LA QUARTA ARMA CONTRO IL CANCRO

LA QUARTA ARMA CONTRO IL CANCRO Paolo A. Ascierto, MD Unit Melanoma, Cancer Immunotherapy and Innovative Therapies Istituto Nazionale Tumori Fondazione G. Pascale, Napoli, Italy

Disclosure Employment or Leadership Position: None Consultant/Advisory Role: Bristol-Meyers Squibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, Amgen, Array, Merck Serono, Pierre Fabre, Incyte, NewLink Genetics, Genmab, Medimmune Stock Ownership: None Research Funding: Bristol-Meyers Squibb, Roche-Genentech, Array Expert Testimony: None Other Remuneration: None

Immunotherapy: The third important wave in the history of oncology 194s end of 199s 211 present Chemotherapy alkylating agents, antimetabolites, CDDP, taxanes Targeted Therapy rituximab, trastuzumab, imatinib Immunotherapy ipilimumab, nivolumab, pembrolizumab CDDP, cisplatin

History of Intralesional Immunotherapy: Coley s Toxins William Bradford Coley Late 19 th Century, NY Surgeon Unresectable sarcomas regress after superinfection with erysipelas Injections of mixed toxins of erysipelas and bacillus prodigiousus Dose to 12-13 o fever Courtesy of Mike Faries

Coley s Toxins: Example Round cell sarcoma 1899 After 63 injections with Coley s toxins Alive and well in 191. After additional injections Balkwill Nat Rev Cancer 21. Courtesy of Mike Faries

Regulating the T cell immune response 1,2a Activating receptors CD28 OX4 CD137 Agonistic antibodies T cell stimulation Inhibitory receptors CTLA-4 PD-1 TIM-3 LAG-3 Antagonistic (blocking) antibodies T cell responses are regulated through a complex balance of inhibitory ( checkpoint ) and activating signals Tumours can dysregulate checkpoint and activating pathways, and consequently the immune response Targeting checkpoint and activating pathways is an evolving approach to cancer therapy, designed to promote an immune response a The image shows only a selection of the receptors/pathways involved LAG-3 = lymphocyte-activation gene 3 1. Adapted from Mellman I, et al. Nature 211:48;481 489; 2. Pardoll DM. Nat Rev Cancer 212;12:252 264

What we learned from Immuno-therapy in melanoma Immune adaptability, and memory offers the potential for long-term survival Unique MoAs offer the opportunity for combination Targeting the immune system not the tumour offers the potential for activity across multiple tumour types Potential to improve clinical outcome In various solid and haematologic malignancies Unique safety profiles Efficacy as adjuvant Dosage may makes a difference Efficacy in brain mtx

Cosa abbiamo imparato dall immunoterapia negli ultimi anni Benficio a lungo termine Possibilità di guarigione Può essere combinate con altri tipi di terapia (chemio, radio, target) Attiva in diversi tipi di cancro Potential to improve clinical outcome In various solid and haematologic malignancies Profilo di safety unico Efficace come adiuvante Dosaggio può fare la differenza Efficace nelle metastasi cerebrali

Overall Survival (%) Immune Checkpoint Inhibitors Provide Durable Long-term Survival for Patients with Advanced Melanoma 1 IPI (Pooled analysis) 1 9 NIVO Monotherapy (Phase 1 CA29-3) 2 NIVO Monotherapy (Phase 3 Checkmate 66) 3 8 PEMBRO Monotherapy (Phase 1 Keynote-1) 4 Naïve Patients 7 5 4 3 2 ~ % 5% N=278 N=21 45% 4% N=655 N=152 N=17 35% N=1,861 4% 2% PEMBRO Monotherapy (Phase 1 Keynote-1) 4 Pretreated and Naïve Patients PEMBRO Monotherapy (Phase 3 Keynote-6) 7 Study mos (mos) 1-yrs OS% 2-yrs OS% 3-yrs OS% 5-yrs OS% CA29-3 2,3 65% 47% 41% 35% CA29-66 NR 7,7% 57,7% NA NA Keynote-1 All Pts 24,4 66% 5 5% 4% NA Keynote-6 32,3 ~7% 55% 5% 7 NA 1 1 2 3 4 5 6 7 8 9 1 Years PA Ascierto Keynote-1 Naive Pts 1. Schadendorf et al. J Clin Oncol 215;33:1889-1894; 2. Current analysis; 2. Hodi FS. AACR 216 3. Poster presentation by Dr. Victoria Atkinson at SMR 215 International Congress. 4. Robert et al. Oral presentation ASCO 216 5. Daud et al. Oral presentation ASCO 215 6. Larkin et al NEJM 215 7. Robert et al. ASCO 217 32,2 73% 5 61% 45% NA

Targeting CTLA-4 and PD-1 pathways Periphery Tumour microenvironment Activation (cytokines, lysis, proliferation, migration to tumour) Dendritic cell MHC B7 TCR CD28 +++ +++ B7 CTLA-4 - - - Anti-CTLA-4 T cell T cell +++ - - - - - - TCR MHC PD-1 PD-L1 Anti-PD-1/PD-L1 PD-1 PD-L2 Anti-PD-1 Tumour cell CTLA-4 pathway PD-1 pathway Wolchock J, et al. JCO 213 Volume 31, Issue 15_suppl ; abstr 912^

Overall Survival (%) Immune Checkpoint Inhibitors Provide Durable Long-term Survival for Patients with Advanced Melanoma 1 IPI (Pooled analysis) 1 9 NIVO Monotherapy (Phase 1 CA29-3) 2 NIVO Monotherapy (Phase 3 Checkmate 66) 3 8 PEMBRO Monotherapy (Phase 1 Keynote-1) 4 Naïve Patients 7 5 4 3 2 ~ % 5% N=278 N=21 N=314 58% 45% 4% N=655 N=152 N=17 35% ~ 45-5% ipi/nivo N=1,861 4% 2% PEMBRO Monotherapy (Phase 1 Keynote-1) 4 Pretreated and Naïve Patients PEMBRO Monotherapy (Phase 3 Keynote-6) 7 Study mos (mos) 1-yrs OS% 2-yrs OS% 3-yrs OS% 5-yrs OS% CA29-3 2,3 65% 47% 41% 35% CA29-66 NR 7,7% 57,7% NA NA Keynote-1 All Pts 24,4 66% 5 5% 4% NA Keynote-6 32,3 ~7% 55% 5% 7 NA 1 1 2 3 4 5 6 7 8 9 1 Years PA Ascierto Keynote-1 Naive Pts 1. Schadendorf et al. J Clin Oncol 215;33:1889-1894; 2. Current analysis; 2. Hodi FS. AACR 216 3. Poster presentation by Dr. Victoria Atkinson at SMR 215 International Congress. 4. Robert et al. Oral presentation ASCO 216 5. Daud et al. Oral presentation ASCO 215 6. Larkin et al NEJM 215 7. Robert et al. ASCO 217 32,2 73% 5 61% 45% NA

Topalian et al; SITC 217 Cross Tumor CA29-3 phase I LTS data

Patient Case 71 year old male with BRAF VE-mutated MEL, ~7 brain mets, no steroids or SRT Baseline 1 year Tawbi et al ASCO 217

Ipilimumab + nivolumab in Brain Metastases Intracranial ORR: 55% Intracranial DCR: % Tawbi et al. ASCO 217

Patients alive (%) EORTC 187: Overall Survival 1 9 8 7 Ipilimumab Placebo Deaths/patients 162 / 475 214 / 476 Hazard ratio (95.1% CI)*.72 (.58 -.88) Log-rank P value*.1 *Stratified by stage at randomization 5 4 65% 54% 3 2 1 CI = confidence interval; NR = not reached. 5-year difference 11% 1 2 3 4 5 6 7 8 O N Number of patients at risk : 162 475 431 369 325 29 199 62 4 214 476 413 348 297 273 178 58 8 Years Ipilimumab Placebo Eggermont et al. NEJM 216

RFS (%) Checkmate 238: Primary Endpoint: RFS NIVO IPI 1 Events/patients 154/453 26/453 9 Median (95% CI) NR NR (16.6, NR) HR (97.56% CI).65 (.51,.83) 8 Log-rank P value <.1 7 5 71% 61% 66% 53% 4 3 2 1 Number of patients at risk NIVO IPI NIVO IPI 3 6 9 12 15 18 21 24 27 Months 453 399 353 332 311 291 249 71 5 453 364 314 269 252 225 184 56 2 Weber et al. NEJM 217

Change From Baseline in Tumor Size, % Change From Baseline in Tumor Size, % Pembrolizumab Demonstrates Broad Antitumor Activity 1 8 Melanoma 1 (N=655) KEYNOTE-1 1 8 NSCLC 2 (N=262) KEYNOTE-1 1 8 H&N 3 (N=132) KEYNOTE-12 1 8 Urothelial 4 (N=33) KEYNOTE-12 1 8 Gastric 5 (N=39) KEYNOTE-12 4 4 4 4 4 2 2 2 2 2-2 -2-2 -2-2 -4-4 -4-4 -4 - - - - - -8-8 -8-8 -8-1 -1-1 -1-1 1 8 4 2-2 -4 - -8-1 TNBC 6 (N=32) KEYNOTE-12 1 8 4 2-2 -4 - -8-1 chl 7 (N=29) KEYNOTE-13 1 8 4 2-2 -4 - -8-1 Mesothelioma 8 (N=25) KEYNOTE-28 1 8 4 2-2 -4 - -8-1 Ovarian 9 (N=26) KEYNOTE-28 1 8 4 2-2 -4 - -8-1 SCLC 1 (N=2) KEYNOTE-28 1 Esophageal 11 (N=23) KEYNOTE-28 8 4 2-2 -4 - -8-1 1. Daud A et al. 215 ASCO; 2. Garon EB et al. ESMO 214; 3. Seiwert T et al. 215 ASCO; 4. Plimack E et al. 215 ASCO; 5. Bang YJ et al. 215 ASCO; 6. Nanda R et al. SABCS 214; 7. Moskowitz C et al. 214 ASH Annual Meeting; 8. Alley EA et al. 215 AACR; 9. Varga A et al. 215 ASCO; 1. Ott PA et al. 215 ASCO; 11. Doi T et al. 215 ASCO.

Tissues of the body affected by autoimmune attack The clinical spectrum of IRAEs (immune-related adverse events) Festino and Ascierto. Oncoimmunology Eds 217

Most frequent iraes Grade 3-4 AEs % % of Pts who permantely discontinued for any grade Ipilimumab 3 mg/kg 1 27 15.4 Ipilimumab 1 mg/kg 1 34 31 Nivolumab 2 13 6 Pembrolizumab 2 mg/kg 3 13.5 4.5 Ipilimumab/Nivolumab 4 56.5 38.7 1. Ascierto et al. ESMO 216 2. Atkinson et al. SMR 215 3. Hamid ESMO 216 4. Wolchock et al ASCO 216

Treatment algorithms/experience aid early diagnosis and management of immune-mediated adverse reactions Result from increased or excessive immune activity Systemic high-dose corticosteroids* may be required for severe events Unless an alternate aetiology has been identified, consider all signs and symptoms Immunemediated adverse reactions Can be severe or life-threatening; may involve various organs Early diagnosis and appropriate management essential to minimise life-threatening complications Patient education for early recognition *With or without additional immunosuppressive therapy

What s the next NeoAdjuvant Better combos with less side effects The right duration of treatments Combination or sequencing

Thank you! Via Mariano Semmola, 8131, Napoli, Italy Tel. +39 81 593 431; Fax +39 81 593 841 Email: p.ascierto@istitutotumori.na.it