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Current Strategies for Adjuvant Therapy:  Ongoing and Future Trial Research

Current Strategies for Adjuvant Therapy:  Ongoing and Future Trial Research. Tracey Evans, MD Abramson Cancer Center University of Pennsylvania, Philadelphia. Current Status of Adjuvant Chemotherapy in NSCLC. It is STANDARD OF CARE How did we get here? . Investigator. # pts.

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Current Strategies for Adjuvant Therapy:  Ongoing and Future Trial Research

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  1. Current Strategies for Adjuvant Therapy: Ongoing and Future Trial Research Tracey Evans, MD Abramson Cancer Center University of Pennsylvania, Philadelphia

  2. Current Status of Adjuvant Chemotherapy in NSCLC It is STANDARD OF CARE How did we get here?

  3. Investigator # pts Chemotherapy Results Hughes 1962 1002 Nitrogen mustard IV + IP No benefit Higgins 1969 1035 Cyclophosphamide IV No benefit Slack 1970 1192 Nitrogen mustard IV + IP No benefit Miller 1971 502 Cyclophosphamide orally No benefit Brunner 1973 189 Cyclophosphamide IV No benefit higher recurrence in treatment arm Shields 1974 909 Cyclophosphamide IV + IP No benefit Shields 1977 417 Cyclophosphamide + MTX No benefit Shields 1982 865 CCNU + Hydrea No benefit Girling 1985 726 Busulfan + Cyclophosphamide No benefit Early Adjuvant Trials in NSCLC

  4. Limitations of Earlier Adjuvant Trials • Regimens with marginal activity in advanced NSCLC • Inclusion of patients with compromised PS and multiple co-morbidities • Difficulty administering systemic therapy in the post-op setting • Inadequate power/overly ambitious survival endpoints

  5. Events Total Surgery+CT 298 706 Surgery 688 316 S u r v i v a l Surgery+CT Surgery BMJ Meta-analysis: Adjuvant Cisplatin-based ChemotherapyOverall Survival 1.0 0.9 0.8 0.7 0.6 0.5 0.4 Survival benefit with cisplatin-based chemotherapy: 3% at 2 years, 5% at 5 years 0.3 0.2 0.1 0.0 at risk 0 12 24 36 48 60 Months 706 590 462 371 295 206 688 548 433 353 258 177 BMJ 311:899-901, 1995.

  6. IALT Schema Cisplatin 300-400mg/m2 over 3-4 cycles with Etoposide, vinorelbine, vinblastine, or vindesine Within 60 days post-op Randomize Surgically resected non-small cell lung cancer Observation Radiation optional, predetermined by N stage for each center

  7. IALT Results Chemo (932)No Chemo (935) 5 yr OS 44.5% 40.4% 5 yr DFS 39.4% 34.3% MS 50.8 mos 44.4 mos MDFS 40.2 mos 30.5 mos NEJM 350; 351-60, 2004.

  8. IALT: 7.5-Year Median Follow-Up 100% chemotherapy: 578 deaths - 495 deaths before 5 years 80% - 83 deaths after 5 years 60% HR: 0.91 (0.81-1.02, P = 0.10) 40% control 590 deaths - 534 deaths before 5 years 20% - 56 deaths after 5 years 0% 0 1 2 3 4 years 5 6 7 8 775 520 125 935 447 372 282 208 619 399 300 932 650 550 208 133 780 487 Le Chevalier T, et al. J ClinOncol. 2008(May 20 suppl). Abstract 7507.

  9. NCIC-BR10 Vinorelbine, IV, 25 mg/m2, weekly  16 wk Cisplatin, 50 mg/m2, d 1, 8 q 4 wk  4 cycles R A N D O MIZE • Select inclusion criteria: • Stage IB-II NSCLC • Complete surgical resection • N=482 No chemotherapy

  10. Overall Survival by Treatment Arm All Patients 5 yr: 67% vs 56% MST 94m vs 72m HR 0.69 5 yr: 69% vs 54% MST 94 m vs 73 m Absolute improvement in 5 yr OS = 15% (69% vs. 54%) Winton et al. NEJM 2005. Absolute improvement in 5 yr OS = 11% (67% vs. 56%); benefit persists at 9+ yrs Vincent, Butts et al, 2009.

  11. NCIC-CTG JBR.10Elderly Analysis • Elderly received less chemotherapy overall • Toxicity differences not seen in this trial by age group • Adjuvant chemotherapy should be offered to the fit elderly Pepe, J ClinOncolVol 25: 1553-1561, 2007.

  12. CALGB 9633: RCT of Adjuvant Chemotherapy in Stage IB NSCLC ADJUVANT CHEMOTHERAPY Paclitaxel, 200 mg/m2 Carboplatin, AUC=6 mg/ml x min 4 cycles over 12 weeks COMPLETE SURGICAL RESECTION T2N0MO stage IB NSCLC randomization within 4 to 8 wks of resection OBSERVATION STRATIFIED squamous vs other poorly differentiated vs other mediastinoscopy: yes vs no Strauss GM, Herndon JE, Maddaus MA, et al. Adjuvant chemotherapy in stage IB non-small cell lung cancer (NSCLC): update of Cancer and Leukemia Group B (CALGB) protocol 9633. Slides presented at: ASCO; June 2-6, 2006; Atlanta, GA. Presentation based on abstract 7007.

  13. Overall Survival: THEN AND NOW 1.0 1.0 Observation Observation Chemo Chemo 0.8 0.8 0.6 0.6 Probability Probability 0.4 0.4 0.2 0.2 HR=0.62; 90% CI: 0.44-0.89; P=0.01 HR=0.80; 90% CI: 0.60-1.07; P=0.10 0.0 0.0 0 0 1 2 2 3 4 4 5 6 6 7 8 8 9 0 0 1 2 2 3 4 4 5 6 6 7 8 8 9 Survival Time (Years) Survival Time (Years) ASCO: 2004 ASCO: 2006 Reproduced with permission (pending) from Strauss et al. Slides presented at: ASCO; June 2-6, 2006; Atlanta, GA. Presentation based on abstract 7007.

  14. Disease-Free Survival: Then and Now 1.0 1.0 Observation Observation Chemo 0.8 0.8 Chemo 0.6 0.6 Probability Probability 0.4 0.4 0.2 0.2 HR=0.69; 90% CI: 0.51-0.92; P=0.02 HR=0.74; 90% CI: 0.57-0.96; P=0.03 0.0 0.0 0 0 1 2 2 3 4 4 5 6 6 7 8 8 9 0 2 4 6 8 Survival Time (Years) Survival Time (Years) ASCO: 2004 ASCO: 2006 Reproduced with permission (pending) from Strauss et al. Slides presented at: ASCO; June 2-6, 2006; Atlanta, GA. Presentation based on abstract 7007.

  15. LACE* Meta-analysis • 5 trials including 4,584 patients • Median follow-up: 5.1 years (3.1 – 5.9) • 80% male • Median age 59 years, 9% > 70 years old • Pathological Stage: IA: 8%,IB: 30%, II: 35%, III: 27% • Surgery: 31% pneumonectomy • Histology: 49% squamous cell, 39% adenocarcinoma, 12% other *Lung Adjuvant Cisplatin Evaluation PignonProc ASCO 2006 abs 7008.

  16. LACE Meta-analysis Overall Survival (%) Disease-free Survival (%) Overall Survival (%) The absolute effect of chemotherapy at 5 years was a decrease of 6.9% for lung cancer death and an increase of 1.4% for non–lung cancer death. Pignon J et al. JCO 2008;26:3552-3559.

  17. LACE Meta-analysis 0.89 (0.82-0.96) 0.84 (0.78-0.91) P=.005 P<.001 Pignon J et al. JCO 2008;26:3552-3559.

  18. NCCN Guidelines

  19. Controversies • Which regimen? • Cisplatinvs Carboplatin? • Stage IB? • Predictive/prognostic biomarkers? • Post-operative XRT (PORT)?

  20. Which regimen?

  21. Regimens: LACE Meta-analysis .02 • Cisplatin/vinorelbine: regimen for 41% LACE pts • Regimen for Anita and JBR10 • 86% patients received >300mg/m2 cisplatin • 13% of IA’s cis/vinorelbinevs. 43% other stages • Drugs used with cisplatinother studies • IALT: vinorelbine, vindesine, vinblastin, etoposide • BLT: vinorelbine, vindesine, mitomycin/vindesine, mitomycin/ifosfamide • ALPI: vindesine/mitomycin .04 .09 .10

  22. Extrapolating Stage IV: Not Vinorelbine? 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 DocetaxelCisplatin Vinorelbine Cisplatin P = 0.044(adjusted log-rank) Cumulative Probability 0 3 6 9 12 15 18 21 24 27 30 33 Survival Time (Mos.) Fossella FV et al. JCO22, 2003.

  23. Extrapolating Stage IV: It’s all the Same? Schiller et al. NEJM.2002; 346:92-98.

  24. Extrapolating stage IV: Cisplatin ≠ Carboplatin: Response Rate Ardizzoni A et al. JNCI J Natl Cancer Inst2007;99:847-857.

  25. Extrapolating Stage IV: Cisplatin ≠ Carboplatin: Overall Survival Ardizzoni A et al. JNCI J Natl Cancer Inst2007;99:847-857.

  26. Randomized Phase 2 Trial on Refinement of Early Stage NSCLC Adjuvant Chemotherapy with Cisplatinand Pemetrexed(CPx) vs. Cisplatinand Vinorelbine(CVb) - TREAT 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

  27. Rationale: Dose delivery: Adjuvant CTX • TREAT Rationale: • Adjuvant CTX: mainly Cisplatin / Vinorelbine • Need: reductionoftoxicity, improvementof dose delivery & compliance • Cisplatin / Pemetrexed in thoracicmalignancies: high dose intensity, lowtoxicities Pignon, JCO, 2008 ; Winton, N Engl J Med, 2005; Alam, Lung Cancer, 2005; Vogelzang, JCO, 2003; Scagliotti, JCO, 2008; Schmid-Bindert, ASCO, 2009.

  28. TREAT: Design Cisplatin / Vinorelbine (CVrb) 50 mg/m2 d1+8 / 25 mg/m2 d1, 8, 15, 22 q d 29 x 4 Cisplatin / Pemetrexed (CPx) 75 mg/m2 d1 / 500 mg/m2 d1 q d 22 x 4 Inclusion • NSCLC stages IB, IIA, IIB, T3N1M0 • ≤ 42 days postoperative, R0, systematic LN-dissection • ECOG 0, 1 • amenable to Cisplatin treatment Stratification • Center • Nodal status (N0 versus N1) • Surgical procedure (lobectomy versus pneumonectomy) Winton et al., N Engl J Med (2005) 352: 258 R0

  29. TREAT: Conduct / Endpoints • Study conduct: • Study concept 2005, Inclusion 10/2006-12/2009 (16 sites, 132 patients) • Treatment until 2/2010, primary endpoint analysis 12/2010 • Primary endpoint: • 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 • Thrombocytopenia grade 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

  30. TREAT: Characteristics

  31. TREAT : Characteristics

  32. Results: Primary Endpoint - Feasibility p = 0.0010 * multiple reasons possible

  33. Results: End of Therapy *multiple reasons possible **delay >2 weeks due to toxicity or in case of G3/4 non-hem toxicity

  34. TREAT: Toxicity p<0.0001 p=0.7988

  35. TREAT: Time to Treatment Failure • TtTF: • Time from surgery • to withdrawal due to • AE • progression / relapse / death • failure to returnto therapy • refusal of treatment / withdrawal of consent p<0.001 Withdrawal probability

  36. TREAT: Conclusions • CPx safe and feasible • less toxicity compared to CVb • superior dose delivery compared to CVb • high dose density (mg/m2/week) • Dose delivery failure in CVb mostly due to Vb (delivery d15, d22) • Efficacy: longer follow up to be awaited

  37. E1505 Chemotherapy Regimens • Therapy to start 6-12 weeks post-operatively • Investigator Choice of Chemo - 4 cycles (12 wks) • Cisplatin/Vinorelbine • Cis 75 mg/m2 d 1, Vin 25 mg/m2 d1,8 q21 d • Cisplatin/Docetaxel • Cis 75 mg/m2 d 1, Docetaxel 75 mg/m2 d 1 q21 d • Cisplatin/Gemcitabine • Cis 75 mg/m2 d 1, Gem 1250 mg/m2 d1,8 q 21 d • Cisplatin/Pemetrexed • Cis 75 mg/m2 d 1; Pem 500 mg/m2 d 1 Q 21 d • Bevacizumab 15 mg/kg q 21 days x 12 months

  38. ECOG 1505: Adjuvant Bevacizumab RANDOM I Z E • ELIGIBLE: • Resected IB^-IIIA • Squamous Allowed! • Lobectomy No prior chemo No planned XRT No h/o CVA/TIA No ATE w/in 1 yr STRATIFIED: Stage Histology Gender Chemo regimen* Chemotherapy X 4 cycles Chemotherapy x 4 cycles Plus Bevacizumab X 1 year Completed accrual/study closed Sept 20, 2013 ^ Now revised to exclude IB < 4cm

  39. 1.0 Median Survival PC 10.3 mo 0.8 BV/PC 12.3 mo 0.6 HR=0.80; P=0.013 Proportion Surviving 0.4 0.2 0.0 12 24 36 0 6 18 30 42 48 Months ECOG 4599: Overall Survival 1-year survival 51% vs. 44% 2-year survival 23% vs. 15% Sandler, et al. NEJM. 355;24. Dec 14 2006.

  40. Stage IB

  41. LACE Meta-analysis: Stage Effects 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)

  42. Stage-Specific Hazard RatiosRecent Adjuvant Trials Negative Positive Indeterminate Not studied

  43. Stage-Specific Hazard RatiosRecent Adjuvant Trials Negative Positive Indeterminate Not studied * Using 3 cm as cut off

  44. New Staging System (IASLC ’07) Staging alteration

  45. Prognostic/Predictive Biomarkers • Using prognostic data to treat fewer patients who are probably cured, more who are probably not • Using predictive data to treat only those likely to benefit with drugs most likely to work

  46. ERCC-1 • DNA repair mechanisms important for resistance to cisplatin • Excision repair cross-complementation group 1 (ERCC1) enzyme plays rate-limiting role in the nucleotide excision repair pathway ERCC-1 Positive ERCC-1 Negative

  47. IALT: ERCC-1 Survival Olaussen et al, NEJM 2006; 355: 983-991

  48. Prospective Biomarker NSCLC Studies

  49. 8F1 antibody in IALT data set • Evaluation of 16 commercially available ERCC1 antibiodies could not distinguish between active and inactive ERCC1 isoforms. Friboulet, et al, NEJM 2013; 368: 1101-1110.

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