practice changing studies in 2017...weekly cisplatin 30 mg/m2/week n=150 conventional radiation (70...

PRACTICE CHANGINGSTUDIES IN 2017

Jean-Pascal Machiels

Department of Medical Oncology

Institut Roi Albert II

Cliniques universitaires Saint-Luc

Université catholique de Louvain, Brussels, Belgium

Presentation outline

• TNM 8th Edition

• Weekly or three-weekly cisplatin concomitantly to RT ?

• Recurrent and/or metastatic disease

TNM unknown primary, 8th edition

Lydiatt et al. CA Cancer J Clin 2017

TNM cervical lymph node, 8th edition


Depth of invasion

TNM oral cancer, 8th edition


TNM oral cancer, 8th edition


Shao Hui Huang et al. JCO 2015;33:836-845

©2015 by American Society of Clinical Oncology

T4 or N3 disease

Huang et al JCO 2015

HPV positive oropharyngeal cancer: prognosis

8

TNM p16+ oropharyngeal cancer, 8th edition


TNM p16 + oropharyngeal cancer, 8th edition


T4 or N3 = stage IIIT3 or N2 = stage II

TNM p16+ oropharyngeal cancer, 8th edition


• TNM 7th classification = N2b

• TNM 8th classification = N1

• The patient shoudl still receive chemoradiation

• WE DOT NOT CHANGE THE TREATMENT !

De-intensification in oropharyngeal cancer

• De-intensification of systemic therapy

- Cetuximab versus cisplatin (RTOG1016, TROG1201, De-escalate)

• De-intensification of radiation therapy

- Surgery to select for de-intensification of radiation (ECOG331, ADEPT)

- Induction chemotherapy to select for de-intensification of radiation (ECO1308, Quarterback study)


• De-intensification of systemic therapy

- Cetuximab versus cisplatin (RTOG1016, TROG1201, De-escalate)

• De-intensification of radiation therapy

- Surgery to select for de-intensification of radiation (ECOG331, ADEPT)

- Induction chemotherapy to select for de-intensification of radiation (ECO1308, Quarterback study)


Key messages • New TNM classification• De-intensication strategies are explored

BUT are not standard of care today


• TNM 8th Edition



Conventional Radiation (70 Gy in 7 weeks)

Weekly cisplatin 30 mg/m2/weekN=150

Conventional Radiation (70 Gy in 7 weeks)

Cisplatin 100 mg/m2 Day 1, 22, 43N=150

Stage III/IV

Primary endpoint = Loco-regional control

Noronha et al. J. Clin Oncol 2017

Weekly cisplatin versus three weekly cisplatin?

17



2-y survival rate: 58 vs 73%

• Toxicity:

– More grade 3 or higher with high-dose: 84% vs 71%

– Hospitalisation more frequent with high-dose: 31% vs 13%

• Weakness:

– 30 mg/m2 of cisplatin in the weekly regimen

– 93% received post-operative CRT


Three weekly concomitant CRT versus weekly cisplatin

N = 520

Randomisation 1:1

Stage III-IVB

Stratification:- Stage- Centers

Concomitant chemoRT 100 mg/m2 every 3 weeks(2 cycles)

Concomitant chemoRT 40 mg/m2 weekly(6 cycles)

Primary endpoint: Failure-free survival

Liang et al ASCO 2017

• Toxicity:

– Grade 3 or 4 toxicities were similar between two arms,

– Leucopenia was significantly higher in weekly 24.8% vs 15.9% (P = 0.015).

– Thrombocytopenia was significantly higher in weekly 5.2% vs 1.1% (P = 0.01).

– Stomatitis (35.2% vs 32.6%, P = 0.576),

– Nausea/vomiting (11.2% vs 12.5%, P = 0.684)


21



Key messages• Standard of care = Concomitant chemoradiation

with high dose cisplatin (100 mg/m2)


• TNM 8th Edition



Design N

Nivolumab(Checkmate 141)

Phase III 361

Pembrolizumab(Keynote-040)

Phase III 495

Durvalumab(Hawk)

Single arm 111

Atezolizumab Single arm 32

Nivolumab 3 mg/kg IV Q2W

Investigator’s Choice

• Methotrexate 40 mg/m² IV

weekly

• Docetaxel 30 mg/m² IV

weekly

• Cetuximab 400 mg/m² IV

once, then 250 mg/m²

weekly

R

2:1

Key Eligibility Criteria• R/M SCCHN of the oral

cavity, pharynx, or larynx

• Progression on or within 6

months of last dose of

platinum-based therapy

• Irrespective of number of

prior lines of therapy

• Documentation of p16 to

determine HPV status

(oropharyngeal cancer only)

• Regardless of PD-L1 status

Stratification factor• Prior cetuximab treatment

Primary endpoint• OS

Other endpoints• PFS

• ORR

• Safety

• DOR

• Biomarkers

• Patient-reported

quality of life

Clinicaltrials.gov NCT02105636

Phase 3 Checkmate 141 study design

Ferris et al NEJM 2016

27

240 169 132 98 76 45 27 12 3

121 88 51 32 22 9 4 3 0

Months

0 3 6 9 12 15 18 21 24

OS

(%)

0

10

20

30

40

50

60

70

80

100

90

Nivo

IC

No. of patients at risk

19.7%

34.0%21.5%

8.3%

Nivolumab

Investigator’s choice

0

0

18-mo OS =

Median OS,

mo (95% CI)

HR

(95% CI) P value

Nivolumab (n = 240) 7.7 (5.7, 8.8) 0.71

(0.55, 0.90)0.0048

Investigator’s choice (n = 121) 5.1 (4.0, 6.2)

Overall survival

Gillison & Ferris ASCO 2017

Key Eligibility Criteria

• SCC of the oral cavity, pharynx, or

larynx

• PD after platinum-containing regimen

• ECOG PS 0 or 1

Pembrolizumab

200 mg IV Q3W

for 2 y

Methotrexate 40 mg/m2 QWd

OR

Docetaxel 75 mg/m2 Q3WOR

Cetuximab 250 mg/m2 QWe

R

1:1

PRIMARY ENDPOINT: Overall survival

N=495

Cohen et al. LBA45

Phase 3 Keynote 040 study design

0 5 1 0 1 5 2 0 2 5 3 0

0

1 0

2 0

3 0

4 0

5 0

6 0

7 0

8 0

9 0

1 0 0

T im e , m o n th s

OS

, %

N o . a t r is k

2 4 7 1 5 9 1 0 3 48 14 2 0

2 4 8 1 4 8 82 34 10 1 0

1 2

37.3%

27.2%

Overall survival (IIT population)

Cohen et al. LBA45

Median OS,

mo (95% CI)

HR

(95% CI)P

value

Pembrolizumab 8.4 (6.4-9.4) 0.81

(0.66-0.99)0.0204

SOC 7.1 (5.9, 8.1)

0 5 1 0 1 5 2 0 2 5 3 0

0

1 0

2 0

3 0

4 0

5 0

6 0

7 0

8 0

9 0

1 0 0

T im e , m o n th s

OS

, %

N o . a t r is k

6 4 4 9 3 5 1 9 7 1 0

6 5 3 8 2 2 9 2 0 0

120 5 1 0 1 5 2 0 2 5 3 0

0

1 0

2 0

3 0

4 0

5 0

6 0

7 0

8 0

9 0

1 0 0

T im e , m o n th s

OS

, %

N o . a t r is k

1 9 6 1 3 1 8 7 4 3 1 4 2 0

1 9 1 1 1 3 6 3 2 8 8 1 0

12

PD-L1 CPS ≥1 PD-L1 TPS ≥50%

40.1%26.7%

8.7 mo (6.9-11.4)

7.1 mo (5.7-8.6)

Median (95% CI)

Events, n HR (95% CI) P

Pembro 137 0.75a 0.0078b

SOC 157 (0.59-0.95)

46.6%25.8%

11.6 mo (8.3-19.5)

7.9 mo (4.8-9.3)

Median (95% CI)

Events, n HR (95% CI) P

Pembro 41 0.54a 0.0017b

SOC 55 (0.35-0.82)

Overall survival by PD-L1 expression

27

240 169 132 98 76 45 27 12 3

121 88 51 32 22 9 4 3 0

Months

0 3 6 9 12 15 18 21 24

OS

(%)

0

10

20

30

40

50

60

70

80

100

90

Nivo

IC

No. of patients at risk

19.7%

34.0%21.5%

8.3%

Nivolumab

Investigator’s choice

0

0

18-mo OS =

Median OS,

mo (95% CI)

HR

(95% CI) P value

Nivolumab (n = 240) 7.7 (5.7, 8.8) 0.71

(0.55, 0.90)0.0048

Investigator’s choice (n = 121) 5.1 (4.0, 6.2)

37% in the pembrolizumab study

27% in the pembrolizumab study

Overall survival

Gillison & Ferris ASCO 2017

Keynote 040 vs checkmate 141: why this difference ?

Type, n (%)

Pembrolizumab

N = 247

SOC

N = 248

Anya 83 (33.6) 100 (40.3)

Chemotherapy 70 (28.3) 76 (30.6)

EGFR inhibitor 20 (8.1) 19 (7.7)

Kinase inhibitor 3 (1.2) 8 (3.2)

Immune checkpoint inhibitor 10 (4.0) 31 (12.5)

Other immunotherapy 4 (1.6) 1 (0.4)

Other 2 (0.8) 2 (0.8)

POST-study treatment

Keynote 040 vs checkmate 141: why this difference ?

Pembrolizumab Nivolumab

Cetuximab 30% 10%

Docetaxel 42% 43%

Methotrexate 27% 38%

Standard arm

Inclusion criteria N Response rate 1 y-Survival

Durvalumab(Hawk)

• PD-L1 high:

Tumor cell > 25%

111 16% 33.6%

Atezolizumab • Enriched with

PD-L1 expression

of > 5% on IC

32 All group: 22%

IC0/1: 14% (n=7)

IC2/3: 24%(n=25)

36%

Zandberg et al 1042OBahleda et al 1044O

Nivolumab

N = 240 randomized

Progressed

n = 146 (61%)

Not included in analysisa

n = 94 (39%)

Treated beyond progression (TBP)

n = 62 (42%)

Not treated beyond progression

(NTBP)

n = 84 (58%)

Treatment beyond progression with nivolumab

Checkmate 141

Haddad et al 1043O

11

-100

-80

-60

-40

-20

0

20

40

60

80

100

* * *

* * ** * * * * * *

* *** * * * * * * * *

*

*

PR PR PR PR PR PR PR PR PR

PR

*

Bes

t re

du

ctio

n f

rom

pro

gres

sio

n in

tar

get

lesi

on

(%

)

>20% increase in target lesion at time of progression

Best overall response from randomization was partial response

• After initial progression, 15 (24%) patients had reduction in target lesion• 3 had >30% reduction• 5 had >20% increase in target lesion at first progression

PR

*

Tumor reduction in patients treated beyond PD

Haddad et al 1043O

Cisplatin/5FU/Pembrolizumab

Pembrolizumab

Cisplatin/5FU/Cetuximab

Primary endpoint: progression-free survival

Recurrent SCCHN: first-line

Stage III/IV SCCHN

Chemoradiation

Chemoradiation + Anti-PD1/PD-L1

R

Chemoradiation +/- Anti-PD1/PD-L1

[email protected]

practice changing studies in 2017...weekly cisplatin 30 mg/m2/week n=150 conventional radiation (70...

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