Il ruolo di PD-L1 (42%) tra la prima e la seconda linea di trattamento

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1 Il ruolo di PD-L1 (42%) tra la prima e la seconda linea di trattamento Alessia Pochesci Divisione di Oncologia Toracica Istituto Europeo di Oncologia, Milano Tutor: Prof.ssa Silvia Novello Dott.ssa Chiara Bennati

2 PD-L1+ testing.

3 Avoiding immune destruction is a hallmark of cancer Chen & Mellman. Immunity 2013

4 Is PD-L1 the Biomarker? The Biomarker? Vansteenkiste J, WCLC 2016

5 Expression of PD-L1 is heterogeneous and varies with antibody used Negative Positive H&E E1L3 N SP14 2 Immunofluorescence shows stroma and epithelial staining are often concordant and adjacent 1 mm McLaughlin, K Schalper, R. Herbst and D Rimm (Yale Pathology) Green = Cytokeratin Blue = Nuclei Red = PD-L1 (SP142) Herbst RS, WCLC 2016

6 PD-L1 assays Shukuya T et al, JTO 2016

7 Brain Lung Dinamics and heterogeneity of PD-L1 expression H& E PD- L1 CD3 By tumor cells: - Agreement of PD-L1 expression 86% - Disagreement of PD-L1 expression 14% By immune cells: - Agreement of PD-L1 expression 74% - Disagreement of PD-L1 expression 26% PD-L1 may be consider an enrichment biomarker Mansfield AS et al, Ann Oncol 2016

8 Pembrolizumab Biomarker Development Pembrolizumab 1 DAKO-22c3 Ab 0 low high 1-49% > 50% 42%? Garon EB et al. NEJM 2015

9 HETEROGENEOUS PD-L1 DINAMIC PREDICTIVE ROLE?

10 KEYNOTE 024 Pembrolizumab as 1L in PD-L1+ ( 50%) cross-over in 50% of the patients Vansteenkiste J. et al., atezolizumab in NSCLC Reck (POPLAR) et al, NEJM 2016

11 ( 1%) Vansteenkiste J. et al., atezolizumab Socinski NSCLC MA, (POPLAR) ESMO 2016.

12 CheckMate 026 vs Keynote 024 Tumor biopsy Keynote 024 CheckMate 026 After metastatic diagnosis Within 6 months PD-L1 cut off 50% (22C3 clone) 5% (28-8 clone) Prevalence 20-30% 50% Imaging interval Q 9 weeks Q 6 weeks for first 48 weeks Primary endpoint PFS (RECIST) PFS (IRRC) Never smokers (PD-1) 3% 11% Squamous histology 19% 24% Time from diagnosis to treatment? 2 months Prior radiation? % 1 Prior radiation therapy of > 30 Gy disallowed within 6 months of first dose of trial treatment Socinski et al, ESMO 2016 Vansteenkiste J. et al., atezolizumab Reck et al, ESMO in NSCLC 2016, (POPLAR) NEJM 2016

13 Birch: Atezolizumab as 1L in PD-L1 selected TC2/3 or IC2/3 group TC3 or IC3 subgroup ORR 25% Responses observed in both TC3/IC3 (34%) and TC2/IC2 (18%) subgroups Garassino MC et al, WCLC 2016; Peters S et al, JCO 2017

14 Avelumab as 1L in PD-L1 unselected Median PFS: 17.6 weeks (95% CI: 11.6, 23.6) PFS rate at 24 weeks: 37.2% (95% CI: 28.6, 45.7) Jerusalem G et al, WCLC 2016.

15 Combination Immunotherapy in first-line Kind of combination: Chemotherapy + Checkpoint Inhibitors PD-1 / PD-L1 + CTLA-4 Combinations Rationale: Improve the number of people who benefit from single-agent immunotherapy Reduce the time to response and symptom control Extend the depth and duration of tumor response for individual patients

16 KEYNOTE-021: CT + pembrolizumab in 1L Clear PFS benefit and no OS advantage mpfs improved by 4.1 months Objective Response Rate by PD-L1 Status CTx + Pembrolizumab ORR: 55% CTx Alone ORR: 29% Estimated rate of 12 months: 75% (Combo) vs 72% (CT) In CT arm cross-over is 51% to PD(L)1 therapies (pembro & others) Vansteenkiste J. et al., atezolizumab Langer CJ et in al, NSCLC Lancet (POPLAR) Oncol 2016.

17 CheckMate 012: 1L Nivolumab ± Ipilimumab Stage IIIB/IV NSCLC (any histology), no prior chemotherapy for advanced disease, ECOG PS 0 or 1 Nivolumab 3 mg/kg IV Q2W a Nivolumab 3 mg/kg IV Q2W + Ipilimumab 1 mg/kg IV Q12W b Until disease progression c or unacceptable toxicity Nivolumab 3 mg/kg IV Q2W + Ipilimumab 1 mg/kg IV Q6W b Primary endpoint: safety and tolerability Secondary endpoints: ORR (RECIST v1.1) and PFS rate at 24 weeks assessed by investigators Exploratory endpoints: OS, efficacy by PD-L1 expression Nivo 3 Q2W (n = 32) Nivo 3 Q2W + Ipi 1 Q12W (n = 23) Nivo 3 Q2W + Ipi 1 Q6W (n = 23) ORR, n (%) 9 (28) 13 (57) 13 (57) Median PFS, mo (95% CI) 3.5 (2.2, 6.6) 10.4 (6.4, NR) 13.2 (3.5, 23.0) 1-year OS rate, % Vansteenkiste J. et al., atezolizumab Hellmann, in NSCLC Lancet (POPLAR) Onc 2016

18 The challenges of combination immunotherapy More is not always better Risk for increased (and new) toxicity Modest gains in efficacy Increased expense Drug development is outpacing our understanding of biology and potential biomarker development Where to begin? Multiple agents and potential combinations

19 PD-L1+ in SECOND-LINE?

20 Published Phase III Trials of PD-1/PD-L1 Agents in 2L Immuno Agent Target Trial Histology N Drug Compariso n Primary Endpoint Outcome NIVOLUMAB Anti-PD1 CHECKMATE Non Squamous NSCLC % 2 nd line vs Docetaxel OS Positive HR 0.73 (96% CI, 0.59 to 0.89) p=0.002 PEMBROLIZUMAB * Anti-PD1 KEYNOTE NSCLC PDL-1 >1% % 2 nd line vs Docetaxel OS Positive HR 0.71 (95% CI, ) p= ATEZOLIZUMAB Anti- PDL1 OAK 4 NSCLC % 2 nd line vs Docetaxel OS Positive HR 0.73 (95% CI ) p= * 2mg/kg 2 Borghaei et al, NEJM Herbst et al, Lancet Rittermeyer et al, Lancet 2017

21 CheckMate 057- Nivolumab as 2L in N-Sq mpfs did not favour nivolumab [2.3 mth vs 4.2 mth] 1-year-PFS 19% vs 8%, favouring nivolumab mos 12.2 mth vs 9.4 mth [HR 0.73; p = 0.002] 1-year-OS 51% vs 39% Borghaei H et al, NEJM 2015

22 OS by PD-L1 Expression Checkmate 057 N-Sq Paz Ares L et al ASCO 2015; Borghaei H et al NEJM 2015; Borghaei H et al ASCO 2016

23 KEYNOTE 010: Pembrolizumab as 2L in PD-L1 1% Herbst RS et al, Lancet. 2015

24 OAK trial Atezolizumab as 2L in NSCLC Rittmeyer A et al, Lancet 2017

25 OS by PD-L1 expression in OAK trial Gadgeel et al, WCLC 2016; Rittmeyer A et al, Lancet 2017

26 Atlantic trial: Ph2 of Durvalumab >2L Garassino MC et al, WCLC 2016

27 Implementation of PD-L1 Testing for Personalized Therapy for Lung Cancer Tsao MS et al, Modified

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