LA QUARTA ARMA CONTRO IL CANCRO

Transcription

1 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

2 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

3 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

4 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 o fever Courtesy of Mike Faries

5 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

6 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; ; 2. Pardoll DM. Nat Rev Cancer 212;12:

7 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

8 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

9 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 Same efficacy in brain mtx

10 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 ~ % 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 Years PA Ascierto Keynote-1 Naive Pts 1. Schadendorf et al. J Clin Oncol 215;33: ; 2. Current analysis; 2. Hodi FS. AACR Poster presentation by Dr. Victoria Atkinson at SMR 215 International Congress. 4. Robert et al. Oral presentation ASCO Daud et al. Oral presentation ASCO Larkin et al NEJM Robert et al. ASCO ,2 73% 5 61% 45% NA

11 Targeting CTLA-4 and PD-1 pathways Periphery Tumour microenvironment Activation (cytokines, lysis, proliferation, migration to tumour) Dendritic cell MHC B7 TCR CD B7 CTLA 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^

12 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 ~ % 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 Years PA Ascierto Keynote-1 Naive Pts 1. Schadendorf et al. J Clin Oncol 215;33: ; 2. Current analysis; 2. Hodi FS. AACR Poster presentation by Dr. Victoria Atkinson at SMR 215 International Congress. 4. Robert et al. Oral presentation ASCO Daud et al. Oral presentation ASCO Larkin et al NEJM Robert et al. ASCO ,2 73% 5 61% 45% NA

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

14 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

15 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

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

17 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 Same efficacy in brain mtx

18 Patients alive (%) EORTC 187: Overall Survival Ipilimumab Placebo Deaths/patients 162 / / 476 Hazard ratio (95.1% CI)*.72 ( ) Log-rank P value*.1 *Stratified by stage at randomization % 54% CI = confidence interval; NR = not reached. 5-year difference 11% O N Number of patients at risk : Years Ipilimumab Placebo Eggermont et al. NEJM 216

19 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 < % 61% 66% 53% Number of patients at risk NIVO IPI NIVO IPI Months Weber et al. NEJM 217

20 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

21 Change From Baseline in Tumor Size, % Change From Baseline in Tumor Size, % Pembrolizumab Demonstrates Broad Antitumor Activity 1 8 Melanoma 1 (N=655) KEYNOTE NSCLC 2 (N=262) KEYNOTE H&N 3 (N=132) KEYNOTE Urothelial 4 (N=33) KEYNOTE Gastric 5 (N=39) KEYNOTE TNBC 6 (N=32) KEYNOTE chl 7 (N=29) KEYNOTE Mesothelioma 8 (N=25) KEYNOTE Ovarian 9 (N=26) KEYNOTE SCLC 1 (N=2) KEYNOTE-28 1 Esophageal 11 (N=23) KEYNOTE 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.

22 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

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

24 Most frequent iraes Grade 3-4 AEs % % of Pts who permantely discontinued for any grade Ipilimumab 3 mg/kg Ipilimumab 1 mg/kg Nivolumab Pembrolizumab 2 mg/kg Ipilimumab/Nivolumab Ascierto et al. ESMO Atkinson et al. SMR Hamid ESMO Wolchock et al ASCO 216

25 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

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

27 Thank you! Via Mariano Semmola, 8131, Napoli, Italy Tel ; Fax