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Maintenance Therapy in Advanced NSCLC: State of the Art or State of Confusion

Maintenance Therapy in Advanced NSCLC: State of the Art or State of Confusion Corey J Langer MD, FACP Director Thoracic Oncology Abramson Cancer Center Professor of Medicine Hematology-Oncology Division University of Pennsylvania Philadelphia, PA 19104 Corey.langer@uphs.upenn.edu.

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Maintenance Therapy in Advanced NSCLC: State of the Art or State of Confusion

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  1. Maintenance Therapy in Advanced NSCLC: State of the Art or State of Confusion Corey J Langer MD, FACP Director Thoracic Oncology Abramson Cancer Center Professor of Medicine Hematology-Oncology Division University of Pennsylvania Philadelphia, PA 19104 Corey.langer@uphs.upenn.edu

  2. Disclosures: Past 5 yrs • Grant/Research Support: • Bristol Myers Squibb, Pfizer, Imclone, Lilly, Schering Plough Research Institute, SanofiAventis, Amgen, Cell Therapeutics Inc., Celgene, Genentech, OSI, Astra Zeneca, Active Biothech, • Scientific Advisor: • Bristol Myers Squibb, Imclone, Sanofi-Aventis, Pfizer-Pharmacia, GlaxoSmithKline, Abbott, Pharmacyclics, Amgen, AstraZeneca, Novartis, Genentech, OSI, Bayer/Onyx, Abraxis; Biodesix; Clarient; Agennix; Vertex • Speakers Bureau: curtailed as of 12/2010 • Bristol Myers Squibb, Imclone, Sanofi- Aventis, Lilly, Genentech, OSI

  3. Terminology: Maintenance Is it maintenance? Is it consolidation? Or is it early salvage?

  4. Terminology: Maintenance • Prolonged Therapy: continuing the original regimen indefinitely until PD or toxicity • Full dose: Identical regimen (Prolonged Chemo) • Attenuated dose: usually to mitigate cumulative toxicity • Continuation Maintenance: continuing Rx with the non-platinum component of Tx (single agent instead of combination) • Switch Maintenance: alternative cytotoxic or targeted agent • AKA: Early Second Line Tx

  5. Carboplatin AUC 6 + Paclitaxel 200 mg/m2 every 21 days x 4 cyc At Progression: Weekly Paclitaxel 80 mg/m2/wk until PD Carboplatin AUC 6 + Paclitaxel 200 mg/m2 every 21 days until PD Phase III: 4 Cycles Chemo vs. Continuous Chemo Followed by Second Line Therapy in Adv NSCLC R A N D O M I Z E • Eligibility • NSCLC IIIb/IV • PS ≥ 70 • Chemonaive • Treated Brain Mets • No neuropathy Endpoints: Survival and Quality of Life Socinski M, et al. J Clin Onc 2005; 20(5). Hensing TA, et al. Lung Cancer 2005; 47:253.

  6. Paclitaxel Carboplatin x 4 Cycles vs Paclitaxel Carboplatin to Progression Socinski et al. J Clin Oncol 20: 1335, 2002

  7. Paclitaxel Carboplatin x 4 Cycles vs Paclitaxel Carboplatin to Progression Socinski et al. J Clin Oncol 20: 1335, 2002

  8. Paclitaxel Carboplatin x 4 Cycles vs Paclitaxel Carboplatin to Progression Socinski et al. J Clin Oncol 20: 1335, 2002

  9. MVP x 3 cycles MVP x 6 cycles Prolonged Chemotherapy Stage IIIB/IV NSCLC PS 0-2 R All patients could receive MVP at progression MVP: mitomycin, vinblastine, cisplatin Smith, JCO 19: 1336, 2001

  10. MVP x 3 Cycles versus MVP x 6 Cycles Smith et al. J Clin Oncol 19: 1336, 2001

  11. MVP x 3 Cycles versus MVP x 6 Cycles Survival, all patients Survival, patients who Survival, PS 0-1 patients received at least 3 cycles Smith et al. J Clin Oncol 19: 1336, 2001

  12. Immediate Versus Delayed Docetaxel After Induction Eligibility & Treatment Plan CR, PR, SD Immediate Docetaxel 75mg/m2 day 1, every 21 days until PD or maximum of 6 cycles R A N D O MI Z E • GC Phase • Gemcitabine, • 1000 mg/m2, • D 1, 8 • Carboplatin • AUC 5, Day 1 • Every 21 d • 4 cycles • Patient Eligibility • NSCLC Stage IIIb/IV • Chemonaïve • ECOG PS = 0-2 • CNS Mets allowed Delayed Docetaxel Best Supportive Care, then start therapy at PD 75mg/m2 on day 1, every 21 days, until PD or maximum of6 cycles Primary endpoint: Overall Survival, HR: 1.43 Fidias et al, ASCO 2007

  13. Immediate Versus Delayed Docetaxel After Induction Eligibility & Treatment Plan Chemonaϊve Stage IIIb/IV NSCLC N = 562 ORR 29% Immediate Treated N = 142 Immediate Docetaxel N = 153 GCb Phase N = 552 (388 (69%) received 4 cycles) SD, PR, CR N = 307 (56%) Treated Randomized Delayed Treated N = 91* Delayed Docetaxel N = 154 Off Study N = 245 *Only 59% of patients randomized to delayed docetaxel received treatment. Fidias et al, ASCO 2007

  14. Fidias et al. J Clin Oncol; 27:591-598 2009

  15. Is this negative for survival benefit or under-powered?? Fidias et al. J Clin Oncol; 27:591-598 2009

  16. Maintenance Pemetrexed Plus Best Supportive Care (BSC) Versus Placebo Plus BSC: A Phase III Study in NSCLC C.P. Belani1, T. Brodowicz2, 3, T. Ciuleanu3, 4, J.H. Kim5, M. Krzakowski3, 6*, E. Laack7, Y.L. Wu8, P. Peterson9, K.Krejcy10, C. Zielinski2, 3 1Penn State Hershey Cancer Institute, Hershey, PA, USA; 2Medical University, Vienna, Austria; 3Central European Cooperative Oncology Group (CECOG); 4Institutul Oncologic I Chiricuta, Cluj, Romania; 5Yonsei Cancer Center, Seoul, Korea; 6 Maria Sklodowska-Curie Memorial Cancer Center & Institute Of Oncology, Warsaw, Poland; 7Cancer Center, University Hospital Hamburg-Eppendorf, Germany; 8Guangdong General Hospital, Guangzhou, China; 9Eli Lilly and Co. IN, USA; 10Lilly Regional Operations, Vienna, Austria

  17. Study Design Double-blind, Placebo-controlled, Multicenter, Phase III Trial • Stage IIIB/IV NSCLC • ECOG PS 0-1 • 4 prior cycles of gem, doc, or tax + cis or carb, with CR, PR, or SD • Randomization factors: • gender • PS • stage • best tumor response • non-platinum drug • brain mets Pemetrexed 500 mg/m2 (d1,q21d) + BSC (N=441)* 2:1 Randomization Primary Endpoint = PFS Placebo (d1, q21d) + BSC (N=222)* *B12, folate, and dexamethasone given in both arms

  18. Objectives Primary Objective • Progression-free survival Secondary Objectives • Overall survival • Objective response rate (CR+PR) • Disease control rate (CR+PR+SD) • Safety

  19. Baseline Characteristics

  20. Initial Therapy

  21. Pemetrexed 4.0 mos Progression-free Survival Placebo 2.0 mos HR=0.60 (95% CI: 0.49 0.73) P <0.00001 Progression-free Probability Time (months)

  22. Pemetrexed 4.4 mos Pemetrexed 2.4 mos Placebo 1.8 mos Placebo 2.5 mos Progression-free Survival by Histology Non-squamous Squamous HR=1.03 (95% CI: 0.77-1.5) P =0.896 HR=0.47 (95% CI: 0.37-0.6) P <0.00001 Progression-free Probability Time (months) Time (months)

  23. Overall Survival (Intent-to-treat Population) Placebo 10.6 mos HR=0.79 (95% CI: 0.65–0.95) P =0.012 Survival Probability Pemetrexed 13.4 mos Time (months)

  24. Pemetrexed 15.5 mos Pemetrexed 9.9 mos Placebo 10.3 mos Placebo 10.8 mos Overall Survival by Histology Non-squamous (n=481) Squamous (n=182) HR=1.07 (95% CI: 0.49–0.73) P =0.678 HR=0.70 (95% CI: 0.56-0.88) P =0.002 Survival Probability Time (months) Time (months)

  25. Efficacy by Histologic Groups There was a statistically significant treatment-by-histology interaction with both PFS (P=0·036) and OS (P=0·033)

  26. Treatment-related Toxicities* *NCI CTC version 3.0 ‡P <0.05 for grade 3/4 rates of neutropenia and fatigue

  27. Treatment HRs for Overall Survival in Subgroups of the ITT Population

  28. Conclusions • First randomized, double-blind, placebo-controlled study to demonstrate a significant overall survival benefit for maintenance treatment with in patients with advanced NSCLC • Non-squamous histology: predictive of the improved efficacy of pemetrexed in patients with advanced NSCLC • Administration of pemetrexed in the maintenance setting is fairly well tolerated and is devoid of any cumulative toxicity

  29. Switch Maintenance Fidias, J Clinc Oncol 28:5116-5123 Zhang et al [INFORM] ASCO 2011

  30. Switch Maintenance Fidias, J Clinc Oncol 28:5116-5123

  31. Potential Criticisms • Significant percentage of pts will not get to enjoy the “fruits of maintenance” pemetrexed • Early 2nd line vs 2nd line at progression, ie. mandatory crossover at time of progression not instituted • Toxicity of pemetrexed, though mild, is not entirely trivial • Early institution of 2nd line Tx unnecessary in sizable proportion of pts • Result of this trial do not apply to those who receive pemetrexed or bevacizumab as part of first-line treatment. • Cost?!

  32. Potential Criticisms • Significant percentage of pts will not get to enjoy the “fruits of maintenance” pemetrexed • Early 2nd line vs 2nd line at progression, ie. mandatory crossover at time of progression not instituted • Toxicity of pemetrexed, though mild, is not entirely trivial • Early institution of 2nd line Tx unnecessary in sizable proportion of pts • Result of this trial do not apply to those who receive pemetrexed or bevacizumab as part of first-line treatment. • Cost?!

  33. Immediate Versus Delayed Docetaxel After Induction Eligibility & Treatment Plan Chemonaϊve Stage IIIb/IV NSCLC N = 562 ORR 29% Immediate Treated N = 142 Immediate Docetaxel N = 153 GCb Phase N = 552 (388 (69%) received 4 cycles) SD, PR, CR N = 307 (56%) Treated Randomized Delayed Treated N = 91* Delayed Docetaxel N = 154 Off Study N = 245 *Only 59% of patients randomized to delayed docetaxel received treatment. Fidias et al, ASCO 2007

  34. Limited Applicability • If we look at the Fidias trial, only 56% of those started on first-line Tx were randomized to maintenance • Reasons: Therapeutic reality • Disease progression • Intercurrent Co-moribidities • Pt opt-out • Benefits of Pemetrexed are confined to the non-squamous population, ~ 2/3 of the remainder • So the benefits of pemetrexed maintenance apply to only 38% of the entire advanced stage good PS NSCLC population (if we use Fidias as our reference)

  35. Potential Criticisms • Significant percentage of pts will not get to enjoy the “fruits of maintenance” pemetrexed • Benefits confined to <50% of those who start first-line therapy, maybe < 40% • Early 2nd line vs 2nd line at progression, ie. mandatory crossover at time of progression not instituted • Toxicity of pemetrexed, though mild, is not entirely trivial • Early institution of 2nd line Tx unnecessary in sizable proportion of pts • Result of this trial do not apply to those who receive pemetrexed or bevacizumab as part of first-line treatment. • Cost?!

  36. Systemic Post-study Therapy • Higher rate of follow-up treatment on the placebo arm • Balanced selection of therapies between arms and low rate of crossover

  37. Systemic Post-study Therapy • Higher rate of follow-up treatment on the placebo arm • Balanced selection of therapies between arms and low rate of crossover

  38. Phase 3 Study of Immediate vs. Delayed Docetaxel After First Line Gemcitabine/Carboplatin in Advanced NSCLCFidias et al. J Clin Oncol; 27:591-598 2009Median Survival • Analysis of those who went onto Docetaxel as “salvage” therapy suggests no compromise in longterm survival

  39. Potential Criticisms • Significant percentage of pts will not get to enjoy the “fruits of maintenance” pemetrexed • Benefits confined to <50% of those who start first-line therapy, maybe < 40% • Early 2nd line vs 2nd line at progression, ie. mandatory crossover at time of progression not instituted • Would have inoculated this study from critique if the OS advantage had been maintained • Toxicity of pemetrexed, though mild, is not entirely trivial • Early institution of 2nd line Tx unnecessary in sizable proportion of pts • Result of this trial do not apply to those who receive pemetrexed or bevacizumab as part of first-line treatment. • Cost?!

  40. Maintenance Pemetrexed: Tx-related Toxicities* *NCI CTC version 3.0 ‡P <0.05 for grade 3/4 rates of neutropenia and fatigue Ciuleanu et al. Lancet 374: 1432-1440 (2009)

  41. Maintenance Pemetrexed: Tx-related Toxicities* *NCI CTC version 3.0 ‡P <0.05 for grade 3/4 rates of neutropenia and fatigue Ciuleanu et al. Lancet 374: 1432-1440 (2009)

  42. Perspectives on ToxicityMaintenance Pemetrexed • Incidence of grade 3+4 toxicity was low • Only 5% dropped out b/o side effects • But the cumulative effect of grade 1 and 2 toxicity, especially fatigue and aesthenia, cannot be discounted

  43. Perspectives on ToxicityMaintenance Pemetrexed • Incidence of grade 3+4 toxicity was low • Only 5% dropped out b/o side effects • But the cumulative effect of grade 1 and 2 toxicity, especially fatigue and aesthenia, cannot be discounted • Particularly in the Palliative Care Setting • Many pts will stay on maintenance Tx far longer than their original “induction” regimens

  44. Potential Criticisms • Significant percentage of pts will not get to enjoy the “fruits of maintenance” pemetrexed • Benefits confined to <50% of those who start first-line therapy, maybe < 40% • Early 2nd line vs 2nd line at progression, ie. mandatory crossover at time of progression not instituted • Would have inoculated this study from critique if the OS advantage had been maintained • Toxicity of pemetrexed, though mild, is not entirely trivial • Cumulative effects of fatigue and aesthenia • Early institution of 2nd line Tx unnecessary in sizable proportion of pts • Result of this trial do not apply to those who receive pemetrexed or bevacizumab as part of first-line treatment. • Cost?!

  45. Progression-free Survival HR=0.60 (95% CI: 0.49–0.73) P <0.00001 Progression-free Probability Pemetrexed 4.0 mos Placebo 2.0 mos Time (months)

  46. Benefits of Therapeutic Holiday • Recovery from platinum-based toxicities • 50% or more will have at least a two month window • Time to travel, participate in family events • “Reconstitute the immune system” • Many will remain asymptomatic at the time of PD • Sufficient time to judiciously implement second line Tx • Unethical if 2nd line Tx is not available

  47. Potential Criticisms • Significant percentage of pts will not get to enjoy the “fruits of maintenance” pemetrexed • Benefits confined to <50% of those who start first-line therapy, maybe < 40% • Early 2nd line vs 2nd line at progression, ie. mandatory crossover at time of progression not instituted • Would have inoculated this study from critique if the OS advantage had been maintained • Toxicity of pemetrexed, though mild, is not entirely trivial • Cumulative effects of fatigue and aesthenia • Early institution of 2nd line Tx unnecessary in sizable proportion of pts • Therapeutic holiday will do the pt (and the clinician) good • Result of this trial do not apply to those who receive pemetrexed or bevacizumab as part of first-line treatment. • Cost?!

  48. Relevance in the setting of First-line Therapy with Bevacizumab and Pemetrexed • 25 to 40% of US pts with newly diagnosed Non-Sq NSCLC are treated with Bevacizumab upfront • An increasing percentage of chemo-naïve pts (~30 to 50%) receive pemetrexed as part of their first-line therapy • Neither of these two groups were included in this trial (probably >50% of potentially eligible pts) • Pem maintenance, arguably, is irrelevant to these two groups, and the robust PFS and OS benefit might have been diluted

  49. Relevance in the setting of First-line Therapy with Bevacizumab and Pemetrexed • 25 to 40% of US pts with newly diagnosed Non-Sq NSCLC are treated with Bevacizumab upfront • An increasing percentage of chemo-naïve pts (~30 to 50%) receive pemetrexed as part of their first-line therapy • Neither of these two groups were included in this trial (probably >50% of potentially eligible pts) • Pem maintenance, arguably, is irrelevant to these two groups, and the robust PFS and OS benefit might have been diluted • Concerns since addressed by Paramount and AvaPERL trials

  50. Potential Criticisms • Significant percentage of pts will not get to enjoy the “fruits of maintenance” pemetrexed • Benefits confined to <50% of those who start first-line therapy, maybe < 40% • Early 2nd line vs 2nd line at progression, ie. mandatory crossover at time of progression not instituted • Would have inoculated this study from critique if the OS advantage had been maintained • Toxicity of pemetrexed, though mild, is not entirely trivial • Cumulative effects of fatigue and aesthenia • Early institution of 2nd line Tx unnecessary in sizable proportion of pts • Therapeutic holiday will do the pt (and the clinician) good • Result of this trial do not apply to those who receive pemetrexed or bevacizumab as part of first-line treatment. • This trial may be “irrelevant to these two cohorts” and the robust PFS and OS advantage might be diluted • Cost?!

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