Immunotherapy and Targeted Therapies: The new face of cancer treatment

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1 Immunotherapy and Targeted Therapies: The new face of cancer treatment Abdulazeez Salawu MBBS, MSc, PhD, MRCP Academic Clinical Lecturer Weston Park Hospital, Sheffield

2 Novel Systemic Anti-cancer Therapies what they are how they work decision making pre-treatment

3 The future cancer burden 1 in 2 cancer Ageing population 70% with complex co-morbidities Improved survival Patients with metastatic disease are living longer

4 Cancer Hallmarks

5 Treating Cancer Local Strategies Surgery Radiotherapy Systemic Strategies Cytotoxic Chemotherapy Targeted Agents Hormone Targeted Molecular Targeted Immune Targeted

6 Molecular Targeted Therapies Drugs that act on specific molecular alterations (in cancer, but not normal cells) Typically: monoclonal antibodies, or small molecule inhibitors

7 Molecular Targeted Therapies Form the basis for Precision Oncology whereby, molecular characteristics of an individual s tumour to tailor personalised treatment right patient' right treatment' right time'

8 Precision Oncology Biomarkers Roychodhury S, Chinnaiyan AM (2014) Annu. Rev. Gemonics. Hum. Genet. 15:

9 Signalling Molecules/Pathways

10 Molecular-targeted Agents

11 Molecular-targeted Agents

12 MAbs: nomenclature Prefix: varies, no special meaning 1st infix: target (e.g. tum - tumour) 2nd infix: source (e.g. o - mouse, xi - chimeric, zu - humanised, u - human) Suffix: -mab Ce-tu-xi-mab: chimeric Mab against tumour

13 Examples of nomenclature Tosi-tum-o-mab: mouse Mab against tumour Ri-tu-xi-mab: chimeric Mab against tumour Tras-tu-zu-mab: humanised Mab against tumour Pani-tum-u-mab: human Mab against tumour Ipil-im-u-mab: human Mab against immune system Vemurafenib: inhibitor against B-raf protein

14 Some (Mab) Targeted treatments in clinical use Trastuzumab (Herceptin): anti-her2-neu Cetuximab (Erbitux): anti-egfr Panitumumab : anti-egfr Denosumab (Xgeva): anti-rankl

15 Small Molecule Inhibitors: nomenclature Less strict Some of them have wide ranging targets (e.g. pazopanib, sunitinib) Prefix: varies, no special meaning Sometimes, Infix: target (e.g. RAF B-raf Pathway), or Suffix: Tyrosine kinase inhibition sub stem -tinib (i.e., imatinib) Proteasome inhibition -zomib (i.e., bortezomib) Cyclin-dependent kinase inhibition -ciclib (i.e., palbociclib, ribociclib)

16 Non Small Cell Lung Cancer (NSCLC)

17 Non Small Cell Lung Cancer (NSCLC) Frequency of gene mutations observed in NSCLC

18 Signalling Pathways - NSCLC

19 Non Small Cell Lung Cancer (NSCLC) EGFR mutations Found in 10% - 15% of all lung cancer patients and 85% who clinically respond to EGFR TKIs Found more commonly in never-smokers, adenocarcinomas, BAC, women, Asians Predominantly located in EGFR exons % of EGFR mutations are either deletion exon 19 or L858 mutation EGFR mutations are not the same. There are sensitive mutations and acquired resistance mutations (T790M).

20 Response to EGFR targeting in NSCLC

21 Non Small Cell Lung Cancer (NSCLC) Crizotinib is clinically effective in EML4-ALK NSCLC

22 Colorectal Cancer

23 Signalling Pathways Colorectal Cancer

24 Colorectal Cancer

25 Signalling Pathways Breast cancer Palbociclib Ribociclib

26 Breast Cancer

27 Cancer Hallmarks

28 Immunotherapy Start clinical trials with anti-ctla-4

29 Immunotherapy

30 Immunotherapy Checkpoint Inhibitors Nivolumab Pembrolizuma b Avelumab Darvalumab Atezolizumab Ipilimumab Tremelimuma b

31 Overall survival (%) Evidence for combination in melanoma Nivolumab + ipilimumab regimen: OS vs nivolumab and ipilimumab monotherapies at 3 years 1 CheckMate NIVO + IPI (N=314) NIVO (N=316) IPI (N=315) Median OS, mo (95% CI) NR (38.2 NR) (29.1 NR) 19.9 ( ) % 59% 45% HR (95% CI) vs. IPI* 0.55 ( ) 0.65 ( ) -- HR (95% CI) vs. NIVO 0.85 ( ) % 52% 34% NIVO + IPI NIVO IPI *p< Months No. at risk: Time (months) NIVO + IPI NIVO IPI Adapted from Wolchok et al 2017 Median follow-up of 36 months in both nivolumab-containing arms. Database lock. May 24, Wolchok JD, et al. N Engl J Med doi: /NEJMoa

32 Objective response rate (%) Evidence for combination in melanoma CheckMate 067 Nivolumab + ipilimumab regimen: Ongoing objective responses after minimum follow up of 36 months ORR 58% (95% CI: 53 64) CR 19.4% ITT population, secondary endpoint ORR 44% (95% CI: 39 50) CR 16.5% ORR 19% (95% CI: 15 24) 20 0 PR 38.9% PR 27.8% CR 5.1% PR 13.7% Nivolumab + ipilimumab (n=314) Nivolumab (n=316) Ipilimumab (n=315) Adapted from Wolchok et al 2017 Median DoR not reached for either nivolumab-containing group after a median follow-up of 36 months (median DoR for ipilimumab: 19.3 months, 95% CI [8.3 NR]) Tumour response was assessed according to RECIST v1.1. Database lock: May 24, 2017 (median follow-up of 36 months in both nivolumab-containing arms). CR, complete response; ITT, intention-to-treat; PR, partial response. 1. Wolchok JD, et al. N Engl J Med doi: /NEJMoa

33 Immunotherapy Indications Melanoma TNBC NSCLC Ovarian Renal Cell Oesophageal Hepatocellular Immune Checkpoint Inhibitors Bladder Cancer HNSCC Mesothelioma Hodgkin's B-Cell NHL Gastric Colorectal MSI-H

34 New/Emerging Immune Checkpoint Inhibitors

35 Costs Ipilimumab 3-weekly doses x 4 19,548 x 4 = 78,192 Pembrolizumab 3-weekly doses until progression 5054 x 35 = 176,890 Nivolumab 2-weekly doses until progression 4738 x 52 = 246,376 Plus OPA, chair time, inpatient beds, supportive measures eg infliximab ( 778 per dose) *Duration studies are coming*

36 Other Limitations and Challenges Funding - genomic analysis has become much cheaper but remains expensive Identification of Biomarker Why do some people not respond