Immunotherapy and Targeted Therapies: The new face of cancer treatment Abdulazeez Salawu MBBS, MSc, PhD, MRCP Academic Clinical Lecturer Weston Park Hospital, Sheffield
Novel Systemic Anti-cancer Therapies what they are how they work decision making pre-treatment
The future cancer burden 1 in 2 cancer Ageing population 70% with complex co-morbidities Improved survival Patients with metastatic disease are living longer
Cancer Hallmarks
Treating Cancer Local Strategies Surgery Radiotherapy Systemic Strategies Cytotoxic Chemotherapy Targeted Agents Hormone Targeted Molecular Targeted Immune Targeted
Molecular Targeted Therapies Drugs that act on specific molecular alterations (in cancer, but not normal cells) Typically: monoclonal antibodies, or small molecule inhibitors
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'
Precision Oncology Biomarkers Roychodhury S, Chinnaiyan AM (2014) Annu. Rev. Gemonics. Hum. Genet. 15:395-415
Signalling Molecules/Pathways
Molecular-targeted Agents
Molecular-targeted Agents
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
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
Some (Mab) Targeted treatments in clinical use Trastuzumab (Herceptin): anti-her2-neu Cetuximab (Erbitux): anti-egfr Panitumumab : anti-egfr Denosumab (Xgeva): anti-rankl
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)
Non Small Cell Lung Cancer (NSCLC)
Non Small Cell Lung Cancer (NSCLC) Frequency of gene mutations observed in NSCLC
Signalling Pathways - NSCLC
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 19-21 85% 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).
Response to EGFR targeting in NSCLC
Non Small Cell Lung Cancer (NSCLC) Crizotinib is clinically effective in EML4-ALK NSCLC
Colorectal Cancer
Signalling Pathways Colorectal Cancer
Colorectal Cancer
Signalling Pathways Breast cancer Palbociclib Ribociclib
Breast Cancer
Cancer Hallmarks
Immunotherapy Start clinical trials with anti-ctla-4
Immunotherapy
Immunotherapy Checkpoint Inhibitors Nivolumab Pembrolizuma b Avelumab Darvalumab Atezolizumab Ipilimumab Tremelimuma b
Overall survival (%) Evidence for combination in melanoma Nivolumab + ipilimumab regimen: OS vs nivolumab and ipilimumab monotherapies at 3 years 1 CheckMate 067 100 NIVO + IPI (N=314) NIVO (N=316) IPI (N=315) Median OS, mo (95% CI) NR (38.2 NR) 37.6. (29.1 NR) 19.9 (16.9 24.6) 80 60 40 20 64% 59% 45% HR (95% CI) vs. IPI* 0.55 (0.45 0.69) 0.65 (0.53 0.80) -- HR (95% CI) vs. NIVO 0.85 (0.68 1.07) -- -- 58% 52% 34% NIVO + IPI NIVO IPI *p<0.001 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 43 48 Months No. at risk: Time (months) 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 NIVO + IPI 314 292 265 247 226 221 209 200 198 192 186 180 177 131 27 3 0 NIVO 316 292 265 244 230 213 201 191 181 175 171 163 156 120 28 0 0 IPI 315 285 253 227 203 181 163 148 135 128 117 107 100 68 20 2 0 Adapted from Wolchok et al 2017 Median follow-up of 36 months in both nivolumab-containing arms. Database lock. May 24, 2017. 1. Wolchok JD, et al. N Engl J Med. 2017. doi: 10.1056/NEJMoa1709684.
Objective response rate (%) Evidence for combination in melanoma CheckMate 067 Nivolumab + ipilimumab regimen: Ongoing objective responses after minimum follow up of 36 months 1 100 80 60 40 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. 2017. doi: 10.1056/NEJMoa1709684.
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
New/Emerging Immune Checkpoint Inhibitors
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*
Other Limitations and Challenges Funding - genomic analysis has become much cheaper but remains expensive Identification of Biomarker Why do some people not respond