Checkpoint Regulators Cancer Immunotherapy takes centre stage. Dr Oliver Klein Department of Medical Oncology 02 May 2015

Transcription

1 Checkpoint Regulators Cancer Immunotherapy takes centre stage Dr Oliver Klein Department of Medical Oncology 02 May 2015

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3 Adjuvant chemotherapy improves outcome in early breast cancer FDA approval of Imatinib for CML FDA approval of Bevacizumab FDA approval of Nivolumab Combination chemotherapy cures lymphoma FDA approval of the monoclonal antibody Rituximab FDA approval of Ipilimumab Identification of EGFR mutation in lung cancer Chemotherapy Tumour specific monoclonal antibody Molecular targeted therapy Anti-angiogenic therapy Immunotherapy

4 Cancer Immunology matters 1 Immunosuppression leads to an increase in cancer incidence

5 Cancer Immunology matters 2 Tumour infiltrating lymphocytes are prognostic

6 Cancer Immunology matters 3 Transfer of tumour infiltrating lymphocytes leading to tumour regression

7 Anti-tumour immune response The participants Dendritc cells NK cells CD8+T cells CD4+T cells B cells (Melman et al, 2012)

8 Checkpoint regulators Antigen-presenting cell or Tumour cell CD8+ or CD4+T cell

9 Immuno-oncology cycle Anti-CTLA-4 Anti-PD-1/PD-L1 Ipilimumab Tremelimumab Nivolumab Pembolizumab MPDL3280A

10 Checkpoint blockade demonstrates efficacy in a wide range of malignancies Tumour Type Ipilimumab PD-1/PD-L1 Ab Melanoma + + Renal Carcinoma + + Prostate carcinoma + - Colon carcinoma - - Gastric cancer? + NSCLC + + Breast cancer- triple neg? + Bladder cancer + + Head and neck cancer? + Ovarian cancer + + Hodgkin Lymphoma? + B cell Non-Hodgkin Lymphoma? +

11 Anti-CTLA-4 blockade and anti-pd-1/pd-l1 blockade differ Ipilimumab Nivolumab/Pembrolizumb Response Rate 10-15% 30-40% Clinical Benefit rate 20-30% 50-60% Grade3/4 AEs ~30% ~10% Response Onset Delayed ~50% at week8

12 Key features of checkpoint regulators compared to other cancer therapeutics Disease response pattern delayed responses Durable responses Unique toxicity -Immune related adverse events

13 Response pattern Ipilimumab Nivolumab (Saenger Y, 2008) (Weber JS, 2015)

14 Durable responses Ipilimumab Nivolumab 3Year OS ~ 40%!! (Schadendorf D, 2015) (Topalian SL, 2014)

15 Immune related adverse events Dermatitis Entero-colitis Hepatitis Endocrinopathies

16 Rare immune related adverse events 58 year old lady with metastatic melanoma who failed treatment with the anti-pd-1 antibody Nivolumab Commenced on 4x3weekly infusions of Ipilimumab Patient presents with severe shortness of breathe Significant clinical improvement after high dose steroid treatment Sep 2014 Dec 2014 Jan 2015

17 Predictive biomarker (Ku, 2010) (Wolchok J, 2014) (Topalian SL, 2012)

18 Nivolumab Fully human IgG4 anti-pd-1 antibody Administered every 2 weeks up to 96 weeks Dose escalation ( mg/kg) with expansion cohorts Patients with metastatic melanoma, renal cell carcinoma, non-small cell lung cancer, castration refractory prostate cancer and colorectal cancer included Disease assessment every 2 months

19 PD-L1 expression on tumour cells as a biomarker Trial Tumour type % PD-L1 Positivity ORR/CBR CheckMate 037 Melanoma 50% (5% cut off) PD-L1+ 44% PD-L1-20% CheckMate 066 Melanoma 35% (5% cut off) PD-L1+ 53% PD-L1-33% CheckMate 063 NSCLC/squamous 33% (5% cut off) PD-L1+ 48% PD-L1-34% CA RCC 27% (5% cut off) PD-L1+ 31% PD-L1-18% Different antibodies (Specificity/sensitivity?) Different definition of PD-L1 positivity Dynamic expression

20 Current anti-pd-1/pd-l1 phase III trials NSCLC CheckMate 026: Nivo vs chemotherapy PD-L1+ required KEYNOTE 042: Pembro vs chemotherapy PD-L1+ required KEYNOTE 010: second line Pembro vs Docetaxel PD-L1 +required MPDL3280A: 3x first line trials + 1 second line (OAK) PD-L1+ not required RCC CheckMate 214: Nivo/Ipi vs Sunitinib PD-L1 + not required CheckMate 025: Nivo vs Everolimus PD-L1 + not required Bladder Ca KEYNOTE 045: Pembro vs chemo PD-L1 + not required MPDL3280A: second line vs chemo- PD-L+ not required Gastric Ca KEYNOTE 061: second line vs Paclitaxel PD-L1 + not required

21 PD-L1 expression as a surrogate for immune cell rich microenvironment

22 Keynote 006 Checkmate 037 Immune cell poor Immune cell rich Checkmate 066

23 (Powles T, 2014) Resistance to anti-pd-1/pd-l1 agents

24 Tumor burden matters Immunological ignorance spontaneous Remission Regulatory T cells Myeloid derived suppressor cells (Powles et al, 2014) (Kwon et al, 2014)

25 Combination approaches Immune- Stimulatory Abs Targeted therapy Anti-PD-1/PD-L1 antibodies Radiotherapy Chemotherapy

26 CheckMate 066 (single agent Nivolumab) Immune- Stimulatory Abs

27 Targeted therapy (Knight DA et al, 2013) (Wilmott JS, 2012)

28 Radiotherapy (Twyman Saint Victor et al, 2015) + anti-pd-1 Ab (Postow MA et al, 2012)

29 (Zitvogel L et al, 2008) Chemotherapy

30 Combination trials Update ASCO/ESMO 2014 ORR 42% - 17%CR (RECIST) 2 year OS 79% (Ipilimumab 24% - Nivolumab 43%) Phase III trial (CheckMate 067) Ipi vs Nivo vs Nivo/Ipi closed to accrual Renal cell carcinoma Phase 1: 44 patients (untreated or previously treated ORR 43% N3/Ipi1; ORR 48% N1/Ipi3 Checkpoint regulators + oral targeted agents RCC: Nivolumab + Sunitinib or Pazopanib- ~50% ORR Melanoma: Ipilimumab + Vemurafenib or Ipilimumab +dabrafenib

31 Checkpoint regulators - more to come...