immuno-oncology · checkmate-171 • phase 2 single-arm with nivolumab for pre-treated squamous...

Immuno-Oncology- Lung Cancer MDT -

The Christie NHS Foundation Trust, Manchester, UK

fabio.gomes@christie.nhs.uk

@FabioGomes_Go

Medical Oncology

Fabio Gomes, MD

Disclosures• Advisory role: Boehringer

• Research grant: Pfizer, Roche, Takeda

• Travel grant: Pizer, Roche

Immuno-oncology and checkpoint inhibitors

CTLA-4

IpilimumabTremelimumab

PD-1 / PD-L1

NivolumabPembrolizumab

AtezolizumabAvelumab

Durvalumab

Pardoll, Nat Rev Cancer 2012

Priming phase

Effector phase

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

Immuno-oncology and checkpoint inhibitors

Does the treatment with checkpoint inhibitors work as well for older cancer patients?

Is the treatment with checkpoint inhibitors well tolerated for older and frail cancer patients?

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.

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.

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.

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)

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)

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

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.

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)

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

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

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

• 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

fabio.gomes@christie.nhs.uk

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