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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
