I CONVEGNO REGIONALE SIFO MEETING DI PRIMAVERA IL FARMACISTA CLINICO E I NUOVI MODELLI DI CURA Taormina, 11/12/13 maggio 217 Stato dell arte dell immunoterapia. Il Paziente con NSCLC Francesco Ferraù Oncologia Medica Ospedale S.Vincenzo, Taormina
Possibilità terpeutiche per personalizzare la terapia nel Paziente con NSCLC Chemotherapy Targeted Therapy Checkpoint Inhibitors Histologic subtyping for chemotherapy Genomicsdriven TKIs: EGFR ALK ROS1 Anti PD-1 Anti PD-L1 Anti CTLA-4 Qual è il setting ottimale per il giusto trattamento nel giusto Paziente (prima linea, seconda linea, linee successive)?
CTLA-4 and PD-1/PD-L1 Checkpoint Blockade for Cancer Treatment Priming phase (lymph node) Effector phase (peripheral tissue) Dendriti c cell T-cell T-cell migration T-cell Cancer cell MH C TC R TC R MH C PD-1 mabs: Nivolumab Pembrolizumab CTLA-4 mabs: Ipilimumab Tremelimumab Dendriti c cell B7 CD 28 CTLA -4 T-cell T-cell PD -1 PD-L1 Cancer cell PD-L1 mabs: Atezolizumab Avelumab Durvalumab Ribas A. N Engl J Med. 212;366:2517-2519.
Frequently asked questions: Check mechanism point of action inhibitors augments T-Cell The mechanism of action of ipilimumab differs from those activation of traditional chemotherapy or small-molecule inhibitors, CTLA-4 were developed as anticancer therapies under the theory that through blockade of the CTLA-4-mediated inhibitory signal, the activity of T-cells may be activated against tumor antigens and their activity harnessed for treatment of cancer. 3,13 A T-cell activation T-cell inhibition T-cell remains activ ated CTLA-4 Activation TCR CD28 Activation TCR CD28 CTLA-4 Inhibition Activation TCR CD28 CTLA-4 Activation MHC APC B7 MHC APC B7 MHC B7 APC Ipilimumab blocks CTLA-4 B TCR: MHC antigen CD28: B7 CTLA-4: B7 lpilimumab T-cell activation T-cell inhibition CTLA-4 blockade/ T-cell proliferation Figure 1 (A and B) Role of CTLA-4 in T-cell responses and the impact of CTLA-4 blockade with ipilimumab. Ipilimumab mechanism of action (A) and brake and pedal analogy (B) as used to explain the mechanism to patients and caregivers. Abbreviations: CTLA, cytotoxic T-lymphocyte antigen; APC, antigen-presenting cell; MHC, major histocompatibility complex; TCR, T-cell receptor. Ledezma B, Cancer Manag Res 214
KEYNOTE-24: Pembrolizumab vs CT as First-line Therapy for Advanced NSCLC Open-label phase III trial Stratified by ECOG PS ( vs 1), histology (squamous vs nonsquamous), and enrollment region Pts with stage IV NSCLC and ECOG PS /1, no previous systemic therapy, no actionable EGFR/ALK mutations, and PD- L1 TPS 5%* (N = 35) Pembrolizumab 2 mg IV Q3W for up to 35 cycles (n = 154) Chemotherapy (histology based) for up to 6 cycles (n = 151) Until PD or unacceptable toxicity Until PD (crossover to pembrolizumab allowed) Primary endpoint: PFS Secondary and exploratory endpoints: ORR, OS, DoR, and safety Reck M, et al. N Engl J Med. 216;375:1823-1833.
PFS (%) OS (%) KEYNOTE-24: Survival Outcomes PFS OS Pembro (n = 154) CT (n = 151) Pembro (n = 154) CT (n = 151) 1 8 6 4 2 Median PFS, mos 1.3 6. HR (95% CI).5 (.37-.68); P <.1 3 6 9 12 15 Mos Reck M, et al. N Engl J Med. 216;375:1823-1833. 18 1 8 6 4 2 Median OS, mos NR NR HR (95% CI).6 (.41-.89); P =.5 3 6 9 12 15 18 Mos 21 Slide credit: clinicaloptions.c
CheckMate-26: Nivolumab vs CT in First-line Therapy for Advanced NSCLC Stratified by PD-L1 expression (< 5% vs 5%) and histology (squamous vs nonsquamous) Pts with stage IV/recurrent NSCLC, no previous systemic therapy, no actionable EGFR/ALK mutations, PD-L1 expression 1%* (N = 541) * 1% tumor cell staining using 28-8 complementary diagnostic IHC assay. Primary endpoint: PFS ( 5% PD-L1 positive) Nivolumab 3 mg/kg IV Q2W (n = 271) Chemotherapy (histology based) for up to 6 cycles (n = 27) Until PD or unacceptable toxicity Until PD (crossover to nivolumab allowed) Secondary endpoints: PFS ( 1% PD-L1 positive), ORR, OS Socinski M, et al. ESMO 216. Abstract LBA7_PR. Slide credit: clinicaloptions.c
IMMUNOTERAPIA DI PRIMA LINEA NEL NSCLC NEL TUMORE POLMONARE NON MICROCITOMA LE EVIDENZE DI LETTERATURA INDICANO CHE PEMBROLIZUMAB E SUPERIORE ALLA CHEMIOTERAPIA NIVOLUMAB NON E SUPERIORE ALLA CHEMIOTERAPIA PEMBROLIZUMAB E NIVOLUMAB SONO MEGLIO TOLLERATI DELLA CHEMIOTERAPIA MAGGIO 217: PEMBROLIZUMAB HA INDICAZIONE MA NON RIMBORSABILITA PER NSCLC IN PRIMA LINEA
Impact of Tumor Mutation Burden on the Efficacy of First- Line Nivolumab in Stage IV or Recurrent Non-Small Cell Lung Cancer: An Exploratory Analysis of CheckMate 26 Solange Peters, 1 Benjamin Creelan, 2 Matthew D. Hellmann, 3 Mark A. Socinski, 4 Martin Reck, 5 Prabhu Bhagavatheeswaran, 6 Han Chang, 6 William J. Geese, 6 Luis Paz-Ares, 7 David P. Carbone 8 1 Oncology Department, Lausanne University Hospital, Lausanne, Switzerland; 2 H. Lee Moffitt Cancer Center, Tampa, FL, USA; 3 Memorial Sloan Kettering Cancer Center, New York, NY, USA; 4 Florida Hospital Cancer Institute, Orlando, FL, USA; 5 LungenClinic Grosshansdorf, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Grosshansdorf, Germany; 6 Bristol-Myers Squibb, Princeton, NJ, USA; 7 Hospital Universitario Doce de Octubre, CNIO and Universidad Complutense, Madrid, Spain; 8 Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
PFS (%) PFS by Tumor Mutation Burden Tertile CheckMate 26 TMB Analysis: Nivolumab in First-line NSCLC Nivolumab Arm Chemotherapy Arm 1 9 8 Median PFS, months (95% CI) Low n = 62 4.2 (1.5, 5.6) Medium High n = 49 n = 47 3.6 9.7 (2.7, 6.9) (5.1, NR) 1 9 8 Median PFS, months (95% CI) Low n = 41 6.9 (5.4, NR) Medium High n = 53 n = 6 6.5 5.8 (4.3, 8.6) (4.2, 8.5) 7 7 6 6 5 5 4 High 4 Low 3 3 2 1 Low 2 1 High Medium Medium 3 6 9 12 15 18 21 24 3 6 9 12 15 18 21 Months Months Data for patients with low and medium TMB were pooled in subsequent analyses
Grade of toxicity Kinetics of Appearance of iraes Diarrhea, colitis Rash, pruritus Hypophysitis Liver toxicity 2 4 6 8 Time course (weeks) 1 12 14 1. Weber JS, et al. J Clin Oncol 212;3:2691 7
LA CHEMIOTERAPIA NELLO SCENARIO TERAPEUTICO ATTUALE DEL NSCLC 2% 8% LA CHEMIOTERAPIA NEL NSCLC : ALIVE AND WELL
CheckMate 17 and 57: Nivolumab vs Docetaxel in Previously Treated Advanced NSCLC Open-label, randomized phase III trials CheckMate 17: Squamous NSCLC CheckMate 57: Nonsquamous NSCLC Pts with stage IIIB/IV squamous NSCLC and ECOG PS -1 with failure of 1 previous platinum doublet chemotherapy (N = 272) Nivolumab 3 mg/kg IV Q2W (n = 135) Docetaxel 75 mg/m 2 IV Q3W (n = 137) Primary endpoint: OS Until disease progression or unacceptabl e toxicity Pts with stage IIIB/IV nonsquamous NSCLC and ECOG PS -1 who failed 1 prior platinum doublet chemotherapy ± TKI therapy (N = 582) Nivolumab 3 mg/kg IV Q2W (n = 292) Docetaxel 75 mg/m 2 IV Q3W (n = 29) Until disease progression or unacceptabl e toxicity Secondary endpoints: ORR, PFS, efficacy by PD-L1 expression, safety, QoL Brahmer J, et al. N Engl J Med. 215;373:123-135. Borghaei H, et al. N Engl J Med. 215;373:1627-1639. Slide credit: clinicaloptions.com
OS (%) OS (%) CheckMate 17 and 57: OS With a Minimum 2-Yr Follow-up 1 CheckMate 17: Squamous Nivo (n = 135) Docetaxe l (n = 137) 1 CheckMate 57: Nonsquamous Nivo (n = 292) Docetaxe l (n = 29) 8 Median OS, mos 9.2 6. 8 Median OS, mos 12.2 9.5 1-yr OS, % 42 24 1-yr OS, % 51 39 6 2-yr OS, % 23 8 6 2-yr OS, % 29 16 HR (95% CI).62 (.47-.8) HR (95% CI).75 (.63-.91) 4 4 2 3 6 9 12 15 18 21 24 27 Nivolumab Docetaxel 3 33 36 39 2 Nivoluma b Docetaxel 3 6 9 12 15 18 21 24 27 3 33 36 39 Mos Mos Borghaei H, et al. ASCO 216. Abstract 925. Slide credit: clinicaloptions.com 22
KEYNOTE-1: Pembrolizumab vs Docetaxel in Advanced PD-L1 Positive NSCLC Multicenter, randomized, open-label phase II/III trial Pts with advanced NSCLC who progressed after platinum-based chemotherapy (and TKI if EGFR+ or ALK+); 1% PD-L1+ tumor cells; ECOG PS /1 (N = 134) Pembrolizumab 2 mg/kg IV Q3W (n = 345) Pembrolizumab 1 mg/kg IV Q3W (n = 346) Docetaxel 75 mg/m 2 IV Q3W (n = 343) Treatment continued for 24 mos or until PD or unacceptable toxicity Primary endpoints: OS, PFS Secondary endpoints: DoR, ORR, safety Herbst RS, et al. Lancet. 216;387:154-155. Slide credit: clinicaloptions.c
OS (%) OS (%) KEYNOTE-1: OS in Pts With PD-L1 TPS 1% and TPS 5% Pembrolizumab 2 mg/kg (n = 344) Pembrolizumab 1 mg/kg (n = 346) Pts With PD-L1 TPS 1% mos, Mos 1-Yr OS, % 1.4 43.2 12.7 52.3 Docetaxel (n = 343) 8.5 34.6 1 8 6 4 2 5 1 1 Mos 5 HR (95% CI).71 (.58-.88).5 (.49-.75) Herbst RS, et al. Lancet. 216;387:154-155. 2 2 5 Pts With PD-L1 TPS 5% Pembrolizumab 2 mg/kg (n = 139) Pembrolizumab 1 mg/kg (n = 151) 1 8 6 4 2 5 1 mos, Mos 14.9 17.3 Docetaxel (n = 152) 8.2 1 Mo5 s HR (95% CI).54 (.38-.77).5 (.36-.7) 2 2 5 Slide credit: clinicaloptions.c
OAK: Atezolizumab vs Docetaxel in Progressive Advanced NSCLC Multicenter, randomized, open-label phase III trial Metastatic or locally advanced NSCLC (2L/3L), PD on prior platinum-based treatment (N = 1225) Stratified by PD-L1 expression, histology, prior chemotherapy regimens Atezolizumab 12 mg IV Q3W (n = 425) Docetaxel 75 mg/m 2 IV Q3W (n = 425) No crossover allowed Until loss of clinical benefit Until PD Primary endpoints (first 85 pts enrolled): OS in ITT population; OS in pts with 1% PD-L1 expression Secondary endpoints: ORR, PFS, DoR, safety Rittmeyer A, et al. Lancet. 216;389:255-265. Slide credit: clinicaloptions.c
OS (%) OAK: OS in ITT Population 1 8 6 4 2 Median: 9.6 mos (95% CI: 8.6- Landmark OS, % 12 Mos 18 Mos Atezolizumab 55 4 Docetaxel 41 27 Median: 13.8 mos 11.2) (95% CI: 11.8-3 6 9 12 15 18 21 24 27 15.7) Mo s HR:.73 (95% CI.62-.87; P =.3) Rittmeyer A, et al. Lancet. 217;389:255-265. Slide credit: clinicaloptions.com
IMMUNOTERAPIA DI LINEE SUCCESSIVE ALLA PRIMA NEL NSCLC NEL TUMORE POLMONARE NON MICROCITOMA LE EVIDENZE DI LETTERATURA INDICANO CHE NIVOLUMAB E SUPERIORE ALLA CHEMIOTERAPIA PEMBROLIZUMAB E SUPERIORE ALLA CHEMIOTERAPIA ATEZOLIZUMAB E SUPERIORE ALLA CHEMIOTERAPIA TUTTI GLI ANTICORPI SONO MEGLIO TOLLERATI DELLA CHEMIOTERAPIA MAGGIO 217: NIVOLUMAB HA INDICAZIONE E RIMBORSABILITA PER NSCLC PRETRATTATO (qualunque istologia)
Select Ongoing Randomized Phase III Trials of PD-1/PD-L1 Therapy in Advanced NSCLC Trial* Disease Setting Treatment CheckMate 227 (NCT2477826) First line Nivolumab or nivolumab + ipilimumab or nivolumab + Plt doublet CT vs Plt doublet CT KEYNOTE-42 (NCT222894) First line/pd-l1+ Pembrolizumab vs Plt doublet CT KEYNOTE-189 (NCT257868) First line (nonsq) Plt/pemetrexed ± pembrolizumab KEYNOTE-47 (NCT2775435) First line (sq) Cb/pac or nab-pac ± pembrolizumab IMpower 11 (NCT249342) First line/pd-l1+ Atezolizumab vs Plt doublet CT IMpower 13 (NCT2367781) First line (nonsq) Cb/nab-pac vs Cb/nab-pac ± atezolizumab IMpower 131 (NCT2367794) First line (sq) Cb/pac or nab-pac + atezolizumab vs Cb/nab-pac IMpower 132 (NCT2657434) First line (nonsq) Plt/pemetrexed ± atezolizumab IMpower 15 (NCT2366143) First line (nonsq) Atezolizumab + Cb/pac ± bev vs Cb/pac/bev JAVELIN Lung 1 (NCT2576574) First line/pd-l1+ Avelumab vs Plt doublet CT JAVELIN Lung 2 (NCT2395172) Post-CT/PD-L1+ Avelumab vs docetaxel NEPTUNE (NCT2542293) First line Durvalumab + tremelimumab vs Plt doublet CT *All trials enrolling pts as of February 217. Slide credit: clinicaloptions.com
Prevenzione primaria?? Grazie per l attenzione