Maintenance therapy for NSCLC Istituto Toscano Tumori-Livorno-Italy Federico Cappuzzo Istituto Toscano Tumori Ospedale Civile 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 Istituto Toscano Tumori-Livorno-Italy CR/PR SD Continuation maintenance SCC: Switch maintenance Non-SCC: cont/switch maintenance SCC Gemcitabine Non-SCC Pemetrexed or beva Erlotinib or Docetaxel Pem or beva Erlot or Docetax
Immediate vs. delayed docetaxel as 2nd line NSCLC treatment MI Z E CR, PR SD Immediate Docetaxel Carboplatin Plus Gemcitabine X 4 Istituto Toscano Tumori-Livorno-Italy Delayed Docetaxel at time of PD
Docetaxel study results Istituto Toscano Tumori-Livorno-Italy Immediate (n=153) Delayed (n=154) LR p-Value Median PFS months (95% CI) 6.5 (4.4, 7.2) 2.8 (2.6, 3.4) <0.0001 12-month PFS, % 20% (13, 26) 9% (5, 14) PFS Istituto Toscano Tumori-Livorno-Italy Immediate (n=153) Delayed (n=154) LR p-Value Median OS, months (95% CI) 11.9 (10.0, 13.7) 9.1 (8.0, 11.2) 0.071 12-mo survival 48.5% (39.9, 57.1) 38.3% (30.0, 46.5) OS
Istituto Toscano Tumori-Livorno-Italy TFINE study: multicenter, randomized phase III study of continuation docetaxel Docetaxel 60 mg/m2 IV Cisplatin 75 mg/m2 IV Docetaxel 60 mg/m2 IV q 3wk Up to six cycles BSC IIIB/IV Chemo-Naïve NSCLC N=382 R1 CR PR SD R2 Docetaxel 75 mg/m2 IV Cisplatin 75 mg/m2 IV q Istituto Toscano Tumori-Livorno-Italy a 50% improvement of PFS Zhang et al. ASCO 2013, Abstract # 8015
TFINE study, C-TONG 0904 PFS results Istituto Toscano Tumori-Livorno-Italy Trial Strategy Induction regimen mPFS (months) Docetaxel dose Fidias et al. Switch Carbo+Gem 5.7 vs 2.7 (early vs. delayed) 75mg/m2 Zhang et al. Continuation Cis+Doc 5.4 vs 2.7 (Doc vs. BSC) 60mg/m2
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/m2 (d1,q21d) + BSC (N=441)* Placebo (d1, q21d) + BSC (N=222)* 2:1 Randomization Istituto Toscano Tumori-Livorno-Italy Continuation maintenance: PARAMOUNT Nonsquamous NSCLC No prior systemic treatment for lung cancer ECOG PS 0-1 500 mg/m2 Pemetrexed + BSC, d1, q21d CR, CP, SD 2:1 randomization Placebo + BSC, d1, q21d 500 mg/m2 Pemetrexed + 75 mg/m2 Cisplatin, d1, q21d Stratified for: PS (0 vs 1) Disease stage (IIIb vs IV) prior to induction Response to induction (CR/PR vs SD) PD 7
Progression-free Survival Continuation maintenance: PARAMOUNT Switch maintenance: JMEN Istituto Toscano Tumori-Livorno-Italy 8
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 Istituto Toscano Tumori-Livorno-Italy Induction response CR/PR 0.81 Induction response SD 0.76 0.4 0.6 0.8 1.0 1.2 Favours pemetrexed HR Favours placebo *Non-squamous group Ciuleanu et al. Lancet 2009; Paz Ares et al. ASCO 2012
Maintenance trials with EGFR-TKIs Erlotinib maintenance: SATURN Erlotinib 150mg/day PD Chemonaïve advanced NSCLC n=1,949 4 cycles of 1st-line platinum-based doublet* Non-PD n=889 1:1 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 Placebo PD Istituto Toscano Tumori-Livorno-Italy Mandatory tumor sampling 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)
Progression-free Survival Istituto Toscano Tumori-Livorno-Italy in ITT population Erlotinib maintenance: SATURN Gefitinib maintenance: INFORM HR=0.71 (0.62–0.82) p<0.0001 HR=0.42 (0.32–0.54) Istituto Toscano Tumori-Livorno-Italy
Istituto Toscano Tumori-Livorno-Italy Overall Survival in ITT population Erlotinib maintenance: SATURN Gefitinib maintenance: INFORM HR=0.81 (0.70–0.95) p=0.0088 HR = 0.83 (0.61, 1.12) p=0.2109 Istituto Toscano Tumori-Livorno-Italy
Istituto Toscano Tumori-Livorno-Italy Effect of erlotinib and gefitinib in EGFR wild-type patients: PFS and OS data PFS and OS in SATURN PFS in INFORM Istituto Toscano Tumori-Livorno-Italy
OS according to response to first-line chemotherapy* SD CR/PR 1.0 0.8 0.6 0.4 0.2 1.0 0.8 0.6 0.4 0.2 HR=0.72 (0.59–0.89) HR=0.94 (0.74–1.20) Istituto Toscano Tumori-Livorno-Italy Log-rank p=0.0019 Log-rank p=0.6181 OS probability Erlotinib (n=252) Placebo (n=235) Erlotinib (n=184) Placebo (n=210) 9.6 11.9 12.0 12.5 0 3 6 9 12 15 18 21 24 27 30 33 36 0 3 6 9 12 15 18 21 24 27 30 33 36 Time (months) Time (months) *OS is measured from time of randomisation into the maintenance phase
IFCT-GFPC 0502 study design PD: off Maintenance treatment Progression: 2nd line A Observation PD Pemetrexed N=155 Cisplatin gemcitabine x 4 cycles N=834 Objective response or stable disease B R* N=464 Gemcitabine PD Pemetrexed N=154 Istituto Toscano Tumori-Livorno-Italy C Erlotinib PD Pemetrexed NSCLC Stage IIIB wet – IV PS 0-1, 18-70 years Asymptomatic brain mets allowed Tumor tissue EGFR IHC EGFR mutation N=155 Primary endpoint: PFS Induction chemo: cisplatin 80mg/m2 d1 + gemcitabine 1,250mg/m2 d1, d8 Arm B: gemcitabine 1,250mg/m2 d1, d8 /3 wks Arm C: erlotinib 150mg daily *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
PFS and OS results with continuation gemcitabine Istituto Toscano Tumori-Livorno-Italy Perol et al. JCO 2012
PFS and OS results with switch erlotinib Istituto Toscano Tumori-Livorno-Italy Perol et al. JCO 2012
Is continuation maintenance with pemetrexed plus bevacizumab better than beva or pem alone? AVAPERL First-line induction 4 cycles, q3w Continuation maintenance q3w until PD Istituto Toscano Tumori-Livorno-Italy Avastin n=125 CR/PR/SD per RECIST§ 1 Previously untreated stage IIIB-IV NSCLC N=376 Avastin‡ + pemetrexed‡ + cisplatin‡ n=253 R 67% Avastin + pemetrexed n=128 1 PD Stratification factors Gender Smoking status Response at randomisation Follow-up
AVAPERL: PFS from randomisation 1.0 0.8 0.6 0.4 0.2 Avastin + Pem 7.4m Avastin 3.7m HR: 0.48; p<0.001 PFS estimate Istituto Toscano Tumori-Livorno-Italy 0 3 6 9 12 15 Time (months) 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
PointBreak: Study Design Pemetrexed + Carboplatin + Bevacizumab Paclitaxel Bevacizumab Istituto Toscano Tumori-Livorno-Italy Last year Dr. Patel reported the results of this trial where carbo/pem bev followed by maintenance peme/bev was compared to carbotaxol bev followed by maintenance bev Patel et al., 2012 Chicago Multidisciplinary symposium in Thoracic Oncology 21
PointBreak: KM Plot for OS (Intent-to-treat) HR=1.0 (95% CI: 0.86–1.16) Log-rank P=0.949 100 Pem Arm Median OS = 12.55 mo (95% CI: 11.30–14.03) Pac Arm Median OS = 13.4 mo (95% CI: 11.86–14.91) 80 60 Istituto Toscano Tumori-Livorno-Italy 40 20% off people are alive at 2 years, maybe the never smokers 20 3 6 9 12 15 18 21 24 27 30 33 36 39
PRONOUNCE: Study Design Randomized, open-label, phase III superiority study conducted in US Pemetrexed 500 mg/m2, Carboplatin AUC 6 (Pem+Cb) Paclitaxel 200 mg/m2, Carboplatin AUC 6, Bevacizumab 15 mg/kg (Pac+Cb+Bev) Induction Phase q21d, 4 cycles Maintenance Phase q21d until PD Bev-Eligible Population Inclusion: - Chemo-naïve patients - PS 0/1 - Stage IV, nonsquam - Stable treated CNS mets Exclusion: - Uncontrolled effusions Pemetrexed (folic acid & vitamin B12) + Carboplatin Pemetrexed (folic acid & vitamin B12) Istituto Toscano Tumori-Livorno-Italy R 1:1 Lo studio è stato disegnato per dimostrare una superiorità per carbo-pme in termini di PFS libera da eventi di grado 4 180 patients each Paclitaxel + Carboplatin + Bevacizumab Bevacizumab Stratified for: PS (0 vs 1); gender (M vs F); disease stage (M1a vs M1b) Zinner ASCO 2013 23
Primary Endpoint: G4PFS (ITT) 100 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) 80 60 Istituto Toscano Tumori-Livorno-Italy 40 20 3 6 9 12 15 18 21 24 27 Number of G4PFS events Pem+Cb n = 152 % Pac+Cb+Bev n = 144 G4 AE 24.3 44.4 PD 62.5 47.2 Death 13.2 8.3 Patients at Risk PC 182 87 44 26 14 7 5 3 1 PC+Bev 179 75 33 17 9 Zinner ASCO 2013
Istituto Toscano Tumori-Livorno-Italy Secondary end-points Istituto Toscano Tumori-Livorno-Italy Zinner ASCO 2013
There is any patient unsuitable for maintenance therapy? Randomization factors: PS status Stage Best tumour repsonse Primary Endpoint OS ~60% of PS2 Patients R A N D O MI Z E Istituto Toscano Tumori-Livorno-Italy Gemcitabine q 21 days + BSC N= 128 CR, PR SD Gemcitabine + Carboplatin X 4 cycles Key Eligibility Criteria Stage IIB (wuth pleural effusion and or positive spravclavicular nodes or stage IV Age greater than or equal to 18 ECOG PS 0-2 Adequate renal, hepatic and bone marrow function Asymptomatic or treated and controlled brain mets were allowed Presence of measurable disease No prior chemotherapy BSC N= 127 PD Off study Belani et al, ASCO 2010
No benefit with maintenance therapy in PS2 patients Survival Probability Overall Survival (months) 0 6 12 18 24 30 36 42 48 54 60 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Gemcitabine 8.0 mos. BSC 9.3 mos. HR=0.97 (95% CI:0.72, 1.30) P =0.838 Istituto Toscano Tumori-Livorno-Italy
The maintenance therapy paradigm No progression after 4 cycles of platinum-based CT, PS irrelevant EGFR mutated Istituto Toscano Tumori-Livorno-Italy EGFR-TKI
Progression-free Survival Istituto Toscano Tumori-Livorno-Italy in mutated patients Erlotinib maintenance: SATURN Gefitinib maintenance: INFORM HR=0.10 (0.04–0.25) P<0.0001 HR=0.17 (0.07–0.42) 100 Erlotinib (n=22) Placebo (n=27) Gefitinib (n=15) Placebo (n=15) 100 Istituto Toscano Tumori-Livorno-Italy 80 80 60 60 PFS (%) PFS (%) 40 40 20 20 0 8 16 24 32 40 48 56 64 72 80 88 96 Time (weeks) 8 16 24 32 40 48 56 64 72 80 88 96 104 112 Time (weeks)
The maintenance therapy paradigm No progression after 4 cycles of platinum-based CT, PS irrelevant ? ALK+ Istituto Toscano Tumori-Livorno-Italy Pemetrexed Crizotinib
TTP on EGFR-TKI monotherapy Istituto Toscano Tumori-Livorno-Italy ALK Fusion not Associated with Sensitivity to Platinum-based Chemotherapy and EGFR –TKIs 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 Istituto Toscano Tumori-Livorno-Italy 100 100 80 80 ALK-positive EGFR mut-positive WT/WT ALK-positive EGFR mut-positive WT/WT 60 60 Progression-free (%) Progression-free (%) 40 40 p=0.004 (ALK vs EGFR) 20 20 0 12 24 36 48 0 12 24 36 48 60 Months Months Shaw AT, et al. J Clin Oncol 2009;27:4247‒53
ALK fusion predictive for pemetrexed sensitivity Istituto Toscano Tumori-Livorno-Italy Low TS levels in ALK+ Takeda M, Clin Lung Cancer 2012; Camidge JTO 2011
Profile 1007: PFS by Independent Radiologic Review (in overall population and according to chemotherapy) Treatment mPFS (mos) HR/p value Crizotinib 7.7 0.49/P<0.001 Chemotherapy 3.0 Istituto Toscano Tumori-Livorno-Italy Treatment mPFS (mos) HR/p value Crizotinib 7.7 Pemetrexed 4.2 0.59/P<0.001 Docetaxel 2.6 0.30/P<0.001 Shaw AT., Lancet Oncol 2013
Istituto Toscano Tumori-Livorno-Italy Overall Survival Treatment mOS (mos) HR/p value Crizotinib 20.3 0.54/P=0.54 Chemotherapy 22.8 Istituto Toscano Tumori-Livorno-Italy * 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 Istituto Toscano Tumori-Livorno-Italy