immuno-oncology · 2019. 11. 24. · checkmate-171 • phase 2 single-arm with nivolumab for...
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Immuno-Oncology- Lung Cancer MDT -
The Christie NHS Foundation Trust, Manchester, UK
@FabioGomes_Go
Medical Oncology
Fabio Gomes, MD
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Disclosures• Advisory role: Boehringer
• Research grant: Pfizer, Roche, Takeda
• Travel grant: Pizer, Roche
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Immuno-oncology and checkpoint inhibitors
CTLA-4
IpilimumabTremelimumab
PD-1 / PD-L1
NivolumabPembrolizumab
AtezolizumabAvelumab
Durvalumab
Pardoll, Nat Rev Cancer 2012
Priming phase
Effector phase
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Checkpoint inhibitors and irAE
The exact pathogenesis of immune toxicity is not well established No clear correlation between dose/exposure <> toxicity No dose reduction
Toxicity with variable onset Toxicity with delayed onset Toxicity with prolonged duration
Long exposure periods >> importance of grade 1-2 irAEs Challenging diagnosis of irAEs Correlation between toxicity <> durable responses is not well established
Michot et al EJC 2016
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Immuno-oncology and checkpoint inhibitors
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Does the treatment with checkpoint inhibitors work as well for older cancer patients?
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Is the treatment with checkpoint inhibitors well tolerated for older and frail cancer patients?
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What do we know from phase 3 RCT?
10-30% 30-60% 55-70%30-70%
Incidence of grade 3-5 TRAEs
CPI = checkpoint inhibitor; RCT = randomized controlled trial; TRAEs = treatment-related adverse events
Single-agent CPI CPI+CPI CPI+chemoChemo
Reck et al. NEJM 2016; Reck et al. JCO 2019; Mok et al. Lancet 2019; Lopes et at. JCO 2018; Gandhi et al. NEJM 2018; Paz-Ares et al. NEJM 2018; Herbst et al. Lancet 2015; Carbone et al. NEJM 2017; Hellmann et al NEJM 2018; Brahmer et al NEJM 2015; Vokes et al Ann Oncol 2018; West et al. Lancet Onc 2019; Socinski et al. Ann Oncol 2018; Socinski et al. NEJM 2018; Rittmeyer et al. Lancet 2017;
Robert C et al NEJM 2011; Larkin et al. NEJM 2015; Hodi et al. NEJM 2010; Robert et al. NEJM 2014; Weber et al Lancet Oncol 2015; Robert et al NEJM 2015; Ribas et al. Lancet Oncol 2015.
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What do we know from phase 3 RCT?
10-30% 30-60% 55-70%30-70%
Incidence of grade 3-5 TRAEs
CPI = checkpoint inhibitor; RCT = randomized controlled trial; TRAEs = treatment-related adverse events
Single-agent CPI CPI+CPI CPI+chemoChemo
5-15% 20-35% 25-30%10-20%
Treatment discontinuation rate
Reck et al. NEJM 2016; Reck et al. JCO 2019; Mok et al. Lancet 2019; Lopes et at. JCO 2018; Gandhi et al. NEJM 2018; Paz-Ares et al. NEJM 2018; Herbst et al. Lancet 2015; Carbone et al. NEJM 2017; Hellmann et al NEJM 2018; Brahmer et al NEJM 2015; Vokes et al Ann Oncol 2018; West et al. Lancet Onc 2019; Socinski et al. Ann Oncol 2018; Socinski et al. NEJM 2018; Rittmeyer et al. Lancet 2017;
Robert C et al NEJM 2011; Larkin et al. NEJM 2015; Hodi et al. NEJM 2010; Robert et al. NEJM 2014; Weber et al Lancet Oncol 2015; Robert et al NEJM 2015; Ribas et al. Lancet Oncol 2015.
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What do we know from phase 3 RCT?
10-30% 30-60% 55-70%30-70%
Incidence of grade 3-5 TRAEs
5-15% 20-35% 25-30%10-20%
Treatment discontinuation rate
60-80% 80-95% 95-99%80-99%
Incidence of any grade TRAEs
Single-agent CPI CPI+CPI CPI+chemoChemo
Reck et al. NEJM 2016; Reck et al. JCO 2019; Mok et al. Lancet 2019; Lopes et at. JCO 2018; Gandhi et al. NEJM 2018; Paz-Ares et al. NEJM 2018; Herbst et al. Lancet 2015; Carbone et al. NEJM 2017; Hellmann et al NEJM 2018; Brahmer et al NEJM 2015; Vokes et al Ann Oncol 2018; West et al. Lancet Onc 2019; Socinski et al. Ann Oncol 2018; Socinski et al. NEJM 2018; Rittmeyer et al. Lancet 2017;
Robert C et al NEJM 2011; Larkin et al. NEJM 2015; Hodi et al. NEJM 2010; Robert et al. NEJM 2014; Weber et al Lancet Oncol 2015; Robert et al NEJM 2015; Ribas et al. Lancet Oncol 2015.
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Bordoni et al, Clin Lung Cancer 2018
What do we know from phase 3 RCT?
HRQoL on OAK study (Ph 3 RCT atezolizumab vs docetaxel, pre-treated advanced NSCLC)
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Who are we treating in the phase 3 RCT?
Younger patients
ECOG PS 0-1
No severe/uncontrolled medical conditions
Median age in RCT: 64 years Median age diagnosis UK: 73 years
ECOG 0-1 RCT: 99%ECOG 0-1 clinic*: 64%
Comorbidity burden RCT: n/aGrade 3-4 comorbidity in clinic*: 66%
*Christie NHS FT data
Cumulative illness rating scale (CIRS)
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Pivotal Ph 3 RCT with no sub-group analysis on safety outcomes.
FDA pooled analysis
• 4 RCT with PD-1/PD-L1 in pre-treated NSCLC (n = 2.824)
• Grade 3-4 TRAEs in older (75+) = 23% versus 47% in younger
Pooled analysis
• 3 RCT with pembrolizumab in advanced NSCLC (n=2.612)
• Grade 3-4 TRAEs in older (75+) = 23% versus 16% in younger
Could we derive any data from clinical trials?
Marur et al, Semin Oncol 2018; Nosaki et al, Ann Oncol 2019
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CheckMate-171
• Phase 2 single-arm with nivolumab for pre-treated squamous NSCLC (n = 809)
• Grade 3-4 TRAEs in older (70+) = 14% versus 12% in all patients
• Any TRAEs in PS-2 (12%) = 45% versus 50% in all patients
PePS2
• Phase 2 single-arm with pembrolizumab for ECOG PS-2 NSCLC (n = 60)
• Median age = 72 years
• Grade 3-4 TRAEs in PS-2 = 8%
IPSOS (NCT03191786)
Ongoing Phase 3 RCT for advanced NSCLC patients with either a PS of 2-3 or 70 yo
atezolizumab or CT (gemcitabine or vinorelbine)
Could we derive any data from clinical trials?
Popat et al, Annals Onc 2017; Middleton et al, Annals Onc 2018.
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But are we correctly identifying frail patients?
•Frail patients have less organ reserve to cope with irAEs
•High dose/chronic use of steroids may result in diabetes decompensation, psychosis, infections, myopathy, fractures…
•Crucial to understand what is driving the frailty
(cancer / comorbidities)
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Can different study designs help us?
• Prospective, observational cohort study
• Single-agent CPI in advanced NSCLC / Melanoma
• Primary endpoint: incidence of grade 3-5 irAE
• Secondary endpoint: HRQoL
• Geriatric assessments incorporated (G8 > CGA)
ELDERS study
Older
(≥ 70 y)
Younger
(45-69 y)
Gomes F; Presented at ESMO2019
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Can different study designs help us?ELDERS study
Older (n= 70)
Younger (n=70)
Age, median 75y 62y
PS 2 27% 16%
Comorbidity grade 3-4 77% 56%
Polypharmacy 61% 37%
n = 140
G8 geriatric screening
50%
50%
p 0.008
p 0.004
p <0.001
PS vs G8
Gomes F; Presented at ESMO2019
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Can different study designs help us?ELDERS study
• Incidence of grade 3-5 irAE• 18.6% in older cohort and 12.9% in younger cohort (p=0.353)• No predictive factors identified• Frailty does not seem to play a role in irAEs incidence
•G8 screening tool was a predictive factor for hospital admission (p=0.031)• 70% of admissions were related with comorbidities and cancer burden (not TRAEs)• Frailty does play a role in coping with any AEs
•Chronological age was not a predictive factor for any safety outcome
Gomes F; Presented at ESMO2019
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• Overall under-representation of frail and older patients in RCT
• Single-agent CPI are well-tolerated and maintain HRQoL• Good match for older/frail cancer patients!
• Newer combination regimens (CPI-CPI / CPI-chemo) with limited data• Concerns regarding tolerability
• Appropriate patient selection is paramount
• Frailty may not play a role in the incidence of irAE BUT it does play a role when coping with irAEs
@FabioGomes_Go
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