Systemic Therapy in Head and Neck

Cancer
Kevin Harrington
RMH Registrar Teaching, 28.10.16

Treatment Options for Late Stage Disease

Surgery
Radiotherapy
Standard Fractionation
Hyperfractionation/Accelerated Concomitant Boost
IMRT

Neo-Adjuvant Therapy
Pre-operative chemotherapy

Adjuvant Therapy
Post-operative Chemoradiotherapy

Curative Combined Modality Treatment

Concomitant chemoradiotherapy
Induction Chemotherapy plus RT
Sequential Therapy
RT plus targeted drugs

 3 cycles CDDP/5-FU

3 toxic deaths in chemo arm

no difference in OS

pCR/MRD in 33%
pCR/MRD in 18% stage IV
PORT in 33% (chemo) vs 46% (control)

Loco-regional relapse

Distant metastasis

Treatment Options for Late Stage Disease

Surgery

Radiotherapy
Standard Fractionation
Hyperfractionation/Accelerated Concomitant Boost
IMRT

Neo-Adjuvant Therapy
Pre-operative chemotherapy

Adjuvant Therapy
Post-operative Chemoradiotherapy

Curative Combined Modality Treatment

Concomitant chemoradiotherapy
Induction Chemotherapy plus RT
Sequential Therapy
RT plus targeted drugs

Post-operative Chemo-RT
459 pts

334 pts

Surgery

Surgery

231

60-66 Gy/30-33F

228

167

167

60-66 Gy/30-33F
CDDP 100 mg/m2 d1, 22, 43

66 Gy/33F

66 Gy/33F
CDDP 100 mg/m2 d1, 22, 43

RTOG 9501 Cooper et al NEJM 2004; 350: 1937

EORTC Bernier et al NEJM 2004; 350: 1945

L-R control HR = 0.61 (95% 0.41-0.91)

5 year PFS = 47% C-RT vs 36% RT

2-year L-R control = 82% C-RT vs 72% RT

OS HR = 0.70 (95% 0.52-0.95)

DFS HR = 0.78 (95% 0.61-0.99)

5-year OS = 53% C-RT vs 40% RT

OS HR = 0.84 (95% 0.65-1.09)

Absolute factors are: R2 resection and ECS in LN

Relative factors are: R1 resection and 2+ LN

EGF102998
SURGERY/
SCREENING

S
U
R
G
E
R
Y

RANDOMIZATION

Eligibility criteria:
SCCHN
Stage II/III/IVa
High-risk (R1, R2
and/or ECS)

R
1:1

Stratification:
Tumor site
Nodal status
EGFR expression
Geographical
region

TREATMENT (RTQA)

MAINTENANCE

Lapatinib
(1500 mg/d)

Cisplatin/RT*
+ Lapatinib
(1500 mg/d)

Lapatinib
(1500 mg/d)

37 days

67 weeks

12 months

Placebo

Cisplatin/RT*
+ Placebo

FOLLOW
-UP

F/U

Placebo

*Cisplatin 100 mg/m2 on Days 1, 22 and 43; RT 2 Gy/day, 5 days/week. Patients were followed-up every 4 months for 2 years and then every
6 months until withdrawal from the study, or death, whichever occurred first.
ECS, extracapsular spread; EGFR, epidermal growth factor receptor; F/U, follow-up; RT, radiotherapy; RTQA, Radiotherapy Quality
Assurance

Harrington et al ASCO 2014

Disease-free survival (%)

1.0

CRT + placebo
CRT + lapatinib

0.8
0.6
HR = 1.10
(95% CI 0.85, 1.43; p=0.4502)

0.4
0.2
0.0

10

20

30

40

50

60

70

Time since randomization (months)

Number at risk
Lapatinib 346
Placebo
342

215
209

177
172

130
127

88
89

42
45

11
8

Treatment Options for Late Stage Disease

Surgery
Radiotherapy
Standard Fractionation
Hyperfractionation/Accelerated Concomitant Boost
IMRT

Neo-Adjuvant Therapy
Pre-operative chemotherapy

Adjuvant Therapy
Post-operative Chemoradiotherapy

Curative Combined Modality Treatment

Concomitant chemoradiotherapy
Induction Chemotherapy plus RT
Sequential Therapy
RT plus targeted drugs

Survival Data

Subgroup Analyses (1)

Subgroup Analyses (2)

Subgroup Analyses (3)

Effects of Chemotherapy on Survival at 5 Years:

Pignon Meta-Analysis (2000)
Trial Category
All trials

No. of Trials
65

No. Patients Difference(%)

10850
+4

P value
<0.0001

Adjuvant

1854

+1

0.74

Induction
PF
Other Chemo

31
15
16

5269
2487
2782

+2
+5
0

0.10
0.01
0.91

Concomitant

26

3727

+8

<0.0001

Monnerat, et al. Annals of Oncology, 13: 995-1006, 2002.

R
A
N
D
O
M
I
Z
E

T
P

F
EUA

P
F

Surgery
Daily Radiotherapy
Hyperfractionated

TPF: Docetaxel 75D1 + Cisplatin 75D1 + 5-FU 750 CI- D1-5 Q 3 weeks x4
PF: Cisplatin 100 D1 + 5-FU 1000 CI-D1-5 Q 3 weeks x 4

Outcome Data

R
A
N
D
O
M
I
Z
E

T
P

Carboplatin - AUC 1.5

Weekly

F
Surgery

EUA
P

Daily Radiotherapy

F
TPF: Docetaxel 75D1 + Cisplatin 100D1 + 5-FU 1000 CI- D1-4 Q 3 weeks x3
PF: Cisplatin 100 D1 + 5-FU 1000 CI-D1-5 Q 3 weeks x 3

Outcome Data

L-R Failure

Distant Failure

5 trials, 1772 patients

Distant Failure

 RTOG 0129 study

Tested accelerated chemo-RT vs standard fractionation chemo-RT
Post-hoc sub-group analysis in OP patients
HPV-16 DNA in situ analysis (if negative tested 18,31,33,35,39,45,51,52,56,58,59,68)
p16 by MTM immunohistochemistry

Stage III/IV SCCHN

OC, OP, L, HP
PS 0 or 1
R
Tobacco use recorded
Stratified by N stage and
PS

RT (6 weeks) + CDDP days 1 and 22

RT (7 weeks) + CDDP days 1, 22, 43

NEJM 2010; 363: 24-35

HPV Status is a Prognostic Biomarker

3-year PFS
HPV+ve = 73.7% (95% CI 67.7-79.8)
HPV-ve = 43.4% (95% CI 34.4-52.4)

NEJM 2010; 363: 24-35

Risk Group Stratification

De-Escalate?

De-Escalate?

Escalate?

Escalate?
NEJM 2010; 363: 24-35

De-Escalate Study (and RTOG1016)

Prof H. Mehanna

Treatment Options
Surgery
Radiotherapy
Standard Fractionation
Hyperfractionation/Accelerated Concomitant Boost
IMRT
Adjuvant Therapy
Post-operative Chemoradiotherapy
Curative Combined Modality Treatment
Concomitant chemoradiotherapy
Induction Chemotherapy plus RT
Sequential Therapy
RT plus targeted drugs

Effects of blockade of EGFR-signaling

Monoclonal antibodies

Small molecule inhibitors

NO DOWNSTREAM SIGNALING
VEGF
angiogenesis

DNA-repair

PI3K-AKT
survival pathway

JAK-STAT pathway
regulating gene
transcription

MMP9
invasion

Pro-proliferative
RAS-MAPK pathway

Cetuximab Plus RT

Bonner et al. NEJM 2006; 354: 567

RTOG 0522 Study

*RT (6 weeks) + CDDP days 1 and 22
N = 448

SCCHN
R
Oro/Hypopharynx, Larynx
T2N2-3, T3-4N(any)
3-DCRT or IMRT
N = 940
Evaluable = 895

*RT (6 weeks) + CDDP days 1 and 22

+ Cetuximab (7 weeks)
N = 447

Primary Endpoint - PFS HR = 1.05 (0.84-1.29)

2-year PFS 63% vs 64%
Secondary Endpoints OS HR = 0.87 (0.66-1.15): 83% vs 80%
Grade 3/4 mucosal and skin reactions significantly greater with Cetuximab

Relapsed Disease: Overview

Approach to recurrence
Palliative chemotherapy
First-line
Second-line
Experimental

Recurrent Disease
Interval from Primary Treatment
< 12 months

> 12 months

Operable to R0
Yes
Surgical
Salvage

No
Palliative
Chemotherapy
or
BSC

Operable to R0
Yes

Surgical
Salvage

No
Surgery +
POre(C)RT
or
ReRT/CRT
or
Pall. chemo
or
BSC

GORTEC 98-03
Re-RT + 5-FU and OH-urea
Recurrence
2nd Primary

Methotrexate
N = 57
Very slow accrual
4 complete responders
OS at 12 months = 23% vs 22%
16 patients had grade 3+ toxicity (11 in Re-RT)
Radiother. Oncol. 2011; 100: 70-75

Active Agents in Head and Neck Cancer

Bleomycin
Vinca alkaloids
Methotrexate
5-FU
Platins (carboplatin, cisplatin)
Taxanes (paclitaxel, docetaxel)
Gemcitabine
Irinotecan
EGFRi

First-Line Therapy

EXTREME Trial Patient Profile (1)

EXTREME Trial Progression-Free Survival

EXTREME Trial Overall Survival

EXTREME Trial Response Summary

EXTREME Trial OS Data, Forest Plot

EXTREME Trial PFS Data, Forest Plot

No significant adverse effect on QoL from addition of cetuximab

Overall Survival

Second-Line Therapy

Zalutumumab Phase III Study

Second-line
Best supportive care (BSC) vs BSC + Zalutumumab
Median OS (months) = 5.2 (BSC) vs 6.7 (BSC + Z) p = 0.065
Median time to next anti-cancer treatment (days) = 79 vs 170

Overall Survival Data

Response Data

QoL Data

Cancer Immunity Cycle

Cyclic and self-propagating

Immune Responses: Activation and Effector Phases

Immune Activation (1)

APC

MHC

TCR

T cell

Signal 1:
MHC Class I CD8 TCR
MHC Class II CD4 TCR
ACTIVATION

B7

CD28

B7
CTLA-4

Provides specificity at level

of TCR recognition of
specific antigen in the
correct MHC context

Immune Activation (2)

APC

MHC

TCR

T cell
Signal 2:
Co-stimulation
ACTIVATION

B7

CD28

B7
CTLA-4

CD28 molecules on T cell

must receive an additional
+ve signal by binding B7 in
order to reinforce Signal 1

Immune Activation (3)

APC

MHC

TCR

T cell
Signal 2:
Inhibition
INHIBITION

B7

B7

CTLA-4

CD28

B7 molecules on APC are

bound to CTLA4 receptor on
T cells. T cell does not
receive positive Signal 2 and
is inhibited

Effector Phase (1)

T cell

ACTIVATION

TCR MHC

PD1

Tumour cell
T cell activation:
Tumour cell does not
express PD-L1.
TCR recognition of antigen
results in T cell activation
against target

Effector Phase (2)

T cell

ACTIVATION

TCR MHC

PD1

IFNg

Tumour cell
T cell activation:
T cell secretes IFNg (and
other cytokines) which
upregulates expression of
PD-L1 on tumour cells

Effector Phase (3)

T cell

TCR MHC

INHIBITION

PD1

PD-L1

Tumour cell
T cell inactivation:
Inhibition of T cell activity
by binding of an inhibitory
ligand (PD-L1) to the
programmed death-1
receptor

Signalling Across the Immune Synapse and Its Modulation

Investigational Immune Checkpoint

Inhibitors in HNC1
Target

Agent

Molecule

Development

PD-1

Pembrolizumab
MK-3475

Humanized IgG4 mAb

Phase 1-3

PD-1

Nivolumab
BMS-936558

Fully human IgG4 mAb

Phase 1-3

PD-L1

Avelumab
MSB0010718C

Fully human IgG1 mAb

Phase 1-3

PD-L1

Durvalumab
MEDI-4736

Engineered human IgG1 mAb

Phase 1-3

(+)
CTLA-4

Tremelimumab

Engineered human IgG2 mAb

CTLA-4

Ipilimumab

Humanized IgG1 mAb

Phase 1

FcR binding: G1 High, G2 v.v. low; G3 High; G4 intermediate

Complement activation: G3 > G1> G2 >> G4
CTLA-4 = cytotoxic T lymphocyte associated protein-4; Ig = immunoglobulin; mAB = monoclonal antibody; PD-1 = programmed death receptor-1; PD-L1
= programmed death ligand 1.
1. Clinical Trials.gov. https://clinicaltrials.gov/. Accessed August 1, 2015 (plus additional information on Aveleumab)

HNC Immunotherapy Trials

Agent
PD-1 inhibitor
Nivolumab
BMS-936558

PD-1 inhibitor
Pembrolizumab

Ph

Line

III

2L

CheckMate 141:
Nivolumab Vs. Investigators choice (CTX, MTX, or DOC) in R/M HNC
after platinum failure

III

1L

CheckMate 651:
Nivolumab + Ipilimumab Vs. EXTREME in patients with R/M HNC

490

III

2L

KEYNOTE 040:
Pembrolizumab Vs. Investigators Choice (MTX, DOC, or CTX) in R/M
HNC after platinum failure

466

III

1L

KEYNOTE-048: Pembrolizumab vs. Pembro + Pt + 5-FU vs EXTREME

(CTX+ Plat + 5-FU) in R/M SCCHN

750

II

2L

KEYNOTE-055: Pembrolizumab in platinum- and cetuximab-resistant R/M

HNC (Single arm)

150

III

1L

KESTREL: Durvalumab + Tremelimumab Vs. EXTREME (CTX + Plat + 5FU)

628

III

2L

EAGLE: Durvalumab or durvalumab + tremelimumab vs. Investigators

choice in R/M SCCHN

720

II

2L

HAWK: Durvalumab in PD-L1(+) R/M HNC (single arm study)

112

II

2L

CONDOR: Durvalumab vs. tremelimumab vs. durvalumab + tremelimumab

in PD-L1(-) R/M SCCHN

240

MK3475

PD-L1 Inhibitor
Durvalumab/
MEDI-4736
+
CTLA-4 Inhibitor
Tremelimumab

Trial Design / Patient Population

360

Pembrolizumab (MK-3475)

High-Affinity, IgG4, Humanized Monoclonal Antibody Against PD-1

Exerts dual ligand blockade of PD-L1 and PD-L2
No cytotoxic (ADCC/CDC) activity
Low occurrence of anti-drug antibodies and no impact on pharmacokinetics
Demonstrated antitumor activity in multiple tumor types1-7
1. Robert C et al. N Engl J Med 2015 [Epub ahead of print], 2. Moskowitz CH et al. Blood. 2014;124(21):abstr 290 3. Garon EB et al. N Engl J Med 2015 [Epub ahead of print], 4.
Chow LQM et al. Ann Oncol. 2014;25(suppl 4):abstr LBA31, 5. Muro K et al. J Clin Oncol. 2015;33(suppl 3):abstr 3, 6. Plimack E et al. J Clin Oncol 2015;33(suppl 7) abstr 2967, 7.
Nanda R et al. Presented at: SABCS 2014; December 9-13, 2014; San Antonio, TX. Abstr 1349.

Pembrolizumab in SCCHN: KEYNOTE 012

60 patients with PD-L1 +ve tumours

10 mg/kg dosing q2weeks
Seiwert et al. Lancet Oncol. 2016

Change (from baseline) in tumour size

Seiwert et al. Lancet Oncol. 2016

Progression-free survival

Seiwert et al. Lancet Oncol. 2016

Overall survival

Seiwert et al. Lancet Oncol. 2016

Association of IFN Signature and PFS in HNC

Progression-Free Survival (Days)

1. IR group: Inflamed Responders

400

Gamma-IFN inflamed
Benefitting from anti-PD1 therapy

2. INR group: Inflamed Nonresponders

300

PFS cutoff
at 5 or 6 months
200

Gamma-IFN inflamed
Not benefitting from antiPD-1 therapy
Given biologic signalcan these patients be
converted into responders, eg, via
combinations, vaccine, etc

3. NI group: Noninflamed

100

0
1.5

2. 0
2. 5
IFN- Signature Score

Other
Partial response
Stable disease

Very high negative predictive value

Not benefitting from antiPD-1 therapy
Clinically potentially useful: Identify patients
who should NOT receive PD-1 therapy
Unclear whether noninflamed phenotype can
be converted into inflamed phenotype

IFN = interferon; PD-1 = programmed death receptor-1; PFS = progression-free survival.

1. Seiwert TY et al. J Clin Oncol. 2015;33(suppl; abstr 6017).

Presented by: Tanguy Seiwert at 2015 ASCO Annual Meeting

6-gene Signature from Keynote-012

Seiwert et al. Lancet Oncol. 2016

Outcome by PD-L1 Status

Second-Line Therapy with Nivolumab

Ferris et al. NEJM (in press)

Demographics

Ferris et al. NEJM (in press)

Planned Interim Analysis

Planned events
required for IA
n (%)

Actual events
observed at IA
n (%)

Critical value for detecting

superiority at IA

195 (70)

218 (78)

P 0.0227

The Data Monitoring Committee declared the statistical boundary for OS

was crossed and the study was stopped early
The OS hazard ratio was 0.70 (97.73% CI, 0.510.96) for nivolumab:IC with
P=0.0101 in favor of nivolumab

IA, interim analysis; IC, investigators choice therapy; OS, overall survival.

Progression-Free Survival
Progression-Free Survival
(% of patients)

100
90
80
70
60
50

6-month PFS rate (95% CI)

21.5% (16.227.4)

40
30
20
10

10.2% (5.117.2)

0
0

12

15

18

Months

No. at Risk

Nivolumab
Investigators
Choice

240

79

32

12

121

43

Median PFS, mo
(95% CI)
Nivolumab (n = 240)

2.0 (1.9, 2.1)

Investigators Choice (n = 121)

2.3 (1.9, 3.1)

HR
(97.73% CI)

P-value

0.89
(0.70, 1.1)

0.3236

Ferris et al. NEJM (in press)

Ferris et al. NEJM (in press)

Overall Survival by PD-L1 Expression

PD-L1 Expression 1%

PD-L1 Expression <1%

100

90

90

80

80

70

70

60

60

50

50

Overall Survival (% of patients)

100

40

40

Nivolumab

30

30

20

20

10

10

Investigators Choice

Investigators Choice

0
0

12

15

18

Months

No. at Risk
Nivolumab
Investigators
Choice

Nivolumab

88
61

67
42

44
20

18
6

12

15

18

Months
6
2

0
0

Median OS,
mo (95% CI)

HR
(95% CI)

Nivolumab (n=88)

8.7 (5.79.1)

IC (n=61)

4.6 (3.85.8)

0.55
(0.360.83)

73

52

33

17

38

29

14

Median OS,
mo (95% CI)

HR
(95% CI)

Nivolumab (n=73)

5.7 (4.412.7)

IC (n=38)

5.8 (4.09.8)

0.89
(0.541.45)

Overall Survival by p16 Status

p16-positive

p16-negative
100

90

90

80

80

70

70

60

60

50

50

Overall Survival (% of patients)

100

40

40

Nivolumab

30
20

20

Investigators Choice

10

10

Investigators Choice

0
0

12

15

18

Months

No. at Risk

Nivolumab
Investigators
Choice

Nivolumab

30

63
29

49
20

35
11

18
4

12

15

18

6
3

1
1

0
0

Months
10
1

3
0

Median OS,
mo (95% CI)

HR
(95% CI)

Nivolumab (n=63)

9.1 (7.210.0)

IC (n=29)

4.4 (3.09.8)

0.56
(0.320.99)

0
0

50
36

32
26

25
13

12
7

Median OS,
mo (95% CI)

HR
(95% CI)

Nivolumab (n=50)

7.5 (3.0NA)

IC (n=36)

5.8 (3.89.5)

0.73
(0.421.25)

Study 1108: SCCHN cohort

Study design
10 mg/kg q2w x 1 year

SCCHN (PD-L1+ and PD-L1)

Durvalumab
0.110 mg/kg q2w
15 mg/kg q3w
x 1 year

Dose expansion

Dose escalation

NSCLC (squamous + non-squamous)

Pancreatic adenocarcinoma

Melanoma (uveal + cutaneous)

Gastroesophageal cancer
Triple-negative breast cancer
Hepatocellular carcinoma
(hepatitis C and B virus-positive)

After one year of treatment, patients enter

follow-up
Treatment beyond progressive disease was
permitted in the absence of clinical deterioration
and if the investigator considered that the patient
continued to receive benefit
Upon progressive disease during the follow-up
period, retreatment was offered for up to an
additional 12 months

Eight additional tumour types

Key inclusion criteria

Key exclusion criteria

Confirmed recurrent/metastatic SCCHN incurable with local

therapy

Active autoimmune disease

ECOG PS 01

Prior severe or persistent irAE

Adequate organ function

Prior anti-PD-1 or anti-PD-L1 therapy

Prior anti-CTLA-4 therapy permitted

PD-L1+ and PD-L1 patients
89

Segal NH, et al. Poster presented at ASCO 2015. Poster 3011

Study 1108: SCCHN cohort

Tumour response overall, and by PD-L1

DCR, ORR, duration of response and ongoing responders by PD-L1 status
Durvalumab 10 mg/kg
All patients
(n=62)

PD-L1+
(n=22)

PD-L1
(n=37)

RECIST response (ORR), n/N (%)

95% CI

7/62 (11)
4.721.9

4/22 (18)
5.240.3

3/37 (8)
1.721.9

DCR 24 weeks*, n/N (%)

95% CI

9/62 (15)
6.925.8

4/22 (18)
5.240.3

4/37 (11)
3.025.4

Range of ongoing DoR, weeks

16.1+55.4+

41.1+53.1+

16.1+55.4+

Ongoing responders, n/N (%)

5/7 (71)

2/4 (50)

3/3 (100)

*DCR (CR + PR + SD 24 weeks) and ORR (confirmed CR and PR) are based on RECIST v1.1. DoR for the 2 patients no longer responding per RECIST were 8.4
and 56.3 weeks. PD-L1 status was determined via the PD-L1 (SP263) immunohistochemical assay

Data cut-off: 7 April, 2015

90

Segal NH, et al. Poster presented at ASCO 2015. Poster 3011

Study 1108:
SCCHN cohort

Tumour response by subgroup

Tumour response by sub-group
Durvalumab 10 mg/kg
HPV+

HPV

Former/current
smoker

RECIST response (ORR),, n/N (%)

95% CI

1/25 (4)
0.120.4

4/25 (16)
4.536.1

2/39 (5)
0.617.3

DCR 24 weeks,, n/N (%)

95% CI

1/25 (4)
0.120.4

5/25 (20)
6.840.7

3/39 (8)
1.620.9

Never smoker
5/23 (22)
7.543.7
6/23 (26)
10.248.4

HPV status was collected at baseline from patient records; ORR (confirmed CR + PR) and DCR (CR + PR + SD 24 weeks) are based on RECIST v1.1; There were
2 responders among the 12 patients with unknown HPV status

Data cut-off: 7 April, 2015

91

Segal NH, et al. Poster presented at ASCO 2015. Poster 3011

Study 1108: SCCHN cohort

Antitumour activity

Tumour shrinkage by PD-L1 status (n=54)

Best change in tumour size from baseline by PD-L1 status

(n=54)

PD-L1
PD-L1+
PD-L1 na

PD-L1+

PD-L1

PD-L1 n/a

Patients with baseline and 1 on-treatment scan

Disease assessment at 6, 12, and 16 weeks, and then every 8 weeks
PD-L1 status determined via the PD-L1 (SP263) immunohistochemical assay

Data cut-off: 7 April, 2015

92

Segal NH, et al. Poster presented at ASCO 2015. Poster 3011

Second-Line Therapy (Durvalumab/Tremelimumab)

First-Line Approaches (Durvalumab/Tremelimumab)

1 EXTREME regimen

R
N= 628

1 Single agent Durvalumab

Primary EP PFS, OS

2 Durvalumab/Tremelimumab
Study Start Date = October 2015

First-Line Approaches (Nivolumab)

1 EXTREME regimen

R
N= 490

Primary EP PFS, OS

1 Nivolumab/Ipilimumab

Study Start Date = August 2016

First-Line Approaches (Pembrolizumab KEYNOTE 048)

1 EXTREME regimen

R
N= 825

1 Single agent pembrolizumab

1 Cisplatin/5-FU/pembrolizumab
Study Start Date = March 2015

Primary EP
PFS, OS