Maintenance Treatment of Advanced NSCLC

Transcription

1 Maintenance Treatment of Advanced NSCLC Giorgio V. Scagliotti University of Torino Department of Clinical & Biological Sciences UNIVERSTY OF TORINO DEPT. OF OF

2 Maintenance /Consolidation/Sequencing Maintenance Therapy (defined as immediate therapy after 4-6 cycles of standard first line treatment) is one of many strategies to optimize first line treatment for advanced NSCLC and an area of active investigation for decades A recently published meta-analysis of 13 trials from demonstrated a substantial improvement in PFS (HR 0.75; p<.00001) and a modest prolongation in OS (HR 0.92; P=.03) Soon YY et al, J. Clin. Oncol. 2009;27:3277

3 Duration of CT for Advanced NSCLC: an updated systematic review and meta-analysis Outcome Patients Hazard Ratio 95% CI P value PFS < PFS (Ciuleanu) < OS OS (Ciuleanu) Soon YY et al, J. Clin. Oncol. 2009;27:3277

4 Terminology Do we really need a definition? The terminology around this issue is confusing and meaningless. Some investigators use the term maintenance, others consolidation, and other sequencing or extended duration chemotherapy or early second line. Latter is necessarily wrong because the initiation of maintenance therapy requires the absence of disease progression

5 Treatment Paradigm in the Pre-maintenance ERA First line platinum based chemotherapy given for 4-6 cycles Treatment break for all patients with either response or stable disease Second-line therapy for patients at the time of documented radiologic progression or symptom worsening

6 Advantages of Maintenance Therapy All patients with advanced NSCLC experience progression despite extent of response to first line therapy Maintenance therapy has the potentialto delay progression and potentially improve survival Ability to administer a mechanistically distinct agent after first line therapy (not necessarily) Patients are in a better overall condition to tolerate additional therapy than in the second line setting

7 How many patients receive second line treatment? Socinski et al Belani et al Brodowicz et al von Plessen et al Barata et al Park et al Ciuleanu et al Pirker et al Scagliotti et al Fidias et al Patients receiving 2nd-line therapy (%)

8 Disadvantages of Maintenance Therapy Exposes patients to prolonged duration of therapy and potentially to prolonged adverse events and toxicity No holiday period free from treatment for the patient We potentially lose a molecule for the second line The efficacy of the agent might be the same whether given as second line or maintenance therapy..if so, why not wait until progression?

9 Maintenance Therapy: Strategies Continuation of a doublet beyond 4 cycles Initiating a new agent ( switch ) Carboplatin and paclitaxel followed by pemetrexed Carboplatin and gemcitabine followed by docetaxel Platinum-based doublets followed by erlotinib Continuation of a targeted agent Carboplatin, paclitaxel and bevacizumab followed by bevacizumab Continuing one of the same agents from the original combination Cisplatin and pemetrexed followed by pemetrexed as maintenance or carboplatin and gemcitabine followed by gemcitabine

10 Paclitaxel Carboplatin x 4 Cycles vspaclitaxel Carboplatin to Progression PC x 4 n=114 PC to PD n=116 Number of cycles 4 ( 0-6) 4 (0-19) P value ORR 22% 24% ns Median survival 6.6 mos 8.5 mos yr survival 28% 34% 2 nd -line therapy 42% 47% 0.42 Grade 2-4 neuro toxicity 14% 27% 0.02 Socinski et al. J. Clin.Oncol.20: 1335, 2002

11 Four versussix Cycles of Cisplatin-Based Doublet Chemotherapy 6 Cycles n=158 4 Cycles n=156 Number of cycles 6 (2-6) 4 (0-4) P value ORR 47.5% 41.6% ns Median survival 14.9 mos 15.9 mos 0.46 TTP 6.2 mos 4.6 mos nd -line therapy 62.7% 74.4% rd -line therapy 38% 45% ns Park et al. J. Clin. Oncol. 25: 5233, 2007

12 Maintenance Therapy: Strategies Continuation of a doublet beyond 4 cycles Initiating a new agent ( switch ) Carboplatin and paclitaxel followed by pemetrexed Carboplatin and gemcitabine followed by docetaxel Platinum-based doublets followed by erlotinib Continuation of a targeted agent Carboplatin, paclitaxel and bevacizumab followed by bevacizumab Continuing one of the same agents from the original combination Cisplatin and pemetrexed followed by pemetrexed as maintenance or carboplatin and gemcitabine followed by gemcitabine

13 E4599 trial design 1 Previously untreated stage IIIB/IV non-squamous NSCLC (n = 878) Bevacizumab in First-Line Phase III Trials CP x 6 (n = 444) Bevacizumab (15 mg/kg) every 3 weeks + CP x 6 (n = 434) Bevacizumab PD* PD AVAiL trial design 2 Previously untreated, stage IIIB, IV or recurrent nonsquamous NSCLC (n = 1043) *No cross over permitted CP = carboplatin + paclitaxel CG = cisplatin + gemcitabine Placebo + CG x 6 (n = 347) Bevacizumb (15 mg/kg) every 3 weeks + CG x 6 (n = 351) Bevacizumab (7.5 mg/kg) every 3 weeks + CG x 6 (n = 345) Bevacizumab Bevacizumab PD* PD PD Sandler A, et al. N Engl J Med. 2006;355(24): Reck M, et al. J Clin Oncol. 2009;27(8):

14 Maintenance Bevacizumab & Cetuximab There are no published studies in lung cancer comparing maintenance bevacizumab (or cetuximab) to stopping therapy when chemotherapy stops Toxicity of these agents (and other targeted therapies) is considerable Is the financial cost of maintenance justified? Some investigators recommend continuation of bevacizumab during second-line therapy

15 Maintenance Therapy: Strategies Continuation of a doublet beyond 4 cycles Initiating a new agent ( switch ) Carboplatin and paclitaxel followed by pemetrexed Carboplatin and gemcitabine followed by docetaxel Platinum-based doublets followed by erlotinib Continuation of a targeted agent Carboplatin, paclitaxel and bevacizumab followed by bevacizumab Continuing one of the same agents from the original combination Cisplatin and pemetrexed followed by pemetrexed as maintenance or carboplatin and gemcitabine followed by gemcitabine

16 Phase III Trial of Maintenance Gemcitabine in Non Progressing Advanced NSCLC Following 4 Cycles of Cis/Gem Primary endpoint: TTP (OS secondary) 352 patients entered 257 non-progressors after 4 cycles 206 randomized (61%) TTP significantly increased in those randomized to GEM (6.6 vs 5.0 months, P<.001) OS not significantly different (13.0 vs 11.0, P=0.2) Toxicity: maintenance GEM well tolerated but more transfusions required Brodowicz T, et al. Lung Cancer. 2006;52(2):

17 IFCT-GFPC 0502: Study Design Primary endpoint : independent review with 80% power to detect 50% improvement in median PFS. PFS by each comparison (Gem vsobsand ErlvsObs) Secondary endpoints: (OS, safety, symptom control, prognostic and predictive effect of tumor EGFR status (IHC, EGFR mut) Perolet al, J ClinOncol28:15s, 2010 (suppl; abstr7507))

18 IFCT-GFPC 0502: Results Patients who received 2 nd -line pemetrexed: 73% (Obs), 55% (Gem), and 60% (Erl) Grade 3-4 treatment-related AEs were more common in Gem (27%) and Erl(14%) than in Obs(2%) Perol et al, J Clin Oncol 28:15s, 2010 (suppl; abstr 7507)

19 S124 -PARAMOUNT: Study Design Pemetrexed 500 mg/m 2 + BSC* (D1, q21d) until disease progression (approximately 372 patients) Induction treatment period (unblinded): Four cycles of pemetrexed (500 mg/m 2, Day 1) + cisplatin (75 mg/m 2, Day 1)* (approximately 900 patients) Patients who have a documented response of CR, PR, or SD and have an ECOG PS of 0 or 1 Blinded maintenance treatment period 2:1 randomization *Patients received folic acid, vitamin B 12, and dexamethasone. Placebo + BSC* (D1, q21d) until disease progression (approximately 186 patients)

20 Maintenance Therapy: Strategies Continuation of a doublet beyond 4 cycles Initiating a new agent ( switch ) Carboplatin and paclitaxel followed by pemetrexed Carboplatin and gemcitabine followed by docetaxel Platinum-based doublets followed by erlotinib Continuation of a targeted agent Carboplatin, paclitaxel and bevacizumab followed by bevacizumab Continuing one of the same agents from the original combination?? Cisplatin and pemetrexed followed by pemetrexed as maintenance or carboplatin and gemcitabine followed by gemcitabine

21 Immediate versusdelayed 2nd-Line Docetaxel in Advanced NSCLC Chemo-naïve Stage IIIB/IV NSCLC Gemcitabine 1,000 mg/m 2 d1, 8 Carboplatin (AUC=5), day 1, every 21 days 4 cycles R Immediate Docetaxel 75 mg/m 2 day 1, every 21 days until PD or maximum 6 cycles (N=153) Primary endpoint: OS measured from date of randomization until death Secondary endpoints: tumor response rate, PFS, toxicity, quality of life PFS=progression free survival. Delayed Docetaxel Best supportive care until PD, then 75 mg/m2 day 1, every 21 days until PD or maximum 6 cycles (N=154) Fidias P, et al. J. Clin. Oncol. 2009;27:591.

22 Immediate vs Delayed 2nd-Line Docetaxel in Advanced NSCLC: Results Overall Survival Immediate Delayed PFS Immediate Delayed Results Immediate Docetaxel Delayed Docetaxel P-Value ORR, % 12% (36*) 11 NR Median OS, mos; HR (95% CI) 12.3 ( ) 9.7 ( ).085 Median PFS, mos (95% CI) 5.7 ( ) 2.7 ( ) * 31% of patients had a CR or PR from gemcitabine/carboplatin phase. PR=partial response. Fidias P, et al. J Clin Oncol. 2009;27 :

23 Maintenance Pemetrexed Plus BSC Versus Placebo Plus BSC in Advanced NSCLC Stage IIIB/IV NSCLC ECOG PS prior cycles of gem, doc, or tax + cisor carb, with CR, PR, or SD Randomization factors: gender PS stage best tumor response non-platinum drug brain mets 2:1 Randomization Pemetrexed 500 mg/m 2 (d1,q21d) + BSC (N=441)* Primary Endpoint = PFS *B 12, folate, and dexamethasone given in both arms Placebo (d1, q21d) + BSC (N=222)* Ciuleanu T. et al. Lancet 374(9699): , 2009 Belani et al, J Clin Oncol 28:15s, 2010 (suppl; abstr 7506)

24 Maintenance Pemetrexed Plus BSC Versus Placebo Plus BSC in Advanced NSCLC Progression-free Pro obability Progression Free Survival HR=0.60 (95% CI: ) P < Pemetrexed 4.0 mos Placebo 2.0 mos Time (months) Ciuleanu T et al., Lancet 374(9699): , 2009 Belani et al, J Clin Oncol 28:15s, 2010 (suppl; abstr 7506)

25 Maintenance Pemetrexed Plus BSC Versus Placebo Plus BSC in Advanced NSCLC Overall Survival Survival Probability Placebo 10.6 mos HR=0.79 (95% CI: ) P =0.012 Pemetrexed 13.4 mos Time (months) Ciuleanu T et al., Lancet 374(9699): , 2009 Belani et al, J Clin Oncol 28:15s, 2010 (suppl; abstr 7506)

26 Maintenance Pemetrexed Plus BSC Versus Placebo Plus BSC in Advanced NSCLC Overall Survival by Histology Survival Probability bility Non-squamous (n=481) Placebo 10.3 mos HR=0.70 (95% CI: ) P =0.002 Pemetrexed 15.5 mos Time (months) Placebo 10.8 mos Squamous (n=182) HR=1.07 (95% CI: ) P =0.678 Pemetrexed 9.9 mos Time (months) Ciuleanu T. et al. Lancet 374(9699): , 2009 Belani et al, J Clin Oncol 28:15s, 2010 (suppl; abstr 7506)

27 Efficacy by Histology in Pemetrexed Studies NSCLC Histologic Group Second-line Pem vs. Docetaxel First-line Pem/Cis vs. Gem/Cis Maintenance Pem vs. Placebo Pem Doc Cis/Pem Cis/Gem Pem Placebo Non-squamous n=205 n=194 n=618 n=634 n=325 n=156 Median OS, months Adjusted HR (95% CI) P value 0.78 ( ) ( ) ( ) Squamous n=78 n=94 n=244 n=229 n=116 n=66 Median OS, months Adjusted HR (95% CI) P value 1.56 ( ) ( ) Non-squamous = adenocarcinoma, large cell carcinoma, and other/indeterminate NSCLC histology 1.07 ( ) Scagliotti GV et al. Oncologist 2009

28 Effect of response to induction on OS in Pemetrexed Maintenance Trial M edian (95% CI) Pem 14.4 (12.3, 18.2) Plac 11.7 (8.5, 15.3) H R (95% CI) 0.81 (0.58, 1.12) P = Patients at Risk Survival Tim e (m onths) Pem Plac Non-Squamous Patients with CR/PR prior to randomization to pem/placebo: Patients at Risk Pem Plac Median (95% CI) Pem 16.6 (13.0, 20.9) Plac 8.6 (7.2, 11.3) HR (95% CI) 0.61 (0.45, 0.83) P = Survival Time (months) Non-Squamous Patients with SD prior to randomization to pem/placebo

29 Chemonaïve advanced NSCLC n=1,949 Mandatory tumour sampling 4 cycles of firstline platinum doublet 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 SATURN Study Design Non-PD n=889 (46%) *Cisplatin/paclitaxel; cisplatin/gemcitabine; cisplatin/docetaxel cisplatin/vinorelbine; carboplatin/gemcitabine; carboplatin/docetaxel carboplatin/paclitaxel Erlotinib 150mg/day 1:1 Placebo Co-Primary Endpoints: PFS in all patients PFS in patients with EGFR IHC+ tumours Secondary Endpoints: PD PD OS in all patients and those with EGFR IHC+ tumours, OS and PFS in EGFR IHC tumours; biomarker analyses; safety; time to symptom progression; QoL

30 OS proba ability SATURN Survival* All Patients (ITT) HR=0.81 ( ) Log-rank p= Erlotinib(n=438) Placebo (n=451) Time (months) *OS is measured from time of randomisation into the maintenance phase; ITT = intent-to-treat population Cappuzzo et al, Lancet Oncol, 2010 ; 11(6):521-9.

31 ility PFS probabi SATURN : Largest PFS Benefit with Erlotinib in Patients with EGFR Mutated Tumours EGFR mutation+ HR=0.10 ( ) Log-rank p< Erlotinib (n=22) Placebo (n=27) EGFR wild-type HR=0.78 ( ) Log-rank p= Erlotinib (n=199) Time (weeks) Time (weeks) Interaction p< Placebo (n=189)

32 OS probability SATURN : OS According to EGFRMutation Status EGFR mutation+ HR=0.83 ( ) Log-rank p= Erlotinib (n=22) Placebo (n=27)* Time (months) *Note that 67% of patients with EGFRmutation+ disease in the placebo arm received a second-line EGFR TKI EGFR wild-type HR=0.77 ( ) Log-rank p= Erlotinib (n=199) Placebo (n=189) Time (months)

33 OS probabili ity SATURN trial: OS according to response to firstline CT (ITT population) SD HR=0.72 ( ) Log-rank p= Time (months) Erlotinib (n=252) Placebo (n=235) CR/PR HR=0.94 ( ) Log-rank p= Time (months) Erlotinib (n=184) Placebo (n=210) Coudert B et al. Proc. ESMO/IASLC 2010

34 Why do patients with SD after chemotherapy benefit more from maintenance treatment? Patients with SD after first-line chemotherapy are likely to have tumours that are at least partially resistant to the administered regimen Immediate treatment with another agent, with a different MoA, may overcome resistance and lead to improved outcomes in SD patients Resistance to cytotoxic agents is associated with enhanced sensitivity to EGFR TKIs Benhar, et al. Oncogene 2002; Dai, et al. Clin Cancer Res 2005 Servidei, et al. Int J Cancer 2008; Wiinograd-Katz & Levitzki, Oncogene 2006

35 Maintenance treatment seems to provide benefit in PFS, but mixed results for OS PFS OS n HR p value HR p value Early vs late docetaxel (ITT) NR* NR* Erlotinib (SATURN ITT) < Erlotinib (IFCT-GFPC 0502) p= NR Pemetrexed (JMEN ITT), < Pemetrexed (JMEN non-squamous), < Gemcitabine (IFCT-GFPC 0502) < NR NR = Not reported *Median PFS (5.7 vs 2.7 months) and median OS (12.3 vs 9.7 months) both favoured early docetaxel Preliminary data; PFS by independent review 1 Fidias et al. JCO 2008; 2 Cappuzzo et al. Lancet Oncol Pérol et al. ASCO 2010; 4 Ciuleanu et al. Lancet 2009

36 Maintenance with Targeted Therapy: WJTOG 0203 Trial NSCLC StageⅢB/Ⅳ Dynamic Balancing histology stage gender Chemotherapy regimen R A N D O M I Z E Arm A: Chemotherapy alone >3 cycles (up to 6 cycles) Arm B: Chemotherapy followed by gefitinib 3 cycles gefitinib 250 mg until PD Sample size n = 600 (n= 300 per arm) Hida T, et al. J Clin Oncol. 2008;26(May 20 Suppl): Abstract LBA8012 UNIVERSTY OF TORINO DEPT. OF OF

37 PFS (%) Maintenance with Targeted Therapy: WJTOG 0203 Trial Chemotherapy followed by gefitinib (PFS= 4.60 mo) Chemotherapy alone (PFS= 4.27 mo) HR= 0.68; 95%CI, p< Time from Randomisation (months) Hida T, et al. J Clin Oncol. 2008;26(May 20 Suppl): Abstract LBA8012

38 Chemo-naïve Advanced NSCLC N=1,160 4 cycles of 1st-line chemotherapy + bevacizumab ATLAS Study Non-PD n=768 (66%) Bevacizumab + Erlotinib to PD 1:1 Bevacizumab + Placebo to PD Unblind at PD Post progression therapy Eligibility Stage III/IV NSCLC ECOG performance status 0-1 Stratification factors Gender Smoking history (never vs former/current) ECOG performance status (0 v 1) Chemotherapy regimen Primary endpoint PFS in all randomized pts Secondary endpoints Overall survival Safety Exploratory endpoints Biomarker analyses (IHC, FISH, EGFR & K-Ras mutation) Miller et al, ASCO 2009; Kabbinavar F. ASCO 2010

39 Without Event Proportion No. of patients at risk: Bev + Plac Bev + Erl ATLAS: Progression Free Survival (ITT Population Investigator Assessment) Progression-Free Survival (months) Bev + Placebo (n=373) Bev + Erlotinib (n=370) HR=0.722 ( ) Log-rank P=0.0012

40 Evaluate Bev 15mg/kg + Erl150mg vsbev + Placebo following Bev + Platinumbased chemotherapy Data cut-off July 18, 2008 (pre-specified) ATLAS : OS RESULTS Patients with events, n/n (%) Median OS (months) Bev+Erl vs Bev HR (95% CI) 228/743 (31) 14.4 vs ( ) Jan 28, /768 (46) 14.4 vs ( ) Jun 19, /768 (57) 15.9 vs ( ) p-value Kabbinavar KK, et al, J Clin Oncol, 28:15s 2010, (suppl; abstr 7526)

41 Comparison of the Recent Maintenance Studies JMEN Pemetrexed vs. Placebo SATURN Erlotinib vs. Placebo ATLAS Bev/Placebo vs. Bev/Erlotinib Type of trial Consolidation Consolidation Consolidation Cross over No No No design? Endpoint Survival PFS PFS Second line therapy? Reported Reported Reported PFS (mos.) 4.0 vs vs vs. 3.8 HR (p) 0.6 (p< 0.001) 0.71 (p=0.0001) 0.71 (p=0.0012) Survival (mos.) 13.4 vs vs vs 13.9 HR (p) 0.79 (p=0.012) ASCO 2009

42 Some Caveats.1 Maintenance supporters are claiming for the impossibility to deliver second line therapies in 40% of the patients. In the pemetrexed maintenance study baseline patients characteristics at the time of their initial treatment with first-line chemo are not known. In the erlotinib maintenance study only 46% of the original population treated with induction chemo went to randomization (66% in ATLAS, 55% in IFCT). PD after 4 cycles of chemo is expected to be around 20% (JMDB data)

43 Some Caveats.2 It would be of some interest to understand more about this 20% of missing patients. (rapidly declining in PS?)

44 FIRST-LINE THERAPY (N=519)* Stage IIIB/IV NSCLC ECOG PS 0-2 Maintenance Gemcitabine in NSCLC 4 cycles of carbo-gem with CR, PR, or SD MAINTENANCE THERAPY (N=255)* Variable Cox Regression Analysis Reference level Hazard Ratio* P value PS 2 PS= *Modeling hazard ratio associated with worsened survival 1:1 Randomization Gemcitabine 1000 mg/m 2 (d1, 8,q21d) + BSC) BSC No survival benefit for maintenance Gemcitabine following G-Cb for patients with advanced NSCLC PFS HR 1.09 ( ), 7.7 vs. 7.4 months OS HR 0.97 ( ), 9.3 vs. 8.0 months IMPACT: Though maintenance therapy is a new treatment opportunity for advanced NSCLC, it is not beneficial in PS 2 patients Belani CP et al, J ClinOncol28:7s, 2010

45 Some Caveats.2 It would be of some interest to understand more about this 20% of missing patients. (rapidly declining in PS?) A majority of patients randomized to placebo arm NEVER received the effective second-line treatment (drug accessability?)

46 Post-dicontinuation Anticancer Systemic JMEN Study CiuleanuT. etal. Lancet 2009; 374: Therapy SATURN Study CappuzzoF. etal. LancetOncol. 2010; 11:521-29

47 Some Caveats.2 It would be of some interest to understand more about this 20% of missing patients. (rapidly declining in PS?) A majority of patients randomized to placebo arm NEVER received the effective second-line treatment (drug accessability?) These studies failed to adequately address the proper timing of these agents. In the erlotinib maintenance study improvement in PFS is largely driven by EGFR mutants as well as the activity of pemetrexed is confined to non-squamous patients.

48 Maintenance Therapy: Grade 3/4 Toxicity by Study Agent Neutropenia Fatigue Rash Diarrhea Docetaxel^ 28% 10% NR 1% Pemetrexed 3% 5% 1% <1% Gefitinib 0% 2% 2% 0% Erlotinib* 0% <1% 6% 2% *No Grade 4 ^All patients received decadron and anti-emetics; 28% had Grade 3/4 thromobcytopenia 10% received an RBC transfusion; 6% received epoand 4% were hospitalized for Grade 3/4 toxicity; all patients received oral decadron, anti-emetics, B12 injections and daily folic acid supplementation

49 Thinking outside of the box NSCLC versus SCLC NSCLC Stage IV versus IIIA/B Adjuvant chemo in resected NSCLC Not all stable diseases are created equal

50 ECOG 7593 : Topotecan vs. Observation after CE in ED-SCLC Schiller J. etal. JCO2001; 19:2114

51 ECOG 7593 : Topotecan vs. Observation after CE in ED-SCLC Schiller J. et al. JCO2001; 19:2114

52 Maintenance Therapy in SCLC A Meta-analysis 21 RCTs (12 chemo, 6 IFs, 4 biological agents), 3688 patients No statistically significant advantage for maintenance in terms of OS (HR 0.93, 95%CI ;p=0.05) or PFS (HR 0.98, 95%CI ) Survival advantage for OS (p0.02) but not for PFS in chemo & IFα studies Is this clinically meaningful? Rossi A. et al. Lung Cancer 2010; Epub ahead of print

53 Consolidation Docetaxel in Stage III NSCLC IIIA/B NSCLC PS 0-1 FEV1 > 1 L WL < 5% Conc. CT-RT P 50 mg/m2 d. 1,8,29,36 E 50 mg/m2 d. 1-5, TRT yg R Docetaxel 75 mg/m2 q3wks x 3 Primary Endpoint: Overall Survival Observation Hanna N. etal. J. Clin. Oncol. 2008; 26:5755

54 Definitive Tx Cis50 mg/m 2 Days 1, 8, 29, 36 Etop mg/m 2 Days 1-5, XRT Gy/d, Total 61 Gy SWOG 0023 Consolidation Docetaxel 75 mg/m 2 x 3 cycles R A N D O M I Z A T I O N Maintenance Placebo Gefitinib 500 mg/day 250 mg/day (5-1-03) 1 o end point: overall survival; 2 o end points: PFS, toxicity, and correlative science Maintenance therapy could continue for a maximum of 5 years Stratification factors: IIIA vs IIIB; measurable vs non-measurable disease; squamous vs non-squamous

55 Progression-Free Survival, % SWOG 0023: Survival Progression-Free Survival Gefitinib Placebo P=.28 N Events Median (mo) Months After Randomization Overall Survival, % Gefitinib Placebo P=.01 Overall Survival n Events Median Follow-up Time: 27 Months Median (mo) Kelly K et al. J ClinOncol26: 2450, Yr OS 73% 81% 2 Yr OS 46% 59% Months After Randomization

56 Adjuvant chemotherapy in completely resected NSCLC Four cycles of cisplatin-based chemotherapy improve 5-year-survival of 4% in stage II and III NSCLC Compliance to 4 cycles of cisplatin-based chemotherapy is ranging between 70 to 82% Prolonged oral administration of adjuvant UFT (only Japanese studies) is no better than 4 cycles of cisplatin-based chemotherapy and long term compliance is overall poor.

57 Better outcomes in patients with SD after first-line chemotherapy SATURN 1 JMEN 2 OS probability SD CR/PR HR=0.72 ( ) Log-rank p= HR=0.94 ( ) Log-rank p= Tarceva (n=252) Placebo (n=235) Tarceva (n=184) Placebo (n=210) Time (months) Time (months) Non-squamous group HR Induction response CR/PR 0.81 Induction response SD Favours pemetrexed HR Favours placebo 1 Coudert, et al. ELCC 2010; 2 Belani, et al. ASCO 2009

58 Survival of stable patients from 3 SWOG trials tracks closer to responders than progressors HR* for survival 95% CI Month 2 Response 0.29 ( ) Stable 0.42 ( ) Month 3 Response 0.34 ( ) Stable 0.50 ( ) Month 4 Response 0.36 ( ) Stable 0.55 ( ) * Comparison group: Patients with progression (HR = 1.0) Lara L. etal. Proc. ASCO 2006

59 Response and Survival in Advanced NSCLC First line Second line 143 trials, patients HottaK. Etal. J. Thorac. Oncol. 2007; 2:402

60 SWOG 8805: Stable Disease after Preoperative Chemoradiotherapy Of 126 patients, 26 had stable disease by CT scan In these 26 patients: major pathologic response(pcr or near pcr) in 12 (46%) of surgical specimens Overall, long-term survival in SWOG 8805 did not correlate with radiographic response by CT scan The best predictor of long-term survival was eradication of N2 disease by preoperative PE/RT AlbainK. etal. Proc. ASCO 1999

61 PFS to evaluate the Maintenance Efficacy OS is the most reliable study endpoint for phase III trials and the preferred one for regulatory approval. Second and third-line therapies could confound the effect of first line OR maintenance (around 40% crossover at PD) This could make the PFS a better choice with some tricks to ensure accurate PFS measurements: - Strict schedule of assessment (i.e. 6 wks) - Independent review of radiographic images - Supplementary info about symptom improvement (to avoid symptomatic progression missing) - QoL informations Mok T, Ramalingam S, Cancer 2009

62 Open Questions.. Are EGFR mutations influencing the outcomes of maintenance studies? Are all SD patients benefiting? Are long lasting SD patients equally benefiting? What about short lasting SD? Is there a role for PET scan in selecting the most appropriate patients, if any? No proven benefit in QoL Chronic toxicities associated with maintenance? Pharmacogenomic markers? Is a strict wait and see strategy unethical?

63 IIIB/IV NSCLC PS0/1 No Prior Tx N=1288 Stratification Factors: Smoking status, Gender Histology, Best response, Stage ECOG 5508: Schema Carboplatin Paclitaxel Bevacizumab X 4 cycles CR PR SD N=897 R A N D O M I Z E Primary endpoint Overall Survival Bevacizumab Pemetrexed Bevacizumab Pemetrexed

64 Primary Endpoint: OS Induction Therapy: up to four 21-day cycles POINTBREAK STUDY Arm A -450 Patients Pemetrexed 500 mg/m 2 iv q21d Carboplatin AUC 6 iv q21d Determination of Eligibility Arm B -450 Patients Paclitaxel 200 mg/m 2 iv q21d Carboplatin AUC 6 iv q21d Patients with CR, PR, or SD After induction therapy Continue on to maintenance therapy Maintenance Therapy: until PD or treatment discontinuation Patients with PD: follow up q90d until death Patients without PD: follow up q6w until PD; thereafter, follow up q90d until death Bevacizumab 15 mg/kg iv q21d Pemetrexed 500 mg/m 2 iv q21d Bevacizumab 15 mg/kg iv q21d Post discontinuation follow up Bevacizumab 15 mg/kg iv q21d Bevacizumab 15 mg/kg iv q21d

65 Scorecard for Maintenance in NSCLC Study Treatment PFS OS Adeno Women Never smoker Fidias Ciuleanu SATURN ATLAS IFTC GPPC 0502 Docetaxel Delayed Docetaxel Immediate +++ trend 47% 38% NR 55% 38% NR Placebo 48% 28% 27% Pemetrexed 50% 26% 27% Placebo 44% 17% 17% Erlotinib 47% 18% 18% Bevacizumab Bevacizumab + Erlotinib % 48% 17% 82% 48% 18% Observation - 67% 27% 38% +++(G) Gemcitabine (early 66% 27% 38% +++ (E) Erlotinib data) 63% 27% 38%

66 Conclusions (1) There is no evidence to support prolonged administration of doublet 1 st line chemotherapy beyond 4-6 cycles. Approximately 30-40% of patients may be unable to receive second line therapy. If the goal of cancer therapy is to make lung cancer a chronic disease, then chronic therapy will be necessary. Pemetrexed provides robust survival advantage in nonsquamous carcinoma. Erlotinibshowed efficacy data in terms of PFS and OS: pts with EGFR mutation should receive an EGFR-TKi as early as possible.

67 Conclusions (2) Even more than in other setting, in maintenance therapy is essential the selection of the right patient population In maintenance studies the impact on quality of life has not been adequately studied. Maintenance approach is ONLY another treatment possibility that we may consider in those pts who tolerated platinum based therapy without relevant clinical toxicities and who desire to continue therapy.