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Immunotherapy in older patients

Alastair Greystoke

Senior Lecturer, Newcastle University

Honorary Consultant in Medical Oncology

w o r k i n g t o g e t h e r a s N e w c a s t l e A c a d e m i c H e a l t h P a r t n e r s

Disclosures

Consultancy and speakers fee for Roche, MSD, Bristol Myers Squib, AstraZeneca, Boehringer-Ingelheim, Pfizer and Novartis

Why the excitement over IO agents?

• Tumour agnostic?

• Higher RR?

• Less Toxicity?

• Long term responders?

• Better QoL?

• Treatment deliverable to patients

with poor PS/ co-morbidities?

Drug Trade Name Target Manufacturer

Ipilimumab Yervoy CTLA4 BMS

Nivolumab

(BMS-936558)

Opvido PD-1 BMS

Pembrolizumab (MK-3475) Keytruda PD-1 MSD

Atezolizumab

(MPDL3280A)

Tecentriq PD-L1 Roche

Durvalumab (MEDI4736) Imfinzi PD-L1 AstraZeneca/Celgene

Avelumab (MSB0010718C) Bavencio PD-L1 Merck/Pfizer

Cavnar et al. Nat Rev Drug Discov. 2017 Feb 2;16(2):83-84.

Why might the older patient respond differently to Immuno-

oncology agents?

• Immunosenescence

• Inflammaging

• Increased MDSCs

• Increased auto-antibodies

• Changes in microbiome

• Poorer performance status

• Increased co-morbiditiesPotential impact on efficacy

Potential impact on toxicity

Potential impact on both

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Immunosenescence; Impact on T-cell

Function• Progressive remodelling/ adaptation

– Adaptive and innate immunity

• Impact on T-cells

– Reduced diversity

– Fewer naïve T-Cells / more memory T-Cells

Weng, et al. Trends Immunol. 2009; 30: 306–312 Daste et al. EJC 2017: 82 :155-166

• Immunosenescence– Impaired TLR function

– Decreased antigen presentation

– Decreased chemotaxis/ phagocytosis of neutrophils

– Decreased NK Killer cell cytolysis

• Inflammaging– Higher levels of pro-inflammatory cytokines

– IL-6/ CRP etc

• Changes in microbiome– Decline in microbiota diversity

– a decrease of the ratio of Firmicutes to Bacteroides

Other Factors that may affect Efficacy Clinical Experience

• Trials experience

– Most IO studies randomised against the SoC at that time (ie docetaxel 2nd line in

NSCLC)

– ~40% of enrolled patients are ≥65y

– Scarce numbers of patients ≥75y

• Selective inclusion criteria: fitter, PS 0-1, no major comorbidity

– Under-representation of real world elderly patients

• No planned analysis or specific assessments for older patients

Efficacy - trial sub-group analysis

Single-agent

Pembrolizumab

1st line Melanoma

Keynote-006

Schachter et al. Lancet 2017

OS

Efficacy - trial sub-group analysis

Single-agent

Nivolumab

2nd line NSCLC

CheckMate-057

Borghaei et al. NEJM 2015

OS

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0.3 3

Anti CTLA-4

<65 yrs

>65 yrs

<65 yrs

65-75 yrs

>75 yrs

Sub-group Analysis of Licensing Studies (multiple disease types)

Anti PD-1

Favours IO agent Favours control arm

Data taken from Nishima et al Cancer Treatment Reviews 45 (2016) 30–37

Checkmate 153 Checkmate 171 Italian EAP

All >70

(39%)

PS2 All >70

(34%)

PS2 All >70

(33%)

Grade 3-4 TRAE 12 12 10 5 5 2 - -

Discontinuation rate

due to TRAE

- - - 4 4 4 5 5

Median OS - - - 9.9 11.2 5.4 11 11.5

Estimated 6/12 survival 63% 63% 41% 67% 66% 46%

Sub-group analysis of Phase IIIB/IV studies and EAPs in NSCLC

Spiegel et al IASLC 2016

Popat et al ESMO 2017

Migliorino et al ESMO 2017

0

7%

1

11%

2

18%

3

17%

4

14%

5

11%

6+

22%

0

11%

1

31%

2

23%

3

25%

4

10%

Performance Status Sum of ACE-27 points

Decreasing physiological reserve

Incr

ea

sin

g t

um

ou

r

bu

rde

n

-1 -1 2>

2+

3.98107170553497

6.30957344480193

10

No Co-morbidity Co-morbidity

Ne

utr

op

hil

:Lym

ph

ocy

tera

tio

PS 2

PS 0-1

Not all PS 2 patients are the same

Newcastle NSCLC patients at 1st presentation

Chemotherapy Immunotherapy

Timing 1st cycle predictive Can be delayed

Predictability Dose Dependent Idiosyncratic

Combo>CTLA->PD1/PDL1

Patients at Risk Poor PS

Older

Co-morbidities

Previous auto-immune disease

? Other

Organs at risk Dividing cells (+other) Almost any (differences between

PD1 and CTLA4)

Treatment Supportive Immunosuppresion (+supportive)

Recovery Days to weeks Can be chronic

Approximate Differences in Chemotherapy/ Immunotherapy Toxicity

Weber et al JCO 2012

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19

Toxicity – trials pooled analysis

• I-O trials did not report specific data on safety for older patients

• Use of nivolumab in lung cancer, renal cell cancer and melanoma– CheckMate-025, 066, 057, 017.

Singh et al. ASCO 2016 (abst #10010)

Any AE

Toxicity - real world data

Friedman et al. ASCO 2016 (abst #10009)

• Safety in melanoma patients ≥ 80 years

Reference trials 25% 15% 55%

Case Study 1• 76 yr man

• No PMH

• PS 2 due to pain and weight loss

• Poorly diff squamous NSCLC

• No toxicity; now PS 0

Day 1 Week 6

Case Study 278 yr old female

Previous PEs

COPD (Exercise tolerance when well around 200m)

PS2 due to co-morbidities, SoB and weight loss

Poorly differentiated lung adeno ca

Day 1 Day 8

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Ongoing questions

• Efficacy/ Toxicity in patients >75 (still under-represented)

• Difference between efficacy:

– PS2 (Tumourogenic inflammation)

– PS 2 (co-morbidity)

– PS 2 (frailty)

• Impact of toxicity

– Direct

– Long term steroids/ immune suppression

• Benefit of CGA in this setting

– Intervention studies?

• Can we treat patients who are not “chemotherapy candidates”

• Use of combination regimens

– IO/IO; IO chemotherapy: IO/ novel agent With thanks to F Gomes