Advances in Personalised Medicine and Potential Impact on the the MDT

Dr Alastair Greystoke

Senior Lecturer and Honorary Consultant Medical Oncologist,

Northern Centre for

Cancer Care, Freeman Hospital, Newcastle

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Newcastle upon Tyne Hospitals NHS Foundation Trust audit data 2013

For better, for worse? A review of the care of patients who died within 30 days of receiving systemic anti-cancer therapy. NCEPOD 2008

Concerns over tolerability in a patient population with multiple co-morbidities impacts on therapy rates

Potential ways to improve treatment outcome in NSCLC

• Optomise chemotherapy

– (bevaciazumab)/nintedanib

• Targeted therapy

– (EGFR/ALK (ROS-1, C-Met……))

• Immunotherapy

• ?Treat more patients with safer drugs?

Acceleration in personalised medicine in NSCLC

Pubmed search for Oncogene and NSCLC

Importance of EGFR-ALK • Different disease

– Demographics

– Pattern of spread

– Prognosis

• Different treatments

– EGFR inhibitors (1st -3rd generation)

– ALK inhibitors (1-2nd generation)

• Paradigm shift in the way we look at NSCLC

– SMP2/Matrix

1959 Discovery

EGF

2001/2 Erlotinib Gefitinib Phase I

2010 I-PASS

2005 Discovery

T790M

2015 Osimertinib/Rociletinib

Phase 1

2008 Afatinib Phase I

2007 EML4-ALK found in NSCLC

1994 Discovery ALK fusion proteins

2010 Crizotinib Phase 1 in

Lung

2013/2014 Alectinib/ Ceritinib Phase I in

Lung

EGFR Mutant

EML4-ALK

Rangachari et al Lung Cancer 2015

Different Disease

Different Treatments

Mok et al NEJM 2010

Different Treatments

A number of EGFR inhibitors which do I use?

Park et al ESMO Asia 2015

A number of EGFR inhibitors which do I use?

Park et al ESMO Asia 2015

ALK inhibitors

Different Treatments (Crizotinib vs 2nd line Chemo)

Shaw NEJM 2013 ALK FISH +ve

CI, confidence interval; HR, hazard ratio; PFS, progression-free survival.

1. Solomon BJ, et al. N Engl J Med 2014;371:2167–77. 2: Shaw et al NEJM 2013; 368:2385-94

PF

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%)

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Time (months)

172 120 65 38 19 7 1 0

171 105 36 12 2 1 0 0

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Crizotinib (n=172)

Chemotherapy (n=171)

Events, n (%) 100 (58) 137 (80)

Median, months 10.9 7.0

HR (95% CI) 0.45 (0.35−0.60)

P-value <0.001

Median duration of treatment: 10.9 months with crizotinib vs 4.1 months with chemotherapy

Crizotinib

Chemotherapy

No. at risk

Different Treatments (Crizotinib vs 2nd line Chemo)

Different Treatments (Grade 3/4 AEs of any

cause in ≥ 3% of patients)

ELEVATED TRANSAMINASESa, n (%) 27 (16) 4 (2)

PULMONARY EMBOLISMa, n (%) 9 (5) 3 (2)

DYSPNOEAa, n (%) 7 (4) 5 (3)

PNEUMONIA, n (%) 6 (4) 3 (2)

HYPOKALAEMIA, n (%) 6 (4) 0

ECG QT PROLONGED, n (%) 6 (4) 0b

NEUTROPAENIAa, n (%) 23 (13) 33 (19)

FEBRILE NEUTROPAENIA, n (%) 1 (1) 16 (9)

ANAEMIAa, n (%) 4 (2) 9 (5)

WBC DECREASED, n (%) 2 (1) 8 (5)

FATIGUE, n (%) 4 (2) 7 (4)

XALKORI (n = 172)

CHEMOTHERAPY (n = 171)

aClustered term; bno on-treatment assessments

AE, adverse event; ECG, electrocardiogram; WBC, white blood cell.

Reference: Supplement to: Shaw AT, et al. N Engl J Med. 2013;368:2385–94.

Reference: Supplement to: Shaw AT, et al. N Engl J Med. 2013;368:2385–94.

OVERALL CHANGE FROM BASELINE IN SYMPTOMS AND GLOBAL QOL

Chemotherapy Xalkori

Different Treatments (with better Quality of Life)

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Time (months)

162 71 40 17 9 2 0 151 30 13 3 1 1 0

No. at risk XALKORI

Chemotherapy

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XALKORI

(n = 162)

Chemotherapy

(n = 151)

Events 91 (56%) 111 (74%)

Median, months 5.6 1.4

HR (95% CI) 0.54 (0.40–0.71)

P < 0.0001

aComposite of chest pain, cough and dyspnoea

CI, confidence interval; HR, hazard ratio.

XALKORI

Chemotherapy

Reference: Shaw AT, et al. N Engl J Med. 2013;368:2385–94.

Different Treatments (with better Quality of Life)

Using 2nd Generation ALK inhibitor on progression

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For distribution in response to an unsolicited request for medical information local NP4 approval.

What’s next?

The Journal of Pathology Volume 232, Issue 2, pages 121-133, 10 DEC 2013 DOI: 10.1002/path.4275 http://onlinelibrary.wiley.com/doi/10.1002/path.4275/full#path4275-fig-0001

Emerging data on new populations to treat with targeted therapy

• Ros-1

• Ret

• B-Raf

• C-Met

• (?K-Ras)

Shaw et al N Engl J Med. 2014 Nov 20;371(21):1963-71.

Crizotinib in ROS-1

Illumina Next Generation

Sequencing – 28 gene panel that covers all genes and aberrations required for trial entry

(mutations, deletions, insertions and amplifications) For ALK, FGFR2, FGFR3, NTRK1, RET, ROS1 translocations can also be detected.

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Genes

AKT1 CCND2 CDK4 FGFR3 MET PIK3CA ROS1

ALK CCND3 CDKN2A Her2 NF1 PTEN STK11

BRAF CCNE1 EGFR HRAS NRAS RB1 TSC1

CCND1 CDK2 FGFR2 KRAS NTRK1 RET TSC2

SMP2 the Story so Far

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Results

SMP2 the Story so Far

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Treatableabnormality

Keygenemissing

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QCFail/Cancelled

AZD2014 – Response of lung adenocarcinoma with TSC2 mutation after 2 cycles

13/10/15 26/8/15

Tumour Tumour

Summary

• Concept of “lung cancer” outdated

• Molecular targeted therapy can be efficacious and well tolerated when we identify the targets

• Trials of stratified medicine ongoing

• However new treatments for patients with lung cancer urgently needed

Reassessment of molecular events on progression

Yu et al CCR 2013

Response rate* in T790M+ (central test)

• ORR* = 64% (69/107; 95% Cl 55%, 73%) in patients with EGFR T790M+ NSCLC

• Overall disease control rate (CR+PR+SD) = 94% (101/107; 95% CI 88%, 98%)

20 mg 40 mg 80 mg 160 mg 240 mg

N (107) 10 29 34 28 6

ORR 50% 62% 68% 64% 83%

Best percentage change from baseline in target lesion: all evaluable T790M+ patients, Part B

*Includes confirmed responses and responses awaiting confirmation; #represents imputed values

Population: all dosed centrally confirmed T790M+ patients with a baseline RECIST assessment and an evaluable response (CR/PR, SD, or PD),

N=107 (from 120 T790M+ patients; 13 patients with a current non-evaluable response are not included). D, discontinued; QD, once daily

Best percentage change from baseline in target lesion:

T790M+ evaluable patients, expansion cohorts only (N=107)

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Presented by: Pasi A. Jänne at the American Society of Clinical Oncology

Annual Meeting 2014; Journal of Clinical Oncology Vol 32, suppl 5: 8009

Targeting Molecular Events on Progression

Patient with EGFR exon 19 mutation and T790M

Tumour Tumour

04/2015 09/2015

Tumour

Targeting Molecular Events on Progression

Patient with EGFR exon 19 mutation and T790M

Figure 3

Hanahan and Weinberg Cell 2011 144, 646-674DOI: (10.1016/j.cell.2011.02.013)

NSCLC as a Disease of the Immune System

Brahmer et al N Engl J Med. 2015 May 31.

CheckMate-017; Nivolumab vs Docetaxel in Squamous NSCLC

Overall Survival in CheckMate 057 (Nivolumab vs docetaxel in 2nd line Non Squamous Ca)

Borghaei H et al. N Engl J Med. 2015 Oct 22;373(17):1627-39.

Bauer et al. ASC0 2015 Poster 339

Squam

ous NSCLC

Non S

quamous

NSCLC

PDL1

Non S

quamous

NSCLC

PDL1

NSCLC

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docetaxel

nivolumab

pembrolizumab (2)

pembroluzimab (10)

Checkmate 017

Checkmate 057 Keynote-010

Immunotherapy improves survival over docetaxel chemotherapy across histologies and trials in NSCLC

Biomarker Prognostic (Estimates survival independent of therapy)

Predictive (Predicts response/resistance)

Histology

Non-Squamous histology ? Pemetrexed

Adenocarcinoma + Nintedanib +docetaxel

Oncogenes

EGFR +++ EGFRi (1st and 2nd generation)

EGFR (T790M on progression on EGFRi)

+ Osimertinib

ALK +++ Crizotinib/ Ceritinib

Ros-1 ++++ Crizotinib

K-Ras - Chemotherapy/ erlotinib

Checkpoint status

PD-L1 Nivolumab/pembrolizumab

Summary • As an oncologist requiring increasing information

about the tumour to guide care • Implications for

– Biopsy size/ site – Biopsy handling/ analysis – Prioritization of tissue for tests that may impact on

patients care – (rebiopsy)

• Communication is key • Things coming in the near future

– cfDNA – Better biomarkers for immune agents

Aden

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(CP)

squam

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(CP)

EGFR

ALK

K-R

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PDL1

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Impact of Biomarkers in NSCLC