Immunotherapy Treatment Developments in Medical Oncology

Transcription

1 Immunotherapy Treatment Developments in Medical Oncology A/Prof Phillip Parente Director Cancer Services Eastern Health Executive MOGA ATC Medical Oncology RACP

2 Summary of The Desired T-cell Response to Tumours APC T-cells T-cell 1 - T-cell activation 2 - T-cell proliferation T-cells T-cells Tumour Destroyed tumour cells 3 - Infiltration of tumour site 4 - Tumour cell destruction However tumours have the ability to evade the immune system, and T-cell activation is under regulatory control. Immunotherapeutic strategies aim to enhance this natural response 2

3 T-Cell Activation Requires Two Signals Signal 1: Antigen recognition 1 The TCR recognises and binds to the antigen peptide MHC complex on the APC This initial signal (signal 1) is insufficient for full T-cell activation APC TCR Non-activated T- cell Peptide-MHC complex Signal 1 1 Sharpe AH & Abbas AK. N Engl J Med 2006; 355(10):

4 T-Cell Activation Requires Two Signals Signal 2: Co-stimulation 1 The co-stimulatory receptor CD-28 on the T-cell s surface interacts with the B7 molecule on the APC s surface This co-stimulation results in activation of the T-cell TCR APC Peptide MHC complex B7 molecule CD-28 Activated T-cell Signals 1 and 2 1 Sharpe AH & Abbas AK. N Engl J Med 2006; 355(10):

5 Summary of the Mode of Action of CTLA-4 in the Immune Response to Tumours Peptide MHC complex B7 APC T-cell TCR CTLA-4 CD-28 Peptide MHC complex B7 molecule Signal 1 TCR CTLA-4 CD-28 Inhibitory signal Binding of B7 to CTLA-4 instead of CD-28 prevents co-stimulatory signalling and induces an inhibitory effect on T-cell activation and proliferation Gabriel EM & Lattime EC. Clin Cancer Res 2007; 13 (3):

6 Immunotherapy

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8 Checkpoint Inhibitor PD1 Programmed death 1 (PD-1) protein is another T-cell coinhibitory receptor with a structure similar to that of CTLA-4 but with a distinct biologic function and ligand specificity. has two known ligands, PD-L1 and PD-L2 In contrast to CTLA-4 ligands (CD80 and CD 86), PD-L1 is selectively expressed on many tumors and on cells within the tumor microenvironment in response to inflammatory stimuli. Blockade of the interaction between PD-1 and PD-L1 potentiates immune responses and mediates preclinical antitumor activity. PD-L1 is the primary PD-1 ligand that is up-regulated in solid tumors, were it can inhibit cytokine production and the cytolytic activity of PD-1+, tumor-infiltrating CD4+ and CD8+ T cells.

9 Clinical Applications PBS Listing Melanoma PD1 Inhibitors (Pembroluzimab & Nivolumab) 1 st Line BRAF wildtype Metastatic Melanoma 2 nd Line BRAF mutant Metastatic Melanoma CTLA 4 inhibtors (ipilumaumab) Combination PD 1 Inhibitors Nivolumab in high burden disease high LDH 2 nd Line/3 rd Line therapy Positive PBAC recommendation PD 1 Inhibitor Nivolumab 2 nd Line Metastatic Adeno or Squamous Cell Carcinoma of Lung 2 nd Line Metastatic Clear Cell Renal Cell Carcinoma Clinical Trials Lymphoma, Colorectal, Mesothelioma, Hepatoma, Gastric, Breast, Prostate

10 PD1 inhibitors Key Phase III trials CheckMate 066 (Robert C et al, NEJM 2015) Nivo vs DTIC KEYNOTE 006 (Robert C et al NEJM 2015) Pembro q2w vs Pembro q3w vs Ipi q3w CheckMate 067 (Larkin J et al NEJM 2015) Ipi plus nivo vs nivo vs ipi

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12 Nivolumab alone Nivolumab + ipilimumab Ipilimumab alone

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14 Updated OS April 2017 AACR 2yr OS Ipi Nivo Nivo Ipi BRAF WT 61% 57% 42% BRAF mutant 71% 62% 51% PDL1 < 5% 63% 55% 41% PDL1 > 5% 68% 72% 54%

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17 NSCLC Nivolumab Studies

18 Checkmate 017 / 057 Phase III RCT, ITT analysis ECOG 0 1 Stable brain mets okay Autoimmune disease, symptomatic ILD, immunosuppression excluded Primary end point: OS Secondary end points: PFS, efficacy according to PD L1 expression

19 Overall survival Checkmate 017 Checkmate 057 Median OS 9.2 vs year survival 42% vs 24% HR 0.59 ( ) Median OS 12.2 vs 9.4 HR 0.73 ( ) p=0.002

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21 Immune Related Adverse Events (IRAEs) Grade III/IV IRAEs generally reversible & most treated with standard anti-inflammatory therapies i.e. Corticosteroids. Immunosuppression with mycophenalate maybe required. Grade IV colitis may require prolonged steroid administration, TNF blockade with infliximab or prolonged bowel rest with TPN. Vast majority of Grade III/IV IRAEs will resolve completely after systemic immunosuppression that is sometimes prolonged. Steroids need to be weaned very slowly or high risk of rebound autoimmune adverse event. Wean over 12 weeks with Bactrim Prophylaxis Ipilimumab treated patients experiencing Grade III/IV IRAEs had a significantly higher rate of tumour regression then those without IRAEs Multiple IRAEs may occur

22 YERVOY Signs and symptoms of iraes Gastrointestinal Monitor for symptoms indicative of immunerelated colitis, diarrhoea or GI perforation including: Increased frequency of bowel movements Diarrhoea Abdominal pain Blood in stool Fever Hepatic Monitor for elevations in liver function tests (LFTs) with or without clinical symptoms: AST >5 x ULN ALT >5 x ULN Bilirubin >3 x ULN NOTE: LFTs must be checked prior to each infusion (summary) Neurological Motor neuropathy Muscle weakness Sensory neuropathy Rare reports of fatal Guillain-Barré syndrome and myasthenia gravis-like symptoms Endocrine May present with non-specific symptoms: Headache Fatigue Visual field defects Behavioural changes Electrolyte disturbances Hypotension Adrenal crisis (severe dehydration, hypotension, shock) Skin Pruritus Rash Erythema Vitiligo Rare reports of fatal toxic epidermal necrolysis, Steven-Johnson Syndrome iraes can affect any organ: Reported but uncommon iraes include uveitis, eosinophilia, lipase elevation, pneumonitis and glomerulonephritis Myocarditis associated with influenza vaccine

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55 Summary IRAEs Always consider IRAE in unwell pts who are on or have had checkpoint inhibitors Pts require education concerning presentation to ED esp. > 5 bowel actions/day Prolonged tapir of records Bactrim Prophylaxis Multiple IRAE are common IRAE high correlation with tumour responses