Rash slide set - Imedex

Maintenance paradigm in non-squamous NSCLC Luis Paz Ares Hospital Universitario Doce de Octubre Madrid, Spain Disclosures Scientific advise: Lilly, Roche, Pfizer, BMS, MSD, Clovis Outline Types and data Supportive evidence Arguments against Trial design Cost Patient Selection Outline Types and data Supportive evidence Arguments against Trial design Cost Patient Selection Maintenance Therapy Rationale Objective: to keep disease (and symptoms) under control Rationale More may be better !!!; Goldman H, Sequential therapy

(Norton H) We do maintenance treatment in other tumor types and respiratory diseases We do continuous treatment in oncogene addicted lung cancer Maintenance in Lung Cancer Oncogene Addicted Erlotinib in EGFR m+ NSCLC EURTAC Trial Simulation- EURTAC Trial 4 months treatment X Rosell R et al., Lancet Oncol 2012 Le Rosell Cesne R et A al., et al., Lancet Lancet Oncol Oncol 2012 2010 Types of Maintenance Continuation therapy: Prolonged platinum doublet chemotherapy Continuation Maintenance: Continuation of non- platinum agent used in doublet chemotherapy e.g. paclitaxel, gemcitabine, pemetrexed Switch Maintenance: Introduction of a new cytotoxic agent e.g. docetaxel, pemetrexed, erlotinib Targeted Maintenance: Triplet induction therapy followed of maintenance with the same targeted agent e.g. bevacizumab (EGOC 4599), cetuximab (Flex),

Necitumumab (Squire) Adapted from Stinchcombe, TE et al. J Thoracic Oncol 2009;4:24350 SATURN Trial Erlotinib Switch Maintenance Erlotinib 150mg/day Chemonave advanced NSCLC (n=1,949) 4 cycles of 1st-line platinumbased doublet Non-PD (n=889) PD 1:1 Placebo PD Mandatory tumour sampling Co-primary endpoints PFS in all patients PFS in IHC+ tumours Secondary endpoints OS in all patients and those with EGFR IHC+ tumours, OS and PFS in EGFR IHC tumours; biomarker analyses; safety; time to symptom progression; quality of life (QoL) Cappuzzo et al., Lancet Oncol 2011 SATURN Trial Erlotinib Switch Maintenance PFS

1.0 Probability 0.8 0.6 Erlotinib (n=437) Placebo (n=447) HR=0.71 (0.620.82) Log-rank p<0.0001 OS 1.0 0.8 0.6 0.4 0.4 0.2 0.2 0 0 Erlotinib (n=438) Placebo (n=451) HR=0.81 (0.700.95) Log-rank p=0.0088 0 8 16 24 32 40 48 56 64 72 80 88 96 0 8 16 24 32 40 48 56 64 72 80 88 96 Time (weeks) Time (weeks) Cappuzzo F al. etLancet al., Lancet

Oncol Cappuzzo et Oncology 2010 2010 Paramount Trial Pemetrexed Continuation Maintenance Patients without disease progression randomized 2:1 Chemotherapynaive patients with stage IIIB/IV nonsquamous NSCLC Pemetrexed + BSC Pemetrexed/Cisplatin for 4 cycles Placebo + BSC (N = 900 planned) Primary endpoint: PFS Other endpoints: OS, ORR, safety, patient-reported outcomes, resource utilization, Paz-Ares LG, et al. BMC Cancer. 2010;10:85. Paramount Trial Pemetrexed Continuation Maintenance PFS: Primary Efficacy Endpoint PARAMOUNT: Final OS PFS: Reassessed at Time of Final OS 1.0 1.0 0.9 Survival Probability 0.7 0.6 0.5 0.4 0.3 0.2

0.1 0.0 0 3 6 9 Time (Months) 12 15 Patients at Risk Pem + BSC 359 132 57 21 4 0 Plac+ BSC 180 52 15 5 0 0 Survival Probability Survival Probability

Pemetrexed Placebo Unadjusted HR: 0.62 (0.49-0.79) 0.8 1.00.9 Pemetrexed Pemetrexed Placebo Placebo Unadjusted HR: 0.60 Unadjusted HR:(0.50-0.73) 0.78 (95% CI: 0.640.96); P=0.0199 0.90.8 0.7 0.80.6 0.70.5 0.60.4 0.3 0.50.2 0.40.1 0.30.0 0.2 0 3 6 9 12 15 18

21 24 27 30 Time (Months) 0.1 at Risk Patients Pem +BSC 0.0 359 215 139 97 67 47 32 22 16 10 5 Plac + BSC 180 75 33 16

9 7 6 4 2 0 0 0 33 3 6 9 12 15 18 21 24 27 Time from Randomization (Months) Paz-Ares L et al., Lancet Oncol 2012 Paz-Ares L, et al., J Clin Oncol 2013 30 33

0 0 36 Maintenance Efficacy PFS & OS N Maintenance drug PFS HR (95% CI) OS HR (95% CI) Westeel et al. 181 Vinorelbine 0.77 (0.56-1.07) 1.08 (0.79-1.47) Fidias et al. 309 Docetaxel 0.71 (0.55-0.92) 0.84 (0.65-1.08) Capuzzo 889 Erlotinib 0.71 (0.620.82)

0.81 (0.70-0.95) Ciuleanu et al. 663 Pemetrexed 0.60 (0.49-0.73) 0.79 (0.65-0.95) Trial Switch Maintenance Continuation Maintenance Paz-Ares et al 539 Pemetrexed 0.62 (0.49-0.79) 0.78 (0.64-0.96) Brodowicz et al. 206 Gemcitabine 0.69 (0.56-0.86) 0.84 (0.52-1.30) Belani et al. 255 Gemcitabine 1.09 (0.81-1.45) 0.97 (0.72-1.30)

Perol et al. 309 Gemcitabine 0.56 (0.44-0.72) 0.89 (0.67-1.15) Maintenance Efficacy PFS & OS N Maintenance drug PFS HR (95% CI) OS HR (95% CI) Westeel et al. 181 Vinorelbine 0.77 (0.56-1.07) 1.08 (0.79-1.47) Fidias et al. 309 Docetaxel 0.71 (0.55-0.92) 0.84 (0.65-1.08) Capuzzo 889

Erlotinib 0.71 (0.620.82) 0.81 (0.70-0.95) Ciuleanu et al. 663 Pemetrexed 0.60 (0.49-0.73) 0.79 (0.65-0.95) Trial Switch Maintenance Continuation Maintenance Paz-Ares et al 539 Pemetrexed 0.62 (0.49-0.79) 0.78 (0.64-0.96) Brodowicz et al. 206 Gemcitabine 0.69 (0.56-0.86) 0.84 (0.52-1.30) Belani et al. 255 Gemcitabine

1.09 (0.81-1.45) 0.97 (0.72-1.30) Perol et al. 309 Gemcitabine 0.56 (0.44-0.72) 0.89 (0.67-1.15) Maintenance Efficacy PFS & OS N Maintenance drug PFS HR (95% CI) OS HR (95% CI) Westeel et al. 181 Vinorelbine 0.77 (0.56-1.07) 1.08 (0.79-1.47) Fidias et al. 309 Docetaxel 0.71 (0.55-0.92)

0.84 (0.65-1.08) Capuzzo 889 Erlotinib 0.71 (0.620.82) 0.81 (0.70-0.95) Ciuleanu et al. 663 Pemetrexed 0.60 (0.49-0.73) 0.79 (0.65-0.95) Trial Switch Maintenance Continuation Maintenance Paz-Ares et al 539 Pemetrexed 0.62 (0.49-0.79) 0.78 (0.64-0.96) Brodowicz et al. 206 Gemcitabine 0.69 (0.56-0.86) 0.84 (0.52-1.30)

Belani et al. 255 Gemcitabine 1.09 (0.81-1.45) 0.97 (0.72-1.30) Perol et al. 309 Gemcitabine 0.56 (0.44-0.72) 0.89 (0.67-1.15) Maintenance Efficacy PFS & OS N Maintenance drug PFS HR (95% CI) OS HR (95% CI) Westeel et al. 181 Vinorelbine 0.77 (0.56-1.07) 1.08 (0.79-1.47) Fidias et al. 309

Docetaxel 0.71 (0.55-0.92) 0.84 (0.65-1.08) Capuzzo 889 Erlotinib 0.71 (0.620.82) 0.81 (0.70-0.95) Ciuleanu et al. 663 Pemetrexed 0.60 (0.49-0.73) 0.79 (0.65-0.95) Trial Switch Maintenance Continuation Maintenance Paz-Ares et al 539 Pemetrexed 0.62 (0.49-0.79) 0.78 (0.64-0.96) Brodowicz et al. 206 Gemcitabine

0.69 (0.56-0.86) 0.84 (0.52-1.30) Belani et al. 255 Gemcitabine 1.09 (0.81-1.45) 0.97 (0.72-1.30) Perol et al. 309 Gemcitabine 0.56 (0.44-0.72) 0.89 (0.67-1.15) Outline Types and data Supportive evidence Arguments against Trial design Cost Patient Selection Arguments Against Trial Design Patient Selection Number of induction courses Post-study treatment Other end-points Cost Induction: 4 v 6 courses Paramount v JMDB

PARAMOUNT Induction JMDB 4 cycles then pemetrexed maintenance 1st-line treatment with 6 cycles Response: Response Rate (CR/PR) Disease control rates (CR/PR/SD) 30.1% 74.5% 28.6% 63.8% Toxicity Laboratory toxicities Nonlaboratory toxicities Possibletreatment-related deaths Serious adverse events 13.7% 14.8% 1.2% 14.2% 21.4% 21.9% 1.0% 16.4% Median number of induction cycles Supportive care More colony-stimulating factors in PARAMOUNT G Scagliotti et al, abstr 203. WCLC 2011

More anti-emetics use in JMDB Paz-Ares LG, et al. Lancet Oncol 2012 Induction: 4 v 6 courses Paramount v JMDB PFS G Scagliotti et al, WCLC 2013 Overall Survival Paz-Ares LG, et al. J Clin Oncol 2013 Post-discontinuation Therapy Switch Maintenance Trials N Maintenance drug Second Line Rate Maintenance Drug Second Line Fidias et al. 309 Docetaxel Delayed Docetaxel ?? 63% ?? 63% Capuzzo et al. 889

Erlotinib Placebo 71% 72% 5% 21% Ciuleanu et al. 663 Pemetrexed Observation 51% 67% <1 19% Perol et al. 309 Erlotinib Observation 67% 91% 2% 50% Trial Switch Maintenance With Docetaxel Patients without disease progression randomized 1:1 Chemotherapynaive patients with stage IIIB/IV NSCLC

Gemcitabine/Carboplatin for 4 cycles Immediate Docetaxel (n = 153) Delayed Docetaxel* (n = 156) (N = 566) Primary endpoint: OS Other endpoints: PFS, ORR, safety, QOL Fidias PM, et al. J Clin Oncol. 2009;27:591-598. Docetaxel Switch Maintenance PFS & OS HR=0.71 (95% CI: 0.550.92) p<0.0001 HR=0.84 (95% CI: 0.650.1.08) p<0.0853 Fidias PM, et al. J Clin Oncol. 2009;27:591-598. IFCT-GFPC 0502 Gemcitabine v Erlotinib v Observation 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 Chemotherapynaive patients with stage IIIB/IV NSCLC Cisplatin/Gemcitabine for 4 cycles (N = 834) Perol M et al, J Clin Oncol 2012; Bylicki o et al., JTO 2013

Gemcitabine (n = 154) Pem 74 % Erlotinib (n = 155) Pem 75% Observation (n = 155) Pem 84% IFCT-GFPC 0502 Gemcitabine v Erlotinib v Observation Perol M et al, J Clin Oncol 2012 Prol M et al. JCO 2012;30:3516-3524 Post-discontinuation Therapy Paramount Trial Pemetrexed (N=359) %* Placebo (N=180) %* Patients Receiving Post Discontinuation Therapy 64 72 Erlotinib Docetaxel Gemcitabine

Vinorelbine Investigational drug Carboplatin Paclitaxel Pemetrexed Cisplatin 40 32 10 8 6 5 3 2 1 43 43 8 6 4 4 3 4 2 Paz-Ares L., et al. J Clin Oncol 2013 Maintenance Efficacy QoL Trial N Maintenance drug QoL & Symptom Control Switch Chemotherapy Maintenance Westeel et al. 181 Vinorelbine

NR Fidias et al. 309 Docetaxel No differences Capuzzo 889 Erlotinib Better pain control Cieleanu et al. 663 Pemetrexed Better pain and hemoptisis control Continuation Chemotherapy Maintenance Paz-Ares et al 539 Pemetrexed No detrimental effect Brodowicz et al. 206 Gemcitabine NR Belani et al.

255 Gemcitabine NR Perol et al. 309 Gemcitabine NR Saturn Trial QoLSaturn Juhasz E, et al. Eur J Cancer 2013 QoL Toxicity: Paramount Trial Possible Drug-related CTCAEs* Pemetrexed (N=359) Placebo (N=180) Grade 1/2 % Grade 3/4 % Grade 1/2 % Grade 3/4 % Fatigue 17.5 4.7 10.6

1.1 Nausea 13.4 0.6 2.2 0 Anemia 11.7 6.4 4.4 0.6 Vomiting 7.5 0.3 1.1 0 Mucositis/stomatitis 5.8 0.6 2.2 0 Neuropathy/sensory 5.3

0.3 6.1 0.6 Neutropenia 5.0 5.8 0.6 0 Leukopenia 2.8 2.2 0 0 ALT (SGPT) 2.5 0.3 0.6 0 Toxicity: Paramount Trial Possible Drug-related CTCAEs* Pemetrexed (N=359) Placebo (N=180) Grade 1/2 %

Grade 3/4 % Grade 1/2 % Grade 3/4 % Fatigue 17.5 4.7 10.6 1.1 Nausea 13.4 0.6 2.2 0 Anemia 11.7 6.4 4.4 0.6 Vomiting 7.5 0.3 1.1

0 Mucositis/stomatitis 5.8 0.6 2.2 0 Neuropathy/sensory 5.3 0.3 6.1 0.6 Neutropenia 5.0 5.8 0.6 0 Leukopenia 2.8 2.2 0 0 ALT (SGPT) 2.5

0.3 0.6 0 Maintenance Treatment Expenses by Improvement Erlotinib Pemetrexed (NSC) Setting Second line Maintenance First Line Maintenance Median courses 2.2 4 5 4 HR 0.73 0.81 0.82 0.78 Shepherd F et al., NEJM 2006; Capuzzo F et al., Lancet Oncol 2010 Scagliotti GV et al, J Clin Oncol 2008; Paz-Ares et al JCO 2013

Outline Types and data Supportive evidence Arguments against Trial design Cost Patient Selection Patient Selection Gemcitabine Maintenance Therapy PS 2 Belani CP, et al. ASCO 2010. Abstract 7506. Patient Selection Tumor Histology PFS JMEN Trial: (n=581) OS (n=663) Ciuleanu et al., Lancet 2010 Patients Selection Tumor Genotype OS SATURN: EGFR(n=663) Act Mut+ disease Probability PFS (n=581) 1.0 PFS1 1.0 0.8

HR=0.10 (0.040.25) Log-rank p<0.0001 0.8 0.6 0.6 0.4 0.4 0.2 0 Erlotinib (n=22) Placebo (n=27) 0 8 16 24 32 40 48 56 64 72 80 88 96 Time (weeks) Significantly improved PFS with erlotinib vs placebo in patients with EGFR MUT +ve disease Li et al. J Clin Oncol 2013 0.2 0 OS2 HR=0.83 (0.342.02) Log-rank p=0.6810 Erlotinib (n=22) Placebo (n=27) 0 3 6 9 12 15 18 21 24 27 30 33 36 Time (months) OS data not yet mature (N.B. 67% of patients with EGFR MUT +ve disease in placebo arm received a second-line EGFR TKI) Brugger et et al., J Clin Oncol 2011

Patient Selection Response to Induction Treatment JMEN OS SATURN OS ITT population (n=889) ITT population (n=663) CR/PR (n=394) CR/PR (n=322) SD (n=487) SD (n=337) Favours placebo 1.0 1.2 1.4 HR Favours pemetrexed Favours placebo Cappuzzo F et al. 2010 Lancet Oncol 11:52129 Ciuleanu et al., Lancet 2010 0.4 0.6 0.8 Favours Tarceva 1.0 HR 1.2 1.4

0.4 0.6 0.8 Patient Selection Response to Induction Treatment Paramount Trial Paz-Ares L., et al. J Clin Oncol 2013 Recent Developments Recent Outline Developments Bevacizumab++Bevacizumab Pemetrexed Pemetrexed A V A P E R L : P F S F r o m R a n d o m iz a tio n a P o ini n tB r e a k : P r e s p e c ifie d A n a l y s is o f K M P F S fr o m R a n d o m iz a tio n ((MM a in te n a n c e P o p u la tio n ) 1 .0 B e v + p e m 7 .4 m o n th s ( 8 1 e v e n t s ) B ev 3 .7 m o n th s ( 1 0 4 e v e n t s ) H R , 0 .4 8 (0 .3 5 0 .6 6 ); P < .0 0 1 75 C o n t. m a in te n a n c e b e v + p e m (n = 1 2 8 ) C o n t. m a in te n a n c e b e v (n = 1 2 5 ) 50 0 .8 0 .7 0 .6 0 .5 0 .4 0 .3 0 .2

25 0 3 6 9 12 15 T im e ( m o n t h s ) P ts a t r is k P e m +C b +B e v P ac +C b +B e v (n = 2 9 2 ) (n = 2 9 8 ) P F S m e d ia n (m o n th s ) 8 .6 6 .9 0 .9 S u r v iv a l P r o b a b ility P r o g r e s s io n -fr e e s u r v iv a l f r o m d a t e o f r a n d o m iz a t io n ( % ) 100 B e v + p e m0 1 2 8 Bev 125 104 73 67 36 25 13

0 .1 0 .0 4 2 0 0 0 3 6 9 12 15 18 21 24 T im e fr o m In d u c tio n (M o n th s ) a M e d ia n f o ll o w -u p tim e in IT T p o p u la tio n ( e x c lu d in g in d u c tio n ): 8 .2 8 m o n th s ( b e v + p e m a r m ), 7 .9 5 m o n th s ( b e v a r m ) b e v , b e v a c iz u m a b ; c o n t., c o n tin u a t io n ; H R , h a z a rd r a tio ; IT T , in te n t to tr e a t; p e m , p e m e tre x e d ; p ts , p a tie n ts . P r e s p e c if ie d e x p lo r a t o r y n o n - c o m p a r a t iv e s u b g r o u p a n a l y s e s C e n s o r in g r a t e f o r P e m + C b + B e v w a s 2 4 . 7 ; f o r P a c + C b + B e v w a s 1 4 . 1 B a r le s i e t a l., E S M O 2 0 1 1 Barlesi F et al., ESMO 2011; Patel J et al., IASLC 2011 27 30 33

36 Summary Summary Maintenance therapy offers the possibility of continued active treatment to delay disease progression and improve survival Pros and cons of maintenance therapy, switch and continuation, should be discussed with the patient Further studies are warranted, in particular those evaluating tumor tailored strategies optimizing patient selection and treatment specificity

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