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