Immunotherapy and Targeted Therapies: The new face of ......Molecular Targeted Therapies • Form...
Transcript of Immunotherapy and Targeted Therapies: The new face of ......Molecular Targeted Therapies • Form...
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 treatment' ‘right patient'
‘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
KeyKeyKeyKey events in events in events in events in thethethethe historyhistoryhistoryhistory of of of of cancercancercancercancer immunotherapyimmunotherapyimmunotherapyimmunotherapy
Start clinical trials
withanti-CTLA-4
Immunotherapy
Immunotherapy – Checkpoint Inhibitors
Ipilimumab
Tremelimuma
b
Nivolumab
Pembrolizuma
b
Avelumab
Darvalumab
Atezolizumab
Evidence for combination in melanoma
Nivolumab + ipilimumab regimen: OS vs nivolumab and ipilimumab monotherapies at 3 years1
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.
CheckMate 067
Ove
rall
su
rviv
al
(%)
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 0NIVO 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
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)
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) -- --
Months
100
80
60
40
20
042153 6 9 12 27 30 3321 24 36 39 43 480 18
NIVO
NIVO + IPI
IPI
*p<0.001
34%
52%
58%
45%
59%
64%
Adapted from Wolchok et al 2017
Evidence for combination in melanoma
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])
Nivolumab + ipilimumab regimen: Ongoing objective responses after minimum follow up of 36 months1
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.
CheckMate 067
Adapted from Wolchok et al 2017
ITT population, secondary endpoint100
80
60
40
20
0
Ob
jective
re
sp
on
se
ra
te (
%)
Nivolumab + ipilimumab
(n=314)
Nivolumab
(n=316)
Ipilimumab
(n=315)
PR 38.9%
CR 19.4%
ORR
58% (95% CI: 53–64)
PR 27.8%
CR 16.5%
ORR
44% (95% CI: 39–50)
PR 13.7%
CR 5.1%
ORR
19% (95% CI: 15–24)
Immunotherapy Indications
Immune Checkpoint Inhibitors
Melanoma
NSCLC
Renal Cell
Bladder Cancer
HNSCC
Hodgkin's
Colorectal
MSI-HGastric
B-Cell NHL
Mesothelioma
Hepatocellular
Oesophageal
Ovarian
TNBC
New/Emerging Immune Checkpoint Inhibitors
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*
Costs
Other Limitations and Challenges
• Funding - genomic analysis has become much cheaper
but remains expensive
• Identification of Biomarker
• Why do some people not respond