Innovation in Prevention, Early Detection & Diagnosis of Colorectal Cancer Heidelberg Workshop Session VI, Oncology Pipeline June 6, 2014
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1 Innovation in Prevention, Early Detection & Diagnosis of Colorectal Cancer Heidelberg Workshop Session VI, Oncology Pipeline June 6, 2014 Bernd Mueller MSD Sharp & Dohme, Germany
2 Normal Immune Surveillance: Activation and Response Tumor derived antigens Tumor antigen presentation Tumor Dendritic cell (professional antigen presenting cells APC) T cell activation in the lymph node Killer T cell response Perforin Granzyme IFN-γ CD4+T H 1 (T helper cell) CD8+ Killer T cells (Cytotoxic T lymphocyte, CTL) IL-2 Motz GT et al. Immunity. 2013;39: Chen DS et al. Immunity. 2013;39:1 10. Pardoll DM. Nat Rev Cancer. 2012;12: Janeway CA, et al. Immunobiology. 6th ed. New York and London: Garland Science; 2004: Liu CC et al. N Engl J Med ;335: Mellman I et al. Nature. 2011;480:
3 Many Tumors Exploit the PD-1 Immune Checkpoint to Evade Immune Eradication PD-L1 Tumor derived antigens Dendritic cell (professional antigen presenting cell, APC) Tumor antigen presentation T cell activation in the lymph node Tumor Killer T cell inactivation CD8+ Killer T cells (Cytotoxic T lymphocyte, CTL) CD4 + T H 1 T reg PD-1 CD4+ T H 1 Treg cells T reg CD4+T H 1 (T helper cell) Zou W et al. Nat Rev Immunol. 2008;8: Janeway CA, et al. Immunobiology. 6th ed. New York and London: Garland Science; 2004: Chen DS et al. Clin Cancer Res. 2012;18: Dong H et al. Nat Med. 2002;8: Francisco LM et al. J Exp Med. 2009;206: Amarnath S et al. Sci Transl Med. 2011:3:111ra120. Mellman I et al. Nature. 2011;480:
4 PD-1 Expression could be a Predictor of Response for PD-1 directed Therapies Brahmer et al /39 patients (pts) with advanced solid cancers had colorectal cancer (CRC); treated with anti PD-1 (BMS ) 1 durable CR in CRC Tumor cell surface expression of B7-H1 (PD-L1) may be a predictor of responsiveness to PD-1 blockade. Topalian et al /296 pts with advanced solid cancers had colorectal cancer, treated with (BMS ) None with colorectal cancer had objective responses or SD 9 of 25 patients (36%) with PD-L1 positive tumors had an objective response (P = 0.006) 7/19 CRC pts had PD-L1 expression measured, 6/7 were none-expressers, 1/7 had expression but no objective response Brahmer et al /207 with advanced solid cancers had colorectal cancer (CRC); treated with anti-pd-l1 (BMS ) None had objective responses PD-L1 receptor occupancy by anti PD-L1 on circulating CD3+ T, no correlation to treatment response Brahmer JR J Clin Oncol (19) ; Topalian SL et al. N Engl J Med 2012 (366) Brahmer JR et al. N Engl J Med 2012 (366)
5 Overview of Pembrolizumab, an Investigational Anti-PD-1 Antibody Pembrolizumab Humanized IgG4- no cytotoxic (ADCC/CDC) activity Blocks the binding of PD-L1 and PD-L2 to PD-1 (dual ligand blockade) Pharmacokinetics supportive of dosing every 2 weeks (Q2W) or every 3 weeks (Q3W) Half-life = ~21 days Low occurrence of anti-drug antibodies and no impact on pharmacokinetics
6 Study Design: Protocol PN001, Part C Eligibility Criteria Locally advanced or metastatic NSCLC 2 prior systemic therapies 1 measurable lesion ECOG PS of 0-1 Submission of a new tumor specimen for PD-L1 analysis Treatment Pembrolizumab 10 mg/kg IV 2 mg/kg Q3W, 10 mg/kg Q3W, or 10 mg/kg Q2W until progression by irrc, intolerable toxicity, or consent withdrawal download May 30, 2014
7 50% Staining Cut Point Appeared to Permit Selection of NSCLC Patients Likely to Derive Greatest Benefit from Pembrolizumab PD-L1 and radiologically evaluable patients (n=129) a ; RECIST v1.1 by independent central review: clinical trial assay Cut point Prevalence Best Overall Response Rate (95% Confidence Interval) by RECIST PD-L1 Positive PD-L1 Negative Total 50% staining ~25% N=41 37% (22%, 53%) N=88 11% (6%, 20%) N=129 19% (13%, 27%) PPV : 37% NPV : 89% 1% staining ~70% N=87 25% (17%,36%) N=42 7% (2%,20%) N=129 19% (13%, 27%) PPV : 25% NPV: 93% NPV=negative predictive value; PPV = positive predictive value Negative staining is no PD-L1 staining in tumor cells. Data cut-off for analysis was Dec 31, a Evaluable patients were those patients in the training set with evaluable tumor PD-L1 expression who had measurable disease at baseline per central review. download May 30, 2014
8 Major bins of Interventions / Strategies increase systemically the frequency of anti-tumor T cells overcome distinct immune suppressive pathways within the tumor microenvironment trigger innate immune activation and inflammation in tumor sites Spranger S; Gajewski T J ImmunoTherapy of Cancer 2013 (1) 16
9 In MSI-H Colorectal Cancer are an attractive Target for PD-1 Checkpoint Targeting Therapies MSI-H colorectal cancer generate multiple novel peptide sequences and derive immunogenic epitopes, as a direct consequence of MMR deficiency Generation of potentially immunogenic frameshift peptides (FSP) could be a direct consequence of MMR deficiency FSP-specific immune responses were detected in the peripheral blood from MSI-H colorectal cancer patients In MSI-H colorectal cancer a high density of tumor-infiltrating lymphocytes is common lymph follicles in the tumor environment arrise (Crohn s-like reaction) Show signs of a pronounced local immune response Kloor M et al. Langenbeck Arch Surg 2014 (399)
10 Frequency of Somatic Mutations Varies by Tumor Type: Does This Influence Immune Recognition? The hypermutation hypothesis: High frequency of somatic hypermutations in tumors may lead to greater immune stimulation and improved responses to immunomodulatory therapies. Lawrence et al. Nature 2013 (499)
11 Frequency of Somatic Mutations Varies by Tumor Type: Does This Influence Immune Recognition? The hypermutation hypothesis: High frequency of somatic hypermutations in tumors may lead to greater immune stimulation and improved responses to immunomodulatory therapies. Lawrence et al. Nature 2013 (499)
12 Increased PD-1 / PD-L1 Expression on Lymphocyte or on Tumor Cells in MSI-H type of CRC Strong PD-L1 expression in 37% of mismatch repair (MMR)-proficient CRC pts In 29% of MMR-deficient CRC pts PD-L1 expression is markedly enhanced in tumour cells in over 30% of CRC PD-L1 expression in MMR-proficient tumor micro-arrays was associated with early tumour stage, absence of lymph node metastases, lower tumor grade, absence of vascular invasion and a significantly improved 5-year survival 1491 corresponding tissue micro-arrays, 47.6% male, 34.9% right-sided tumors, mean tumor diameter was 4.75 cm, predominant tumor stage was pt3; overall 5-year survival was 56.4% Droeser RA et al. Eur J Cancer 2013 (49)
13 Increased PD-1 / PD-L1 Expression on Lymphocyte or on Tumor Cells in MSI-H type of CRC Methods: 87 CRC case (primary and metastatic); 60 MSS and 27 MSI-H PD-1 on lymphocytes and PD-L1 measured with commercial availbable Ab Colon cancer subtypes (n=87) PD-1 expression (TILs) (% and range) PD-L1 expression (tumor cells) (%) Concurrent PD-1/PD-L1 expression (%) MSS colon cancers (n=60) MSI-H colon cancers (n=27) 39% (1-11) 13% 4% 77% (1 - >20)* 38%* 32%* * Significantly higher (p=0.05) MSI-H cases were predominantly stage I and II (75%) whereas the majority of the MSS cases were at advanced stage (III and IV, 93%) (p<0.001) Therapy with immune checkpoint inhibitors needs to consider presence/location of PD-1 lymphocytes and PD-L1 expressing tumor cell Gatalica Z et al. J Clin Oncol 32:5s, 2014 (suppl; abstr 3625)
14 Pembrolizumab 2 Trial in Colorectal Cancer will use MSIstatus Status for Stratification Effectivity of Pembrolizumab in patients with MSI positive colon cancer (planned n= 25) patients with MSI negative colon cancer (planned n= 25) patients with other (small bowel, endometrial, gastric cancer) MSI positive cancers (planned n= 21) Pembrolizumab, 10mg/kg q2w Primary Endpoint: ir PFS / irorr rate at 20 weeks in patients with MSI positive and negative colorectal adenocarcinoma Correlative studies Exome sequencing, PD-L1 expression, immune infiltration analysis, ctdna biomarker analysis, peripheral blood lymphocyte characterization, antibody and proteomic analysis Sponsor: Sidney Kimmel Comprehensive Cancer Center Le TD et al. J Clin Oncol 32:5s, 2014 (suppl; abstr TPS3128)
15 Application of stimulated Immune Cells can booster the Host Immunsystem Mode of Action ClinTrialsGov # Status Cytokin induced killer cells (CIK) NCT Autologous NK, NKT NCT study has suspended participant recruitment NCT study is currently recruiting participants Anti-CD3 x Anti-Erbitux Armed Activated T Cells NCT study is currently recruiting participants Carcinoembryonic Antigen RNA-Pulsed, Autologous Human Cultured Dendritic Cells NCT study has been completed Carcinoembryonic Antigen-loaded Dendritic Cells NCT study has been completed Intranodal DC Vaccine in Patients With NY-ESO-1 Expressing Solid Tumors NCT study is currently recruiting participants autologous DC loaded with vaccinia-cea-muc-1-tricom (PANVAC- V) DC and fowlpox-cea-muc-1-tricom (PANVAC-F) vaccine NCT study has been completed Autologous DC Infected With CEA-6D Expressing Fowlpox-Tricom NCT study has been completed Dendritic Cell Immunotherapy NCT study is currently recruiting participants CEA a/o frameshift-derived neoantigens peptide-loaded DC NCT study is currently recruiting participants deplete patient's lymphocytes from regulatory T cells. Autologous Treg-depleted lymphocytes will be administered NCT study has been completed download May 30, 2014
16 Additional Ways to improve Immune Reactions Mode of Action ClinTrialsGov # Status CTLA-4 ipilimumab intratumorally study has suspended participant recruitment TLR-9 MGN1703 Maintenance Treatment in Patients With mcrc NCT study is not yet open for participant recruitment Enhance local inflammation Photodynamic NCT Vaccination CEA(6D) VRP Vaccine (AVX701) NCT study is currently recruiting participants NCT study has been completed Ad5[E1-,E2b-]-CEA Vaccine NCT study has been completed Cytokin application (interferon, CSF) Interferon NCT download May 30, 2014
17 Pembrolizumab will be developed in Monotherapy and Combinations in various other Tumors
18 The Opportunity: Targeting Immunomodulators Pembrolizumab MK-4166 Mellmann et al. Nature 2011 (480)
19 Merck seeks Collaboration to Target the Immune System in different Ways Nanobody technology Pazopanib T-Vec Axitinib IDO-1 inhibitor INCB24360
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