Il Futuro dell Immunoterapia

Transcription

1 Attualità e Prospettive in Immuno-oncologia Istituto Superiore Di Sanità Roma 4 Novembre, 2016 Il Futuro dell Immunoterapia Anna Maria Di Giacomo Medical Oncology and Immunotherapy-Department of Oncology University Hospital of Siena, Istituto Toscano Tumori SIENA, ITALY

2 Science, 2013 Science 2013

3 Evolving Therapeutic Options for Cancer Treatment Surgery Chemotherapy Radiotherapy Immunotherapy

4 Immunological properties of BRAF/MEK inhibitors Tumor Host? expression of HLA molecules circulating anti-tumor T cells expression of tumor-associated antigens tumor infiltrating lymphocytes immunosuppressive cytokines or molecules(e.g., IL-6, IL-8, B7- H1) peripheral lymphocyte counts modificationsof CD4 + T cells phenotype and functions maturation and antigen processing functions of DC

5 CA A Phase 1/2 Trial of Vemurafeniband Ipilimumabin Patients with BRAF V600E Mutation-positive Metastatic Melanoma Ribas A, et al. N Engl J Med 368;14, 2013

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7 Phase I study combining MEDI4736 and Dabrafenib and/or Trametinib in advanced melanoma Clinical activity to date Presented By Antoni Ribas at 2015 ASCO Annual Meeting

8 KEYNOTE 022 A phase 1b/2 study of D+T in combination with pembrolizumab/placebo Unresectable stage III or IV melanoma BRAF mut Untreated Dabrafenib+Trametinib Pembrolizumab 200mg IV Q3W No clinically active brain mets

9 Preliminary safety and clinical activity of atezolizumab combined with cobimetinib and vemurafenib in BRAF V600-mutant metastatic melanoma 13/14 pts achieved an objetive responses ORR=93% Revesible and manageable G3-4 AEs No SAE or G5 AEs Atezolizumab + Cobimetinib + Vemurafenib (A+C+V) A + C + V combination therapy results in a manageable safety profile and promising anti-tumor activity in pts with BRAFV600-mutant metastatic melanoma. Hwu P et al, ESMO 2016

10 Upcoming trials of anti-pd-1/pd-l1 therapy in advanced NSCLC Population/setting Treatment arms Phase Clinicaltrial.gov Monotherapy NSCLC PDL1+ 1st line NSCLC PDL1+ 1st line NSCLC 2nd/3rd line squamous NSCLC 2nd/3rd line non squamous NSCLC pretreated NSCLC 2nd line Nivolumab vs Chemotherapy (investigator choice) Pembrolizumab in NSCLC versus CT (platinum-based) Nivolumab vs Docetaxel (BMS017) Nivolumab vs Docetaxel (BMS057) Nivolumab (BMS153) Pembrolizumab versus Docetaxel III III III III III II/III NCT NCT NCT NCT NCT NCT Combination with CT NSCLC multi-arm, 1st line Nivolumab + Cisplatin/Gemcitabine or Cisplatin/Pemetrexed, or Carboplatin/Paclitaxel, or Bevacizumab maintenance I NCT NSCLC first line NSCLC+solid tumors Pembrolizumab with CT (platinum based) MPDL3280A with Beva+/-CT I/II II NCT NCT Combination with target therapy NSCLC EGFR mut NSCLC EGFR mut NSCLC EGFR mut NSCLC + solid tumors Pembrolizumab with Gefitinib or Erlotinib MEDI-4736+Gefinitib MDPL3280A with erolotinib MDPL3280A with cobimetinib (GDC-0973) I/II I I I NCT NCT NCT NCT Combination with IT NSCLC NSCLC NSCLC NSCLC + solid tumors NSCLC NSCLC SCLC + solid tumors Pembrolizumab with Ipilimumab MEDI-4736 with Tremelimumab MEDI-4736 with antipd1 (AMP514) Nivolumab +IL-21 Anti-LAG-3+/-Nivolumab Nivolumab +anti-kir Nivolumab +/- Ipilimumab Azacitidine oral or Azacitidine/Entinostat Nivolumab WCLC All NSCLC nd/3rd line Mercury ID: ONCHQ13NP10127; Approved 5Nov2013; Expires 5 Nov I/II I I I I I I II NCT NCT NCT NCT NCT NCT NCT NCT

11 Immune check-point(s) blockade-based combinations/sequences holding the most promise for future development Vaccines Epigenetic therapies Tumor microenvironment modulating agents Selected chemotherapeutic agents Targeted therapies Cytokines

12 Talimogene Laherparepvec: Oncology Oncolytic Immunotherapy Platform Selective viral replication in tumor tissue Tumor cells rupture for an oncolytic effect Systemic tumor-specific immune response Death of distant cancer cells Local Effect: Tumor Cell Lysis Systemic Effect: Tumor-Specific Immune Response Product is not suitable for systemic administration. This mechanism of action is investigational. 1. Varghese S, et al. Cancer Gene Ther. 2002;9: Hawkins LK, et al. Lancet Oncol. 2002;3: Fukuhara H, et al. Curr Cancer Drug Targets. 2007;7: Sobol PT, et al.. Mol Ther. 2011;19: Liu BL, et al. Gene Ther. 2003;10: Melcher A, et al. Mol Ther. 2011;19: Fagoaga OR In: McPherson RA, Pincus MR, eds. Henry s Clinical Diagnosis and Management by Laboratory Methods, 22nd ed. Philadelphia, PA: Elsevier; 2011: Dranoff G. Oncogene. 2003;22:

13 Clinically meaningful improvement in primary overall survival analysis with T-VEC vs GM-CSF* Kaplan Meier (%) Survival, months 2015 Amgen Inc. All rights reserved GM-CSF, % T-VEC, % Difference % (95% CI) ( ) ( ) ( ) ( ) Events/n (%) Median (95% CI), months T-VEC 189/295 (64) 23.3 ( ) GM-CSF 101/141 (72) 18.9 ( ) HR, 0.79 (95% CI, ) Log-rank P = Median follow-up = 44.4 months (range ) Patients at risk: T-VEC GM-CSF Time (months) *Secondary endpoint was not met. Andtbacka RHI, et al. J Clin Oncol 2015 [Epub ahead of print].

14 Change from baseline (%) Response to T-VEC + ipilimumab N = 18 Best irrc confirmed response Per irrc n (%) ORR* 9 (50) CR 4 (22.2) PR 5 (27.8) SD 4 (22.2) PD 4 (22.2) Unevaluable 1 (5.6) Disease control rate (CR + PR + SD) 13 (72.2) The waterfall plot shows best reductions in tumour burden at a single time point. For the immune-related response criteria (irrc) response table, CR, PR and PD needed to be confirmed by consecutive assessments no less than 4 weeks apart to be considered confirmed with the following exception: if PD was the last evaluable tumour assessment, it was considered as confirmed. *The actual number of overall responders by irrc at time of data analysis was 10, but subsequently one was found to be incorrectly reported as a confirmed PR instead of the correct assessment of SD. The table has been updated to reflect the corrected data; Last response was PD followed by unevaluable response. This subject was incorrectly reported to have best overall response 2015 Amgen Inc. All rights reserved (BOR) of 100% at time of data analysis, but the corrected BOR is 46%; Unconfirmed CR. d Stage IIIB (n = 1) Stage IIIC (n = 3) Stage IV M1a (n = 4) Stage IV M1b (n = 5) Stage IV M1c (n = 4) Puzanov I, et al. ASCO 2015: Abstract 9063.

15 N=21 Unresectable stage III or IV melanoma Treatment naive Injectable lesions No clinically active brain mets No active herpetic skin lesions or prior complications from herpetic infection Phase 1b: Study design T-VEC intralesional Up to 4 ml per treatment 1 st dose 10 6 PFU/mL Then 10 8 PFU/mL Q2W Wk -5 Wk -2 Wk 0 T-VEC Intralesional Pembrolizumab 200mg IV Q2W DLT Window Wk 6 Treatment until whichever occurs first: Progressive disease (PD) per irrc Intolerance 2 Years All injectable tumors disappeared (T-VEC only) S A F E T Y F O L L O W - U P 30 (+7) days after end of treatment

16 Next steps Phase 3 part of MASTERKEY-265 Unresectable stage III or IV melanoma Treatment naive Injectable lesions No clinically active brain mets No active herpetic skin lesions or prior complications from herpetic infection T-VEC Intralesional Pembrolizumab 200mg IV Q2W Pembrolizumab 200mg IV Q2W

17 Ongoing clinical studies in solid tumors NCT Neoadjuvant Intralesional Injection of Talimogene Laherparepvec With Concurrent Preoperative Radiation in Patients With Locally Advanced Soft Tissue Sarcomas NCT A Phase 1, Multi-center, Open-label, Dose De-escalation Study to Evaluate the Safety and Efficacy of Talimogene Laherparepvec in Pediatric Subjects With Advanced Non Central Nervous System Tumors That Are Amenable to Direct Injection NCT A Phase II Randomized Trial of Intralesional Talimogene Laherparepvec With or Without Radiotherapy for Cutaneous Melanoma, Merkel Cell Carcinoma, or Other Solid Tumors

18 Immune check-point(s) blockade-based combinations/sequences holding the most promise for future development Vaccines Epigenetic therapies Tumor microenvironment modulating agents Selected chemotherapeutic agents Targeted therapies Cytokines

19 EPIGENETICS Heritable changes in gene expression not based on modifications of the DNA sequence

20 EPIGENETIC MODIFICATIONS Histone modifications DNA methylation PHARMACOLOGICALLY REVERSIBLE HDAC inhibitors (HDACi) MicroRNA gene silencing DNMTs inhibitors (DNMTi) Maio et al, unpublished

21 Immunomodulatory activities of DNMTi and HDACi Effect target DNMTi HDACi ref CTA expression X SigalottiL, Blood,CCR, CR, MHC class I expression X X Sigalotti L Pharmacology & Therapeutics 2014 MHC class II expression X X Gialitakis M, Nucleic Acids Res co-stimulatory molecules expression X X MagnerWJ, J Immunology 2000 NKG2D ligands expression X ArmeanuS,CancerRes FOXP3 expression X X Licciardi PV, ISRN Hematology 2012 functionof DC X Licciardi PV, ISRN Hematology 2012 TRAIL and FAS expression X Sigalotti L Pharmacology & Therapeutics 2014 pro-apoptotic genes expression X Sigalotti L Pharmacology & Therapeutics 2014 CD4 proliferation X KroesenM, Oncotarget 2014 functionof CD8 X X KroesenM, Oncotarget 2014

22 Epigenetic Immunomodulation of Cancer cell Maio M. et al., CCR 2015

23 Epigenetic immuno-sequencing COMBOS Improve host s immune system activity HOST Modulate tumor immunogenicity and immune recognition TUMOR Check-point mab Epigenetic drugs

24 Epigenetic immuno-sequencing: the NIBIT-M4 Study (NCT ) SGI days q21 W0 W3 W6 W9 TA W 12 WK Ipilimumab 4 x q21 W1 W4 W7 W10 FPFV October 12, 2015 A.M. Di Giacomo et al. Semin Oncol, 2015

25 Immune check-point(s) blockade-based combinations/sequences holding the most promise for future development Vaccines Epigenetic therapies Tumor microenvironment modulating agents Selected chemotherapeutic agents Targeted therapies Cytokines

26 Multiple immune inhibitory and co-stimulatory pathways in the tumor microenvironment are targets of therapeutic manipulation by antibodies or drugs. Drew Pardoll, and Charles Drake J Exp Med 2012;209:

27 IDO-mediated immunesuppression

28 IDO1 Expression Is Associated With Poor Patient Outcome in Various Tumor Types IDO1 is highly expressed in multiple tumor types Melanoma NSCLC Ovarian cancer Pancreatic cancer CRC Glioblastoma Squamous cell carcinoma Endometrial carcinoma DLBCL RCC TCC TNBC Kaplan-Meier survival curves in melanoma based on IDO1 accumulation in the lymph node 1 IDO negative IDO positive TCC=transitional cell carcinoma; TNBC=triple negative breast cancer 1. Munn DH, et al. J Clin Invest 2004;114(2):

29 IDO1 Inhibition Correlates With Increases in TIL Number and Function Infiltrating cells Cytokines PD-1 expression IDO1 inhibition leads to increased number of TILs and decreased suppressor cells in tumors Enhanced IFN-γ secretion from TILs was observed following IDO1 inhibitor treatment IFN=interferon Koblish HK, et al. AACR Poster

30 Combinations of Epacadostat and Checkpoint Inhibition Showed Synergistic Inhibition in Preclinical Models Epacadostat + anti CTLA4 Epacadostat + anti PD-L1 Days Postinoculation Days Postinoculation Combinations of epacadostat and checkpoint inhibition were associated with enhanced T-cell proliferation and cytokine secretion in vivo 1. Spranger S, et al. J Immunother Cancer. 2014;2:3. Data on file, Incyte Corporation 30

31 A Phase 1/2 Study Exploring the Safety, Tolerability, and Efficacy of Pembrolizumab (MK-3475) in Combination With Epacadostat (INCB024360) in Subjects With Selected Cancers (KEYNOTE-037)

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33 Phase 1/2 (ECHO-202): Epacadostat + Pembrolizumab 25 mg BID 50 mg BID 100 mg BID 300 mg BID Off study treatment Percentage Change From Baseline in Target Lesions: RCC and NSCLC RCC RCC NSCLC NSCLC NE=not evaluable; PD=progressive disease *Overall response is NE Overall response is PD (target lesions not assessed; PD per new lesions) ClinicalTrials.gov Identifier: NCT Gangadhar TC, et al. SITC 2015 Hamid O, et al. SMR 2015 COPYRIGHT 2016 INCYTE CORPORATION. ALL RIGHTS RESERVED

34 ECHO-301 / KEYNOTE- 252 Trial Design Phase 3 began enrolment in June 2016 (NCT ): 600 patients who are treatment-naïve for advanced melanoma Trial Design at Subject Level 7 Epacadostat 100 mg BID + pembrolizumab

35 Ongoing clinical studies in solid tumors ECHO-202, KEYNOTE-037 (w/ pembrolizumab) Non-small cell lung cancer, genitourinary transitional cell carcinoma, head & neck cancer, renal cell carcinoma, triple-negative breast cancer, ovarian cancer, DLBCL, melanoma ECHO-203 (w/ durvalumab) Non-small cell lung cancer, head & neck cancer, triple-negative breast cancer, genitourinary transitional cell carcinoma, gastric cancer, melanoma ECHO-204 (w/ nivolumab) Non-small cell lung cancer, glioblastoma, head & neck cancer, melanoma, DLBCL, colorectal cancer, ovarian cancer ECHO-110 (w/ atezolizumab) Non-small cell lung cancer

36 Melanoma Lung cancer CTLA-4 PD1-PDL1 CTLA-4/PD1 Breast Mesothelioma Glioblastoma Renal Other tumors Colorectal Urothelial Ovarian Head-Neck Combos Novel targets LAG-3 4-1BB CD40 TIM-3 OX-40 ICOS IDO KIR

37 Medical Oncology and Immunotherapy, University Hospital of Siena