Terapia di mantenimento / early shift: si o no?

Transcription

1 Terapia di mantenimento / early shift: si o no? Giovanni Luca Ceresoli, MD - U.F. Toracica e Urologica Humanitas Gavazzeni - Bergamo

2 CURRENT POSSIBLE CHOICES SWITCH PEMETREXED DOCETAXEL ERLOTINIB CONTINUATION PEMETREXED

3 Maintenance target therapy: Erlotinib The SATURN Trial Erlotinib 15mg/day PD Chemonaïve advanced NSCLC n=1,949 4 cycles of 1st-line platinumbased doublet Non-PD n=889 1:1 Mandatory tumor sampling Placebo PD Stratification factors: EGFR IHC (positive vs negative vs indeterminate) Stage (IIIB vs IV) ECOG PS ( vs 1) CT regimen (cis/gem vs carbo/doc vs others) Smoking history (current vs former vs never) Region Co-primary endpoints: PFS in all patients PFS in patients with EGFR IHC+ tumors Secondary endpoints: OS in all patients and those with EGFR IHC+ tumors, OS and PFS in EGFR IHC tumors; biomarker Cappuzzo analyses; et safety; al. Lancet time to symptom Oncol progression; 21 QoL

4 Probability The Saturn Trial ITT Population PFS OS 1. Erlotinib (n=437) 1. Erlotinib (n=438).8.6 Placebo (n=447) HR=.71 (.62.82) Log-rank p< Placebo (n=451) HR=.81 (.7.95) Log-rank p= Time (weeks) Time (weeks) Cappuzzo et al. Lancet Oncol 21

5 Probability EGFR Act Mut+ disease The Saturn Trial 1. PFS 1. OS.8 HR=.1 (.4.25) Log-rank p<.1.8 HR=.83 ( ) Log-rank p= Erlotinib (n=22).2 Erlotinib (n=22) Placebo (n=27) Placebo (n=27) Time (weeks) Time (months) Significantly improved PFS with erlotinib vs placebo in patients with EGFR MUT +ve disease OS data not yet mature (N.B. 67% of patients with EGFR MUT +ve disease in placebo arm received a second-line EGFR TKI) Cappuzzo et al. Lancet Oncol 21

6 The Saturn Trial EGFR wt PFS OS 1. HR=.78 (.63.96) Log-rank p= HR=.77 (.61.97) Log-rank p= Erlotinib (n=199) Placebo (n=189).8.6 Erlotinib (n=199) Median 11.3 Placebo (n=189) Median Time (weeks) Time (months) Cappuzzo et al. Lancet Oncol 21

7 PFS probability The Saturn Trial PFS according to response to first-line chemotherapy SD CR/PR HR=.68 (.56.83).8 HR=.74 (.6.92).6 Log-rank p<.1.6 Log-rank p=.59 Erlotinib (n=252) Erlotinib (n=184).4 Placebo (n=235).4 Placebo (n=21) Time (weeks) Time (weeks) Cappuzzo et al. Lancet

8 The Saturn Trial Toxicity Withdrawal due to AEs in 5% of treated pts Cappuzzo et al. Lancet Oncol 21

9 Moran T & Sequist L, JCO 212

10 JMEN Study Stage IIIB/IV NSCLC ECOG PS -1 4 prior cycles of gem, doc, or tax + cis or carb, with CR, PR, or SD 2:1 Randomization Pemetrexed 5 mg/m2(d1,q21d) + BSC (N=441) Primary Endpoint: PFS Placebo (d1, q21d) + BSC (N=222) Ciuleanu et al, Lancet 29

11 Progression-free Probability Progression-free Survival HR=.6 (95% CI:.49.73) P <.1 Pemetrexed 4. mos Placebo 2. mos Time (months)

12 Survival Probability Overall Survival (Intent-to-treat Population) HR=.79, P=.12 Pemetrexed 13.4 mos Placebo 1.6 mos Time (months)

13 Progression-free Survival by Histology Non squamous Squamous HR=.47, P <.1 HR=1.3, P=.896 Pemetrexed 4.4 mos Placebo 1.8 mos Pemetrexed 2.4 mos Placebo 2.5 mos Time (months) Time (months)

14 Survival Probability Survival Probability Overall Survival by Histology Non squamous (n=481) Squamous (n=182) HR=.7, P=.2 HR=1.7, P=.678 Pemetrexed 15.5 mos Pemetrexed 9.9 mos Placebo 1.3 mos Placebo 1.8 mos Time (months) Time (months)

15 Toxicity Pemetrexed (n=441) Placebo (n=222) Toxicity Grade 3/4 (%) Grade 3/4 (%) Neutropenia 3 Anemia 3 1 Leukopenia 2 1 Fatigue 5 1 Anorexia 2 Infection 1 Diarrhea 1 Nausea 1 1

16 Post-study Therapy Pemetrexed (N=441) Placebo (N=222) Patients with post-study therapy 52% 67% Docetaxel Erlotinib Pemetrexed 1 19 Carboplatin 7 1 Gefitinib 13 1 Gemcitabine 9 14

17 Immediate vs. Delayed Second-Line Docetaxel Adv. NSCLC Chemonaive PS 2 N = 562 Gem/Carbo q21d x 4 cycles If no PD R A N D O M I Z E Immediate Docetaxel Up to 6 cycles Delayed Docetaxel Primary endpoint: OS N = 37 Fidias et al, J Clin Oncol 29

18 Efficacy Progression-Free Survival Overall Survival 5.7 vs. 2.7 mos p= vs. 9.7 mos p=.853 Fidias et al, J Clin Oncol 29

19 Delayed Docetaxel...Only 62.8% of patients in the delayed arm received at least one cycle of Docetaxel...

20 LBA757: PARAMOUNT: Final overall survival (OS) results of the phase III study of maintenance pemetrexed (pem) plus best supportive care (BSC) versus placebo (plb) plus BSC immediately following induction treatment with pem plus cisplatin (cis) for advanced nonsquamous (NS) non-small cell lung cancer (NSCLC) L Paz-Ares et al Randomised, placebo-controlled, double-blind Phase III study Pemetrexed 5mg/m 2 ; cisplatin 75mg/m 2 Folic acid and vitamin B12 administered to both arms Induction therapy Continuation maintenance therapy 4 cycles, every 21 days every 21 days until PD Previously untreated PS /1 Stage IIIB-IV NS-NSCLC Stratified for: PS ( vs 1) Pemetrexed + Cisplatin CR/PR/SD per RECIST R 2:1 Disease stage (IIIB vs IV) prior to induction Response to induction (CR/PR vs SD) Pemetrexed + BSC Placebo + BSC Paz-Ares et al. J Clin Oncol 3, 212 (suppl; abstr LBA757)

21 Survival probability PARAMOUNT final OS from randomisation Pemetrexed Placebo Log-rank P=.195 Unadjusted HR:.78 (95% CI:.64.96) Time from randomisation (Months) Paz-Ares et al. J Clin Oncol 3, 212 (suppl; abstr LBA757)

22 Survival probability Survival probability PARAMOUNT: PFS from randomisation PFS: Primary efficacy endpoint PFS: Reassessed at time of final OS Unadjusted HR:.62 (.49.79).8 Unadjusted HR:.6 (.5.73) Pemetrexed.2 Placebo Time (Months).4.2. Placebo Pemetrexed Time (Months) Patients at risk Patients at risk Pem + BSC Plac + BSC Pem + BSC Plac + BSC Paz-Ares et al. J Clin Oncol 3, 212 (suppl; abstr LBA757)

23 PARAMOUNT possible drug-related CTCAEs* Maintenance safety similar to known profile of single-agent pemetrexed Pemetrexed (N=359) Grade 1/2 % Grade 3/4 % Grade 1/2 % Placebo (N=18) Grade 3/4 % Fatigue Nausea Anemia Vomiting Mucositis/stomatitis Neuropathy/sensory Neutropenia Leukopenia ALT (SGPT) *Data derived from the March 211 safety update. Toxicities of any grade, occurring in 5% of patients in either arm, are listed, along with some select toxicities. P<.5 Fisher s exact test of Grade 3/4 toxicities. Combined term Paz-Ares et al. J Clin Oncol 3, 212 (suppl; abstr LBA757)

24 Conclusions These final results show that survival is significantly improved when patients are treated with pemetrexed continuation maintenance therapy compared with placebo (HR=.78) The survival results were internally consistent across all subgroups, including response to induction (complete/partial response versus stable disease) (data not shown in this summary) PARAMOUNT is the first study to show continuation maintenance has an impact on the disease course of advanced NSCLC (including PFS and OS), supporting a change in the treatment paradigm in this setting Paz-Ares et al. J Clin Oncol 3, 212 (suppl; abstr LBA757)

25 Studio Paramount: punti critici Randomizzati dopo 4 cicli anche pazienti in PR Mancanza di ritrattamento alla PD nel braccio di controllo Preferenze del paziente Costi aggiuntivi A. Ardizzoni, AIOM 212