Istituto Toscano TumoriLivornoItaly Maintenance therapy for NSCLC Federico

Istituto Toscano Tumori-Livorno-Italy Maintenance therapy for NSCLC Federico Cappuzzo Istituto Toscano Tumori Ospedale Civile Livorno-Italy

Istituto Toscano Tumori-Livorno-Italy The maintenance therapy paradigm No progression after 4 cycles of platinum-based CT, PS=0 -1 Stratification for EGFR, ALK, histology, response to CT EGFR WT/ALK-: Response to CT /Histology CR/PR Continuation maintenance SCC Gemcitabine Non-SCC Pemetrexed or beva SD SCC: Switch maintenance Erlotinib or Docetaxel Non-SCC: cont/switch maintenance Pem or beva Erlot or Docetax

Istituto Toscano Tumori-Livorno-Italy Immediate vs. delayed docetaxel as 2 nd line NSCLC treatment Carboplatin Plus Gemcitabine X 4 CR, PR SD R A N D O M I Z E Immediate Docetaxel Delayed Docetaxel at time of PD

Istituto Toscano Tumori-Livorno-Italy Docetaxel study results LR Immediate Delayed (n=153) (n=154) p-Value PFS OS Median PFS months (95% CI) 6. 5 (4. 4, 7. 2) 12 -month PFS, % (95% CI) 20% (13, 26) 9% (5, 14) Immediate (n=153) Delayed (n=154) 2. 8 <0. 0001 (2. 6, 3. 4) Median OS, months (95% CI) 11. 9 9. 1 (10. 0, 13. 7) (8. 0, 11. 2) 12 -mo survival (95% CI) 38. 3% 48. 5% (39. 9, 57. 1) (30. 0, 46. 5) LR p-Value 0. 071

Istituto Toscano Tumori-Livorno-Italy TFINE study: multicenter, randomized phase III study of continuation docetaxel Docetaxel 75 mg/m 2 IV Cisplatin 75 mg/m 2 IV q Docetaxel 60 mg/m 2 IV q 3 wk Up to six cycles IIIB/IV Chemo. Naïve NSCLC N=382 CR PR SD R 1 Docetaxel 60 mg/m 2 IV Cisplatin 75 mg/m 2 IV R 2 BSC Zhang et al. ASCO 2013, Abstract # 8015

Istituto Toscano Tumori-Livorno-Italy TFINE study, C-TONG 0904 PFS results Trial Strategy Induction regimen m. PFS (months) Docetaxel dose Fidias et al. Switch Carbo+Gem 5. 7 vs 2. 7 (early vs. delayed) 75 mg/m 2 Zhang et al. Continuation Cis+Doc 5. 4 vs 2. 7 (Doc vs. BSC) 60 mg/m 2

Istituto Toscano Tumori-Livorno-Italy Maintenance trials with pemetrexed Switch maintenance: JMEN § § § Stage IIIB/IV NSCLC ECOG PS 0 -1 4 prior cycles of gem, doc, or tax + cis or carb, with CR, PR, or SD § Randomization factors: • gender • PS • stage • best tumor response • non-platinum drug • brain mets Pemetrexed 500 mg/m 2 (d 1, q 21 d) + BSC (N=441)* 2: 1 Randomization Placebo (d 1, q 21 d) + BSC (N=222)* Continuation maintenance: PARAMOUNT § § § Nonsquamous NSCLC No prior systemic treatment for lung cancer ECOG PS 0 -1 500 mg/m 2 Pemetrexed + BSC, d 1, q 21 d CR, CP, SD 2: 1 randomization Placebo + BSC, d 1, q 21 d 500 mg/m 2 Pemetrexed + 75 mg/m 2 Cisplatin, d 1, q 21 d PD Stratified for: -PS (0 vs 1) -Disease stage (IIIb vs IV) prior to induction -Response to induction (CR/PR vs SD)

Istituto Toscano Tumori-Livorno-Italy Progression-free Survival Continuation maintenance: PARAMOUNT Switch maintenance: JMEN

Istituto Toscano Tumori-Livorno-Italy Overall Survival: pemetrexed maintenance data Continuation maintenance: PARAMOUNT Switch maintenance: JMEN

Istituto Toscano Tumori-Livorno-Italy JMEN & PARAMOUNT: OS according to response to first-line chemotherapy HR Induction response CR/PR* 0. 81 Induction response SD* 0. 61 Induction response CR/PR 0. 81 0. 76 Induction response SD 0. 4 0. 6 0. 8 Favours pemetrexed *Non-squamous group 1. 0 HR 1. 2 Favours placebo Ciuleanu et al. Lancet 2009; Paz Ares et al. ASCO 2012

Istituto Toscano Tumori-Livorno-Italy Maintenance trials with EGFR-TKIs Erlotinib maintenance: SATURN Chemonaïve advanced NSCLC n=1, 949 Mandatory tumor sampling Erlotinib 150 mg/day 4 cycles of 1 st-line platinumbased doublet* Non-PD n=889 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 Gefitinib maintenance: INFORM Patients • Age ≥ 18 years • Completed 4 cycles of first-line platinum-based chemotherapy without PD or unacceptable toxicity • Life expectancy ≥ 12 weeks • WHO PS 0 -2 • Measurable Stage IIIB/IV disease Gefitinib (250 mg/day) 1: 1 randomization Placebo (once daily) PD 1: 1 Placebo PD

Istituto Toscano Tumori-Livorno-Italy Progression-free Survival in ITT population Erlotinib maintenance: SATURN HR=0. 71 (0. 62– 0. 82) p<0. 0001 Gefitinib maintenance: INFORM HR=0. 42 (0. 32– 0. 54)

Istituto Toscano Tumori-Livorno-Italy Overall Survival in ITT population Erlotinib maintenance: SATURN HR=0. 81 (0. 70– 0. 95) p=0. 0088 Gefitinib maintenance: INFORM HR = 0. 83 (0. 61, 1. 12) p=0. 2109

Istituto Toscano Tumori-Livorno-Italy Effect of erlotinib and gefitinib in EGFR wildtype patients: PFS and OS data PFS and OS in SATURN PFS in INFORM

SD CR/PR 1. 0 HR=0. 72 (0. 59– 0. 89) 0. 8 OS probability Istituto Toscano Tumori-Livorno-Italy OS according to response to first-line chemotherapy* HR=0. 94 (0. 74– 1. 20) 0. 8 Log-rank p=0. 0019 0. 6 Log-rank p=0. 6181 0. 6 Erlotinib (n=252) 0. 4 Placebo (n=235) 0. 2 0 Erlotinib (n=184) 0. 4 Placebo (n=210) 0. 2 9. 6 0 3 6 11. 9 9 12 15 18 21 24 27 30 33 36 0 12. 5 0 3 6 Time (months) *OS is measured from time of randomisation into the maintenance phase 9 12 15 18 21 24 27 30 33 36 Time (months)

Istituto Toscano Tumori-Livorno-Italy IFCT-GFPC 0502 study design Maintenance treatment PD: off A Objective response or stable disease R* N=464 B Pemetrexed Tumor tissue EGFR IHC EGFR mutation Induction chemo: cisplatin 80 mg/m 2 d 1 + gemcitabine 1, 250 mg/m 2 d 1, d 8 Arm B: gemcitabine 1, 250 mg/m 2 d 1, d 8 /3 wks Gemcitabine PD Pemetrexed N=154 C Arm C: erlotinib 150 mg daily PD N=155 Cisplatin gemcitabine x 4 cycles N=834 NSCLC Stage IIIB wet – IV PS 0 -1, 18 -70 years Asymptomatic brain mets allowed Observation Progression: 2 nd line Erlotinib N=155 Primary endpoint: PFS *Stratification factors: – – – gender histology: adenocarcinoma vs other histology smoking status: non-smokers vs current/former smokers center response vs stabilization to induction chemotherapy EGFR = epidermal growth factor receptor IHC = immunohistochemistry; PD = progressive disease

Istituto Toscano Tumori-Livorno-Italy PFS and OS results with continuation gemcitabine Perol et al. JCO 2012

Istituto Toscano Tumori-Livorno-Italy PFS and OS results with switch erlotinib Perol et al. JCO 2012

Istituto Toscano Tumori-Livorno-Italy Is continuation maintenance with pemetrexed plus bevacizumab better than beva or pem alone? AVAPERL First-line induction 4 cycles, q 3 w Previously untreated stage IIIB-IV NSCLC N=376 Stratification factors • Gender • Smoking status • Response at randomisation Continuation maintenance q 3 w until PD CR/PR/SD per RECIST§ Avastin‡ + pemetrexed‡ + cisplatin‡ n=253 1 R 67% 1 PD Follow-up Avastin n=125 Avastin + pemetrexed n=128

1. 0 Avastin + Pem 7. 4 m Avastin 3. 7 m HR: 0. 48; p<0. 001 0. 8 PFS estimate Istituto Toscano Tumori-Livorno-Italy AVAPERL: PFS from randomisation 0. 6 0. 4 0. 2 0 0 3 6 9 Time (months) 12 15 OS for Pem/Bev was better than for Bev (17. 1 vs 13. 2 months), p=0. 29, HR 0. 87 (CI 0. 63 -1. 21) EMCC 2011, ASCO 2013

Istituto Toscano Tumori-Livorno-Italy Point. Break: Study Design Pemetrexed + Carboplatin + Bevacizumab Pemetrexed + Bevacizumab Paclitaxel + Carboplatin + Bevacizumab Patel et al. , 2012 Chicago Multidisciplinary symposium in Thoracic Oncology

Istituto Toscano Tumori-Livorno-Italy Point. Break: KM Plot for OS (Intent-to-treat) HR=1. 0 (95% CI: 0. 86– 1. 16) Log-rank P=0. 949 100 80 60 40 20 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39

Istituto Toscano Tumori-Livorno-Italy PRONOUNCE: Study Design ¨ Randomized, open-label, phase III superiority study conducted in US ¨ Pemetrexed 500 mg/m 2, Carboplatin AUC 6 (Pem+Cb) ¨ Paclitaxel 200 mg/m 2, Carboplatin AUC 6, Bevacizumab 15 mg/kg (Pac+Cb+Bev) Induction Phase q 21 d, 4 cycles Maintenance Phase q 21 d until PD Pemetrexed Bev-Eligible Population Inclusion: - Chemo-naïve patients - PS 0/1 - Stage IV, nonsquam - Stable treated CNS mets (folic acid & vitamin B 12) + Carboplatin R 1: 1 Exclusion: - Uncontrolled effusions (folic acid & vitamin B 12) 180 patients each Paclitaxel + Carboplatin + Bevacizumab Stratified for: PS (0 vs 1); gender (M vs F); disease stage (M 1 a vs M 1 b) Zinner ASCO 2013

Istituto Toscano Tumori-Livorno-Italy Primary Endpoint: G 4 PFS (ITT) 100 Pem+Cb: median G 4 PFS = 3. 9 (mo) ---- Pac+Cb+Bev: median G 4 PFS = 2. 9 (mo) 80 Log-rank p-value HR (90% CI) = 0. 176 = 0. 85 (0. 70, 1. 04) 60 40 20 0 0 3 6 9 87 75 44 33 26 17 12 15 18 21 24 7 3 5 0 3 0 1 0 27 Patients at Risk PC PC+Bev 182 179 14 9 0 0 Zinner ASCO 2013

Istituto Toscano Tumori-Livorno-Italy Secondary end-points Zinner ASCO 2013

Istituto Toscano Tumori-Livorno-Italy There is any patient unsuitable for maintenance therapy? Randomization factors: • • • ~60% of PS 2 Patients PS status Stage Best tumour repsonse Primary Endpoint OS Gemcitabine + Carboplatin X 4 cycles PD CR, PR SD R A N D O M I Z E Gemcitabine q 21 days + BSC N= 128 BSC N= 127 Off study Belani et al, ASCO 2010

Istituto Toscano Tumori-Livorno-Italy No benefit with maintenance therapy in PS 2 patients 1. 0 HR=0. 97 (95% CI: 0. 72, 1. 30) P =0. 838 0. 9 0. 8 0. 7 0. 6 BSC 9. 3 mos. 0. 5 Survival Probability 0. 4 0. 3 0. 2 0. 1 Gemcitabine 8. 0 mos. 0. 0 0 6 12 18 24 30 36 42 48 54 60 Overall Survival (months)

Istituto Toscano Tumori-Livorno-Italy The maintenance therapy paradigm No progression after 4 cycles of platinum-based CT, PS EGFR mutated EGFR-TKI irrelevant

Erlotinib maintenance: SATURN Gefitinib maintenance: INFORM HR=0. 10 (0. 04– 0. 25) P<0. 0001 100 HR=0. 17 (0. 07– 0. 42) Erlotinib (n=22) Gefitinib (n=15) 100 Placebo (n=27) 80 Placebo (n=15) 80 60 60 PFS (%) Istituto Toscano Tumori-Livorno-Italy Progression-free Survival in mutated patients 40 40 20 20 0 8 16 24 32 40 48 56 64 Time (weeks) 72 80 88 96 0 8 16 24 32 40 48 56 64 72 80 88 96 104 112 Time (weeks)

Istituto Toscano Tumori-Livorno-Italy The maintenance therapy paradigm No progression after 4 cycles of platinum-based CT, PS irrelevant ? ALK+ Pemetrexed Crizotinib

• ALK-positive patients display similar sensitivity to platinum-based chemotherapy compared with ALK-negative patients • Patients with the ALK fusion gene may not benefit from EGFR TKIs TTP on platinum-based chemotherapy TTP on EGFR-TKI monotherapy 100 80 ALK-positive EGFR mut-positive WT/WT 60 40 20 0 12 24 Months 36 48 Progression-free (%) 100 Progression-free (%) Istituto Toscano Tumori-Livorno-Italy ALK Fusion not Associated with Sensitivity to Platinum-based Chemotherapy and EGFR –TKIs 80 ALK-positive EGFR mut-positive WT/WT 60 p=0. 004 (ALK vs EGFR) 40 20 0 12 24 36 48 60 Months Shaw AT, et al. J Clin Oncol 2009; 27: 4247‒ 53

Istituto Toscano Tumori-Livorno-Italy ALK fusion predictive for pemetrexed sensitivity Low TS levels in ALK+ Takeda M, Clin Lung Cancer 2012; Camidge JTO 2011

Profile 1007: PFS by Independent Radiologic Review Istituto Toscano Tumori-Livorno-Italy (in overall population and according to chemotherapy) Treatment m. PFS (mos) Crizotinib 7. 7 Pemetrexed 4. 2 0. 59/P<0. 001 Docetaxel 2. 6 0. 30/P<0. 001 Treatment m. PFS (mos) Crizotinib 7. 7 Chemotherapy 3. 0 HR/p value 0. 49/P<0. 001 HR/p value Shaw AT. , Lancet Oncol 2013

Istituto Toscano Tumori-Livorno-Italy Overall Survival Treatment m. OS (mos) Crizotinib 20. 3 Chemotherapy 22. 8 HR/p value 0. 54/P=0. 54 * 112 patients crossed over to crizotinib Shaw AT. , Lancet Oncol 2013

Istituto Toscano Tumori-Livorno-Italy Conclusions • Maintenance therapy is a relevant option to discuss with patients • Treatment choice should be based on EGFR, ALK, histology, response to front-line therapy and patient preferences • In EGFR/ALK wild-type maintenance is not recommended for patients with low performance status • In EGFR mutated patients EGFR-TKIs are the best option • In ALK+ any effort should be done for reducing the risk to preclude crizotinib therapy