Take home message. Emilio Bria. II SESSIONE: Immunoterapia nel tumore del polmone

Transcription

1 II SESSIONE: Immunoterapia nel tumore del polmone Take home message Emilio Bria Oncologia, Dipart. di Medicina, Università di Verona, Az. Osp. Univ. Int., Verona Roma, 28 Marzo 2017

2 Disclosures Advisory Boards/Honoraria/Speakers fee/consultant for: MSD, Astra-Zeneca, Celgene, Pfizer, Helsinn, Eli-Lilly, BMS, Novartis, Roche Research Support / Grants from: A.I.R.C. (Associazione Italiana Ricerca sul Cancro) I.A.S.L.C. (International Association for the Study of Lung Cancer) L.I.L.T. (Lega Italiana per la Lotta contro i Tumori) Fondazione Cariverona

3 Deriving Take-Home Messagges for First Line

4 Evidence-Based Algorythm Suspect NSCLC Morphology IHC [TTF-1, p63] Pathology Report Squamous Non-Squamous Clinical Indication #1 Clinical Indication #2 IHC [PD-L1 Assay] EGFR wt ALK/ROS1 non-rearr. EGFR mut ALK/ROS1 rearr. TKIs

5 Clinical Indication Immunoterapia nel tumore del polmone What if. Suspect NSCLC Morphology IHC [TTF-1, p63] IHC [ab-alk D5F3] Ventana IHC [ab-pd-l1 22C3] Dako Pathology Report Squamous Non-Squamous ALK+ EGFR wt EGFR mut TPS>50% TPS<50% ROS1 non-rearr. ROS1 rearr. PEMBRO Chemo TKIs

6 Patients Characteristics Median age Immunoterapia nel tumore del polmone Molecular Testing in the Real World 1787 patients included % (N) 68 years (24-94) < 45 years-old 3% (51) Females 36% (642) Males 64% (1145) Current smokers 31% (551) Former smokers 47% (848) Never smokers 22% (388) Adenocarcinoma 75.3% (1345) Squamous 15.7% (280) NSCLC NOS 3.9% (69) 17,8% Molecular analysis positive samples* 31,9% 15,8% 3,7% 4% N *AT ANY TIME, during the history of the disease Predictive feature EGFR test EGFR mut ALK test ALK trans Predictive histology (n=1448) 88% (1273) 24% (310) 61% (885) 9% (80) Younger than 45 years (n= 51) 80% (41) 31.7% (13) 65% (33) 24% (8) Never smokers (n= 386) 89% (345) 48.6% (168) 57% (220) 16.8% (37) Females (n= 642) 86.6% (556) 35.4% (197) 56% (362) 11.3% (41) 20% 3,3% Gobbini E et al, AIOM 2016

7 NSCLC: Molecular Portrait PD-L1 TPS 0-49% 59% megfr 15% re-alk 5% re-ros1 1% PD-L1 TPS>50% 20% megfr re-alk re-ros1 PD-L1 TPS>50% PD-L1 TPS 0-49% Time-to-report: 3-4 weeks?

8 How much HISTOLOGY assessment does contribute to Survival Improvement? HISTOLOGY allows to improve survival months Scagliotti G et al, JCO 2008

9 How much MAINTAINANCE does contribute to Survival Improvement? MAINTAINANCE allows to improve survival months Scagliotti G et al, Lung Cancer 2014

10 How much MOLECULAR PATHOLOGY does contribute to Survival Improvement? MOLECULAR PATHOLOGY allows to globally improve survival..over 3 yrs! Zhou C et al, ASCO 2012 Ann Oncol 2015

11 How much targeting PD-L1-ADDICTION does contribute to Survival Improvement? If Target HR for PFS reached, tested for OS superiority TOO EARLY TO ESTABLISH for: High Patients Attrition (Eligible 20-30%) Missing OS data considering cross-over High censoring rate Reck M et al, ESMO 2016 & NEJM 2016

12 Upcoming First-line Strategies for I-O? Remon J et al, BMC Cancer 2017

13 Deriving Take-Home Messagges for Second Line

14 PD-L1 TPS 0-49% 59% Immunoterapia nel tumore del polmone NSCLC: Molecular Portrait megfr 15% re-alk 5% re-ros1 1% megfr re-alk re-ros1 PD-L1 TPS>50% PD-L1 TPS 0-49% PD-L1 TPS>50% 20% How much will be the relative benefit of I-O for these (pre-treated) patients?

15 2 line Nivolumab: no restrictions according to histology or PD-L1 EVEN IF Squamous Non-Squamous Boundary p<0.03 Boundary < Reckamp KL et al, WCLC 2015 Borghaei H et al, NEJM 2015

16 2 line Nivolumab (CM 057): Clinical (Prognostic) Benefit According to PD-L1 Marginal benefit Relevant benefit a Kaplan Meier estimates, with error bars indicating 95% Cls b For the comparison of the full Kaplan Meier survival curves for each treatment group Borghaei H et al ASCO 2016

17 Probability of Survival Probability of Survival Immunoterapia nel tumore del polmone Nivo vs. DOC: OS in PD-L1 <1% Randomized Pts with PD-L1 <1% Randomized Pts with PD-L1 <1% Alive at Month Nivolumab Docetaxel Overall Survival (Months) Overall Survival (Months) Death Rate (0 to 3 months) NIVO (292 pts) DOC (N = 290 pts) 59 (20.2%) 44 (15.2%) The majority of patients with no PD- L1 expression are alive at month 3 OS HR and separation of curves favoring NIVO are observed in the landmark analysis Peters S et al WCLC 2016

18 Patients with factor in OS subgroup (%) Immunoterapia nel tumore del polmone Nivo vs. DOC: OS in PD-L1 <1% <3 mo from last TX OS 3 months PD best resp. No maint. TX >5 sites with lesions Bone mets OS >3 months Liver mets Current/ former Never 0 1 <1% 1% 5% 10% Prior therapy Baseline disease site Smoking status ECOG PS PD-L1 expression a EGFR mut.-pos. Post-hoc, exploratory multivariate analysis suggested that nivolumab-treated patients with poorer prognostic features and/or aggressive disease when combined with lower or no tumor PD-L1 expression may be at higher risk of death within the first 3 months These included the following known prognostic factors: <3 months since last treatment, PD as best response to prior treatment, and ECOG PS = 1 Peters S et al WCLC 2016

19 2 line Atezolizumab: no restrictions according to histology or PD-L1 EVEN IF OAK [Ph. III] Barlesi F et al, ESMO 2016

20 2 line Pembrolizumab: PD-L1 will matter TPS 1% TPS 50% HR 0.54 (p=0.0002) HR 0.50 (p<0.0001) Target HR 0.60 HR 0.71 (p=0.0008) HR 0.61 (p<0.0001). HR 0.71 (p=0.0008) HR 0.61 (p<0.0001) Garon P et al, AACR 2015 Herbst R et al, Lancet 2016

21 TPS 0/1-49%: how much is the benefit? TPS 1-24% TPS 25-49% Baas P et al, ASCO 2016

22 Efficacy of I-O in EGFR-Mutant patients [RCTs] Phase III RCTs, I-O vs. DOC PFS OS KN010 CM057 OAK High probability of differential effect of I-O vs. Chemo according to EGFR mutation. High risk of qualitative (and quantitative) interaction Herbst R et al, Lancet 2016 Borghaei et al, NEJM 2015 Barlesi F et al, ESMO 2016

23 OS Immunoterapia nel tumore del polmone Efficacy of I-O in EGFR-Mutant patients [EAP] EAP NIVO 2nd line NSCLC ORR 18% [95% CI %] Overall 8% [95% CI %] EGFR+ EGFR-Mutant - Median OS: 8.3 months ( ) Overall - Median OS: 12.1 months ( ) Median F.U.: 6.2 months (max 18.8 months) BORR n (%) CR PR SD Mixed PD Not determ. General Population (n = 1585) (<1) 274 (17) 398 (25) 18 (1) 664 (42) 221 (14) EGFR + (n=101) (8) 19 (19) 2 (2) 52 (51) 20 (20)

24 Conclusions As for EGFR, ALK (and ROS1), PD-L1 assay is going to identify a subset of patients whereas I-O might represent a game-changer. Pathologists must be supported (with resources and technologies) to find the more cost-effective strategy to integrate multiple IHC platforms for disease characterization and subsequent treatment optimization. 2 nd -line data support I-O for all patients, although many (serious) concerns are emerging: In the near future, patients candidate to receive 2 nd -line I-O will be those with PD-L1 expression of 1-49% or undetermined. Thus, if we target not simply a survival advantage but a clinically relevant benefit, PD-L1, as well as clinical (i.e. prognostic features) and molecular parameters (EGFR mutation) should be considered

25