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Raul E. Storey M.D. PGY 5 Fellowship Program Hematology-Oncology Department

Maintenance Chemotherapy in NSCLC. Raul E. Storey M.D. PGY 5 Fellowship Program Hematology-Oncology Department James G. Brown Cancer Center University of Louisville. Advanced NSCLC: Maintenance Therapy.

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Raul E. Storey M.D. PGY 5 Fellowship Program Hematology-Oncology Department

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  1. Maintenance Chemotherapy in NSCLC Raul E. Storey M.D. PGY 5 Fellowship Program Hematology-Oncology Department James G. Brown Cancer Center University of Louisville

  2. Advanced NSCLC: Maintenance Therapy • For patients without disease progression after first-line treatment, maintenance therapy is an option, but no clear standard yet exists • Goal is to prolong the duration of response and/or stable disease for as long as possible • Thereby enhancing PFS and overall survival • Maintenance may involve • Continuation maintenance (retaining a component of the original regimen) • Switch maintenance (substituting a new agent in the absence of PD)

  3. Advanced NSCLC: Initial Chemotherapy • Standard frontline chemotherapy consists of a platinum doublet selected based on disease histology[1] • Pemetrexed-based regimens preferred for nonsquamous carcinoma[2,3] • Gemcitabine- or taxane-based regimens preferred for squamous carcinoma[1-3] • Pemetrexed and Cb/Tax, Avastin are SOC in nonsquamous • Studies indicate that no additional clinical benefit gained with 6 vs 4 cycles of initial therapy[4] 1. Schiller JH, et al. N Engl J Med. 2002;346:92-98. 2. Scagliotti GV, et al. J ClinOncol. 2008;26:3543-3551. 3. Scagliotti GV, et al. Oncologist. 2009;14:253-263. 4. Socinski MA, et al. J ClinOncol. 2002;20:1335-1343.

  4. Agents Investigated in the Maintenance Setting • Pemetrexed • Gemcitabine • Docetaxel • EGFR TKIs • Erlotinib • Gefitinib

  5. Agents Investigated in the Maintenance Setting • Pemetrexed • Gemcitabine • Docetaxel • EGFR TKIs • Erlotinib • Gefitinib Approved agents noted in yellow

  6. Switch Maintenance With Docetaxel Patients without disease progression randomized 1:1 Immediate Docetaxel (n = 153) Chemotherapy-naive patients with stage IIIB/IV NSCLC (N = 566) Gemcitabine/Carboplatin for 4 cycles Delayed Docetaxel* (n = 156) *Initiated at first evidence of progressive disease • Primary endpoint: OS • Other endpoints: PFS, ORR, safety, QOL Fidias PM, et al. J ClinOncol. 2009;27:591-598.

  7. Docetaxel Switch Maintenance: PFS 1.0 DelayedImmediate 0.8 0.6 Probability of PFS 0.4 0.2 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 Mos Patients at Risk, nDelayed 156 59 28 18 13 6 1Immediate 153 109 72 42 26 5 2 • Median PFS immediate vs delayed: 5.7 vs 2.7 mos (P = .0001) Fidias PM, et al. J Clin Oncol. 2009;27:591-598.

  8. Docetaxel Switch Maintenance: OS • Median OS immediate vs delayed: 12.3 vs 9.7 mos (P = .0853) • 1-yr survival immediate vs delayed: 51.1% vs 43.5% 1.0 DelayedImmediate 0.8 0.6 Probability of OS 0.4 0.2 0 0 6 12 18 24 30 36 42 48 54 60 Mos Patients at Risk, nDelayed 156 109 65 42 21 6 2Immediate 153 119 73 49 28 13 2 Fidias PM, et al. J ClinOncol. 2009;27:591-598.

  9. October 2009

  10. Study Design • Double-blind, multicenter, placebo-controlled, phase III trial Randomized 2:1 according to sex, PS, stage, best response, nonplatinum drug, brain metastases Pemetrexed 500 mg/m2 (d1,q21d) + BSC (n = 441)* Patients with stage IIIB/IV NSCLC, ECOG PS 0-1, 4 prior cycles of gem, doc, or tax + cis or carb, with CR, PR, or SD Placebo (d1, q21d) + BSC (n = 222)* • Primary endpoint = PFS *B12, folate, and dexamethasone given in both arms.

  11. Pemetrexed Maintenance vs Placebo in Nonsquamous NSCLC • Primary endpoint: PFS • Other endpoints: OS, ORR, patient-reported outcomes, resource utilization, toxicity Patients without disease progression randomized 2:1 Chemotherapy-naive patients with stage IIIB/IV nonsquamous NSCLC (N = 900 planned) Pemetrexed + BSC Pemetrexed/Cisplatin for 4 cycles Placebo + BSC 1. Paz-Ares LG, et al. BMC Cancer. 2010;10:85. 2. ClinicalTrials.gov. NCT00789373.

  12. Pem/Bev vs Bev as Maintenance in Nonsquamous NSCLC • Primary endpoint: OS • Other endpoints: PFS, ORR, safety, QOL, PK Patients without disease progression Chemotherapy-naive patients with stage IIIB/IV nonsquamous NSCLC (N = 900 planned) Pemetrexed/Carboplatin/ Bevacizumab for 4 cycles Pemetrexed/Bevacizumab Paclitaxel/Carboplatin/ Bevacizumab for 4 cycles Bevacizumab 1. Patel JD, et al. Clin Lung Cancer. 2009;10:252-256. 2. ClinicalTrials.gov. NCT00762034.

  13. ECOG E5508: Pemvs Bev vsPem/Bev as Maintenance in Nonsquamous NSCLC • Primary endpoint: OS • Other endpoints: PFS, ORR, toxicity, PK Patients without disease progression randomized 1:1:1 Bevacizumab Chemotherapy-naive patients with stage IIIB/IV nonsquamous NSCLC (N = 1282 planned) Carboplatin/Paclitaxel/ Bevacizumab for 4 cycles Pemetrexed Pemetrexed/Bevacizumab ClinicalTrials.gov. NCT01107626.

  14. Advanced NSCLC: Gemcitabine Maintenance Therapy • Primary endpoint: median time to progression RANDOMIZE Stage IV NSCLC (n = 352) CR / PR / SD after cisplatin + gemcitabine (n = 206) Maintenance gemcitabine 1250 mg/m2 Day 1, 8 Q3W plus BSC (No cisplatin) n = 138 BSC only (n =68) Brodowicz T, et al. Lung Cancer. 2006;52:155-163.

  15. Advanced NSCLC: Gemcitabine Maintenance Therapy – PFS • Overall survival: 13.0 mos vs 11.0 mos, P = .19 PFS from the date of randomization to maintenance: P < .001 PFS from the date of starting first-line chemotherapy: P < .001 Brodowicz T, et al. Lung Cancer. 2006;52:155-163.

  16. ECOG: Gemcitabine Maintenance Brodowicz T, et al. Lung Cancer. 2006;52:155-163.

  17. IFCT-GFPC 0502: GemcitabinevsErlotinibvs Observation as Maintenance • Patients stratified by sex, histology, smoking status, treatment center, and response/stabilization following first-line therapy • Primary endpoint: PFS • Other endpoints: OS, safety, symptom control, effect of EGFR status Patients without disease progression randomized 1:1:1 Gemcitabine (n = 154) Chemotherapy-naive patients with stage IIIB/IV NSCLC (N = 834) Cisplatin/Gemcitabine for 4 cycles Erlotinib (n = 155) Observation (n = 155) Perol M, et al. ASCO 2010. Abstract 7507.

  18. IFCT-GFPC 0502: Treatment Outcomes Perol M, et al. ASCO 2010. Abstract 7507.

  19. Gemcitabine Maintenance + BSC vs BSC Alone • Patients stratified by PS, stage, best tumor response • Primary endpoint: OS • Other endpoints: PFS, ORR, safety Patients without disease progression randomized 1:1 Gemcitabine + BSC (n = 128) Chemotherapy-naive patients with stage IIIB/IV NSCLC (N = 519) Gemcitabine/Carboplatin for 4 cycles BSC (n = 127) Belani CP, et al. ASCO 2010. Abstract 7506.

  20. Gemcitabine + BSC vs BSC: Treatment Outcomes • Benefits of gemcitabine maintenance may have been nullified by patient population studied • Median patient age: 66.6 yrs • ECOG PS 2: 64% Belani CP, et al. ASCO 2010. Abstract 7506.

  21. Phase III Studies of EGFR TKI Maintenance 1. Cappuzzo F, et al. ASCO 2009. Abstract 8001. 2. Cappuzzo F, et al. Lancet Oncol. 2010;11:521-529. 3. Miller VA, et al. ASCO 2009. Abstract LBA8002. 4. Kabbinavar FF, et al. ASCO 2010. Abstract 7526. 5. Perol M, et al. ASCO 2010. Abstract 7507. 6. Gaafar RM, et al. ASCO 2010. Abstract 7518.

  22. Management of Treatment-Related Adverse Effects

  23. EGFR TKI Toxicities and Management

  24. Pemetrexed Toxicities and Management • No difference in the incidence of serious toxicities observed in a retrospective analysis of pts who received vitamin B12 on the day of pemetrexed vs 1 wk earlier[1] Socinski MA, et al. J ThoracOncol. 2008;3:1308-1316.

  25. Cost-Effectiveness of Maintenance Therapy • Few formal cost-effective analyses available • Recent economic analyses provide new insights • Pemetrexed as first-line maintenance in advanced nonsquamous NSCLC[1] • First study evaluate cost-effectiveness of maintenance • BR.21: erlotinib in second-line or third-line setting[2] 1.Klein R, et al. J ThoracOncol. 2010;5:1263-1272. 2. Bradbury PA, et al. J Natl Cancer Inst. 2010;102:298-306.

  26. Cost-Effectiveness of Pemetrexed as First-Line Maintenance in Advanced NSCLC • Data sources: RCTs, Medicare reimbursement rates, retrospective claims database analysis • Pemetrexed may be cost-effective vs observation or other maintenance approaches, according to investigators • Incremental cost per life-yr gained, pemetrexedvs observation • $122,371 for patients with nonsquamous histology only • $205,597 for all patients with advanced NSCLC • Results suggest importance of histology in selecting patients for maintenance therapy with pemetrexed Klein R, et al. J ThoracOncol. 2010;5:1263-1272.

  27. Economic Analysis of Erlotinib in Advanced NSCLC • BR.21: randomized, placebo-controlled trial of erlotinibvs placebo in patients with previously treated advanced NSCLC (N = 731) • Use of single-agent erlotinib in patients who had failed first-line or second-line therapy associated with incremental cost-effectiveness ratio of $94,638 per life-yr gained • Molecular markers (eg, EGFR gene copy number) may identify more/less cost-effective subgroups Bradbury PA, et al. J Natl Cancer Inst. 2010;102:298-306.

  28. Maintenance Individualization: Future Directions • Studies needed to distinguish between patients who benefit from maintenance therapy vs those who can receive a treatment break • Response to first-line therapy • Objective response • SD • Clinical characteristics • Age • Gender • Performance status • Tumor burden and symptomatology • Molecular markers (eg, EGFR mutations)

  29. Individualization of Maintenance Therapy

  30. Selection of Maintenance Therapy Based on Histology vs Biomarkers NCCN. Available at: http://www.nccn.org.

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