ESMO advanced Course on · Stéphane Champiat, MD, PhDc Drug Development Department (DITEP) Gustave Roussy 16-17th February 2018 Amsterdam, Netherlands The issue of fast progression

Stéphane Champiat, MD, PhDcDrug Development Department (DITEP)Gustave Roussy

16-17th February 2018Amsterdam, Netherlands

The issue of fast progression

ESMO advanced Course on Unsolved questions in Immuno-Oncology

Conflicts of interestAstraZeneca, BMS, Janssen, MSD, Novartis, Roche

Stéphane Champiat, MD, PhDcDrug Development Department (DITEP)Gustave Roussy


New Types of Responses in Oncology

Immune-Related Response Criteria

Prolonged stable disease

PseudoprogressionMixed

responses

09/11/201606/10/2016

Urothelial carcinoma 49 yo maleCOMBO anti-PDL1 + other immunotherapyC1J1 18/10/2016

Rapid disease progression occuring under IO

Baseline 1st Evaluation(+8 weeks)

Before(-8 weeks)

Rapid disease progression occuring under IO

58-year-old woman with metastatic urothelial carcinoma

Urothelial carcinoma, 40yo femaleAnti-PD1, C1D1 31/03/2017

22/03/20176/02/2017 17/04/2017

Dec 19 2017 Jan 30 2018Nov 2 2017

41 yo maleNSCLC adenocarcinoma PDL1+ (60% TC) KRAS mutation2nd line : Anti-PD1 monotherapy : 1st and only injection on January2018 Pt was hospitalized 18 days after 1st infusion for general condition alteration

Before(-7 weeks)

Baseline 1st Evaluation(+6 weeks)

CT evaluations

Crossing survival curves in phase 3 trials

Nivolumab vs Docetaxelin non-sq. NSCLC

Checkmate 057, Borghaei et al. (NEJM 2015).

Pembrolizumab vs chemotherapy in Urothelial Carcinoma.

Keynote 045, Bellmunt et al. (NEJM 2017).

Nivolumab vs standard therapyin HNSCC

Checkmate 141, Ferris et al. (NEJM 2016)

% variation

of the SLD

of target lesions

BEFORE

treatment

Time

?

Progression (PD)

Stable disease (SD)

Tumor

Response (PR, CR)

Tumor response evaluation by RECIST 1.1

ON

treatment- 32%

+ 10%

+ 30%

+ 50%

RECIST(-1)R-1

RECIST(0)R0

RECIST(+1)R+1

t-1 t+1

mm

months

What is needed ?

Integrating Tumor Kinetics in clinical practice

RECIST(-1)R-1

RECIST(0)R0

RECIST(+1)R+1

t-1 t+1

mm

months

What is needed ?

Integrating Tumor Kinetics in clinical practice

TGR+1

100 [exp(3 log(R+1/ R0) ) – 1]t+1

TGR-1

100 [exp(3 log(R0/ R-1) ) – 1]t-1

TGR method :

TGK method : TGK-1 = R0-R-1

t-1

TGK+1 = R+1- R0

t+1

TGR ratio :TGR+1

TGR-1

Delta TGR : TGR+1 – TGR-1 TGK ratio :

TGK+1

Champiat et al. Saada-Bouzid et al.Ferrara et al.

TGK-1

Compare Tumor Growth Kinetics

Hyperprogressive DiseaseDefinition ?

Champiat et al. Clin. Cancer Research 2016

Kato et al. Clin. Cancer Research

2017

Saada-Bouzid et al.Annals of Oncology

2017

Ferrara et al.WLC presentation

Oct. 2017

HPD definition

• RECIST PD at first evaluation

and

• TGR EXP/TGR Ratio ≥ 2

• time-to-treatment failure (TTF) <2 months

• >50% increase in tumor burden compared with pre-immunotherapy imaging

• >2-fold increase in “progression pace”

acceleration of tumor growth kinetics (TGK)

TGK ratio (TGKR) ≥2• RECIST PD at first

evaluation

and

• TGR EXP/TGR Ratio > 1,5

HPD on non-target lesions ? New lesions ?

Champiat et al. Clin. Cancer

Research 2016

Kato et al. Clin. Cancer

Research 2017

Saada-Bouzid et al.Annals of Oncology 2017


Oct. 2017

Population

N = 131

Metastatic cancers

phase 1 trials

PD1 or PD-L1 inhibitors

monotherapy

N = 155

Metastatic cancers

with molecular profiling

CTLA-4, PD-1/PD-L1 inhibitors or other

investigational agents

N= 34

recurrent and/or

Metastatic head and neck squamous cell

carcinoma

PD-1/PD-L1 inhibitors

N= 406

Advanced NSCLC

PD-1/PD-L1 inhibitors + IO combo

HPD rate ?9%

(12/131)6%

(6/102)29%

(10/34)14%

(56/406)

Reported studies integrating tumor kinetics

0 5 10 15 20 25 30 35

0.0

0.2

0.4

0.6

0.8

1.0

Months

Overa

ll surv

ival (%

)

CR or PR (n=16)

SD (n=64)

PD non−HPD (n=36)

HPD (n=10)

overall log−rank test

P= 1e−05

landmark survival analysis, landmark point set to 2 months

Champiat et al.Ferrara et al.

HPD and Survival

Champiat et al. Clin. Cancer

Research 2016

Kato et al. Clin. Cancer

Research 2017

Saada-Bouzid et al.Annals of Oncology 2017


Oct. 2017

Population

N = 131

Metastatic cancers

phase 1 trials

PD1 or PD-L1 inhibitors

monotherapy

N = 155

Metastatic cancers

with molecular profiling

CTLA-4, PD-1/PD-L1 inhibitors or other

investigational agents

N= 34

recurrent and/or

Metastatic head and neck squamous cell

carcinoma

PD-1/PD-L1 inhibitors

N= 406

Advanced NSCLC

PD-1/PD-L1 inhibitors + IO combo

HPD rate ?9%

(12/131)6%

(6/102)29%

(10/34)14%

(56/406)

Associated factors

Age(66 vs 55, p = 0.007)

All analysis were performed

for TTF < 2months only, no correlation was

evaluated for hyperprogression

Regional recurrence

(TGKR≥2: 90% vs TGKR<2 : 37%, p=0.008)

Metastatic sites > 2

(9% vs 19%, p = 0.005)

Reported studies integrating tumor kinetics

No association with tumor PD-L1 status, baseline tumor burden, number or type of previous therapeutic lines, baseline corticosteroid use, presence of inflammatory markers at baseline

MDM2 amplification and HPD ? Kato et al. (CCR 2017). Hyperprogressors after Immunotherapy: Analysis of

Genomic Alterations Associated with Accelerated Growth Rate.

• MDM2 amplification : found in 7 % of cancers, Inhibit the P53 tumor suppressor

• Statistical analyzes were performedfor a time to treatment failure (TTF) <2 months

No analysis done for hyperprogression

• => MDM2 amplifications and EGFR abnormalities are correlated withtime to treatment failure (FTT) <2 months

Primary resistance= Fast Progressors ?

= Hyperprogressors ?

% (RECIST)

BEFORE

treatment

Time

?+ 10%

- 32%

+ 30 %

+ 50 %

Response

by RECIST

Progression (PD)

Stable disease (SD)

Tumor

Response (PR, CR)

Response evaluation by RECIST

ON

treatment

Primary resistance= Fast Progressor ?

= Hyperprogressor ?

Changing radiological metrics for IO progression evaluation

% (RECIST)

BEFORE

treatment

Time

?+ 10%

- 32%

+ 30 %

+ 50 %

Response

by RECIST

Progression (PD)

Stable disease (SD)

Tumor

Response (PR, CR)


ON

treatment

Primary resistance= Fast Progressor ? = Hyperprogressor ?



% (RECIST)

BEFORE

treatment

Time

?+ 10%

- 32%

+ 30 %

+ 50 %

Response

by RECIST

Progression (PD)

Stable disease (SD)

Tumor

Response (PR, CR)


ON

treatment

Primary resistance= Fast Progressor ?≠ Hyperprogressor

Ferté et al. (2014). Tumor growth rate is an early indicator of antitumor drug activity in phase I clinical trials. Clinical Cancer Research

TGR profiling across 12 phase I clinical trialsIs HPD only observed with IO ?

Patients

characteristics

N=406

(%)Age

≥ 70 years 102 (25%)

Smoking history

Non-smokers 35 (9%)

Former/Current 371 (91%)

Histology

Non-squamous 294 (72%)

PD-L1 status

PDL-1 negative 39 (10%)

PDL-1 positive 78 (19%)

Unknown 289 (71%)

Stage (advanced

disease)

IVA or IVB 336 (83%)

N° met sites IO

baseline

> 2 184 (45%)

Performance

status

0-1 360 (89%)

IO Line

≥ 2 (range 2-9) 402 (99%)

IO drug type

PD-1 inhibitor 377 (93%)

PD-L1 inhibitor 29 (7%)

Mono or combo

Monotherapy 380 (94%)

Molecular Status

EGFR mutation 16 (4%)

ALK

rearrangement

4 (1%)

KRAS mutation 87 (21%)

0%

5%

10%

15%

20%

25%

30%

35%

40%

45%

19%

39%42%

5%

14%

Immunotherapy

Ferrara et al., WLC presentation Oct 2017

HPD = (TGR IO – TGR PRE IO) > 50% + PD RECIST AT 1st CT SCAN

Is HPD only observed with IO ?

Patients

characteristics

N=406

(%)Age

≥ 70 years 102 (25%)

Smoking history

Non-smokers 35 (9%)

Former/Current 371 (91%)

Histology

Non-squamous 294 (72%)

PD-L1 status

PDL-1 negative 39 (10%)

PDL-1 positive 78 (19%)

Unknown 289 (71%)

Stage (advanced

disease)

IVA or IVB 336 (83%)

N° met sites IO

baseline

> 2 184 (45%)

Performance

status

0-1 360 (89%)

IO Line

≥ 2 (range 2-9) 402 (99%)

IO drug type

PD-1 inhibitor 377 (93%)

PD-L1 inhibitor 29 (7%)

Mono or combo

Monotherapy 380 (94%)

Molecular Status


ALK

rearrangement

4 (1%)

KRAS mutation 87 (21%)

0%

5%

10%

15%

20%

25%

30%

35%

40%

45%

19%

39%42%

5%

14%

0%

10%

20%

30%

40%

50%

60%

10%

59%

31%

5%

0%

Immunotherapy Chemotherapy

Patients

characteristics

N=59

(%)Age

≥70 years 14

(24%)

Smoking history

Non-smokers 6 (10%)

Former/Current 53

(90%)

Histology

Non-squamous 47

(80%)

N° met sites chemo

baseline

≥ 3 16

(27%)

Performance status

≥2 8 (13%)

Chemo Line

≥ 3rd line (3-8) 17

(29%)

Chemo drug type

Taxane 43

(73%)

Pemetrexed 7 (12%)

Vinorelbine 4 (7%)

Gemcitabine 5 (8%)

Molecular Status


ALK rearr 3 (5%)

KRAS mutation 17

(29%)

vsFerrara et al., WLC presentation Oct 2017

HPD = (TGR IO – TGR PRE IO) > 50% + PD RECIST AT 1st CT SCAN

Is HPD only observed with IO ?

Oncogenic drivers activationImmuno-selection

of aggressive tumor clones

• Intra-cellular activation of oncogenic escape mechanisms ?

• Predisposing tumor genetic alterations?EGFR ? MDM2?

Hyperprogressive DiseaseHypothesis ?

Immune compensatory mechanisms

• Alternative immune checkpoints

• Modulation of protumor immune subsets: T-regs, Innate immunity

• Inflammation mediated angiogenesis, matrix/tissue remodeling, metabolism

modification

• Which patients ?: ✓ NSCLC, HNSCC, others ? ✓ Associated factors ? : age ? Number of metastatic sites > 2 ? Regional recurrence ?

HyperprogressorsWhat should we do ?


• Change tumor evaluation metrics✓ pre-baseline CT scan ✓ Early evaluation✓ Integrate new lesions in HPD definition ?

• Change the use of biomarkersResponse Biomarkers => Progression biomarkers





=> Integrate tumor kinetics evaluation in IO trials

=> Translationnal : biopsies when accelerated growth

=> « Back to the lab »





=> Integrate tumor kinetics evaluation in IO trials

=> Translationnal : biopsies when accelerated growth

=> « Back to the lab »


Primum non nocere

Understand HPD mechanisms to improve IO efficacy … and patients survival

% variation

of the SLD

of target lesions

BEFORE

treatment

Time

?

Progression (PD)

Stable disease (SD)

Tumor

Response (PR, CR)

Tumor response evaluation by RECIST 1.1

ON

treatment- 32%

+ 10%

+ 30%

+ 50%

Progressive tumors assessment under IO therapy

exposure to an ineffective or deleterious IO therapy

Progressive tumors assessment under IO therapy

Integrating PRE and ON treatment tumor kinetics

exposure to an ineffective or deleterious IO therapy

@iTOXreport

Stéphane CHAMPIAT MD, PhDcGustave [email protected]

Get updates on last publications about irAEs



Charles FertéJean-Charles SoriaAurélien MarabelleSamy AmmariLaurent DercleChristophe Massard

R

• Tumor size (D) was defined as the sum of the largest diameters (RECIST sums).• Let t be the time between each tumor evaluation.

=> Consecutively, TG = 3 log(Dt / D0) / t

To report the TGR results in a clinically meaningful way,

we expressed TGR as a percentage increase in tumor volume during 1 month : TGR = 100 [exp(TG) – 1]

TGomez-Roca C, Koscielny S et al, Eur J Cancer 2011

Defining TGR

Tumor volumeat time t Tumor volume

at baseline

TumorGrowth

Assuming the tumor growthfollows an exponential law

Vt =V0 exp(TG.t)

Tumor volume (V) was approximatedby V = 4 π R3 where R= D/2

3

RECIST(-1)R-1

RECIST(0)R0

RECIST(+1)R+1

t-1 t+1

mm

months

TG-1 TG+1

3 log(R0/ R-1)t-1

3 log(R+1/ R0)t+1

TGR-1

100 [exp(TG-1) – 1]

Percentage increasein tumor volume during 1 month

TGR+1

100 [exp(TG+1) – 1]

TGR ratio

TGR+1

TGR-1

Calculating TGRin clinical practice

What do I need ?

3 RECISTs evaluations

Days of CT scan

evaluation

Enter the values in an excel file

with the formula

Patients treated by monotherapyanti PD1 or anti PD-L1 agents

in phase I trials at Gustave Roussybetween Dec. 2011 and Jan. 2014

N=218

Progressionbefore the first evaluation

N=18

Toxicitybefore the first evaluation

N=5

TGR evaluable patientsduring the REFERENCE

and the EXPERIMENTAL periodN=166

REFERENCE periodshorter than 2 weeks

or longer than 3 monthsN=35

No tumor burdenmeasurable by RECISTon previous CT-scan

N=2

No previous CT-scanN=27

CT-scan evaluationafter baseline available

(on treatment)N= 195

Clinically meaningfulTGR evaluable patients

N=131

Flowchart of study selection process

Analysis of the TGR between the REFERENCE and the EXPERIMENTAL periods

Analysis of the TGR between the REFERENCE and the EXPERIMENTAL periods

A subset of progressive patients presenting a marked increase in tumor growth

HPD definitionPD by RECIST at the first evaluation

and a ≥ 2-fold increase in the TGR experimental compared to reference period

1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5

5

10

15

20

25

Number of patients with TGR EXP > TGR REF x t

Threshold (t)

Fre

que

ncy (

N)

Number of patients with TGR EXP > TGR REF x t

stabilizes after t > 2, suggesting specific subset

of hyperprogressing patients

How HPD was defined ?

A subset of progressive patients presenting a marked increase in tumor growth

Association between HPD and overall survival

0 5 10 15 20 25 30 35

0.0

0.2

0.4

0.6

0.8

1.0

Months

Overa

ll surv

ival (%

)

CR or PR (n=16)

SD (n=64)

PD non−HPD (n=36)

HPD (n=10)

overall log−rank test

P= 1e−05

landmark survival analysis, landmark point set to 2 months

19

−3

4

34

−4

9

49

−6

4

64

−7

9

−100

−50

0

50

100

Age

RE

CIS

T (

%)

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HPD is associated with older age

non HPD HPD

20

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wilcoxon test

P= 0.0066

REC

IST

(%)

Age (years) < 35 35-49 50-64 ≥65Fisher-exact test :

15.4% 13.3% 15.4% 5.6%Overall Response Rate (%)

8% 0% 8% 19%HPD Rate (%)

P=1.9 e-4

P=0.046

HPD in patients treated by anti-PD-1/PD-L1



we identified 12 patients as HPD, representing 9% of the evaluable patients (12/131)

= 24% of progressing patients by RECIST at the first evaluation (12/49)

HPD is associated with older age and worse outcome






This analysis did not evaluate accelerated progressions within : • PD patients due to new lesions• Early clinical PD without on treatment CT evaluation







This analysis did not evaluate accelerated progressions within : • PD patients due to new lesions• Early clinical PD without on treatment CT evaluation


no association between HPD and tumor burden at baseline (RECIST sum) (P=0.64)number of metastatic sites (P=0.76) Royal Marsden Hospital (RMH) prognostic score (P=0.43)number of previous lines (P=0.69)corticosteroids at baseline (P=0.16) type of previous treatment line blood characteristics at baseline : lymphocytes (P=0.64), neutrophils (P=0.69), albumin (P=0.23), fibrinogen (P= 0.43) or LDH (P=0.097)

Crossing survival curves in phase 3 trials

Nivolumab vs Docetaxelin non-sq. NSCLC

Checkmate 057, Borghaei et al. (NEJM 2015).

Pembrolizumab vs chemotherapy in Urothelial Carcinoma.

Keynote 045, Bellmunt et al. (NEJM 2017).

Nivolumab vs standard therapyin HNSCC

Checkmate 141, Ferris et al. (NEJM 2016)

Ferté et al. (2014). Tumor growth rate is an early indicator of antitumor drug activity in phase I clinical trials. Clinical Cancer Research

TGR profiling across 12 phase I clinical trials

Ferté et al. (2014). Tumor Growth Rate Provides Useful Information to Evaluate Sorafenib and Everolimus Treatment in Metastatic Renal Cell Carcinoma Patients: An Integrated Analysis of the TARGET and RECORD Phase 3 Trial Data. European Urology

Tumor Growth Rate of RCC with Sorafenib

Assessment of the tumor growth kinetics ratio (TGKR) based on TGK on immunotherapy (TGKPOST) and

TGK before starting immunotherapy (TGKPRE)

254x190mm (96 x 96 DPI)

Regional recurrenceLocal recurrence

Hyperprogression during anti-PD-1/PD-L1 therapy in patients with recurrent and/or metastatic head and neck squamous cell carcinoma.

Saâda-Bouzid et al. (2017) Annals of Oncology

Hyperprogression : TGK ratio (TGKR) ≥229% (10/34)

PFS (RECIST)

OS

Saâda-Bouzid et al. (2017). Hyperprogression during anti-PD-1/PD-L1 therapy in patients with recurrent and/or metastatic head and neck squamous cell carcinoma. Annals of Oncology

Hyperprogression during anti-PD-1/PD-L1 therapy in patients with recurrent and/or metastatic head and neck squamous cell carcinoma.

Saâda-Bouzid et al. (2017) Annals of Oncology

Table 1. Patients characteristics

TGKR<2

N (%)

TGKR≥2

N (%)

P value

Total 24 10

Immune checkpoint inhibitor 0.23

PD-1 inhibitor 18 (75) 5 (50)

PD-L1 inhibitor 6 (25) 5 (50)

Number of previous lines of treatment in the R/M setting 0.70

0 2 (8) 0

1 14 (58) 6 (60)

>2 8 (34) 4 (40)

Gender 1

female 5 (21) 2 (20)

male 19 (79) 8 (80)

Tobacco 1

yes 20 (83) 8 (80)

no 4 (17) 2 (20)

HPV status 1

p16 negatif 10 (42) 2 (20)

p16 positif 4 (17) 1 (10)

unknown 10 (42) 7(70)

Previous neck irradiation 1

yes 23 (96) 10 (100)

no 1 (4) 0

Local recurrence 0.46

yes 11 (46) 3 (30)

no 13 (54) 7 (70)

Regional recurrence 0.008

yes 9 (38) 9 (90)

no 15 (62) 1 (10)

Distant metastases 0.70

yes 15 (62) 5 (50)

no 9 (38) 5 (50)

Tumor size at baseline (S0) 0.7

≤ median 11 (46) 6 (60)

> median 13 (54) 4 (40)

TGKR = Tumor growth kinetics ratio; PD-1: Programmed death 1 receptor; PD-L1 Programmed death

ligand 1 receptor; R/M: Recurrent and/or metastatic; HPV: Human papilloma virus

Saâda-Bouzid et al., Annals of Oncology 2017

MDM2Mouse double minute 2

• MDM2 amplification is found in 7 % of cancers

• Inhibit the P53 tumor suppressor

• Immune checkpoint blockade can lead to Elevated interferon gamma

Activation of JAK-STAT signaling

Increase in interferon regulatory factor 8 (IRF-8)

binds to MDM2 promoter

Kato et al. (CCR 2017). Hyperprogressors after Immunotherapy: Analysis of Genomic Alterations Associated with Accelerated Growth Rate.

RECIST(-1)R-1

RECIST(0)R0

RECIST(+1)R+1

t-1 t+1

mm

months

TG-1 TG+1

3 log(R0/ R-1)t-1

3 log(R+1/ R0)t+1

TGR-1

100 [exp(TG-1) – 1]

Percentage increasein tumor volume during 1 month

TGR+1

100 [exp(TG+1) – 1]

TGR ratio

TGR+1

TGR-1

Calculating TGRin clinical practice

What do I need ?

RECIST(-1)R-1

RECIST(0)R0

RECIST(+1)R+1

t-1 t+1

mm

months

TGK-1 TGK+1

R0-R-1

t-1

R+1- R0

t+1

TGK ratioTGK+1

TGK-1

Calculating TGKR

Saâda-Bouzid et al. (2017). Hyperprogression during anti-PD-1/PD-L1 therapy in patients with recurrent and/or metastatic head and neck squamous cell carcinoma. Annals of Oncology

Saâda-Bouzid et al. (2017)

@iTOXreport

Stéphane CHAMPIAT MD, PhDcGustave [email protected]

Get updates on last publications about irAEs



Charles FertéJean-Charles SoriaAurélien MarabelleSamy AmmariLaurent DercleChristophe Massard

Documents

ESMO advanced Course on · Stéphane Champiat, MD, PhDc Drug Development Department (DITEP) Gustave Roussy 16-17th February 2018 Amsterdam, Netherlands The issue of fast progression