = H-R = % 63% Pepe C, et alPepe C, et al Adjuvant vinorelbine and cisplatin in elderly patients: National Cancer Institute of Canada and Intergroup Study JBR.10. J Clin Oncol Apr 20;25(12):

48 Ideal Platinating Agent

49 Argument Favoring Carboplatin The best results obtained in stage IB have been observed with CbPac (not with DDP- based regimens)The best results obtained in stage IB have been observed with CbPac (not with DDP- based regimens) –Subset analysis in > 4 cm tumors demonstrates a survival benefit CbPac has not been tested in stage II/IIIA in the adjuvant settingCbPac has not been tested in stage II/IIIA in the adjuvant setting –Absence of data does not prove absence of benefit (….absence of proof is not proof of absence….) Finally, a substantial percentage of adj pts are poor candidates for cisplatin-based therapy due to age, co-morbidities, etcFinally, a substantial percentage of adj pts are poor candidates for cisplatin-based therapy due to age, co-morbidities, etc

50 Which Agents Partner Best with Platinum

51 M. Kreuter, J. Vansteenkiste, J. Fischer, W. Eberhardt, H. Zabeck, J. Kollmeier, M. Serke, N. Frickhofen, M. Reck, W. Engel-Riedel, S. Neumann, M. Thomeer, C. Schumann, P. De Leyn, T. Graeter, G. Stamatis, I. Zuna, F. Griesinger and M. Thomas on behalf of the TREAT investigators

52 LACE-MetaanalysisNCIC-JBR.10 No treatment9%4.5% Treatment incomplete24 % (≤ 2 cycles) 50% (< 4 cycles) early death or progression9%5% toxicity34%13% patient refusal35%29% Therapy delay55% Dose reductions77% Pignon, JCO, 2008 ; Winton, N Engl J Med, 2005; Alam, Lung Cancer, 2005; Vogelzang, JCO, 2003; Scagliotti, JCO, 2008; Schmid-Bindert, ASCO, 2009 TREAT Rationale: Adjuvant CTX: mainly Cisplatin / Vinorelbine Need: reduction of toxicity, improvement of dose delivery & compliance Cisplatin / Pemetrexed in thoracic malignancies: high dose intensity, low toxicities Rationale: Dose delivery: Adjuvant CTX

53 TREAT: Design Cisplatin / Vinorelbine (CVrb) Cisplatin / Pemetrexed (CPx) 50 mg/m 2 d1+8 / 25 mg/m 2 d1, 8, 15, 22 q d 29 x 4 75 mg/m 2 d1 / 500 mg/m 2 d1 q d 22 x 4 R0 Winton et al., N Engl J Med (2005) 352: 258 Inclusion Inclusion NSCLC stages IB, IIA, IIB, T3N1M0 ≤ 42 Tage postoperatively, R0, systematic LN-dissection ECOG 0, 1 amenable to Cisplatin treatment Stratification Stratification Center Nodal status (N0 versus N1) Surgical procedure (lobectomy vs pneumonectomy)

54 Study conduct Study concept 2005, Inclusion 10/ /2009 (16 sites, 132 patients) Treatment until 2/2010, primary endpoint analysis 12/2010 Primary endpoint Clinical Feasibility No death due to cancer, toxicity, comorbidity No Non-acceptance by patients leading to premature withdrawal No observation of DLT  Neutropenia grade 4 > 7 d  Neutropenia grade 3/4 with fever/infection  Thrombocytopeniagrade 4 > 7 d  Thrombocytopenia any grade with bleeding  Non-hematologic toxicity grade 3/4 related to CTX Secondary endpoints Dose delivery, safety, TTTF, RFS, OS, DMFS, LRFS, site of relapse TREAT: Conduct / endpoints Kreuter et al., BMC Cancer, 2007

55 Study conduct Study concept 2005, Inclusion 10/ /2009 (16 sites, 132 patients) Treatment until 2/2010, primary endpoint analysis 12/2010 Primary endpoint Clinical Feasibility Clinical Feasibility [considered promising if > 80%] No death due to cancer, toxicity, comorbidity No Non-acceptance by patients leading to premature withdrawal No observation of DLT  Neutropenia grade 4 > 7 d  Neutropenia grade 3/4 with fever/infection  Thrombocytopeniagrade 4 > 7 d  Thrombocytopenia any grade with bleeding  Non-hematologic toxicity grade 3/4 related to CTX Secondary endpoints Dose delivery, safety, TTTF, RFS, OS, DMFS, LRFS, site of relapse TREAT: Conduct / endpoints Kreuter et al., BMC Cancer, 2007

56 CharacteristicsCPx(n=67)CVb(n=65)Total(n=132) Age (years [range])58 [40-73]60 [38-74]59 [38-74] Gender (%) male female Smoking status (%) Smoker Ex-smoker Non-smoker Not available Stage (%) IB3738 IIA IIB T3N1565 TREAT: Characteristics

57 CharacteristicsCPx(n=67)CVb(n=65)Total(n=132) Surgical procedures (%) Lobectomy Pneumonectomy Complex resections433 Histology (%) Squamous cell carcinoma Non-squamous Adenocarcinoma Large cell carcinoma999 Mixed cell carcinoma957 TREAT : Characteristics

58 CPxCVb Feasibility rate (%) 95.5 (CI ) 75.4 (CI ) Death (%) Withdrawal of consent (%)06.2 DLT (%) Reasons for DLT (events) * patients (n=2) patients (n=10) G4 neutropenia >7d04 G4 thrombocytopenia >7d00 G3/4 febrile neutropenia15 Thrombocytopenia with bleeding00 G3/4 non-hematologic toxicity21 Results: Primary endpoint - feasibility * multiple reasons possible p =

59 EOTCPxCVb Regular EOT (%) Earlier termination of therapy (%) Reasons for earlier termination (events)* patients (n=15) patients (n=41) Unacceptable toxicity according to protocol**419 Unacceptable toxicity perceived by patient 67 Relapse of disease0 2 Withdrawal of consent 04 Death (therapy related)1 (0) 2 (0) Non-compliance to protocol02 Medical decision by investigator45 Major protocol violation01 Other reasons04 Results: End of therapy *multiple reasons possible **delay >2 weeks due to toxicity or in case of G3/4 non-hem toxicity

60 ToxicityCPxCVb Mean Number (AE / SAE) 6.8 / / 0.2 Hematologic Toxicity G3/4 (%) Non-hematologic Toxicity G3/4 (%) 3331 Hematologic Toxicity (%) G3/4 Anemia01.5 Thrombocytopenia00 Neutropenia969 Febrile Neutropenia1.56 TREAT: Toxicity p< p=0.7988

61 TREAT: Time to treatment failure TREAT: Time to treatment failureTtTF: Time from surgery to withdrawal due to AE AE progression / relapse / death progression / relapse / death failure to return to therapy failure to return to therapy refusal of treatment / withdrawal of consent refusal of treatment / withdrawal of consent p<0.001 Withdrawal probability

62 CPx safe and feasibleCPx safe and feasible  less toxicity compared to CVb  superior dose delivery compared to CVb  high dose density (mg/m 2 /week) Dose delivery failure in CVb mostly due to Vb (delivery d15, d22)Dose delivery failure in CVb mostly due to Vb (delivery d15, d22) Efficacy: longer follow up to be awaitedEfficacy: longer follow up to be awaited TREAT: Conclusions

63 Molecular Selection

64 Immunohistochemical (IHC) Staining of the Excision Repair Cross-Complementing 1 (ERCC1) Protein as Predictor of Benefit from adjuvant chemotherapy (CT) in the International Lung Cancer Trial (IALT)  761 pts. (28 centers,14 countries) evaluable for ERCC1 expression  ERCC1 repairs cisplatin-DNA adducts, so expression indicates platinum resistance  ERCC1 a “double-edged sword”; worse prognosis of NSCLC if low expression, but more responsive to platinum Soria, Proc ASCO 2006 A#7010; Olaussen K et al. N Engl J Med 2006;355:

65 ERCC1-Negative: Overall Survival Adjusted HR = % PI [ ], p = Adjusted HR = 1.14, 95% CI [ ], p = 0.40 ERCC1-Positive: Overall Survival 47% 39% 46% 40% Soria, Proc ASCO 2006 A#7010; Olaussen K et al. N Engl J Med 2006;355:

66 IFCT-0801 TASTE TAilored post-Surgical Therapy in Early stage NSCLC Principal Investigator Jean-Charles SORIA Institut Gustave Roussy - Villejuif Biological Coordinator Marie Wislez Hôpital Tenon - Paris

67 Erlotinib CDDP-Pemetrexed Observation ERCC1- ERCC1+ EGFR wt Experimental Arm Customized Control Arm CDDP - pemetrexed EGFR mutated TASTE design Non-SCC NSCLC stage II and IIIA (non-N2)

68 TASTE Results 150 pts randomized between May 2009 and July 2012,150 pts randomized between May 2009 and July 2012, 74 in arm A (PEM/DDP) and 76 in arm B (Selected)74 in arm A (PEM/DDP) and 76 in arm B (Selected) Most pts were male (61%), > 60 years (51%), and smokers (91%)Most pts were male (61%), > 60 years (51%), and smokers (91%) Pathological stage was IIA in 69 pt, IIB in 48 pt and IIIA in 32 pt.Pathological stage was IIA in 69 pt, IIB in 48 pt and IIIA in 32 pt. ERCC1 was positive in 38 pts (19 in each arm) – only 25%, not 44% expectedERCC1 was positive in 38 pts (19 in each arm) – only 25%, not 44% expected EGFR mutation was identified in 10 pts (3 in arm A, 7 in arm B).EGFR mutation was identified in 10 pts (3 in arm A, 7 in arm B). –Arm A, all pts received CP. –Arm B, 7 pts received erlotinib,7 pts received erlotinib, 53 pts received CP53 pts received CP 16 were observed16 were observed Median exposure time to erlotinib was 276 days (10-365).Median exposure time to erlotinib was 276 days (10-365). Out of 127 pts allocated to CP, 82% received the expected 4 cycles with a very good tolerability profile (no febrile neutropenia).Out of 127 pts allocated to CP, 82% received the expected 4 cycles with a very good tolerability profile (no febrile neutropenia). Success rate was 80% (120 out of 150 pts): appropriate Tx assignment and TxSuccess rate was 80% (120 out of 150 pts): appropriate Tx assignment and Tx 68 Soria J-C et al A-7505, ASCO ‘13

69 TASTE Conclusions Met its primary end point for the phase II component, demonstrating feasibility of a national biology-driven trial in the adjuvant setting.Met its primary end point for the phase II component, demonstrating feasibility of a national biology-driven trial in the adjuvant setting. Nevertheless, the phase III was canceled due to the unexpected unreliability of the ERCC1 IHC read-out.Nevertheless, the phase III was canceled due to the unexpected unreliability of the ERCC1 IHC read-out. – Current commercial antibodies are unable to distinguish all isoforms of ERCC1 TASTE Needs to be redone with accurate ERCC1 IHC AbTASTE Needs to be redone with accurate ERCC1 IHC Ab May have been responsible for the (-) MadeIT phase III trial in advanced NSCLC (relied on PCR mRNA probes and AQUA)May have been responsible for the (-) MadeIT phase III trial in advanced NSCLC (relied on PCR mRNA probes and AQUA) 69 TASTE Implications Soria J-C et al A-7505, ASCO ‘13

70 Role of Targeted Therapy

71 ECOG 1505: Adjuvant Bevacizumab RANDOMIRANDOMIZZEERANDOMIRANDOMIZZEEZE STRATIFIED:StageHistologyGender Chemo regimen* Chemotherapy X 4 cycles ELIGIBLE: Resected IB^-IIIA  Lobectomy No prior chemo No planned XRT No h/o CVA/TIA No ATE w/in 1 yr Chemotherapy x 4 cycles PlusBevacizumab X 1 year *Investigator Choice of 4 chemo regimens ^ Revised to exclude IB < 4cm N >1500; closed to accrual summer 2013

72 ECOG 4599: Overall Survival Proportion Surviving Months HR=0.80; P =0.013 BV/PC 12.3 mo PC 10.3 mo Median Survival 1-year survival 51% vs 44% 2-year survival 23% vs 15% Sandler, et al. NEJM. 355;24. Dec

73 Chemotherapy Regimens Therapy to start 6-12 weeks post-operativelyTherapy to start 6-12 weeks post-operatively –Investigator Choice of Chemo - 4 cycles (12 wks) Cisplatin/VinorelbineCisplatin/Vinorelbine –Cis 75 mg/m2 d 1, Vin 25 mg/m2 d1,8 q21 d Cisplatin/DocetaxelCisplatin/Docetaxel –Cis 75 mg/m2 d 1, Docetaxel 75 mg/m2 d 1 q21 d Cisplatin/GemcitabineCisplatin/Gemcitabine –Cis 75 mg/m2 d 1, Gem 1250 mg/m2 d1,8 q 21 d +/- Bevacizumab 15 mg/kg q 21 days x 12 mos+/- Bevacizumab 15 mg/kg q 21 days x 12 mos

74 Chemotherapy Regimens: amended 2010 Therapy to start 6-12 weeks post-operativelyTherapy to start 6-12 weeks post-operatively –Investigator Choice of Chemo - 4 cycles (12 wks) Cisplatin/PemetrexedCisplatin/Pemetrexed –Cis 75 mg/m2 d1, Pemetrexed 500 mg/m2 d1 Cisplatin/VinorelbineCisplatin/Vinorelbine –Cis 75 mg/m2 d 1, Vin 25 mg/m2 d1,8 q21 d Cisplatin/DocetaxelCisplatin/Docetaxel –Cis 75 mg/m2 d 1, Docetaxel 75 mg/m2 d 1 q21 d Cisplatin/GemcitabineCisplatin/Gemcitabine –Cis 75 mg/m2 d 1, Gem 1250 mg/m2 d1,8 q 21 d +/- Bevacizumab 15 mg/kg q 21 days x 12 mos+/- Bevacizumab 15 mg/kg q 21 days x 12 mos

75 RADIANT Trial: Adjuvant Trial of Erlotinib in NSCLC Stage IB, II, or IIIA NSCLC* Complete surgical resection And subsequent adjuvant chemo No prior or concurrent neoadjuvant or adjuvant N=1654 Arm A Erlotinib qd  2 years Arm B Placebo qd  2 years RANDOMIZE٭RANDOMIZE٭ *Enriched Population: FISH and/or IHC (+) 2 1

76 RADIANT Trial: Adjuvant Trial of Erlotinib in NSCLC Stage IB, II, or IIIA NSCLC* Complete surgical resection And subsequent adjuvant chemo No prior or concurrent neoadjuvant or adjuvant N=1654 Arm A Erlotinib qd  2 years Arm B Placebo qd  2 years RANDOMIZE٭RANDOMIZE٭ *Enriched Population: FISH and/or IHC (+) 2 1 Accrual Completed April, 2010

77 IPASS: Progression-free survival in EGFR mutation positive and negative patients Cox analysis with covariates; HR <1 implies a lower risk of progression on gefitinib; ITT population EGFR mutation positiveEGFR mutation negative Treatment by subgroup interaction test, p< HR (95% CI) = 0.48 (0.36, 0.64) p< No. events gefitinib, 97 (73.5%) No. events C/P, 111 (86.0%) Median PFS G, 9.5 months Median PFS C/P, 6.3 months HR (95% CI) = 2.85 (2.05, 3.98) p< No. events gefitinib, 88 (96.7%) No. events C/P, 70 (82.4%) Median PFS G, 1.5 months Median PFS C/P, 5.5 months Gefitinib C/P Probability of progression-free survival Patients at risk : Probability of progression-free survival Gefitinib (n=91) Carboplatin/paclitaxel (n=85) Months Gefitinib (n=132) Carboplatin/paclitaxel (n=129) Fukuoka et al, abstract 8006, ASCO 2009; Mok et al NEJM 2010

78 Phase II trial SELECT trial: adjuvant erlotinib in resected, early stage NSCLC pts with EGFR mutations PI L Sequist Resected stage IA-IIIA NSCLC Screen tumor for activating EGFR mutations (del 19, L858R) Adjuvant erlotinib x 2 years +/- adjuvant chemo Enroll if: screen + or documented EGFR mutation positive –and- No evidence recurrence on baseline CT scans Surveillance CT scans and CTC analysis q 6 mos x 3 years then q 12 mos x 2 years Biopsy at recurrence, sequence EGFR gene for new mutations, FISH for EGFR and MET copy number surveillance SCREENING PHASE TREATMENT PHASE N=100 Primary Endpoint: Two year disease-free survival

79 SELECT Trial: Adjuvant Erlotinib in Resected NSCLC Disease Free Survival

80 BR 19: Adjuvant Trial of Gefitinib in NSCLC Stage IB, II, or IIIA NSCLC Complete surgical resection No prior or concurrent neoadjuvant or adjuvant N=1242 ٭ Modified 2004 to allow adjuvant chemotherapy Arm A Gefitinib qd  2 years Arm B Placebo qd  2 years CAN-NCIC-BR19, CTSU, ECOG-CAN-NCIC-BR19, SWOG-CAN-NCIC-BR19 Protocol. Clinical Trials (PDQ ® ). At: Commenced October RANDOMIZE٭RANDOMIZE٭

81 Goss ASCO 2010 Abstr LBA7005 * Trend toward impaired outcome for EGFR mutation pts receiving Gef [HR of OS: 1.51]

82

83 ALCHEMIST E4512A081105A TargetALK+EGFRmutRegistry Prevalence~5%~10%All comers n Primary EndptDFS-OSOS-- Power80%85%-- One-sided α HR Adjunct Peripheral screening for ALK; RTPCR to identify fusion partners Targeted sequence and kinome analysis; PRO and QOL Extended sequencing for additional targets; correlation with local testing

84 Vaccines

85 MAGE-A3 Antigen (melanoma antigen family A, 3) Truly tumor-specific Truly tumor-specific –Not expressed on normal cells (RT-PCR) –Expressed by various tumor types Lung 35-50%Lung 35-50% Bladder35%Bladder35% Head & Neck 49%Head & Neck 49% Melanoma74%Melanoma74% Associated with poorer prognosis Associated with poorer prognosis (Bolli et al.,2002; Gure et al.,2005) Member of a large family of genes (portfolio) Member of a large family of genes (portfolio)

86 MAGE A3 ASCI* randomized phase II Stage pIB or pII: double-blind, randomly assigned 2:1 to postoperative MAGE-A3 vaccination or placebo.Stage pIB or pII: double-blind, randomly assigned 2:1 to postoperative MAGE-A3 vaccination or placebo. Vaccination was started >6 weeks after surgery, with 5 vaccinations at 3-week intervals, followed by 8 vaccinations every 3 months.Vaccination was started >6 weeks after surgery, with 5 vaccinations at 3-week intervals, followed by 8 vaccinations every 3 months. Other anti-cancer adjuvant therapy was not allowed.Other anti-cancer adjuvant therapy was not allowed. Primary endpoint was time-to-recurrence, other endpoints were recurrence rates at different times, and survival.Primary endpoint was time-to-recurrence, other endpoints were recurrence rates at different times, and survival. * antigen-specific cancer immune therapeutic Vansteenkiste et al, ASCO 2006, abstract 7019

87 Safety Status 182 patients / 1214 MAGE-A3 doses administered182 patients / 1214 MAGE-A3 doses administered Well toleratedWell tolerated Mild grade 1 or 2 toxicitiesMild grade 1 or 2 toxicities Local or systemic reactions,  48 hoursLocal or systemic reactions,  48 hours 29 grade 3 or 4 adverse events in 21 patients29 grade 3 or 4 adverse events in 21 patients Three grade 3 events, possibly related to treatmentThree grade 3 events, possibly related to treatment Leading to withdrawal of 2 patientsLeading to withdrawal of 2 patients –(local pain, COPD exacerbation)

88 HR=0.73 (95% CI = ) p= % one-sided  Disease-Free Interval Vansteenkiste et al, ASCO 2006, abstract 7019

89 Disease-Free Interval Final analysis 05 Oct, 2006 Cox regression model (95% confidence interval) P-value from Cox regr. model adjusted for stratification covariates HR with a 10% one-sided  Hazard ratio « Control » better « MAGE-A3 » better HR = 0.73 ( ) HR = 0.73 ( ) HR = 0.66 ( ) 0.73 Disease-Free Survival Overall Survival Efficacy Endpoints Overview P=0.107

90 Resectable NSCLC Surgery Pathological stage IB, II, IIIA R MAGE-A3 +AS15 Placebo No chemotherapy Chemotherapy (up to 4 cycles platinum based chemotherapy) R MAGE-A3 +AS15 Placebo MAGE Trial Design MAGRIT Trial

91 MAGRIT: Phase III Largest lung cancer study EVERLargest lung cancer study EVER Began in October 2007Began in October 2007 Goal: 2270 patients from 400 centers in 33 countries in Europe, North and South America, Asia, AustraliaGoal: 2270 patients from 400 centers in 33 countries in Europe, North and South America, Asia, Australia 2289 ultimately enrolled2289 ultimately enrolled

92 Role of Adjuvant RT in Stage II and Stage IIIA

93 Should the pt receive adj RT? 1)Yes 2)No 3)Maybe

94 Adjuvant Radiotherapy: Meta-analysis 1998 Individual data from 9 randomized trials including 2128 patientsIndividual data from 9 randomized trials including 2128 patients Treatment details (staging, surgery, RT) highly variable among seriesTreatment details (staging, surgery, RT) highly variable among series PORT: better local control: 29% fewer local recurrences LR vs 276 LR for no RTPORT: better local control: 29% fewer local recurrences LR vs 276 LR for no RT Overall HR = 1.21 ( ) ~ survival decrement of 7 % at two years (55% vs 48%)Overall HR = 1.21 ( ) ~ survival decrement of 7 % at two years (55% vs 48%) Increase risk greater for early stage patients(Stage I/II vs. III)Increase risk greater for early stage patients(Stage I/II vs. III) Lancet 25 July 1998

95 PORT Meta-analysis Survival Curves Stewart et al Lancet 1998

96 PORT - Heterogeneity of Hazard No increased risk for patients with N2 disease No increased risk for patients with N2 disease Patients with the least to gain have the most to lose Patients with the least to gain have the most to lose Stewart et al Lancet 1998

97 PORT Meta-analysis Methodologic Flaws Variable and unspecified stagingVariable and unspecified staging Variable and unspecified interval between resection and PORTVariable and unspecified interval between resection and PORT Inadequate RTInadequate RT –Suboptimal doses; large fields –Poor treatment planning –Outmoded techniques (e.g.: use of low-energy photons or 60 Co for a substantial proportion of patients) Inclusion of N 0 patientsInclusion of N 0 patients Unpublished data (2 of 9 studies)Unpublished data (2 of 9 studies) Relatively short F/U (< 4 yrs)Relatively short F/U (< 4 yrs) Stewart et al Lancet 1998

98 Risks of PORT with Modern Technology Retrospective reviewRetrospective review –202 patients treated with surgery and PORT for Stage II and III disease –Median dose 55 Gy –Actuarial rate of death from intercurrent disease was 13.5% compared to expected rate of 10% Machtay et al JCO 2001

99 ANITA TRIAL: N2 Disease – Influence of RT

100 RT Effect? Or Serendipity?

101 ANITA - PORT Evaluation PORT: 33% on obs, 22% on chemoPORT: 33% on obs, 22% on chemo For all Chemo > XRT = chemo/XRT > 0For all Chemo > XRT = chemo/XRT > 0 For N2 Chemo/XRT > chemo > XRT > 0For N2 Chemo/XRT > chemo > XRT > 0 XRTNo Yes ChemoNoYesNoYes All pts MST26mo93mo50mo46mo N2 MST13mo24mo23mo47mo Rosell, IASLC 11, Abs Pr3, 2005

102 Lally, B. E. et al. J Clin Oncol; 24: Plot of overall survival for N2 patients stratified by postoperative radiotherapy (PORT) use – SEER data

103 PORT Conclusions PORT has no role in N0 or N1 diseasePORT has no role in N0 or N1 disease Role of PORT in N2 is controversialRole of PORT in N2 is controversial –Recent subset and retrospective analyses hint at benefit –Ongoing “Lung ART” trial in France 700 pts with resected N2 randomized to PORT or not700 pts with resected N2 randomized to PORT or not Adjuvant chemo allowed 1 stAdjuvant chemo allowed 1 st Accrual sluggishAccrual sluggish

104 “Lung ART” P.I. Dr Cécile Le Pechoux Completely resected N2 NSCLC SURGERY Conformal RT No post-op RT 54 Gy/27-30 fxs Primary end-point: DFS (Sample size: 700 patients) Pre or post-op chemotherapy allowed Concomitant chemo not allowed Sponsors: FNCLCC, IFCT, LARS-G, EORTC

105 Conclusions: Adjuvant Therapy Adjuvant Platinum-based Chemotherapy is the Standard of Care for Resected Stage II-IIIA NSCLCAdjuvant Platinum-based Chemotherapy is the Standard of Care for Resected Stage II-IIIA NSCLC –Improves OS 5%-15% at 5 years with newer drugs Fit elderly patients (< 75 yrs) benefit as much as younger patientsFit elderly patients (< 75 yrs) benefit as much as younger patients Ongoing trials with molecularly determined Tx, erlotinib, bevacizumab, vaccinesOngoing trials with molecularly determined Tx, erlotinib, bevacizumab, vaccines ControversiesControversies –Benefit in IB –Neoadjuvant vs adjuvant therapy –Which chemotherapy to use –PORT


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