the changing nature of cancer treatments, and the

© Sygnature Discovery 2019Enabling Success

www.sygnaturediscovery.com

The changing nature of cancer treatments, and

the implications for Research Nurses

Allan JordanDirector of Oncology Drug Discovery

© Sygnature Discovery 2019

• Activate, deactivate or inhibit a process

• “Lock and key” theory of drug action Emil Fischer, 1895

A quick reminder of how drugs work


What makes a good drug?• Potency

• Selectivity

• Pharmacokinetics

• Pharmacodynamics

• Safety

• Stability

• Novelty

• Ease of synthesis

• Formulation

• Commercially viable


• Cure vs control

• Secondary disease limitation / eradication

• Safer

• More effective

• Fewer side effects

• Better Quality of Life

• Convenience


• Because we have traditionally not listened to the needs and views of patients and nurses?

• Because we get the science wrong?

• Because biology is exquisitely complicated?

• Because tumours are highly evasive and rapidly evolving?

Why aren’t our drugs very good?


Where do new treatment ideas come from?

Mutations in CookieMonster Kinase drive oncogenic transformation and lead to aggressive pancreatic ductal adenocarcinomaOscar T. Grouch1, Count V. Count1 & Bunsen Honeydew2

1Sesame Street Medical Center, Kaufman, New York, USA and 2MuppetLabs Oncology Inc., Kaufman, New York, USA

Nature, 547, 1-10. April 1, 2019 doi: 10.1038/nature10128


Repeating novel biology.• For “exciting, novel” targets, most early information is derived from

the literature…

Industry studies suggest only 20-25% of all published biological data are truly and fully repeatable…


“For both iniparib and tivantinib, a more rigorous preclinical analysis would have permitted unbiased clinical testing of these drugs, preventing clinical trial failure on one hand and patient mistreatment on the other.” NRCO, 2013, 11, 373

Getting the science wrong matters…

HN

OHNO

N

O

NH2N+O

-O

I

IniparibPARP inhibitor

PhIII trials

TivantinibSelective MEK inhibitor

PhIII trials

Activity independent of PARPGeneral cytotoxic

Activity independent of MEKAffects tubulin dynamics


• …and yet this compound still failed to deliver efficacy in Phase II…

And for the good compounds…?

O N O

HN

NO

HO

OH

VER-52296 / NVP-AUY-922Luminespib


• Tumour load unrepresentative

• Metabolism/Toxicology

• Heterogeneity/genetic complexity Models driven by single/limited genetic factor (e.g. single kinase driver) Patient tumour variability/evolution Underlying interactions with surrounding tissue?

So why do we keep failing?

© Sygnature Discovery 2019 Nature (2010) 467: 1114

Pancreatic cancer

Heterogeneity within primary tumors


Tumour evolution

Nature (2010) 416: 1147

Includes subclone of 3 x 103 resistant cells

Pancreatic Cancer


Implications for treatment…


Drug 2 (3, 4,..)Drug 1


Simple in principle, but…

KRASEGFRALKHer-2BRAFPIK3CAMETNRASAKTMEKRETROS

Unknown


• To identify a 4% genomic subset for a clinical trial or for treatment… Screen 250 patients to gain just 10 responders 96% ineligibility

o Unfair on patients – Up/Down hope-despair cycles? Ca £0.5M per identified patients

• Requires a new approach…. “Basket Trials” Multi-combo, multi-arm, multi-centre trial infrastructure Many-fold 1-10% segments, perhaps 40-60% eligibility overall? Adaptive design, data- and science-led evolution of arms Obvious cost, and more importantly, patient benefit

• The UK NHS setup makes this particularly practicable

Practicalities of targeted therapeutics


“We need to stop finding patients for trials and start finding trials for patients ”

Why are we doing this?


• Multi-Centre NSCLC trial

• Multiple different gene alterations 18 of which will link directly to treatment arms on the trial 21 biomarker/drug combinations in place Exome sequencing, genotyping of CTCs, cfDNA 9 treatment arms

o AZD4547 (FGFRi), AZD2014 (mTORi), Palbociclib (mAb, ER+, Her2-), Crizotinib (ALKi), Selumetinib (MEKi) plus docetaxel, Osimertinib (mtEGFRi), AZD5363 (AKTi), Sitravatinib(multiple kinases), MEDI4763 (anti-PD-L1 mAb)

22 centres in place, 7 further sites in progress

MATRIX trial


• Trials like MATRIX will become increasingly prevalent Will eventually become SOC mode of treatment

• Considerable demands on: Patient selection Logistics and planning Tailoring of treatments to limited numbers of individuals

Looking forward…


• Cholangiosarcoma (1600 cases p.a.)

• Salivary gland cancers (800 cases p.a.)

• Infantile febrile sarcoma (~ 4 cases p.a.)

• (c.f. lung, 63k cases p.a., 55k cases p.a.)

• TRK kinase fusions – identified across a diversity of tumour types

• Highly sporadic and disparate nature complicates patient identification

But it can be worth it…


• Data presented at ASCO, 2017 and ESMO, 2018


• Patient recruitment was sporadic and slow

• Establishing cross-department genetic profiling for gene fusions required significant effort and influencing

• Only 3 patients recruited in the first year despite a 70% FTE commitment Sponsor expectations?

• Driven by Sandra Montez, MD Anderson Cancer Center, Texas This was a nurse-led, major clinical undertaking…

Not without significant challenges…


• Small patient subsets demand many sites of 1-2 recruits per site Lots of hassle for seemingly little contribution Many centres to deliver recruitment for sequencing, then feed to major centres for Tx?

• These trials deliver significant and meaningful benefits to patients with rare cancers Remember, all but the top 6 cancers are considered “rare”…

• Can only happen with your support and active participation!

Where does the research nurse community fit in?

Enabling Successwww.sygnaturediscovery.com

Thank you!

[email protected]

https://www.linkedin.com/company/sygnature-discovery

@SygnatureDiscov

the changing nature of cancer treatments, and the

Documents