Checkpoint regulators a new class of cancer immunotherapeutics Dr Oliver Klein Medical Oncologist ONJCC Austin Health
Cancer...Immunology matters
Anti-tumour immune response The participants Dendritc cells NK cells CD8+T cells CD4+T cells B cells (Melman et al, 2012)
Hallmarks of Cancer (Weinberg, Cell 2000) (Weinberg, Cell 2011)
(Pardoll, 2012) Checkpoint Regulators The immunological synapse
Anti-CTLA-4 Antibodies Anti-PD-1/PD-L1 Antibodies Fong et al, 2008 Topalian et al, 2012 Ipilimumab - Yervoy Tremelimumab Nivolumab Pembrolizumab Pidilizumab MPDL3280A BMS935559 Medi4736
Ipilimumab Phase III trials 1. Delayed responses 2. Small percentage of long term survivors
Second-line 3mg/kg; no maintenance - reinduction Comparator arm peptide alone HLA-A2 MDX010-020
(Robert C, 2013) Ipilimumab - Reinduction
First line Chemotherapy combination 10mg/kg; maintenance MDX010-024
EAP CA 184-045 906 patients enrolled Included pat with ECOG2, brain metastases (27%), ocular (5%) and mucosal melanoma (4%) 10mg/kg dose with maintenance tx 20% Gde3/4 AE s 12% GI toxicity 4% Hepatotoxicity Survival 2 year 22% 3 year 17% (O Hamid, ASCO 2012)
Ipilimumab (Yervoy ) Response kinetics (Saenger YM et al., Cancer Immun, 2008) Do not look to early!
(Wolchok et al,2009) Immune related Response Criteria
(Wolchok J et al, 2013) Long term benefit
Immune related adverse events (irae) Dermatitis ~ 50% (Entero-)colitis ~ 15%
Immune related adverse events (irae) Uveitis ~1-2% Hypophysitis ~5%
(Wolchok,2010) Ipilimumab - Dose
Ipilimumab / NSCLC
Ipilimumab / Prostate cancer (Slovin et al, 2013) (Kwon et al, 2014)
Ipilimumab / Combination therapy Chemotherapy (Fotemustine/Temozolomide) Vaccines Radiotherapy Cytokines (INFα, GM-CSF) Checkpoint regulators (Nivolumab) Antiangiogenic agents (Bevacizumab) Oral tyrosine kinase inhibitors (Vemurafenib)
Ipilimumab Adjuvant therapy EORTC 18071
Predictive biomarker (Hamid, 2011) (Ku, 2010) (Wolchok, 2014)
TGA approved since July 2011 as monotherapy for patients with advanced/metastatic melanoma who have failed or are intolerant to prior therapy PBS reimbursed since August 2013 (reinduction permitted) PBS does not allow Ipilimumab treatment prior to BRAF inhibitor treatment in patients with BRAF mutated melanoma
PD-1/PD-L1 Nivolumab Pembrolizumab Pidilizumab BMS935559 MPDL3280A MEDI4736 (Topalian, 2012)
Nivolumab Fully human IgG4 anti-pd-1 antibody Administered every 2 weeks up to 96 weeks Dose escalation (0.1-0.3-1-3-10 mg/kg) with expansion cohorts Patients with metastatic melanoma, renal cell carcinoma, nonsmall cell lung cancer, castration refractory prostate cancer and colorectal cancer included Disease assessment every 2 months
Nivolumab 107 patients of melanoma cohort Longest follow up of any PD-1/PD-L1 trials 3Year OS ~ 40%!!
(Topalian S et al, 2014) Nivolumab
Nivolumab Phase III CheckMate 066 First line treatment in patients advanced metastatic BRAF wild type melanoma 418 patients Nivolumab 3mg/kg q2weekly vs DTIC 1000mg/m2 Stopped early as interim analysis demonstrated superior overall survival
Nivolumab Phase III- CheckMate 037 Randomized Phase III trial in previously treated patients with advanced/metastatic melanoma (Ipilimumab+/- Braf inhibitor) Nivolumab 3mg/kg q2weekly vs chemotherapy of investigators choice; 2:1 randomization; 370 patients 9%Grade 3/4 AEs with Nivolumab (Weber J, ESMO 2014)
Pembrolizumab Humanized monoclonal IgG4κ antibody No maximum tolerated dose reached 10mg/kg q2weekly, 10mg/kg or 2mg/kg q 3weekly
Pembrolizumab Keynote 01
Pembrolizumab Keynote 01 Update ASCO 2014 411 patients enrolled 221 prior Ipilimumab ORR (RECIST) 34% 40% Ipilimumab naive 28% Ipilimumab pre-treated Keynote06 Phase III Pembro q2weeks vs Pembro 3weeks vs Ipilimumab 3mg/kg
Pembrolizumab Keynote 01 NSCLC ASCO 2014 84 previously untreated patients with IV NSCLC Pembolizumab 10mg/kg q 3or 2 weeks ORR 26% (RECIST) ORR 47% (irrc) Adverse events comparable to melanoma cohort Keynote 024 First line PD-L1 positivity of tumour Versus platin doublet chemotherapy
Predictive Biomarker Not correct! PD-L1 expression enriches for responders; but still ~10% responders in PD-L1neg population
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
Tumour Type Ipilimumab PD-1/PD-L1 Ab Melanoma + + Renal Carcinoma + + Prostate carcinoma + - Colon carcinoma - - Bladder cancer? + Head and neck cancer _ + Ovarian cancer + +
Anti-CTLA-4/Anti-PD-1-The difference (Ribas, 2011) (Sznol,2011)
Nivolumab/Ipilimumab Combination 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 accural 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
Pembrolizumb Keytruda FDA approved in September 2014 for treatment of metastatic melanoma after failure of Ipilimumab +/- Braf inhibitor Available in Australia on patient access program on selected sites Nivolumab - Opdivo Approval in Japan for treatment of advanced melanoma Available in Australia on patient access program
Checkpoint regulators - more to come... (Melman et al,2011)
Challenges ahead How to best combine/sequence new agents? (Melanoma, NSCLC, RCC) Are new agents active in the adjuvant therapy setting? No biomarkers for immunotherapy agents identified Funding!!!!!