Immunoterapia di 1 linea Evidenze e Prospettive Future

Transcription

1 Immunoterapia di 1 linea Evidenze e Prospettive Future Sara Pilotto Oncologia Medica, Dipart. di Medicina, Università di Verona, A.O.U.I. Verona sara.pilotto@univr.it Negrar, 30 ottobre 2018

2 Disclosures Advisory Boards/Honoraria/Speakers fee/consultant for: Astra-Zeneca, Eli-Lilly, Boeringher Ingelheim, BMS, 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) Fondazione Cariverona Open Innovation Astra-Zeneca

3 Proportion Alive Hypothetical Goals of Immunotherapy Immunotherapy monotherapy Long-term survival Control Chemotherapy/TKI Time from Treatment TKI = tyrosine kinase inhibitor. Adapted from Sharma P, Allison JP. Cell. 2015;161(2): Horn, WCLC 2018

4 1 st Line Treatment Landscape in NSCLC Today Wild-Type Non-squamous Squamous PD-L1 0-49% PD-L1 50% KN 024 pembro PD-L1 50% PD-L1 0-49% Platinumbased CT PD-L1 50% Platinumbased CT WILD-TYPE for oncogene-addicted alterations Pembrolizumab

5 Wild-Type 1 st Line Treatment Landscape in NSCLC What s New? Non-squamous Squamous PD-L1 0-49% PD-L1 50% KN 024 pembro PD-L1 50% PD-L1 0-49% Platinumbased CT IMpower 132 atezo + platinum-pem KN 189 pembro + platinum-pem IMpower 130 atezo + carbo-nab-txl IMpower 150 atezo + beva carbo-txl KN 042 pembro CM 227 nivo + ipi CM 227 nivo + platinum-based CT KN 407 pembro + carbo-tax IMpower 131 atezo + carbo-nab-txl Platinumbased CT

6 Immuno alone? Immuno or chemo + immuno? Antiangiogenic? Patients characteristics? Age-PS? Histology? Oncogeneaddicted? Sequence? Steroids? Antibiotics? PD-L1 or TMB? Immunological profile Toxicity? Molecular background

7 The invasion of clinical trials MONOTHERAPY CHEMOTHERAPY COMBINATIONS IT + IT KN-024 Pembro mono CM026 Nivo mono KN-042 Pembro mono IM150 Atezo + bev + carbo + pac IM132 Atezo + cis/carbo + pem IM130 Atezo + carbo + nab-pac KN-189 Pembro + cis/carbo + pem IM131 Atezo + carbo + tax KN-407 Pembro + carbo + tax CM227 Nivo + chemo CM227 Nivo mono or + ipi or + chemo Non-squamous & squamous Non-squamous Squamous Non-squamous & squamous TPS 50% TPS 1% All PD-L1 All PD-L1 PD-L1 <1% TMB?

8 O S, % Updated Analysis of KEYNOTE-024: Pembro in PD-L1 high ( 50%) months follow-up 70.3% 54.8% 51.5% 34.5% Events, n HR (95% CI) Pembrolizumab a Chemotherapy 96 ( ) P = b Median (95% CI) 30.0 mo (18.3 mo NR) 14.2 mo (9.8 mo 19.0 mo) Control Arm: 63% of discontinued pts received IO N o. a t ris k T im e, m o n th s P e m b r o C h e m o Censoring rate (55% of pts with event) Brahmer J et al, WCLC 2017

9 IO single agent versus platinum-based CT: low PD-L1 expression KEYNOTE 042: Study design CheckMate 026: Study design Key eligibility criteria: Stage IV or recurrent NSCLC No prior systemic therapy for advanced disease No EGFR/ALK mutations sensitive to available targeted inhibitor therapy 1% PD-L1 expression a CNS metastases permitted if adequately treated at least 2 weeks prior to randomization Randomize 1:1 Nivolumab 3 mg/kg IV Q2W n = 271 Chemotherapy (histology dependent) b Maximum of 6 cycles n = 270 Tumor scans Q6W until wk 48 then Q12W Disease progression Disease progression or unacceptable toxicity Crossover nivolumab c (optional) Stratification factors at randomization: PD-L1 expression (<5% vs 5%) a Histology (squamous vs non-squamous) Primary endpoint: PFS ( 5% PD-L1+) d Secondary endpoints: PFS ( 1% PD-L1+) d OS ORR d Lopes G, ASCO 2018; Carbone, NEJM 2017

10 Lopes G, ASCO 2018; Carbone, NEJM 2017 IO single agent versus platinum-based CT: OS PD-L1 low expression KEYNOTE 042 CheckMate 026

11 Proportion Alive Hypothetical Goals of Immunotherapy in Combination Mono immunotherapy Combination ICI Long-term survival Control Chemotherapy/TKI Time from Treatment Horn, WCLC 2018

12 Chemotherapy No treatment Chemotherapy Does Tumor cell killing by cytotoxic chemotherapy expose immune system to high levels of tumor cell antigens? Weak antigen presentation Weak PD-1/PD-L1 expression Immunotherapy High immunosuppressive cytokines Weak antigen presentation Low PD-1/PD-L1 expression Low T-cell infiltration T-cell infiltration High immunosuppressive cytokines Antigen presentation PD-L1 expression PD-L1 expression Antigen presentation Potential impaired T- cell function Immunosuppressive cytokines T-cell infiltration Regulatory T-cells Potential impaired T- cell function Immunosuppressive cytokines Regulatory T-cells Tumor cell Apoptotic tumor Antigen-specific T-cell Regulatory Apoptotic Apoptotic antigen- Neutrophil Macrophage MHC1Danger signal PD-1 / PD-L1 Anti-PD-1 Cytokines Immunosuppressive cell T-cell T-cell T-cell specific T-cell or CTLA-4 Anti-PD-L1 cytokines. Horn, WCLC 2018

13 The invasion of clinical trials MONOTHERAPY CHEMOTHERAPY COMBINATIONS IT + IT KN-024 Pembro mono CM026 Nivo mono KN-042 Pembro mono IM150 Atezo + bev + carbo + pac IM132 Atezo + cis/carbo + pem IM130 Atezo + carbo + nab-pac KN-189 Pembro + cis/carbo + pem IM131 Atezo + carbo + tax KN-407 Pembro + carbo + tax CM227 Nivo + chemo CM227 Nivo mono or + ipi or + chemo Non-squamous & squamous Non-squamous Squamous Non-squamous & squamous TPS 50% TPS 1% All PD-L1 All PD-L1 PD-L1 <1% TMB?

14 Non-Squamous NSCLC [KEYNOTE-021G] Overall Survival, % No. at risk Median (95% CI) NR (22.8 NR) 20.9 (14.9 NR) 18.7 months follow-up 77% 69% 70% 56% Time, months Censoring rate (42% of pts with event) Median Follow-Up: 18.7 mo Events, n/n HR (95% CI) Pembro + PC 20/60 a 0.59 PC alone 31/63a ( ) P = 0.03 b Control Arm: 75% of discontinued pts received IO Borghaei, WCLC 2017

15 Non-Squamous NSCLC [KEYNOTE-189] Key Eligibility Criteria Untreated stage IV nonsquamous NSCLC No sensitizing EGFR or ALK alteration ECOG PS 0 or 1 Provision of a sample for PD-L1 assessment No symptomatic brain metastases No pneumonitis requiring systemic steroids R (2:1) N = 410 N = 206 Pembrolizumab 200 mg + Pemetrexed 500 mg/m 2 + Carboplatin AUC 5 OR Cisplatin 75 mg/m 2 Q3W for 4 cycles Placebo (normal saline) + Pemetrexed 500 mg/m 2 + Carboplatin AUC 5 OR Cisplatin 75 mg/m 2 Q3W for 4 cycles Pembrolizumab 200 mg Q3W for up to 31 cycles + Pemetrexed 500 mg/m 2 Q3W Placebo (normal saline) for up to 31 cycles + Pemetrexed 500 mg/m 2 Q3W Stratification Factors PD-L1 expression (TPS a <1% vs 1%) Platinum (cisplatin vs carboplatin) Smoking history (never vs former/current) Pembrolizumab 200 mg Q3W for up to 35 cycles PD b (616 patients) Gandhi, NEJM 2018

16 O S, % P F S, % Non-Squamous NSCLC [KEYNOTE-189] N o. a t R is k OS: HR 0.49 [95% CI: ]; p < M o n th s 12-mo rate 69.2% 49.4% Median (95% CI) NR (NE-NE) 11.3 mo ( ) PFS: HR 0.52 [95% CI: ]; p < mo rate 34.1% 17.3% Median (95% CI) 8.8 mo ( ) 4.9 mo ( ) N o. a t R is k M o n th s Subgroup Analyses OS: Positive across all subgroups PFS: Positive across all subgroups except for PD-L1 TPS <1% Gandhi, NEJM 2018

17 Non-Squamous NSCLC [KEYNOTE-189] OS TPS <1% TPS 1-49% TPS 50% TPS <1% TPS 1-49% TPS 50% PFS HR 0.59 ( ) HR 0.55 ( ) HR 0.42 ( ) HR 0.75 ( ) HR 0.55 ( ) HR 0.36 ( ) Gandhi, NEJM 2018

18 Non-Squamous NSCLC [IMpower132] Papadimitrakopoulou, WCLC 2018 Co-primary endpoints: INV-assessed PFS and OS Secondary endpoints: INV-assessed ORR and DOR, PRO and safety measures Exploratory analyses: clinical and biomarker subgroup analyses Biomarker-evaluable tissue not mandatory for enrolment (was available from 60% of patients)

19 Non-Squamous NSCLC [IMpower132] Papadimitrakopoulou, WCLC 2018 PFS OS

20 Barlesi F, ESMO 2018 Non-Squamous NSCLC [IMpower132] PFS benefit in key subgroups 75-84y HR % never smoker

21 Non-Squamous NSCLC [IMpower130] Cappuzzo F, ESMO 2018

22 Non-Squamous NSCLC [IMpower130] ITT Cappuzzo F, ESMO 2018 PFS OS

23 Non-Squamous NSCLC [IMpower150] Socinski M, ASCO 2018 Co-Primary Endpoint Analysis

24 Non-Squamous NSCLC [IMpower150] Socinski M, ASCO 2018 PFS (B vs C) OS (B vs C)

25 The invasion of clinical trials MONOTHERAPY CHEMOTHERAPY COMBINATIONS IT + IT KN-024 Pembro mono CM026 Nivo mono KN-042 Pembro mono IM150 Atezo + bev + carbo + pac IM132 Atezo + cis/carbo + pem IM130 Atezo + carbo + nab-pac KN-189 Pembro + cis/carbo + pem IM131 Atezo + carbo + tax KN-407 Pembro + carbo + tax CM227 Nivo + chemo CM227 Nivo mono or + ipi or + chemo Non-squamous & squamous Non-squamous Squamous Non-squamous & squamous TPS 50% TPS 1% All PD-L1 All PD-L1 PD-L1 <1% TMB?

26 Squamous NSCLC [KEYNOTE-407] Paz-Ares L, ASCO 2018

27 Squamous NSCLC [KEYNOTE-407] Paz-Ares L, ASCO 2018

28 Squamous NSCLC [KEYNOTE-407] Halmos, WCLC 2018

29 KN 407: PROs Results Mazieres, ESMO 2018

30 Squamous NSCLC [IMpower131] Jotte R, ASCO 2018

31 Squamous NSCLC [IMpower131] Jotte R, ASCO 2018 PFS (B vs C) OS (B vs C) In PD-L1 low (TC1/2 or IC1/2) OS has an opposite trend

32 The invasion of clinical trials MONOTHERAPY CHEMOTHERAPY COMBINATIONS IT + IT KN-024 Pembro mono CM026 Nivo mono KN-042 Pembro mono IM150 Atezo + bev + carbo + pac IM132 Atezo + cis/carbo + pem IM130 Atezo + carbo + nab-pac KN-189 Pembro + cis/carbo + pem IM131 Atezo + carbo + tax KN-407 Pembro + carbo + tax CM227 Nivo + chemo CM227 Nivo mono or + ipi or + chemo Non-squamous & squamous Non-squamous Squamous Non-squamous & squamous TPS 50% TPS 1% All PD-L1 All PD-L1 PD-L1 <1% TMB?

33 Hellman, AACR 2017 CheckMate-227 N = 1189 Nivolumab 3 mg/kg Q2W Ipilimumab 1 mg/kg Q6W n = 396 Patients for PD-L1 co-primary analysis Nivolumab + ipilimumab n = 396 1% PD-L1 expression R 1:1:1 Histology-based chemotherapy b n = 397 Chemotherapy b n = 397 Key Eligibility Criteria Stage IV or recurrent NSCLC No prior systemic therapy No known sensitizing EGFR/ALK alterations ECOG PS 0 1 Nivolumab 240 mg Q2W n = 396 Patients for TMB co-primary analysis c Nivolumab + ipilimumab n = 139 Chemotherapy b n = 160 Stratified by SQ vs NSQ N = 550 <1% PD-L1 expression R 1:1:1 Nivolumab 3 mg/kg Q2W Ipilimumab 1 mg/kg Q6W n = 187 Histology-based chemotherapy b n = 186 Nivolumab 360 mg Q3W + histology-based chemotherapy b n = 177 Co-primary endpoints: Nivolumab + ipilimumab vs chemotherapy OS in PD-L1 selected populations PFS in TMB-selected populations

34 PFS (%) Co-primary Endpoint: PFS With Nivolumab + Ipilimumab vs Chemotherapy in Patients With High TMB ( 10 mut/mb) 100 Nivo + ipi (n = 139) Chemo (n = 160) RR Median PFS, b mo HR c 97.5% CI 45.3% , 0.81 P = % y PFS = 43% Nivolumab + ipilimumab 20 1-y PFS = 13% No. at risk Chemotherapy Months Nivo + ipi Chemo PFS benefit was independent of PD-L1 and histology In patients with TMB <10 mut/mb treated with nivo + ipi vs chemo, the HR was 1.07 (95% CI: 0.84, 1.35) d Hellman, AACR 2017

35 PFS With Nivolumab + Chemotherapy and Nivolumab + Ipilimumab by TMB Status Borghaei H, ASCO 2018

36 CM 227: PROs Results PRO measures assessed LCSS: ASBI; 3-IGI EQ-5D (3-level): VAS; UI Mean (95% CI) change from baseline MID Nivo + ipi Chemo LCSS ASBI MID Worse Better Mean (95% CI) change from baseline MID Nivo + ipi Chemo LCSS Fatigue MID Worse Better Mean (95% CI) change from baseline MID Nivo + ipi Chemo LCSS Dyspnea MID Worse Better Weeks n n Weeks n n Weeks n n Proportion of patients with symptom deterioration on treatment or followup by week 12 Disease-related deterioration rate by 12 weeks, % Absolute risk reduction, % (95% CI) 12.7 ( ) 22.3 c 35.0 d n/n 31/139 56/160 Nivo + ipi Chemo Probability of not worsening n Nivo + ipi (n = 139) Chemo (n = 160) Median TTD, mo e NR 6.2 HR 95% CI Months Nivo + ipi n Chemo 5 3 Time to first disease-related deterioration on treatment Brahmer, WCLC 2018

37 B-F1RST Kim, ESMO 2018

38 B-F1RST: Feasibility Kim, ESMO 2018

39 Kim, ESMO 2018 B-F1RST PFS OS

40 Burning Questions for Tomorrow 1. What treatment according to PD-L1 expression level? 2. There is a role for the quadruplet with bevacizumab? 3. Patient characteristics: age and PS? Toxicity? 4. Concomitant treatment: steroids and antibiotics?

41 1. What treatment according to PD-L1 expression level?

42 Besse, ESMO 2018 PD-L1 <50%: ICI + Chemo vs Chemo? CT + immuno - OS PDL1 negative - OS

43 PD-L1 50%: Pembro w/o Chemo? OS Treatment Options (no comparative RCTs): PEMBRO PEMBRO + Chemotherapy PFS No significant Interaction in OS Significant Interaction in PFS and ORR in favour of the combo strategy ORR Clinical decision should be individualized considering patients overall health and comorbidities, disease characteristics (i.e. is rapid response required?), and safety concerns. Pilotto S et al, Semin Oncol 2018 [in press]

44 2. There is a role for the quadruplet with bevacizumab? Besse, ESMO 2018

45 Liver Metastasis

46 Liver Metastasis

47 3. Patient characteristics: immunological age?

48 3. Patient characteristics: PS?

49 Adverse events with IO single agent versus IO+CT combo IMPOWER IMPOWER

50 Safety Summary of Treatment-Related AEs: Nivo + Ipi could be less toxic than other combinations Nivolumab + chemotherapy (n = 172) Any grade Grade 3 4 Any grade Nivolumab + ipilimumab (n = 185) Grade 3 4 Chemotherapy (n = 183) Any grade Grade 3 4 Any TRAE, a % TRAE leading to discontinuation, b % Median number of doses received, n 8.5 for nivolumab (Q3W) 4 7 for chemo (Q3W) 8.0 for nivolumab (Q2W) 3.0 for ipilimumab (Q6W) 4 7 for chemo (Q3W) There were 4 treatment-related deaths in the nivolumab + chemo arm, 7 in both nivolumab + ipilimumab arms in Part 1, c and 6 in both chemo arms in Part 1 d Borghaei H et al. ASCO 2018

51 Arbour, JCO 2018 Fucà, WCLC Concomitant treatment: steroids?

52 4. Concomitant treatment: antibiotics? Routy, Science 2018 Multiple reports on n=1744 demonstrate the negative influence of ATB on immune checkpoint inhibitors. Shorter course of ATB 6 days vs 9 days might be safer [Gallio et al. WCLC 2018] Patients hospitalized or receiving IV ATB should be considered separately [Rubio et al. WCLC 2018] Citrulline may represent a surrogate marker of GI health [Leprieur et al. WCLC 2018]

53 Immuno alone? Immuno or chemo + immuno? Antiangiogenic? Patients characteristics? Age-PS? Histology? Oncogeneaddicted? Sequence? Steroids? Antibiotics? PD-L1 or TMB? Immunological profile Toxicity? Molecular background

54