Maintenance Therapy in NSCLC

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Published on September 23, 2018

Author: beniwal.surendra

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MAINTENANCE THERAPY V/S EARLY 2nd LINE THERAPY ADVANCED NSCLC : MAINTENANCE THERAPY V/S EARLY 2 nd LINE THERAPY ADVANCED NSCLC Dr Surender Beniwal Associate Professor Dept of Medical Oncology ATRCTRI BIKANER INTRODUCTION: INTRODUCTION Systemic therapy is the standard approach. Should be individualized. Presence or absence of a somatic driver mutation. Expression of programmed death-ligand 1 (PD-L1 ). INTRODUCTION: INTRODUCTION INTRODUCTION: INTRODUCTION What is the d uration of initial chemotherapy ? A meta-analysis of five trials. Six cycles versus three or four cycles F ailed to demonstrate a statistically significant improvement in OS (9.5 versus 8.7 months) although the difference PFS was significant (6.1 versus 5.3 months) . Rossi A et al . Lancet Oncol 2014; 15:1254. MAINTENANCE THERAPY : MAINTENANCE THERAPY Extending the duration of treatment with the initial platinum based chemotherapy beyond four to six cycles is not recommended. Concept of maintenance therapy: Maintain response of induction treatment in responsive or stable disease with single or rarely double non-platinum less toxic agent. Which increases progression-free survival and may improve overall survival. Clinical and Biologic Rationales for Maintenance Chemotherapy : Clinical and Biologic Rationales for Maintenance Chemotherapy Rationale Explanation Increase exposure to effective therapies At time of disease progression, only 20%–80% of patients with advanced NSCLC receive potentially effective second-line therapies. With a switch maintenance ( ie , sequential or early second-line) strategy, > 90% of eligible patients receive the intended therapy. Decrease chemotherapy resistance Because resistance depends on spontaneous mutations and therefore increases with time (Goldie and Coldman hypothesis), early use of non–cross-resistant therapies may increase the likelihood of killing more cancer cells before resistance develops. Maximize antitumor efficacy of therapy Solid tumors are composed of faster growing cells, which are sensitive to therapy, and slower growing, more resistant cells (Norton-Simon hypothesis). Maximum antitumor effect is therefore achieved with sequential, non–cross-resistant regimens. Antiangiogenic effects Metronomic chemotherapy reduces tumor blood vessel formation via direct cytotoxic effects on endothelial cells; altering the balance of angiogenic growth factors and inhibitors Alter antitumor immunity Metronomic CT decreases CD4+CD25+ regulatory T cells, in turn augmenting antitumor immune responses. Goal of Maintenance therapy: Goal of Maintenance therapy Maintenance Therapy Strategies: Maintenance Therapy Strategies CONTINUATION MAINTENANCE refers to the continuation of one or more non-platinum agents , initially used during induction, until progression. SWITCH MAINTENANCE is the introduction of an additional, potentially non-cross-resistant agent , immediately after completion of first-line chemotherapy in patients who achieved an objective response or a stable disease. CONTINUATION MAINTENANCE: CONTINUATION MAINTENANCE Phase III ECOG 4599 Trial: Chemo ± Bevacizumab in Nonsquamous NSCLC: Phase III ECOG 4599 Trial: Chemo ± Bevacizumab in Nonsquamous NSCLC Sandler A, et al. N Engl J Med. 2006;355:2542-2550. Stratified by RT vs no RT, stage IIIB or IV vs recurrent, weight loss < 5% vs ≥ 5%, measurable vs nonmeasurable Treatment-naive patients with confirmed stage IIIB or IV NSCLC; adequate hematologic, hepatic, and renal function (N = 878) PC Paclitaxel 200 mg/m 2 + Carboplatin AUC 6 mg/mL/min (once every 3 wks ) x 6 cycles (n = 433*) PCB PC (once every 3 wks ) x 6 cycles + Bevacizumab 15 mg/kg (once every 3 wks ) until disease progression (n = 417*) *Eligible patients included in analysis. Primary endpoint: OS Secondary endpoints: ORR, PFS, toxicity ECOG 4599 Trial of Chemo ± Bevacizumab in Nonsquamous NSCLC: Key Outcomes: ECOG 4599 Trial of Chemo ± Bevacizumab in Nonsquamous NSCLC: Key Outcomes Sandler A, et al. N Engl J Med. 2006;355:2542-2550. Sandler A, et al. ASCO 2005. Abstract 4. Response: 15% carboplatin/paclitaxel vs 35% for chemo + bevacizumab 0 6 12 18 24 30 36 0 20 40 60 80 100 Mos P = .003; HR: 0.79 Median OS: 12.3 vs 10.3 mos 1-yr OS: 51% vs 44% 2-yr OS: 23% vs 15% Patients Surviving (%) OS Patients With PFS (%) P < .001; HR: 0.66 Median PFS: 6.2 vs 4.5 mos 6-mo PFS: 55% vs 33% 1-yr PFS: 15% vs 6% PFS Carboplatin / paclitaxel Carboplatin / paclitaxel + bevacizumab Carboplatin / paclitaxel Carboplatin / paclitaxel + bevacizumab 0 6 12 18 24 30 36 0 20 40 60 80 100 Mos Phase III ECOG 4599 Trial: Chemo ± Bevacizumab in Nonsquamous NSCLC: Phase III ECOG 4599 Trial: Chemo ± Bevacizumab in Nonsquamous NSCLC Sandler A, et al. N Engl J Med. 2006;355:2542-2550. Stratified by RT vs no RT, stage IIIB or IV vs recurrent, weight loss < 5% vs ≥ 5%, measurable vs nonmeasurable Treatment-naive patients with confirmed stage IIIB or IV NSCLC; adequate hematologic, hepatic, and renal function (N = 878) PC Paclitaxel 200 mg/m 2 + Carboplatin AUC 6 mg/mL/min (once every 3 wks ) x 6 cycles (n = 433*) PCB PC (once every 3 wks ) x 6 cycles + Bevacizumab 15 mg/kg (once every 3 wks ) until disease progression (n = 417*) *Eligible patients included in analysis. Primary endpoint: OS Secondary endpoints: ORR, PFS, toxicity Incremental benefit of maintenance bevacizumab unknown, but standard practice is to continue therapy FLEX: Phase III Evaluation of Cetuximab Plus Chemotherapy: FLEX: Phase III Evaluation of Cetuximab Plus Chemotherapy Pirker et al. Lancet 373, 1525-1531, 2009 Advanced-stage, previously untreated NSCLC patients with EGFR+ in ≥ 1 tumor cell and no brain metastases (N = 1125) Cisplatin 80 mg/m2 on Day 1 Vinorelbine 25 mg/m2 on Days 1 and 8 Six 3-wk cycles Cetuximab 400 mg/m2 over 2 hrs on Day 1 250 mg/m2 over 1 hr wkly from Day 8 Continued until disease progression Cisplatin 80 mg/m2 on Day 1 Vinorelbine 25 mg/m2 on Days 1 and 8 Six 3-wk cycles *Eligible patients included in analysis. Primary endpoint: OS Secondary endpoints: ORR, PFS, toxicity, QoL FLEX: Efficacy Outcomes: FLEX: Efficacy Outcomes Outcome Cisplatin/ Vinorelbine + Cetuximab (n = 557) Cisplatin/ Vinorelbine (n = 568) HR (95% CI) P Value Median OS, mos 11.3 10.1 0.871 (0.762-0.996) .044 Median PFS, mos 4.8 4.8 0.943 (0.825-1.077) .39 Median TTF, mos 4.2 3.7 0.860 (0.761-0.971) .015 Response rate, % 36 29 .010 Slide16: SQUIRE Trial : A randomized, multicenter, open-label, phase III study of gemcitabine–cisplatin plus necitumumab versus gemcitabine–cisplatin alone in the first-line treatment of patients with stage IV squamous non-small-cell lung cancer NECITUMUMAB: NECITUMUMAB Second-generation , recombinant, human immunoglobulin IgG1 EGFR antibody. C ompeting with natural ligands and preventing receptor activation and downstream signaling . Necitumumab inhibits EGFR-dependent tumor-cell proliferation E xert cytotoxic effects in tumor cells through ADCC. Phase III SQUIRE Trial:: Phase III SQUIRE Trial: Pirker et al. Lancet 373, 1525-1531, 2009 Patients with previously untreated stage IV squamous NSCLC Gemcitabine 1250 mg/m 2 day 1,8 + Cisplatin 75 mg/m2 d1 +NECITUMUMAB 800 MG DAY 1, 8 ( n = 462 ) f/b continued on NECITUMUMAB until progression (n-242 ) Gemcitabine 1250 mg/m 2 day 1,8 + Cisplatin 75 mg/m2 d1 (n = 473 ) *Eligible patients included in analysis. Primary endpoint: OS Secondary endpoints: ORR, PFS, TTF , QoL 1:1 randomization Slide19: Correlation of EGFR-expression with safety and efficacy outcomes in SQUIRE : Kaplan–Meier estimates of (A) overall survival and progression-free survival (B) (intention-to-treat epidermal growth factor receptor > 0 subpopulation). Figure Legend: Slide20: Date of download: 3/12/2017 : Correlation of EGFR-expression with safety and efficacy outcomes in SQUIRE : Subgroup analyses. Forest plots of overall survival and progression-free survival (intention-to-treat epidermal growth factor receptor > 0 subpopulation) in subgroups defined by baseline characteristics. HR, hazard ratio; NA, North America; EU, Europe; SA, South America; S Africa, South Africa. Figure Legend: Phase III Trials: Continuation Maintenance With Gemcitabine in NSCLC: Phase III Trials: Continuation Maintenance With Gemcitabine in NSCLC 1. Perol M, et al. J Clin Oncol . 2012;30:3516-3524. 2. Brodowicz T, et al. Lung Cancer. 2006;52:155-163. 3. Belani C, et al. ASCO 2010. Abstract 7506. Phase III PARAMOUNT: Maintenance Pem Following Pem/Platinum in NSCLC: Phase III PARAMOUNT: Maintenance Pem Following Pem /Platinum in NSCLC Pemetrexed 500 mg/m 2 + Cisplatin 75 mg/m 2 both administered on Day 1 of a 21-day cycle (n = 939) Patients with previously untreated advanced-stage nonsquamous NSCLC CR, PR, or SD Pemetrexed 500 mg/m 2 on Day 1 of a 21-day cycle + BSC (n = 359) Placebo on Day 1 of a 21-day cycle + BSC (n = 180) PD Both arms received folic acid and vitamin B 12 therapy Induction phase (4 cycles) Maintenance phase (until PD) 21-42 days Paz-Ares LG, et al. J Clin Oncol . 2013;31:2895-2902. 2:1 randomization; stratified by ECOG PS (0 vs 1), disease stage prior to induction therapy (IIIB vs IV), response to induction therapy (CR/PR vs SD) Primary endpoint: PFS Secondary endpoints: OS, safety PARAMOUNT Study of Maintenance Pemetrexed vs BSC in NSCLC: PFS: PARAMOUNT Study of Maintenance Pemetrexed vs BSC in NSCLC: PFS Paz-Ares LG, et al. J Clin Oncol. 2013;31:2895-2902. 1.0 0.8 0.6 0.4 0.2 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 PFS (%) Mos Pts at Risk, n Pemetrexed + BSC Placebo + BSC 359 180 215 75 139 33 97 16 67 9 47 7 32 6 22 4 16 2 10 0 5 0 0 0 Pemetrexed + BSC Placebo + BSC Pemetrexed: median 4.4 mos (range: 4.1-5.7 mos ) Placebo: median 2.8 mos (range: 2.6-3.0 mos ) Log-rank P < .001 Unadjusted HR: 0.60 (95% CI: 0.50-0.73) PARAMOUNT Study of Maintenance Pemetrexed vs BSC in NSCLC: OS: PARAMOUNT Study of Maintenance Pemetrexed vs BSC in NSCLC: OS Paz-Ares LG, et al. J Clin Oncol. 2013;31:2895-2902. Pemetrexed Placebo Median OS, mos (95% CI) 13.9 (12.8-16.0) 11.0 (10.0-12.5) HR: 0.78 (95% CI: 0.64-0.96; P = .0195) OS, % (95% CI) 1 yr 58 (53-63) 45 (38-53) 2 yrs 32 (27-37) 21 (15-28) 1.0 0.8 0.6 0.4 0.2 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 Overall Survival (%) Mos From Random Assignment Pts at Risk, n Pemetrexed + BSC Placebo + BSC 359 180 333 169 272 131 235 103 200 78 166 65 138 49 105 35 79 23 43 12 15 8 2 3 0 0 Pemetrexed + BSC Placebo + BSC AVAPERL: Maintenance Pem/Bev Following Pem/Bev/Platinum in NSCLC: AVAPERL: Maintenance Pem /Bev Following Pem /Bev/Platinum in NSCLC Barlesi F, et al. ESMO 2011.[Abstract 34LBA]. . Previously untreated stage IIIB-IV nsNSCLC Arm A: Bevacizumab N = 125 Arm B: Bevacizumab + pemetrexed N = 128 Bevacizumab b + pemetrexed b + cisplatin b N = 376 N = 253 67% Follow-Up R First-line induction 4 cycles, q3w Continuation maintenance q3w until PD CR/PR/SD Per RECIST C PD Stratification factors: Gender Smoking status Response at randomization Primary objective : PFS Secondary objectives : OS, response rate, DCR, duration of response, duration disease control, safety, QOL a Randomized open-label phase 3 study b Dose of bevacizumab = 7.5 mg/kg; dose of pemetrexed = 500 mg/m 2 ; dose of cisplatin = 75 mg/m 2 . RECIST-related end points measured from the preinduction phase AVAPERL: PFS: AVAPERL: PFS Barlesi F, et al. ESMO 2011.[Abstract 34LBA]. 100 – 75 – 50 – 25 – 0 – Bev+pem 7.4 months (81 events) Bev 3.7 months (104 events) HR, 0.48 (0.35-0.66); P < 0.001 Cont. maintenance bev+pem (n = 128) Cont. maintenance bev (n = 125) Patients at risk Bev+pem 128 104 67 25 4 0 Bev 125 73 36 13 2 0 Time, months | 0 | 3 | 6 | 9 | 15 | 12 PFS From Date of Randomization, % Median follow-up time in ITT population (excluding induction): 8.28 months ( bev+pem arm), 7.95 months ( bev arm) PointBreak: Pemetrexed/Carboplatin/Bevacizumab* vs. Paclitaxel/Carboplatin/Bevacizumab: PointBreak : Pemetrexed /Carboplatin/Bevacizumab* vs. Paclitaxel/Carboplatin/Bevacizumab Inclusion Criteria: Stage IIIB/IV NSCLC ECOG PS 0-1 No prior systemic Rx for lung cancer Exclusion Criteria: Peripheral neuropathy ≥ grade 1 Uncontrolled pleural effusions Pemetrexed 500 mg/m 2 IV q21d Carboplatin AUC of 6 IV q21d Bevacizumab ‡ 15 mg/kg IV q21d Arm A 450 patients Pemetrexed* 500 mg/m 2 IV q21d Bevacizumab ‡ 15 mg/kg IV q21d Paclitaxel 200 mg/m 2 IV q21d Carboplatin AUC of 6 IV q21d Bevacizumab ‡ 15 mg/kg IV q21d Arm B 450 patients Bevacizumab ‡ 15 mg/kg IV q21d Induction Therapy: Up to four 21-day cycles Patients with CR, PR, or SD after 4 cycles of induction therapy continue on to maintenance therapy Maintenance Therapy: Until PD or treatment discontinuation R A N D O M I Z E *Investigational PointBreak: OS and PFS for the Maintenance Population: PointBreak : OS and PFS for the Maintenance Population | 33 | 3 | 30 1.0 — 0.9 —0.8 —0.7 —0.6 —0.5 —0.4 —0.3 —0.2 —0.1 —0.0 — Survival Probability Time From Induction, months | 6 | 12 | 9 | 0 | 15 | 18 | 21 | 24 | 27 | 33 | 36 Pem+Cb+Bev Pac+Cb+Bev (n = 292) (n = 298) OS median ( mos ) 17.7 15.7 Censoring (%) 3 6.0 30.2 | 39 Pem -Bev Bev | 3 | 30 1.0 — 0.9 —0.8 —0.7 —0.6 —0.5 —0.4 —0.3 —0.2 —0.1 —0.0 — Survival Probability Time From Induction, months | 6 | 12 | 9 | 0 | 15 | 18 | 21 | 24 | 27 Pem+Cb+Bev Pac+Cb+Bev (n = 292) ( n = 298) PFS median ( mos ) 8.6 6.9 Censoring (%) 24.7 14.1 | 36 Pem -Bev Bev Prespecified exploratory non-comparative subgroup analyses OS PFS PRONOUNCE STUDY: Comparison of Pemetrexed and Bevacizumab in Maintenance of NSCLC: PRONOUNCE STUDY: Comparison of Pemetrexed and Bevacizumab in Maintenance of NSCLC Stratified for: PS (0 vs 1); gender (M vs F); disease stage (M1a vs M1b) Bev-Eligible Population Inclusion: - Chemo-naïve patients - PS 0/1 - Stage IV, nonsquam - Stable treated CNS mets Exclusion: - Uncontrolled effusions Induction Phase q21d, 4 cycles Maintenance Phase q21d until PD Pemetrexed (folic acid & vitamin B 12 ) + Carboplatin Paclitaxel + Carboplatin + Bevacizumab R 1:1 Pemetrexed (folic acid & vitamin B 12 ) Bevacizumab 180 patients each Zinner R et al, J Thorac Oncol . 2015 Jan; 10(1): 134–142 Primary Endpoint: G4PFS: Primary Endpoint: G4PFS Pem+Cb: median G4PFS = 3.9 (mo) -------- Pac+Cb+Bev: median G4PFS = 2.9 (mo) Log-rank p-value = 0.176 HR (90% CI) = 0.85 (0.70, 1.04) Pem+Cb 182 87 44 26 14 7 5 3 1 0 Pac+Cb+Bev 179 75 33 17 9 3 0 0 0 0 Patients at Risk Zinner R et al, J Thorac Oncol . 2015 Jan; 10(1): 134–142 Secondary Endpoint: OS: Secondary Endpoint: OS Pem+Cb : median OS = 10.5 ( mo ) --------- Pac+Cb+Bev : median OS = 11.7 ( mo ) Log-rank p-value = 0.615 HR (95% CI) = 1.07 (0.83, 1.36) Pem+Cb N = 182 % Pac+Cb+Bev N = 179 % 1-Year 43.7 48.8 2-Year 18.0 17.6 Patients at Risk Pem+Cb 182 156 125 102 72 48 33 20 11 11 5 5 5 5 5 Pac+Cb+Bev 179 151 121 96 73 59 38 28 10 3 1 1 0 0 0 Zinner R et al, J Thorac Oncol . 2015 Jan; 10(1): 134–142 TFINE study: multicenter, randomized phase III study of continuation docetaxel: TFINE study: multicenter , randomized phase III study of continuation docetaxel Docetaxel 60 mg/m 2 IV Cisplatin 75 mg/m 2 IV Docetaxel 60 mg/m 2 IV q 3wk Up to six cycles BSC IIIB/IV Chemo-Naïve NSCLC N=382 R 1 CR PR SD R 2 Docetaxel 75 mg/m 2 IV Cisplatin 75 mg/m 2 IV q Primary endpoint: PFS Secondary endpoints: DCR, TTP OS, safety TFINE Study: PFS after R2 : TFINE Study: PFS after R2 SWITCH MAINTENANCE: SWITCH MAINTENANCE Phase III Trial: Immediate vs Delayed 2nd-line Docetaxel in Stage IIIB/IV NSCLC: Phase III Trial: Immediate vs Delayed 2nd-line Docetaxel in Stage IIIB/IV NSCLC Primary endpoint: OS from randomization Other endpoints: PFS, ORR, safety, QoL Chemotherapy-naive patients with stage IIIB/IV NSCLC (N = 566) Immediate Docetaxel 75 mg/m 2 on Day 1 every 21 days until PD or maximum 6 cycles (n = 153) Delayed Docetaxel* BSC until PD, then 75 mg/m 2 on Day 1 every 21 days until PD or maximum 6 cycles (n = 154) Fidias PM, et al. J Clin Oncol. 2009;27:591-598. Gemcitabine/Carboplatin for 4 cycles Patients without disease progression *Initiated at first evidence of PD. Immediate vs Delayed Second-line Docetaxel in Advanced NSCLC: PFS, OS: Immediate vs Delayed Second-line Docetaxel in Advanced NSCLC: PFS, OS Results, Mos (95% CI) Immediate Docetaxel Delayed Docetaxel P Value Median PFS 5.7 (4.4-6.9) 2.7 (2.6-2.9) .0001 Median OS 12.3 (10.4-15.2) 9.7 (8.4-12.5) .0853 Fidias PM, et al. J Clin Oncol . 2009;27:591-598. No difference in median OS in pts actually receiving immediate vs delayed docetaxel (12.5 mos for both groups) Probability of PFS Delayed Immediate Pts at Risk, n Delayed Immediate 156 153 59 106 28 72 18 42 13 26 6 5 1 2 1.0 0.8 0.6 0.4 0.2 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 Mos A Probability of OS Delayed Immediate Pts at Risk, n Delayed Immediate 156 153 109 119 65 73 42 49 21 28 6 3 2 2 B 1.0 0.8 0.6 0.4 0.2 0 0 6 12 18 24 30 36 42 48 60 Mos 54 JMEN Phase III Study: Maintenance Pemetrexed vs Placebo in Stage IIIB/IV NSCLC: JMEN Phase III Study: Maintenance Pemetrexed vs Placebo in Stage IIIB/IV NSCLC Ciuleanu T , et al. Lancet. 2009;374:1432-1440 . *B 12 , folate, and dexamethasone given in both arms. Randomized 2:1 according to sex, PS, stage, best response, nonplatinum drug, brain metastases Pemetrexed 500 mg/m 2 on Day 1, q21d + BSC (n = 441)* Placebo on Day 1 q21d + BSC (n = 222)* Patients with stage IIIB/IV NSCLC, ECOG PS 0-1, 4 previous cycles of gem, doc, or tax + cis or carb, with CR, PR, or SD (N = 663) Primary endpoint: PFS Secondary endpoints: OS, ORR, DCR, toxicity Maintenance Pemetrexed vs Placebo in Stage IIIB/IV NSCLC: PFS by Histology: Maintenance Pemetrexed vs Placebo in Stage IIIB/IV NSCLC: PFS by Histology Pemetrexed 4.4 mos* Pemetrexed 2.4 mos* Placebo 1.8 mos* Placebo 2.5 mos* Nonsquamous Squamous Mos Probability of PFS HR: 0.47 (95% CI: 0.37-0.6; P < .0001) HR: 1.03 (95% CI: 0.71-1.49; P = .896) Ciuleanu T, et al. Lancet. 2009;374:1432-1440. 1.0 0.8 0.6 0.4 0.2 0 0 3 6 9 12 15 24 18 21 Mos 1.0 0.8 0.6 0.4 0.2 0 0 3 6 9 12 15 18 21 24 Probability of PFS *Median. Maintenance Pemetrexed vs Placebo in Stage IIIB/IV NSCLC: OS by Histology: Maintenance Pemetrexed vs Placebo in Stage IIIB/IV NSCLC: OS by Histology Pemetrexed 15.5 mos Pemetrexed 9.9 mos Placebo 10.3 mos Placebo 10.8 mos Nonsquamous (n = 481) Squamous (n = 182) HR: 0.70 (95% CI: 0.56-0.88; P = .002) HR: 1.07 (95% CI: 0.77-1.50; P = .678) Survival Probability Ciuleanu T, et al. Lancet. 2009;374:1432-1440. Mos 1.0 0.8 0.6 0.4 0.2 0 0 3 9 15 21 27 48 33 39 6 12 18 24 30 36 45 42 Mos 1.0 0.8 0.6 0.4 0.2 0 0 9 15 21 27 48 33 39 6 12 18 24 30 36 45 42 3 Survival Probability SATURN: Maintenance Erlotinib Following First-line Platinum-Based Chemotherapy: SATURN: Maintenance Erlotinib Following First-line Platinum-Based Chemotherapy Stratification factors: EGFR IHC (positive vs negative vs indeterminate) Stage (IIIB vs IV) ECOG PS (0 vs 1) CT regimen (cis/gem vs carbo/doc vs others) Smoking history (current vs former vs never) Region 1:1 Chemo-naive advanced NSCLC (N = 1949) Non-PD (n = 889) 4 cycles of first-line platinum doublet chemotherapy* Placebo PD Erlotinib 150 mg/day PD Mandatory tumor sampling Coprimary endpoints: PFS in all patients PFS in patients with EGFR IHC+ tumors Secondary endpoints: OS in all patients and those with EGFR IHC+ tumours, OS and PFS in EGFR IHC- tumors; biomarker analyses; safety; time to symptom progression; QoL *Cisplatin/paclitaxel; cisplatin/gemcitabine; cisplatin/docetaxel; cisplatin/vinorelbine; carboplatin/gemcitabine; carboplatin/docetaxel; carboplatin/paclitaxel Cappuzzo F, et al. Lancet Oncol. 2010;11:521-529. SATURN Study of Maintenance Erlotinib Following Chemotherapy in NSCLC: PFS: SATURN Study of Maintenance Erlotinib Following Chemotherapy in NSCLC: PFS Wks HR: 0.71 (95% CI: 0.62-0.82; log-rank P < .0001) Erlotinib (n = 437) Placebo (n = 447) Erlotinib Placebo Median PFS (months) 3 2.8 *PFS (ITT population) measured from time of randomization into the maintenance phase; assessments every 6 wks until Wk 48 then every 12 wks. Probability of PFS* 1.0 0.8 0.6 0.4 0.2 0 0 8 16 24 32 40 48 56 64 72 80 88 96 Cappuzzo F, et al. Lancet Oncol. 2010;11:521-529. SATURN Study of Maintenance Erlotinib Following Chemotherapy in NSCLC: OS: SATURN Study of Maintenance Erlotinib Following Chemotherapy in NSCLC: OS Mos Probability of OS* Erlotinib ( n = 438 ) Placebo ( n = 451 ) 11.0 12.0 *OS (ITT population) measured from time of randomisation into the maintenance phase. HR: 0.81 (95% CI: 0.70-0.95; log-rank P = .0088) 1.0 0.8 0.6 0.4 0.2 0 0 3 6 9 12 15 18 21 24 27 30 33 36 Cappuzzo F, et al. Lancet Oncol . 2010;11:521-529. SATURN: OS Subgroup Analyses for EGFR IHC and EGFR Mutations: SATURN: OS Subgroup Analyses for EGFR IHC and EGFR Mutations All EGFR IHC+ EGFR IHC- *EGFR mutation+ EGFR wild type 0.4 0.6 0.8 1.0 1.2 Favors erlotinib Favors placebo HR 1.6 1.4 1.8 2.0 HR (95% CI) n 0.81 (0.70-0.95) 889 0.77 (0.64-0.93) 621 0.91 (0.59-1.38) 121 0.83 (0.34-2.02) 49 0.77 (0.61-0.97) 388 *67% of patients with EGFR mutation+ disease in the placebo arm received a second-line EGFR TKI. Cappuzzo F, et al. Lancet Oncol. 2010;11:521-529. ATLAS Phase III Trial: combination of bev and erlotinib in maintenance in Stage IIIB/IV NSCLC: ATLAS Phase III Trial: combination of bev and erlotinib in maintenance in Stage IIIB/IV NSCLC Primary endpoint: PFS Other endpoints: OS, ORR, safety, QoL Chemotherapy-naive patients with stage IIIB/IV NSCLC (N = 1160) Bevacizumab (15 mg/kg ) + Erlotinib (150 mg/day ) Bevacizumab (15 mg/kg ) + Placebo Johnson B , et al. LungCancerJCO (2013) 2012:47.3983. Four cycles of first-line chemotherapy + bevacizumab (15 mg/kg) Patients without disease progression PD ATLAS Phase III Trial: Outcomes: ATLAS Phase III Trial: Outcomes Johnson B , et al. LungCancerJCO (2013) 2012:47.3983. IFCT-GFPC 0502 Study: IFCT-GFPC 0502 S tudy Observation Progression: 2 nd line Primary endpoint: PFS A C Maintenance treatment PD *Stratification factors: gender histology: adenocarcinoma vs other histology smoking status: non-smokers vs current/former smokers center response vs stabilization to induction chemotherapy Induction chemo: cisplatin 80mg/m 2 d1 + gemcitabine 1,250mg/m 2 d1, d8 Arm B: gemcitabine 1,250mg/m 2 d1, d8 /3 wks Arm C: erlotinib 150mg daily N=155 N=154 N=155 EGFR = epidermal growth factor receptor IHC = immunohistochemistry; PD = progressive disease PD: off Objective response or stable disease Cisplatin gemcitabine x 4 cycles N=834 NSCLC Stage IIIB wet – IV PS 0-1, 18-70 years Asymptomatic brain mets allowed Tumor tissue EGFR IHC EGFR mutation R* N=464 B Gemcitabine Erlotinib PD PD Pemetrexed Pemetrexed Pemetrexed Perol et al. JCO 2012 PFS and OS results with switch Erlotinib: PFS and OS results with switch Erlotinib Perol et al. JCO 2012 Maintenance erlotinib versus erlotinib at disease progression in patients with advanced NSCLC who have not progressed following platinum-based chemotherapy (IUNO study): Maintenance erlotinib versus erlotinib at disease progression in patients with advanced NSCLC who have not progressed following platinum-based chemotherapy (IUNO study) Primary endpoint: OS from randomization Other endpoints: PFS, ORR, DCR Chemotherapy-naive patients with stage IIIB/IV NSCLC (N = 643) Early Erlotinib 150 mg/day orally (n = 322) Late Erlotinib * 150 mg/day orally (n = 321) Lung Cancer, Volume 102, 2016, 30–37 Platinum based doublet chemotherapy for 4 cycles Patients without disease progression *Initiated at first evidence of PD. Patients with known EGFR-activating mutations were excluded IUNO Study: Outcomes: IUNO Study: Outcomes Slide50: On October 18, 2016, the U.S. FDA modified the indication for erlotinib for NSCLC to limit use to patients whose tumors have specific EGFR mutations. Erlotinib no longer approved for maintenance therapy in wild type EGFR NSCLC patients. Switch Maintenance with Gefitinib: Switch Maintenance with Gefitinib Gaafar RM et al. EuroJCancer (2011) 47 (15): 2331–40 Zhang et al. J ClinOncol (2011) 29 :abstrLBA7511 Takeda et al. J ClinOncol (2010) 28 :753–60 Switch maintenance with newer TKIs: Switch maintenance with newer TKIs Platinum-based chemotherapy Maintenance study agent Primary outcome Remark CALGB 30607 1 Platinum doublet Sunitinib Placebo PFS No OS benefit No room for future investigations EORTC 08092 2 Platinum doublet Pazopinib Placebo OS Stopped due to lack of efficacy  Baggstrom MQ et al J Thorac Oncol . 2017 Feb 1 ME O'Brien et al.  Eur J Cancer 51 (12), 1511-1528. 2015 Jun 11 Comparison of progression-free survival between maintenance therapy and placebo or observation: Comparison of progression-free survival between maintenance therapy and placebo or observation Thierry L, Chemo Open Access 2015, 4:3 Comparison of overall survival between maintenance treatment and placebo or observation: Comparison of overall survival between maintenance treatment and placebo or observation ARGUMENTS AGAINST MAINTENANCE : ARGUMENTS AGAINST MAINTENANCE Patients look for a symptom free and drug free holiday. Switch maintenance has the added inconvenience of exposing the patient to new toxicities. Interpretation of many trials is also bound with controversy. ARGUMENTS AGAINST MAINTENANCE : ARGUMENTS AGAINST MAINTENANCE There are no randomized trials conducted in patients known to have an EGFR mutation or other driver abnormality prior to the initiation of maintenance chemotherapy . Criteria for selection of the best candidates for Maintenance therapy: Criteria for selection of the best candidates for Maintenance therapy Toxicity profile in first-line treatment Residual toxicity after first-line treatment PS after first-line therapy Patient preference Histology Molecular profile of the disease Response to first-line therapy ASCO Guidelines: ASCO Guidelines CLINICAL QUESTION A9 What is the optimal treatment for patients with stable disease or response after four cycles of cytotoxic chemotherapy ? Recommendation A9 In patients with stage IV NSCLC, first-line cytotoxic chemotherapy should be stopped at disease progression or after four cycles in patients whose disease is stable but not responding to treatment; two-drug cytotoxic combinations should be administered for no more than six cycles. For patients with stable disease or response after four cycles of a first-line pemetrexed -containing regimen, continuation maintenance treatment with pemetrexed is recommended. For patients with stable disease or response after four cycles of a regimen that did not include a pemetrexed -containing combination, alternative single-agent chemotherapy, such as pemetrexed in patients with nonsquamous histology, docetaxel in unselected patients, or erlotinib in unselected patients, or a break from cytotoxic chemotherapy with initiation of second-line chemotherapy at disease progression ( addition of pemetrexed : type: evidence based, benefits outweigh harms; evidence quality: intermediate; strength of recommendation: moderate) Journal of Clinical Oncology  33, no. 30 (October 2015) 3488-3515. NCCN Guidelines Version 4.2017 – Continuous Maintenance Therapy: NCCN Guidelines Version 4.2017 – Continuous Maintenance Therapy Single agent Bevacizumab ( Category 1 ) may be continued beyond 4-6 cycles of initial chemotherapy (i.e. platinum doublet therapy with bevacizumab) in patients with Non-squamous NSCLC and negative or unknown test results of Driver mutations and PD-L1 expression. Single agent Pemetrexed ( Category 1 ) may also be given as maintenance therapy in patients with Non-squamous NSCLC and negative or unknown test results . Continuous maintenance therapy with Pemetrexed /Bevacizumab ( Category 2A ) is also an option in patients with Non-squamous NSCLC and negative or unknown test results. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf NCCN Guidelines Version 4.2017 – Continuous Maintenance Therapy: NCCN Guidelines Version 4.2017 – Continuous Maintenance Therapy Gemcitabine can be used as continuous maintenance therapy ( Category 2B ) regardless of histology in patients without ALK and ROS rearrangements, sensitizing EGFR mutations and PD-L1 expression. A drug vacation ( Category 2A ) may be appropriate for some patients. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf NCCN Guidelines Version 4.2017 – Switch Maintenance Therapy: NCCN Guidelines Version 4.2017 – Switch Maintenance Therapy Category 2B recommendation for Pemetrexed and Docetaxel. Switch maintenance therapy with Erlotinib ( Category 2B ) may be given in patients with Non-squamous NSCLC and negative or unknown test results . Recently, NCCN panel deleted the recommendation for Switch maintenance therapy with Erlotinib in Squamous NSCLC as no improvement seen in OS and QoL https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf SUMMARY: SUMMARY Only for patients with PS- 0 to 1 after first line chemotherapy therapy Continuation bevacizumab is a standard practice option for patients with nonsquamous NSCLC Switch and continuation maintenance pemetrexed therapy has shown PFS and OS benefit in patients with nonsquamous NSCLC SUMMARY: SUMMARY Switch docetaxel has shown PFS benefit but no OS benefit Erlotinib maintenance therapy : Indicated for switch maintenance treatment- for only patients with EGFR activating mutation Observation is an option for some patients SUMMARY: SUMMARY Maintenance chemotherapy is clearly not applicable to all patient subsets. We are heartily welcome to all of you upcoming “North West Regional Lung Cancer Conference-2017” ATRCTRI (RCC), S.P.Medical College & AG of Hospitals at Bikaner ‘The city of Oasian Thar desert’ held on 26, 27 August 2017.: We are heartily welcome to all of you upcoming “ North West Regional Lung Cancer Conference-2017” ATRCTRI (RCC), S.P.Medical College & AG of Hospitals at Bikaner ‘The city of Oasian Thar desert’ held on 26, 27 August 2017 . Organising Secretary Dr.Surender Kr Beniwal 09414370484

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