Transitioning Survival from Months to Years in Advanced Non-Small Cell Lung Cancer

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Dr. Jack West reviews the evolution of new treatment options for advanced NSCLC that have steadily improved survival. This progress has been incremental but now means that an ever-growing proportion of patients with advanced NSCLC have a realistic promise of potentially living several years after their diagnosis and the start of treatment. Note that this presentation does not address advances in immunotherapy, which were covered in a separate talk at the same conference at which Dr. West delivered this presentation.

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  • Belani CP, Brodowicz T, Ciuleanu T, et al. Maintenance pemetrexed (Pem) plus best supportive care (BSC) versus placebo (Plac) plus BSC: A randomized phase III study in advanced non-small cell lung cancer (NSCLC). J Clin Oncol. 2009;27(18s):CRA8000.
  • Notes:
    Based on the results of the phase II study, a placebo controlled phase III trial was designed and conducted in the 1st line setting for patients with non-squamous cell NSCLC.
    The trial randomized 878 patients to receive carbo/taxol with or without bevacizumab. Patients that were on the placebo arm were not allowed to cross over.
    Patients on the bevacizumab arm received carbo/taxol/bev x 6 cycles and then bevacizumab until progression.
    The primary endpoint of the trial is survival.
    This trial completed accrual in April 2004 and results of a planned interim analysis were presented at ASCO 2005.
  • Notes:
    Based on the results of the phase II study, a placebo controlled phase III trial was designed and conducted in the 1st line setting for patients with non-squamous cell NSCLC.
    The trial randomized 878 patients to receive carbo/taxol with or without bevacizumab. Patients that were on the placebo arm were not allowed to cross over.
    Patients on the bevacizumab arm received carbo/taxol/bev x 6 cycles and then bevacizumab until progression.
    The primary endpoint of the trial is survival.
    This trial completed accrual in April 2004 and results of a planned interim analysis were presented at ASCO 2005.
  • Notes:
    Based on the results of the phase II study, a placebo controlled phase III trial was designed and conducted in the 1st line setting for patients with non-squamous cell NSCLC.
    The trial randomized 878 patients to receive carbo/taxol with or without bevacizumab. Patients that were on the placebo arm were not allowed to cross over.
    Patients on the bevacizumab arm received carbo/taxol/bev x 6 cycles and then bevacizumab until progression.
    The primary endpoint of the trial is survival.
    This trial completed accrual in April 2004 and results of a planned interim analysis were presented at ASCO 2005.
  • Notes:
    Based on the results of the phase II study, a placebo controlled phase III trial was designed and conducted in the 1st line setting for patients with non-squamous cell NSCLC.
    The trial randomized 878 patients to receive carbo/taxol with or without bevacizumab. Patients that were on the placebo arm were not allowed to cross over.
    Patients on the bevacizumab arm received carbo/taxol/bev x 6 cycles and then bevacizumab until progression.
    The primary endpoint of the trial is survival.
    This trial completed accrual in April 2004 and results of a planned interim analysis were presented at ASCO 2005.
  • Transitioning Survival from Months to Years in Advanced Non-Small Cell Lung Cancer

    1. 1. TRANSITIONING SURVIVAL FROM MONTHS TO YEARS IN ADVANCED NSCLC H. Jack West, MD Swedish Cancer Institute Seattle, WA Global Resource for Advancing Cancer Education (GRACE) www.cancerGRACE.org
    2. 2. Metastatic NSCLC in a Historical Context • Treatment is not curative: goal is to prolong survival survival with minimal treatment-related toxicity and risk, also hoping to reduce cancer-related symptoms • Debate through 1990s: is treatment “worth it” for what was typically a two month benefit? • This was with a platinum- based doublet that was widely considered toxic (cisplatin-based) • Can we do better? • One year OS? ~30% Median OS
    3. 3. Searching for the “Best Doublet” Schiller, NEJM 2004 1 yr OS – 33% 2 yr OS – 11%
    4. 4. Second Line Therapy? • ~2000, docetaxel, followed by erlotinib and pemetrexed, are all tested and demonstrate comparable survival benefit in previously treated patients with advanced NSCLC. • This is despite response rates below 10% and is largely driven by up to 50% of patients achieving minor tumor shrinkage or stable disease.
    5. 5. Optimizing Survival by Histology • Over last 6-8 years, we begin to see value in distinguishing between NSCLC histologies (squamous and non- squamous, primarily) • Cisplatin-pemetrexed vs. cisplatin-gemcitabine Scagliotti, JCO 2008
    6. 6. Tailoring Regimen by Histology to Approach a 1 Year Median OS • As we approach a median survival of 1 year, this means that half of patients are living beyond a year Median OS
    7. 7. Adding Bevacizumab & Integrating Maintenance Therapy Advanced NSCLC, Non-squamous carbo/paclitaxel/be v x 6 cycles carbo/paclitaxel x 6 cycles Maintenance bev until progression Sandler, NEJM 2006 Response rate: 15% with chemo alone, vs. 35% with chemo/bev
    8. 8. New Era of Targeted Therapies and Maintenance Therapy • With ECOG 4599, we now have nearly ¼ of patients living 2 yrs Median OS
    9. 9. “Down-Shifting” to a Less Challenging but Still Effective Therapy wo Basic Mechanisms (neither proven better or worse) First Line ChemoFirst Line Chemo Continuation MaintContinuation Maint “Continuation” maintenance: after 4-6 cycles 1st line, drop >1 drug, keep others going until progression Switch MaintSwitch Maint “Switch” maintenance: after 4-6 cycles 1st line, stop all, switch directly to new drug(s) Both approaches less intensive than first line combo therapy First Line ChemoFirst Line Chemo
    10. 10. Refining Maintenance Therapy: Switch Maintenance with Pemetrexed Advanced NSCLC, Not progressing after 4 cycles non-pem doublet Placebo infusion every 3 weeks Switch maintenance pemetrexed every 3 weeks Ciuleanu, Lancet 2009 24% censored HR = 0.599 (95% CI: 0.49–0.73) p < .00001 Time (mos) PFSProbability(%) 0 3 6 9 12 15 18 21 24 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Pemetrexed: 4.04 mos (95% CI: 3.06–4.44) Placebo: 1.97 mos (95% CI: 1.54–2.76) 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 SurvivalProbability(%) Time (mos) HR = 0.79 (95% CI: 0.65–0.95) p = .012 Pemetrexed 13.4 mos Placebo 10.6 mos Progression-Free Survival Overall Survival
    11. 11. Non-Squamous (n = 481) Squamous (n = 182) JMEN: OS by Histology 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 HR = 0.70 (95% CI: 0.56–0.88) p = .002 HR = 1.07 (95% CI: 0.49–1.73) p = .678 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 SurvivalProbability(%) Time (mos) Time (mos) Pemetrexed 15.5 mos Placebo 10.3 mos Pemetrexed 9.9 mos Placebo 10.8 mos Ciuleanu, Lancet 2009
    12. 12. Continuation Maintenance Pemetrexed advanced non-squam NSCLC, no prior systemic Rx placebo every 3 weeks continuation maintenance pemetrexed every 3 weeks Paz-Ares, J Clin Oncol 2013 Progression-Free Survival (from rand) Overall Survival (from 1L chemo) cis/pemetrexed x 4 cycles 1 yr OS: 58% vs. 45%; 2 yr OS: 32% vs.21%
    13. 13. AVAPERL: Continuation Maintenance Therapy after Chemo/Bevacizumab advanced non-squam NSCLC, no prior systemic Rx continuation maintenance bevacizumab continuation maintenance pemetrexed/bevacizumabcis/pem/bev x 4 cycles Progression-Free Survival (from rand) Overall Survival (from 1L chemo) Rittmeyer, Proc ASCO 2013
    14. 14. AVAPERL: Continuation Maintenance Therapy with Pemetrexed vs. Pemetrexed/Bevacizumab 0 2 4 6 8 10 12 14 16 18 20 NaturalHx Plat Doublet Doublet +2L HistolSpecific Bv+ Maint Switch/Cont Maint Maint w/Bev 2 yr. survival now up to 1/3 of patients Median OS
    15. 15. EGFR Mutations & Molecular Oncology Sequist, JCO 2007 Before & after gefitinib (2 mo) Courtesy of Dr. D. Gandara
    16. 16. IPASS: Molecular Oncology Overrides Clinical Features advanced lung adenocarcinoma, Asian no prior systemic Rx Never or light ex-smoker Gefitinib daily until progression Carbo/paclitaxel x 6 cycles Mok, NEJM 2009
    17. 17. IPASS: Objective Response Rate by EGFR Mutation Status 0 10 20 30 40 50 60 70 80 Mutation positive patients Mutation negative patients Gefitinib Carboplatin / paclitaxel EGFR M+ odds ratio (95% CI) = 2.75 (1.65, 4.60), p=0.0001 EGFR M- odds ratio (95% CI) = 0.04 (0.01, 0.27), p=0.0013 Overall response rate (%) (n=132) (n=129) (n=91) (n=85) Odds ratio >1 implies greater chance of response on gefitinib 71.2% 47.3% 1.1% 23.5% Mok, NEJM 2009
    18. 18. Prospective Trials of EGFR TKIs vs. Chemo in EGFR Mutation (Exons 19, 21) Population Trial N Rx RR PFS (mo) OS (mo) TKI Chemo TKI Chemo TKI Chemo Maemondo NEJ002 230 Gefitinib vs. Carbo/Pac 74% 31% 10.8 5.4 30.5 23.6 Mistudomi WJTOG340 5 172 Gefitinib vs. Cis/Doce 62% 32% 9.2 6.3 30.9 N.R. Zhao OPTIMAL 165 Erlotinib vs. Carbo/Gem 83% 36% 13.1 4.6 22.6 28.8 Rosell EURTAC 174 Erlotinib vs. Plat Doublet 58% 15% 9.4 5.2 19.3 19.5 Sequist LUX-Lung 3 345 Afatinib vs. Cis/Pem 56% 23% 13.6 6.9 NR NR Wu LUX-Lung 6 364 Afatinib vs. Cis/Gem 67% 23% 11.0 5.6 NR NR Maemondo, NEJM 2010; Mistudomi, Lancet Oncol 2010; OPTIMAL, Lancet Oncol 2011; Rosell, Lancet 2012 Sequist, JCO 2013; Wu, Lancet Oncol 2014 NR = not reported
    19. 19. EML4-ALK Translocations in NSCLC EML4-ALK frequency: ~4% (64/1709) Primarily adenoCa, minimial or no smoking history Soda et al., Nature 448: 561-566, 2007 Bang, NEJM, 2010
    20. 20. New Mutation ROS-1 Identified in ~1% of NSCLC Tumors
    21. 21. Bergethon, J Clin Oncol 2012 Response to Crizotinib in ROS-1 Patients
    22. 22. • 67% response rate in T790M+ patients (WCLC, 2013) • Dosing 900 mg PO BID • No rash (c/w absence of systemic wt EGFR inhibition) Soria, WCLC 2013, Sydney CO-1686: Oral Inhibitor of EGFR Mutations & T790M Mutations (not EGFR wild type)
    23. 23. 89 patients with documented radiological PD while on EGFR-TKI No DLTs at 20-160 mg/d (dosing to 240 mg/d) No dose reductions AZD9291: Best % change from baseline in target lesions Ranson, WCLC 2013, Sydney
    24. 24. Ceritinib: Activity in Patients with Advanced ALK+ NSCLC Shaw, NEJM 2014
    25. 25. Ceritinib: Approved for Crizotinib-Pretreated ALK-Positive NSCLC April 29, 2014 …but $13,500/month!
    26. 26. A mutation found in 54% of tumors completely tested HER 2 LCMC: Incidence of mutations detected
    27. 27. LCMC: Protocols linked to specific mutations HER 2 Crizotinib (complete) BKM120 GSK2118434 Erlotinib + ARQ197 MM-121 Dacomitinib GSK1120212 Crizotinib STA-9090 Erlotinib + OSI906
    28. 28. BRAF V600E Mutations in NSCLC Response rate – 40%, disease control 60% Planchard, Proc ASCO, 2013
    29. 29. Before and After Dabrafenib in BRAF V600E Mutation-Positive NSCLC Planchard, Proc ASCO, 2013
    30. 30. Next Generation Sequencing to Broadly Test Patients for Wide Array of Mutations • Fast • Accurate • Relatively cheap • Scalable • Able to detect heterogeneity
    31. 31. Molecular Oncology Offers Survival of Years To More & More Advanced NSCLC Patients 0 5 10 15 20 25 30 35 NaturalHx Plat Doublet Doublet +2L HistolSpecific Bv+ Maint Switch/Cont Maint Maint w/Bev TargetedRx Median OS
    32. 32. Conclusions: Transitioning Survival from Months to Years in Advanced NSCLC • 15 years ago, we were asking the question of whether treatment of advanced NSCLC was worth it at all, providing an improvement in median OS of only weeks to a couple of months. • Since then, treatments have become less toxic, and we have identified several minimally toxic agents that can improve survival further, following first line. • Selection of optimized chemo by histology, and addition of bevacizumab, has improved median OS to a year in broad population. • Maintenance therapy and second and third line therapies have improved survival, especially in patients who haven’t progressed early, to a median OS of 15-18 months. • About 1/3 are living 2 years and longer, even independent of targeted therapies.
    33. 33. Conclusions (2): Transitioning Survival from Months to Years; Molecular Oncology • Detection of driver mutations such as EGFR mutations or ALK rearrangements profoundly increase the response rate to 60-75% and median survival to 2-3 years. – Some are beginning to have new agents for “acquired resistance”, to extend response and survival further • While this applies to only a minority of patients now, other targets, such as ROS1, BRAF, and HER2 are being identified and have agents with potential to bring this unprecedented efficacy to an ever-growing population of patients. • We are just now moving to next generation genomic sequencing, which will lead to a new ability to detect these populations and facilitate studies for the 1-5% populations. These groups will add up. • The new era will lead to delivery of targeted therapies to targeted populations, with an expectation that these patients will live YEARS.

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