Immunotherapy and Targeted Therapies: The new face of cancer … and... · 2020-03-04 · Molecular...
Transcript of Immunotherapy and Targeted Therapies: The new face of cancer … and... · 2020-03-04 · Molecular...
![Page 1: Immunotherapy and Targeted Therapies: The new face of cancer … and... · 2020-03-04 · Molecular Targeted Therapies • Form the basis for Precision Oncology whereby, • molecular](https://reader033.fdocuments.us/reader033/viewer/2022050117/5f4d94a268593756d475da9c/html5/thumbnails/1.jpg)
Immunotherapy and Targeted Therapies:
The new face of cancer treatment
Abdulazeez Salawu MBBS, MSc, PhD, MRCP
Academic Clinical Lecturer
Weston Park Hospital, Sheffield
![Page 2: Immunotherapy and Targeted Therapies: The new face of cancer … and... · 2020-03-04 · Molecular Targeted Therapies • Form the basis for Precision Oncology whereby, • molecular](https://reader033.fdocuments.us/reader033/viewer/2022050117/5f4d94a268593756d475da9c/html5/thumbnails/2.jpg)
Novel Systemic Anti-cancer Therapies
• what they are
• how they work
• decision making pre-treatment
![Page 3: Immunotherapy and Targeted Therapies: The new face of cancer … and... · 2020-03-04 · Molecular Targeted Therapies • Form the basis for Precision Oncology whereby, • molecular](https://reader033.fdocuments.us/reader033/viewer/2022050117/5f4d94a268593756d475da9c/html5/thumbnails/3.jpg)
The future cancer burden
• 1 in 2 cancer
• Ageing population
• 70% with complex co-morbidities
• Improved survival
• Patients with metastatic disease are living longer
![Page 4: Immunotherapy and Targeted Therapies: The new face of cancer … and... · 2020-03-04 · Molecular Targeted Therapies • Form the basis for Precision Oncology whereby, • molecular](https://reader033.fdocuments.us/reader033/viewer/2022050117/5f4d94a268593756d475da9c/html5/thumbnails/4.jpg)
Cancer Hallmarks
![Page 5: Immunotherapy and Targeted Therapies: The new face of cancer … and... · 2020-03-04 · Molecular Targeted Therapies • Form the basis for Precision Oncology whereby, • molecular](https://reader033.fdocuments.us/reader033/viewer/2022050117/5f4d94a268593756d475da9c/html5/thumbnails/5.jpg)
Treating Cancer
Local Strategies
• Surgery
• Radiotherapy
Systemic Strategies
• Cytotoxic Chemotherapy
• Targeted Agents
• Hormone Targeted
• Molecular Targeted
• Immune Targeted
![Page 6: Immunotherapy and Targeted Therapies: The new face of cancer … and... · 2020-03-04 · Molecular Targeted Therapies • Form the basis for Precision Oncology whereby, • molecular](https://reader033.fdocuments.us/reader033/viewer/2022050117/5f4d94a268593756d475da9c/html5/thumbnails/6.jpg)
Molecular Targeted Therapies
• Drugs that act on specific molecular
alterations (in cancer, but not normal cells)
• Typically:
• monoclonal antibodies, or
• small molecule inhibitors
![Page 7: Immunotherapy and Targeted Therapies: The new face of cancer … and... · 2020-03-04 · Molecular Targeted Therapies • Form the basis for Precision Oncology whereby, • molecular](https://reader033.fdocuments.us/reader033/viewer/2022050117/5f4d94a268593756d475da9c/html5/thumbnails/7.jpg)
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'
![Page 8: Immunotherapy and Targeted Therapies: The new face of cancer … and... · 2020-03-04 · Molecular Targeted Therapies • Form the basis for Precision Oncology whereby, • molecular](https://reader033.fdocuments.us/reader033/viewer/2022050117/5f4d94a268593756d475da9c/html5/thumbnails/8.jpg)
Precision Oncology
Biomarkers
Roychodhury S, Chinnaiyan AM (2014)
Annu. Rev. Gemonics. Hum. Genet. 15:395 - 415
![Page 9: Immunotherapy and Targeted Therapies: The new face of cancer … and... · 2020-03-04 · Molecular Targeted Therapies • Form the basis for Precision Oncology whereby, • molecular](https://reader033.fdocuments.us/reader033/viewer/2022050117/5f4d94a268593756d475da9c/html5/thumbnails/9.jpg)
Signalling Molecules/Pathways
![Page 10: Immunotherapy and Targeted Therapies: The new face of cancer … and... · 2020-03-04 · Molecular Targeted Therapies • Form the basis for Precision Oncology whereby, • molecular](https://reader033.fdocuments.us/reader033/viewer/2022050117/5f4d94a268593756d475da9c/html5/thumbnails/10.jpg)
Molecular-targeted Agents
![Page 11: Immunotherapy and Targeted Therapies: The new face of cancer … and... · 2020-03-04 · Molecular Targeted Therapies • Form the basis for Precision Oncology whereby, • molecular](https://reader033.fdocuments.us/reader033/viewer/2022050117/5f4d94a268593756d475da9c/html5/thumbnails/11.jpg)
Molecular-targeted Agents
![Page 12: Immunotherapy and Targeted Therapies: The new face of cancer … and... · 2020-03-04 · Molecular Targeted Therapies • Form the basis for Precision Oncology whereby, • molecular](https://reader033.fdocuments.us/reader033/viewer/2022050117/5f4d94a268593756d475da9c/html5/thumbnails/12.jpg)
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
![Page 13: Immunotherapy and Targeted Therapies: The new face of cancer … and... · 2020-03-04 · Molecular Targeted Therapies • Form the basis for Precision Oncology whereby, • molecular](https://reader033.fdocuments.us/reader033/viewer/2022050117/5f4d94a268593756d475da9c/html5/thumbnails/13.jpg)
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
![Page 14: Immunotherapy and Targeted Therapies: The new face of cancer … and... · 2020-03-04 · Molecular Targeted Therapies • Form the basis for Precision Oncology whereby, • molecular](https://reader033.fdocuments.us/reader033/viewer/2022050117/5f4d94a268593756d475da9c/html5/thumbnails/14.jpg)
Some (Mab) Targeted treatments in clinical use
• Trastuzumab (Herceptin): anti-Her2-neu
• Cetuximab (Erbitux): anti-EGFR
• Panitumumab : anti-EGFR
• Denosumab (Xgeva): anti-RANKL
![Page 15: Immunotherapy and Targeted Therapies: The new face of cancer … and... · 2020-03-04 · Molecular Targeted Therapies • Form the basis for Precision Oncology whereby, • molecular](https://reader033.fdocuments.us/reader033/viewer/2022050117/5f4d94a268593756d475da9c/html5/thumbnails/15.jpg)
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)
![Page 16: Immunotherapy and Targeted Therapies: The new face of cancer … and... · 2020-03-04 · Molecular Targeted Therapies • Form the basis for Precision Oncology whereby, • molecular](https://reader033.fdocuments.us/reader033/viewer/2022050117/5f4d94a268593756d475da9c/html5/thumbnails/16.jpg)
Non Small Cell Lung Cancer (NSCLC)
![Page 17: Immunotherapy and Targeted Therapies: The new face of cancer … and... · 2020-03-04 · Molecular Targeted Therapies • Form the basis for Precision Oncology whereby, • molecular](https://reader033.fdocuments.us/reader033/viewer/2022050117/5f4d94a268593756d475da9c/html5/thumbnails/17.jpg)
Non Small Cell Lung Cancer (NSCLC)
Frequency of gene mutations observed in NSCLC
![Page 18: Immunotherapy and Targeted Therapies: The new face of cancer … and... · 2020-03-04 · Molecular Targeted Therapies • Form the basis for Precision Oncology whereby, • molecular](https://reader033.fdocuments.us/reader033/viewer/2022050117/5f4d94a268593756d475da9c/html5/thumbnails/18.jpg)
Signalling Pathways - NSCLC
![Page 19: Immunotherapy and Targeted Therapies: The new face of cancer … and... · 2020-03-04 · Molecular Targeted Therapies • Form the basis for Precision Oncology whereby, • molecular](https://reader033.fdocuments.us/reader033/viewer/2022050117/5f4d94a268593756d475da9c/html5/thumbnails/19.jpg)
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).
![Page 20: Immunotherapy and Targeted Therapies: The new face of cancer … and... · 2020-03-04 · Molecular Targeted Therapies • Form the basis for Precision Oncology whereby, • molecular](https://reader033.fdocuments.us/reader033/viewer/2022050117/5f4d94a268593756d475da9c/html5/thumbnails/20.jpg)
Response to EGFR targeting in NSCLC
![Page 21: Immunotherapy and Targeted Therapies: The new face of cancer … and... · 2020-03-04 · Molecular Targeted Therapies • Form the basis for Precision Oncology whereby, • molecular](https://reader033.fdocuments.us/reader033/viewer/2022050117/5f4d94a268593756d475da9c/html5/thumbnails/21.jpg)
Non Small Cell Lung Cancer (NSCLC)
Crizotinib is clinically effective in EML4-ALK NSCLC
![Page 22: Immunotherapy and Targeted Therapies: The new face of cancer … and... · 2020-03-04 · Molecular Targeted Therapies • Form the basis for Precision Oncology whereby, • molecular](https://reader033.fdocuments.us/reader033/viewer/2022050117/5f4d94a268593756d475da9c/html5/thumbnails/22.jpg)
Colorectal Cancer
![Page 23: Immunotherapy and Targeted Therapies: The new face of cancer … and... · 2020-03-04 · Molecular Targeted Therapies • Form the basis for Precision Oncology whereby, • molecular](https://reader033.fdocuments.us/reader033/viewer/2022050117/5f4d94a268593756d475da9c/html5/thumbnails/23.jpg)
Signalling Pathways – Colorectal Cancer
![Page 24: Immunotherapy and Targeted Therapies: The new face of cancer … and... · 2020-03-04 · Molecular Targeted Therapies • Form the basis for Precision Oncology whereby, • molecular](https://reader033.fdocuments.us/reader033/viewer/2022050117/5f4d94a268593756d475da9c/html5/thumbnails/24.jpg)
Colorectal Cancer
![Page 25: Immunotherapy and Targeted Therapies: The new face of cancer … and... · 2020-03-04 · Molecular Targeted Therapies • Form the basis for Precision Oncology whereby, • molecular](https://reader033.fdocuments.us/reader033/viewer/2022050117/5f4d94a268593756d475da9c/html5/thumbnails/25.jpg)
Signalling Pathways – Breast cancer
Palbociclib
Ribociclib
![Page 26: Immunotherapy and Targeted Therapies: The new face of cancer … and... · 2020-03-04 · Molecular Targeted Therapies • Form the basis for Precision Oncology whereby, • molecular](https://reader033.fdocuments.us/reader033/viewer/2022050117/5f4d94a268593756d475da9c/html5/thumbnails/26.jpg)
Breast Cancer
![Page 27: Immunotherapy and Targeted Therapies: The new face of cancer … and... · 2020-03-04 · Molecular Targeted Therapies • Form the basis for Precision Oncology whereby, • molecular](https://reader033.fdocuments.us/reader033/viewer/2022050117/5f4d94a268593756d475da9c/html5/thumbnails/27.jpg)
Cancer Hallmarks
![Page 28: Immunotherapy and Targeted Therapies: The new face of cancer … and... · 2020-03-04 · Molecular Targeted Therapies • Form the basis for Precision Oncology whereby, • molecular](https://reader033.fdocuments.us/reader033/viewer/2022050117/5f4d94a268593756d475da9c/html5/thumbnails/28.jpg)
Immunotherapy
KeyKeyKeyKey events in events in events in events in thethethethe historyhistoryhistoryhistory of of of of cancercancercancercancer immunotherapyimmunotherapyimmunotherapyimmunotherapy
Start clinical trials
withanti-CTLA-4
![Page 29: Immunotherapy and Targeted Therapies: The new face of cancer … and... · 2020-03-04 · Molecular Targeted Therapies • Form the basis for Precision Oncology whereby, • molecular](https://reader033.fdocuments.us/reader033/viewer/2022050117/5f4d94a268593756d475da9c/html5/thumbnails/29.jpg)
Immunotherapy
![Page 30: Immunotherapy and Targeted Therapies: The new face of cancer … and... · 2020-03-04 · Molecular Targeted Therapies • Form the basis for Precision Oncology whereby, • molecular](https://reader033.fdocuments.us/reader033/viewer/2022050117/5f4d94a268593756d475da9c/html5/thumbnails/30.jpg)
Immunotherapy – Checkpoint Inhibitors
Ipilimumab
Tremelimuma
b
Nivolumab
Pembrolizuma
b
Avelumab
Darvalumab
Atezolizumab
![Page 31: Immunotherapy and Targeted Therapies: The new face of cancer … and... · 2020-03-04 · Molecular Targeted Therapies • Form the basis for Precision Oncology whereby, • molecular](https://reader033.fdocuments.us/reader033/viewer/2022050117/5f4d94a268593756d475da9c/html5/thumbnails/31.jpg)
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
![Page 32: Immunotherapy and Targeted Therapies: The new face of cancer … and... · 2020-03-04 · Molecular Targeted Therapies • Form the basis for Precision Oncology whereby, • molecular](https://reader033.fdocuments.us/reader033/viewer/2022050117/5f4d94a268593756d475da9c/html5/thumbnails/32.jpg)
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)
![Page 33: Immunotherapy and Targeted Therapies: The new face of cancer … and... · 2020-03-04 · Molecular Targeted Therapies • Form the basis for Precision Oncology whereby, • molecular](https://reader033.fdocuments.us/reader033/viewer/2022050117/5f4d94a268593756d475da9c/html5/thumbnails/33.jpg)
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
![Page 34: Immunotherapy and Targeted Therapies: The new face of cancer … and... · 2020-03-04 · Molecular Targeted Therapies • Form the basis for Precision Oncology whereby, • molecular](https://reader033.fdocuments.us/reader033/viewer/2022050117/5f4d94a268593756d475da9c/html5/thumbnails/34.jpg)
New/Emerging Immune Checkpoint Inhibitors
![Page 35: Immunotherapy and Targeted Therapies: The new face of cancer … and... · 2020-03-04 · Molecular Targeted Therapies • Form the basis for Precision Oncology whereby, • molecular](https://reader033.fdocuments.us/reader033/viewer/2022050117/5f4d94a268593756d475da9c/html5/thumbnails/35.jpg)
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
![Page 36: Immunotherapy and Targeted Therapies: The new face of cancer … and... · 2020-03-04 · Molecular Targeted Therapies • Form the basis for Precision Oncology whereby, • molecular](https://reader033.fdocuments.us/reader033/viewer/2022050117/5f4d94a268593756d475da9c/html5/thumbnails/36.jpg)
Other Limitations and Challenges
• Funding - genomic analysis has become much cheaper
but remains expensive
• Identification of Biomarker
• Why do some people not respond