head and neck cancer · dissection . final pathology report c/w t2n2b disease (stage 4): primary...

Head and Neck Cancer

Robert Haddad, MD

Disease Center Leader

Head and Neck Oncology Program

Dana Farber Cancer Institute

Harvard Medical School

Boston, MA

Case 1

John is a 65 year old teacher with a new diagnosis of squamous cell carcinoma(SCC) of right floor of mouth approaching midline . He is treated with surgery and bilateral neck

dissection . Final pathology report c/w T2N2b disease (Stage 4): Primary tumor is 2.5 cm,

margins are clear and no PNI. 2/36 nodes with SCC, largest is 2 cm. No ECE . He is

referred to see you to discuss adjuvant therapy . He is healthy and does not smoke

cigarettes. You recommend:

1. Close monitoring and no further treatment now.

2. Concurrent chemoradiotherapy with bolus cisplatin at 100 mg/m2 every 3 weeks

3. Post operative Radiotherapy alone

4. Adjuvant chemotherapy with cisplatin and 5-Fluorouracil

5. Concurrent Cetuximab and Radiotherapy

Case 2

you are seeing a 45 year old male with metastatic squamous cell carcinoma (SCC). He

has a history of HPV related SCC of the left tonsil and ipsilateral neck and received

concurrent bolus cisplatin and radiation 5 years ago . Recent Chest CT shows multiple

lung nodules. Biopsy c/w p16+ SCC. He has a PS 0. PDL-1 staining is negative. His

only medication is atenolol for HTN. You recommend:

1. Single agent PD1 inhibitor (Nivolumab or Pembrolizumab)

2. Cisplatin, 5-Fluorouracil and Pembrolizumab

3. Cisplatin,5-fluorouracil and cetuximab

4. Carboplatin/Paclitaxel/Bevacizumab

5. Nivolumab+ Ipilumumab

3

4


• Introduction:

Epidemiology, Clinical Features, Prevention, Treatment Modalities

• Concurrent Chemoradiotherapy

• Sequential Chemoradiotherapy

• Adjuvant Chemoradiotherapy

• Palliative Therapy

• Nasopharyngeal Carcinoma

5

Head and Neck Cancer Primary Disease Sites

Oral Cavity

Pharynx

Larynx

Nasal Cavity

Paranasal

Sinuses

6

Epidemiology

• 48000 new cases per year in US.

• Median age of diagnosis: ~60 years

• Male>Female

• Strongly associated with tobacco and alcohol

• Epstein-Barr virus risk factor for nasopharynx cancers

• Human papillomavirus increasingly appreciated as a risk

factor

Circular 8 kB dsDNA Genomes

Only One Coding Strand

Infect Epithelial Cells

~ 200 HPV types

~ 30 Mucosal HPVs

Low-Risk: Genital Warts

High-Risk: Lesions That Progress to Cancer

HPV E6/E7 Oncoproteins

Small, Non-Enzymatic Proteins

(~ 150aa E6; ~ 100aa E7)

Associate With and Functionally Modify

Host Cellular Protein Complexes

HPV GENOME INTEGRATION

LCR E6 E7

Frequent Event During Malignant Progression

Terminates Viral Life Cycle

Expression of E6 and E7 Is Retained

HPV-Associated Cancers

> 99% of Cervical Carcinoma

~ 90% Anal Carcinomas

~ 40% Vulvar and Vaginal Carcinomas

~ 60% of Oropharynx Cancers

Human Papillomavirus (HPV)

Münger et al, 2004.

7

8

Human Papillomavirus (HPV)-Positive


• HPV 16 is the viral subtype in the vast majority of

patients.

• Half of oropharynx cancers will have HPV 16 DNA.

• Often occurs in nonsmokers, nondrinkers

• Median age younger than HPV-negative patients;

incidence increasing

• Men and women at more similar risk.

• Associated with ↑ number of sexual partners and high-

risk sexual practices

• Favorable prognosis

Fakhry C, et al. J Clin Oncol. 2006:24(17):2606-2617. Chaturvedi AK, et al. J Clin Oncol. 2008;26(4):612-619.

HPV testing in tumors

• In situ hybridization

• p16 immunohistochemistry

• PCR

Rising Incidence of HPV-Associated Cancers

Chaturvedi et al, 2008.

Smoking related

HPV- related

Survival Outcomes by HPV Status in

Oropharyngeal Cancer in RTOG 0129

Ang et al NEJM 2010

RTOG 0129 Phase III Trial:

Concomitant CRT With Standard Vs. Accelerated Fractionation RT in

Advanced SCCHN

Stage III/IV (T2, N2–3, M0,

or T3–4, any N, M0) SCCHN❖ Oral cavity, oropharynx,

hypopharynx, larynx

❖ No prior RT to head and neck

except radioactive iodine

therapy

❖ No prior surgery to primary

tumor or nodes except for

diagnostic biopsy

Expected N = 720

Cisplatin

(IV on D1, 22, 43)

Standard fractionation RT

(5 d/wk for 7 wks)

CRT

R

A

N

D

O

M

I

Z

E

Cisplatin

(IV on D1, 22)

Accelerated fractionation RT

(5 d/wk for 3.5 wks; then twice

daily, 5 d/wk for 2.5 wks)

US NIH, 2010c.

HPV Analysis

▪ 433 (60%) of 721 had oropharynx primary

▪ 323 (75%) of 433 had HPV determination by ISH

▪ 206 (64%) of 323 were HPV-positive

▪ 198 (96%) of 206 were HPV16-positive

P16-positive P16-negative

HPV-positive 192 (96%) 7 (4%)

HPV-negative 22 (19%) 94 (81%)

Ang et al, NEJM 2010 ISH: in situ hybridization

P16 determined by immunohistochemical analysis

RTOG 0129: OS and PFS by HPV Status

Ang. N Engl J Med. June 7, 2010

3-Year Outcomes HPV Positive (%) HPV Negative (%) P Value

OS 82.4 57.1

Two distinct HNSCC entities

HPV positive HPV negative

Anatomic site Tonsil /Base of Tongue All sites

Histology Basaloid Keratinized

Age Younger Older

Gender 3:1 men 3:1 men

SE status High Low

Risk factors Sexual behavior ETOH/tobacco

Cofactors Marijuana/?immune

suppression

ETOH/tobacco

Incidence Rising Declining

Survival Improved Worse

There is a major change in the etiology of head and neck cancer, the incidence

of OPC rapidly increasing mostly North America and Europe

should we treat them

the same ?

Cisplatin 75mg/m2 d1

Paclitaxel

90mg/m2d1,8,15

Cetuximab 250mg/m2

d1,8,15

Q 21 days for 3 cycles

E

R V

E A

S L

P U

O A

N T

S I

E O

N

CLINICAL CR

Low dose IMRT 54Gy/27fx* +

Cetuximab qWeek

CLINICAL PR/SD

Full dose IMRT 69.3Gy/33fx* +

Cetuximab qWeek

Induction

Chemotherapy

Concurrent

Chemoradiation

Eligibility

• Oropharynx

SCC

• HPV ISH + and

/ or p16+

• Stage III, IVA

ECOG 1308: Phase II Schema

Marur et al : JCO 2016

E 1308: OS and PFS

17

PFS (A) and OS (B) in cohort with clinical complete response to induction

chemotherapy treated with low-dose radiation of 54 Gy (n = 51).

E 1308: OS and PFS

18

PFS (A) and OS (B) in favorable cohort (non-T4, non-N2c, ≤ 10 pack-year

smokers) with clinical complete response to induction chemotherapy treated

with low-dose radiation of 54 Gy (n = 27).

INTERMEDIATE:

Close margins

< 1mm ENE

2-4 metastatic LN

PNI/LVI

HIGH RISK Arm D:

Positive Margins

>1mm ENE or

≥5 metastatic LN

Radiation Therapy

IMRT 60 Gy/30 Fx

Evaluate 2-year PFS

Local-Regional

Recurrence, Functional

Outcomes/QOL

Transoral Resection

(any approach)

with neck dissection

Radiation Therapy

IMRT 50Gy/25 Fx

ECOG 3311 HPV+ trial schema

Assess

Eligibility:

HPV (p16)+

SCC

oropharynx

Stage III-IV:

cT1-2, N1-2b

Baseline

Functional/

QOL

Assessment

Observation

R

A

N

D

O

M

I

Z

E

Radiation Therapy

IMRT 66 Gy/33 Fx +

CDDP 40 mg/m2 weekly

LOW RISK Arm A :

pT1-T2N0-N1

negative margins

Accrual

= 519

20

Evaluation and Staging

• Clinical exam of the head and neck

• Endoscopy

– Fiberoptic flexible laryngopharyngoscopy

– Exam under anesthesia: laryngoscopy, esophagoscopy, bronchoscopy

• Biopsy

– Fine needle aspiration of a neck node

– Punch/core biopsy

– Excisional biopsy

• Computed axial tomography/magnetic resonance imaging of primary

site and neck

• Chest imaging

• Positron emission tomography

• Tumor-Node-Metastasis system applied

21

Treatment Approach

Disease Extent Treatment

T1N0-1 or T2N0 Surgery or RT

T2N1 or T3-4 or N2-3 Combined modality

Recurrent or M1

Surgery and/or RT

Combined modality

Chemotherapy

NCCN Clinical Practice Guidelines in Oncology. Head and Neck Cancers. V.2.2010.

http://www.nccn.org/professionals/physician_gls/f_guidelines.asp.

22

Surgical Therapy: General Principles

• Oncologically adequate resection: Clear surgical margins

• Comprehensive versus selective neck dissection

• Factors suggesting disease unresectable for cure:

– Massive skull base infiltration

– Involvement of prevertebral fascia

– Invasion of the cervical vertebrae or brachial plexus

– Encasement of the carotid artery

– Skin infiltration

– Rapid local or regional recurrence after surgery

23

Radiation Therapy

Standard Fraction Dosage

Treatment Setting Dose*

Definitive RT

Primary & gross lymph nodes > 70 Gy

Neck: low-risk nodal stations > 50 Gy

Adjuvant RT (4-6 weeks after surgery)

Primary > 60 Gy

Neck: high-risk nodal stations > 60 Gy

Neck: low-risk nodal stations > 50 Gy

*Fractions are 2.0 Gy/day


http://www.nccn.org/professionals/physician_gls/f_guidelines.asp

24

Toxicities of Radiation Therapy

• Mucositis/edema → dysphagia → feeding tube

• Xerostomia and loss of taste

• Hypothyroidism

• Lhermitte’s syndrome

• Long-term induration and fibrosis

• Osteoradionecrosis of the jaw

• Cervical myelopathy

25

Treatment Approach




Recurrent or M1 Surgery and/or RT

Combined modality

Chemotherapy

Concurrent Chemoradiotherapy

27

The Debate Over Therapeutic Sequence:

MACH-NC Findings

MACH-NC: Meta-Analysis of Chemotherapy in Head and Neck Cancer; PF=cisplatin + fluorouracil

1. Pignon JP, et al. Lancet. 2000;355(9208):949-955. 2. Monnerat C, et al. Ann Oncol. 2002;13(7):995-

1006..

Design

(No. of Studies/

No. of Subjects)

Hazard Ratio

(95% CI)

Chemotherapy

Effect

(P -value)

Absolute Benefit

2 Years 5 Years

Adjuvant1

(8/1854)

0.98

(0.85-1.19)0.74 1% 1%

Neoadjuvant1

(31/5269)

0.95

(0.88-1.01)0.10 2% 2%

Concurrent1

(26/3727)

0.81

(0.76-0.88)< 0.0001 7% 8%

Total1

(65/10,850)

0.90

(0.85-0.94)< 0.0001 4% 4%

No. of Trials No. of Subjects Difference at 5 Years P -value

PF induction2 15 2487 5% 0.01

Concurrent Therapy: Standard of Care

• RT standard fractionation, 70 Gy over 7 weeks (2-Gy fractions)

• Alternative Chemotherapy regimens: 1- Weekly cisplatin 40mg/m2

2- Weekly Cetuximab

3- Weekly carboplatin AUC1.5-2 + Paclitaxel 30-45mg/m2

• Cisplatin 100 mg/m2 days 1, 22, and 43 of RT

29

RTOG 91-11 Induction Cisplatin/5-FU vs Concomitant

Cisplatin vs RT Alone in

Resectable SCC

Forastiere AA, et al. Presented at: American Society of Clinical Oncology 2006 Annual Meeting. Abstract 5517. Published as

Forastiere AA, et al. J Clin Oncol. 2006;24(18S):5517.

Forastiere AA, et al. N Engl J Med. 2003;349(22):2091-2098.

Resectable stage III/IV

SCC

• Glottic or supraglottic

cancer

• Previously untreated

N = 515

Cisplatin (100 mg/m2, d1)

5-FU (1000 mg/m2/day, d1-5 C-I)

every 3 wks, 2 cycles

CRT (N = 171)

R

A

N

D

O

M

I

Z

E

ICT→RT (N = 173)

Cisplatin (100 mg/m2, every 3

wks, 3 cycles)

RT (2 Gy/fr, 35 fr, total 70 Gy)

RT (2 Gy/fr, 35 fr, total 70 Gy)

RT (N = 171)

RT

(2 Gy/fr, 35 fr,

total 70 Gy)

• Primary end point: larynx preservation

• Secondary end point: LFS

LFS=laryngectomy-free survival

30

RTOG 91-11

Larynx Preservation (LP) Trial

Arm Stomatitis*LP rate

(5yrs)DFS (5yrs)

OS

(5yrs)

RT 24% 65.7% 27.3% 53.5%

Chemo →RT 24% 70.5% 38.6% 59.2%

ChemoRT 43% 83.6% 39.0% 54.6%

Conclusion: Concomitant chemoradiation is superior to induction chemotherapy followed by RT and RT alone for laryngeal preservation.

There is no difference in overall survival between the 3 arms.

* > or = Grade 3

Forastiere AA, et al. Presented at: American Society of Clinical Oncology 2006 Annual Meeting. Abstract 5517. Published

as Forastiere AA, et al. J Clin Oncol. 2006;24(18S):5517.

Forastiere AA, et al. N Engl J Med. 2003;349(22):2091-2098.

RTOG 91-11 Study: 10-year Update

Forastiere A A et al. JCO 2013;31:845-852

©2013 by American Society of Clinical Oncology

38.8%

27.5%

Primary Endpoint LFS

os

33 Bonner JA, et al. N Engl J Med. 2006;354(6):567-578.

Phase III Trial: Cetuximab + RT for SCC

Advanced SCC

• Stage III/IV

• N = 424

RT*

+

Cetuximab (400 mg/m2, then

250 mg/m2/wk)

R

A

N

D

O

M

I

Z

E

RT* alone

*Choice of:

• Once-daily RT: 70 Gy in 35 fractions

• Twice-daily RT: 72.0-76.8 Gy in 60-64 fractions

• Concomitant boost: 72 Gy in 42 fractions

Grade 3-5 Toxicity

RT Alone

(N = 212)

RT + Cetuximab

(N = 208) P-value

Mucositis 52% 56% .44

Acneiform Rash 1% 17% < .001

Infusion Reaction 0% 3% .01

Anemia 6% 1% .006

34Bonner JA, et al. N Engl J Med. 2006;354(6):567-578.

Phase III: Cetuximab + RT for SCC

47% vs 34% at 3 years

P < .01 at 3 years

55% vs 45% at 3 years

P = .05 at 3 years

Locoregional Control OS

JAVELIN Head and Neck 100: Study Design

LA SCCHN

Avelumab 10

mg/kg IV

R

Placebo IV

Placebo IV

+ SOC

Chemoradiation

Avelumab 10 mg/kg IV

+ SOC

Chemoradiation

Placebo IV Q2W

Up to 12 months

Avelumab 10 mg/kg IV Q2W

Up to 12 months

Lead in Phase CRT Phase Maintenance Phase

1:1 Randomization

Inclusion criteria:

• LA SCC oral cavity, oropharynx,

larynx, hypopharynx

• HPV-; stage II, Iva, Ivb

• HPV+: T4 or N2c (AJCC 7) or N3

• ECOG PS = 0 or 1

• No prior therapy

Primary Endpoint: PFS by investigator per modified RECIST v1.1

Stratification Factors

• T stage (

Sequential Chemoradiotherapy

37

TAX 324: Sequential Combined Modality Therapy

R

A

N

D

O

M

I

Z

E

P

P

F

F

Carboplatinum - AUC 1.5 Weekly

Daily Radiotherapy

T

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

Surgery

as

Needed

Posner MR, et al. N Engl J Med. 2007;357(17):1705-1715.

38

Patient Characteristics: TPF vs PFIntent to Treat Population

Posner MR, et al. N Engl J Med. 2007;357(17):1705-1715.Posner. N Engl J Med. 2007;357:1705

TAX 324: Results

❖ TPF significantly improves survival and PFS compared with PF in an ICT

regimen followed by CRT

Posner et al, 2007.

TPF 62%

PF 48%

TPF 67%

PF 54%

Log-rank p = .0058

HR = 0.70

TPF 53%

PF 42%TPF 49%

PF 37%

Log-rank p = .004

HR = 0.701

Survival PFS

Time (mos)

Su

rviv

al P

rob

ab

ility

(%

)

0 6 12 18 24 30 36 42 48 54 60 66 72

0

10

20

30

40

50

60

70

80

90

100

TPF (N = 255)

PF (N = 246)

Time (mos)P

FS

Pro

babili

ty (

%)

0 6 12 18 24 30 36 42 48 54 60 66 72

0

10

20

30

40

50

60

70

80

90

100

TPF (N = 255)

PF (N = 246)

TPF significantly improves survival and PFS compared with PF in an ICT regimen followed by CRT

Posner. N Engl J Med. 2007;357:1705

40 Posner MR. N Engl J Med. 2007;357(17):1705-1715.

TAX 324 Phase III Trial: Docetaxel/Cisplatin/5-FU vs Cisplatin/5-FU

Sequential Therapy in Advanced SCCHN: Toxicity

Grade 3/4 Toxicity TPF PF

Stomatitis 21% 27%

Nausea 14% 14%

Lethargy 5% 10%

Vomiting 8% 10%

Diarrhea 7% 3%

Anorexia 12% 12%

Neutropenia 83% 56%

Febrile neutropenia 12% 7%

Neutropenic infection 12% 8%

Stomatitis 37% 38%

Dysphagia 23% 24%

Mouth, nose dryness 5% 4%

Nausea 6% 6%

Rash/itch 5% 2%

During ICT

N = 251 TPF,

243 PF

During CRT

N = 203 TPF,

184 PF

41

Taxane + PF Phase III Trials

Vermorken (2007)1 Hitt (2005)2

Chemo PF DPF PF PaPF

Subjects 181 177 193 189

Med PFS* 8.2 mo 11.0 mo 12 mo 20 mo

Med OS* 14.5 mo 18.8 mo 37 mo 43 mo

RR* 54% 68% 68% 80%

P < 0.05 for all outcomes except P = 0.06 for OS in Hitt study

1. Vermorken JB, et al. N Engl J Med. 2007;357(17):1695-1704. 2. Hitt R, et al. J Clin Oncol. 2005;23(34):8636-8645

42

Conclusions

• Overall survival advantage > 3 years with TPF sequential therapy

– 40.5 month improvement in median overall survival at 3 years

– 30% reduction in the risk of mortality (P = 0.0058)

• Consistent with prior phase III trial (TAX 323)

• Patients received a median of 3 cycles of induction chemotherapy in the TPF and PF arms.

• In the TPF arm, 81% of patients went on to receive CRT.

• Grade 3/4 treatment-emergent adverse events:

– Less stomatitis, thrombocytopenia, and lethargy in the TPF arm

– More neutropenia and febrile neutropenia (any grade) in the TPF arm

43

Impact of Induction Chemotherapy (CT):

Opposing Views and Ongoing Controversy

• Pro: Allows time to optimize patient medical status; Possible customization of RT dosing based on response to treatment; provides early treatment of distant micrometastatic disease

• Con: Induction CT may affect adversely compliance to subsequent concurrent CT/RT or choice of CT/RT regimen; adds 2-4 months to treatment

44

Clinical Scenarios to Consider Induction Therapy

1. Potential distant metastasis

2. Delay in radiation simulation

3. Impending local issue (eg, airway)

4. Markedly advanced disease (eg, bulky, N2c, N2b,

N3, low neck, dermal infiltration)

5. Organ preservation strategy in patients with markedly

advanced disease

45

Neck Dissection (ND)

After Chemoradiotherapy

• Indicated for gross residual disease

• Not indicated for pretreatment N1 disease that has

achieved clinical complete response

• For pretreatment N2-3 disease, opinions vary:

– When pretreatment neck disease is N2-3, some centers

recommend routine ND regardless of response to

chemoradiotherapy.

– However, others will observe if a clinical complete response on

PET scan 12 weeks post-therapy is achieved with

chemoradiotherapy.

Pellitteri PK, et al. Head Neck. 2006;28(2):166-175. Ong SC, et al. J Nucl Med. 2008;49(4):532-540.

Adjuvant Chemoradiotherapy

47

EORTC and RTOG Phase III Trials: Adjuvant RT ±

Concomitant Cisplatin

Bernier J, et al. N Engl J Med. 2004;350(19):1945-1952. Cooper JS, et al. N Engl J Med. 2004;350(19):1937-1944.

Resectable SCC

• Oral cavity, oropharynx, hypopharynx,

larynx

• Stage III/IV (EORTC), high risk (RTOG)

• Previously untreated

N = 334 (EORTC)

N = 459 (RTOG)

Surgery

R

A

N

D

O

M

I

Z

E

RT+

Cisplatin (100 mg/m2, d1,22,43)

EORTC: 66 Gy over 6.5 wks

RTOG: 60-66 Gy over 6-6.6 wks

48

Poor Risk Criteria

RTOG 95011

≥ 2 nodes

ECE

+Margins

EORTC 229312

Level IV/V (OC/OP)

ECE

+Margins

Perineural disease

Vascular emboli

ECE = extracapsular nodal extension; OC = oral cavity; OP = oropharynx

1. Cooper JS, et al. N Engl J Med. 2004;350(19):1937-1944.

2. Bernier J, et al. N Engl J Med. 2004;350(19):1945-1952.

49

OS (EORTC)1 OS (RTOG)2

EORTC and RTOG : Adjuvant RT ± Concomitant

Cisplatin

P=0.02

P=0.19

Months After Randomization

1. Bernier J, et al. N Engl J Med. 2004;350(19):1945-1952.

2. Cooper JS, et al. N Engl J Med. 2004;350(19):1937-1944.

50

RTOG 9501/EORTC 22931Which prognostic risk factors are most important?

• Extracapsular nodal extension and + margins: significant

benefit from chemoradiotherapy

• Trend toward benefit for stage III-IV disease, perineural

invasion, vascular embolisms, and/or clinically enlarged

level IV/V lymph nodes secondary to tumors in oral

cavity or oropharynx

• No benefit in patients with 2 or more nodes but no

extracapsular extension

Bernier J, et al. Head Neck. 2005;27(10):843-850.

51

Survivorship /Follow-Up

• Assess for recurrence/2nd primary/premalignant lesions

– 1st year: Q 1-3 mos

– 2nd year: Q 2-4 mos

– 3rd – 5th year: Q 4-6 mos

– > 5 years: Q 6-12 mos

• TSH q 6-12 months if neck irradiated

• Chest imaging as indicated

• Speech/Swallowing evaluation/rehabilitation as indicated

• Counsel regarding tobacco and alcohol use

• Integrate general medical care

• Once felt disease free, imaging of primary and neck not routinely

indicated unless suspicious signs or symptoms


http://www.nccn.org/professionals/physician_gls/f_guidelines.asp.

52

Treatment Approach




Recurrent or M1 Surgery and/or RT

Combined modality

Chemotherapy

Palliative Chemotherapy

54

Palliative Chemotherapy

• Treatment for recurrent disease without surgical or

radiotherapy option

• 1st line therapy:

– historically platinum-based doublet

– overall RR 30-40%

– median survival 6-9 months regardless of treatment

– randomized controlled trials fail to demonstrate clear

improvement in OS compared to RX with single agents

• Active agents: cisplatin, carboplatin, 5-FU, taxanes,

methotrexate, cetuximab, ifosfamide, gemcitabine (for

nasopharynx cancer) and others

DeVita VT, et al. Cancer: Principles & Practice of Oncology. 8th ed. Lippincott Williams & Wilkins; 2008.

55

EXTREME: Study Design

5-FU 1000 mg/m2 d1-4

with

Cisplatin 100 mg/m2 d1

or

Carboplatin AUC 5 d1

plus

Cetuximab 250 mg/m2/week*

q 3 weeks

*Loading dose of 400 mg/m2 on week 1

R

A

N

D

O

M

I

Z

E

N = 442

5-FU 1000 mg/m2 d1-4

with

Cisplatin 100 mg/m2 d1

or

Carboplatin AUC 5 d1

No

treatment

6 cycles maximum

POD or

toxicity

POD or

toxicity

Cetuximab

Vermorken JB, et al. N Engl J Med. 2008;359(11):1116-1127.

56

EXTREME: First-Line Platinum/5-FU ± Cetuximab in

Recurrent/Metastatic SCC

10.1 mos

7.4 mos

Survival Time (months)Patients at Risk:

Platinum/5-FUCetuximab + Platinum/5-FU

220 173 127 83 65 47 19 8 1222 184 153 118 82 57 30 15 3

HR (95% CI)=0.797 (0.644-0.986)

Strat. log-rank test: 0.0362

Platinum/5-FUCetuximab + Platinum/5-FU

Su

rviv

al

Pro

bab

ilit

y

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 3 6 9 12 15 18 21 24

OSRR

18%

35%


57

EXTREME: Overall Survival

C225+Platinum+FU Platinum+5-FU HR P-value

N = 222 N = 220

10.1 months 7.4 months 0.80 .04

Conclusion: Addition of cetuximab to standard first-line platinum-based chemotherapy improves overall survival.


CheckMate 141 Study Design

R

2:1

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)

Key Eligibility Criteria

• R/M SCCHN of the oral cavity,

pharynx, or larynx

• Not amenable to curative therapy

• Progression on or within 6 months of

last dose of platinum-based therapy

• ECOG PS 0–1

• Documentation of p16 to determine

HPV status

• No active CNS metastases

Stratification factor• Prior cetuximab treatment

CNS, central nervous system; DOR, duration of response; ECOG PS, Eastern Cooperative Oncology Group performance status; HPV, human papillomavirus; ORR, objective response rate;

OS, overall survival; PFS, progression-free survival; R, randomized; R/M, recurrent/metastatic; SCCHN, squamous cell carcinoma of the head and neck; Clinicaltrials.gov. NCT02105636.

Primary endpoint

• OS

Other endpoints

• PFS

• ORR

• Safety

• DOR

• Biomarkers

• Quality of life

Randomized, global, phase 3 trial of the efficacy and safety of nivolumab versus investigator’s choice in patients with R/M SCCHN

Ferris et al : NEJM 2016

Nivolumab

(n = 240)

n (%)

Investigator’s

Choice

(n = 121)

n (%)

Total

(N = 361)

n (%)

Median age (years) 59.0 61.0 60.0

< 65 172 (71.7) 76 (62.8) 248 (68.7)

≥ 65 68 (28.3) 45 (37.2) 113 (31.3)

Gender

Male 197 (82.1) 103 (85.1) 300 (83.1)

Race

White 196 (81.7) 104 (86.0) 300 (83.1)

Asian 29 (12.1) 14 (11.6) 43 (11.9)

Other 15 (6.3) 3 (2.5) 18 (5.0)

Smoking/tobacco use

Current/former 191 (79.6) 85 (70.2) 276 (76.5)

Never 39 (16.3) 31 (25.6) 70 (19.4)

Demographics (1)

Nivolumab

(n = 240)

n (%)

Investigator’s

Choice

(n = 121)

n (%)

Total

(N = 361)

n (%)

ECOG performance status

0 49 (20.4) 23 (19.0) 72 (19.9)

1 189 (78.8) 94 (77.7) 283 (78.4)

≥ 2 1 (0.4) 3 (2.5) 4 (1.1)

Not reported 1 (0.4) 1 (0.8) 2 (0.6)

Number of prior lines of

systemic cancer therapy

1 105 (43.8) 58 (47.9) 163 (45.2)

2 81 (33.8) 45 (37.2) 126 (34.9)

≥ 3 54 (22.5) 18 (14.9) 72 (19.9)

Site of primary tumor

Oral cavity 108 (45.0) 67 (55.4) 175 (48.5)

Pharynx 92 (38.3) 36 (29.8) 128 (35.5)

Larynx 34 (14.2) 15 (12.4) 49 (13.6)

Other 6 (2.5) 3 (2.5) 9 (2.5)

Demographics (2)

Nivolumab

(n = 240)

Investigator’s

Choice

(n = 121)

Total

(N = 361)

Patients receiving ≥ 1 dose, n

(%)236 (98.3) 111 (91.7) 347 (96.1)

Investigator’s choice therapy, n

(%)

Methotrexate – 46 (38.0) –

Docetaxel – 52 (43.0) –

Cetuximab – 13 (10.7) –

Median time on therapy, mo

(95% CI)1.9 (1.6–2.3) 1.9 (1.6–2.0) –

Median duration of follow-up,

mo (range)5.3 (0–16.8) 4.6 (0–15.2) –

Number of deaths, n (%) 133 (55.4) 85 (70.2) 218 (60.4)

Ongoing treatment, n (%) 41 (17.4) 3 (2.7) 44 (12.7)

Treatment Administration

0 3 6 9 12 15 18

Median OS,

mo (95% CI)

HR

(97.73% CI)p-value

Nivolumab (n = 240) 7.5 (5.5–9.1)0.70

(0.51–0.96)0.0101

Investigator’s Choice (n = 121) 5.1 (4.0–6.0)

Overall Survival

Months

Nivolumab 240 167 109 52 24 7 0

Investigator’s

Choice 121 87 42 17 5 1

No. at Risk

0

0

10

20

30

40

50

60

70

80

90

100

Ove

rall

Su

rviv

al (%

of

pa

tie

nts

)

1-year OS rate (95% CI)

36.0% (28.5–43.4)

16.6% (8.6–26.8)

MID

MID

Social Contact ProblemsSensory ProblemsPain

Week

P = .001P = .258P = .012 P

64

Pembrolizumab vs Standard of Care For Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: Phase 3 KEYNOTE-040 TrialEzra EW Cohen,1 Kevin J. Harrington,2 Christophe Le Tourneau,3 José Dinis,4 Lisa Licitra,5 Myung-Ju Ahn,6

Ainara Soria,7 Jean-Pascal Machiels,8 Nicolas Mach,9 Ranee Mehra,10 Barbara Burtness,11 Yang Wang,12

Alba Tuozzo,12 Jonathan D Cheng,12 Ramona Swaby,12 Denis Soulières13

1University of California, San Diego Moores Cancer Center, La Jolla, CA, USA; 2The Institute of Cancer Research/The Royal Marsden NHS Foundation Trust, London, UK; 3Institut Curie, Paris, France; 4Instituto Português de Oncologia do Porto Francisco Gentil, Porto, Portugal; 5Fondazione IRCCS Istituto Nazionale dei Tumori and University of Milan, Milan, Italy; 6Samsung Medical Center, Seoul, South Korea; 7Hospital Universitario Ramón y Cajal, Madrid, Spain; 8Cliniques Universitaires Saint-Luc, Brussels, Belgium; 9Hôpitaux Universitaires de Genève, Geneva, Switzerland; 10Fox Chase Cancer Center, Philadelphia, PA, USA (currently at Sidney Kimmel Cancer Center of Johns Hopkins University, Baltimore, MD, USA); 11Yale University School of Medicine and Yale Cancer Center, New Haven, CT, USA; 12Merck & Co., Inc., Kenilworth, NJ, USA; 13Centre Hospitalier de l’Université de Montréal, Montréal, QC, Canada

Phase 3 KEYNOTE-040 Study (NCT02252042)

Key Eligibility Criteria

• SCC of the oral cavity, oropharynx,

hypopharynx, or larynx

• PD after platinum-containing regimen

for R/M HNSCC or recurrence or PD

within 3-6 mo of multimodal therapy

using platinuma

• ECOG PS 0 or 1

• Known p16 status (oropharynx)b

• Tissue samplec for PD-L1 assessmentd

Pembrolizumab

200 mg IV Q3W

for 2 y

Stratification Factors

• ECOG PS (0 vs 1)

• p16 statusb (positive vs negative)

• PD-L1 TPSd (≥50% vs

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

Overall Survival in ITT Population

aCox proportional hazards model with treatment as a covariate stratified by the randomization stratification factors. Initially reported data: HR 0.82 (95% CI, 0.67-1.01), P = 0.0316. After the initial report, updated survival data were obtained for 4 patients. bOne-sided P value based on the log-rank test stratified by the randomization stratification factors. Data cutoff date: May 15, 2017.

37.3%

27.2%

8.4 mo (6.5-9.4)7.1 mo (5.9-8.1)

Median (95% CI)

Events, n HR (95% CI) P

Pembrolizumab 179 0.81a (0.66-0.99) 0.0204b

SOC 201

Nivolumab+ Ipilimumab

Key Eligibility Criteria• No prior systemic therapy for R/M disease except if

chemotherapy was part of multimodal treatment ≤6 months prior to enrollment

• Tumor tissue required for HPV p16 (for OPC) and PD-L1 testing prior to randomization

Primary Endpoints: OS, PFS

Other Endpoints: ORR, time to deterioration, PD-L1 expression as biomarker

Start Date: August 2016

Randomized

EXTREME

Cetuximab +

cisplatin/carboplatin + 5-

FU

PD-1

CTLA-4

PD-L1

Adapted from Mellman I et al 2011.2

Platinum Sensitive

CHECKMATE-651: Phase III randomized, open-label study of

nivolumab + ipilimumab compared to the EXTREME regimen as 1L

treatment in patients with R/M SCCHN

Pembrolizumab

Key Eligibility Criteria• No prior systemic therapy in R/M setting, except if completed

>6 months prior to locally advanced disease

• Available tumor biopsy for PD-L1 analysis

• Have results for HPV status for oropharyngeal cancer

Primary Endpoint: PFS

Other Endpoints: OS, PFS (by Immune-Related Response), ORR

Start Date: March 2015

Randomized

Pembrolizumab

+ Platinum + 5FUActive Comparator

(cetuximab+ platinum+5-

FU)

Platinum Sensitive

PD-1

PD-L1

Adapted from Mellman I et al 2011.3

KEYNOTE-048: Phase III, randomized, open-label, clinical trial of

pembrolizumab in first line treatment versus active comparator in

patients with R/M SCCHN without prior systemic chemotherapy1

Nasopharyngeal Carcinoma

Clinical Characteristics

Nasopharyngeal Carcinoma

Neoplasm in the

nasopharynx

Skull base erosionCranial nerve

involvement

Regional Lymph node

metastasis

Distant metastasis

Standard Therapy for NPCAl-Sarraf Regimen, Intergroup 0099

R

A

N

D

O

M

I

Z

E

Cisplatin

XRT

XRT

147 pts•NPC

•St III & IV

5FU

Cisplatin

Al-Sarraf, JCO, 1998

Standard Therapy for NPCAl-Sarraf Regimen, Intergroup 0099

• 3Y PFS:

– 24% (RT alone) vs. 69% (CRT)

p < 0.001

• 3Y OS:

– 47% (RT alone) vs. 78% (CRT)

p = 0.005

Al-Sarraf, JCO, 1998

Study design

NPC

T3-4N1/N2-3M0

Investigational Group

CCRT:

DDP 40mg/m2 , QW

Adjunvant: 3 cycles

DDP 80mg/m2

5-FU 800mg/m2

Control Group

CCRT:

DDP 40mg/m2 , QW

Chen et al : The Lancet Oncology Volume 13, Issue 2 2012 163 - 171

Kaplan-Meier survival curves for the CCRT plus adjuvant chemotherapy group and the CCRT only group Failure-free survival (A),

overall survival (B), distant failure-free survival (C), and locoregional failure-free survival (D). Hazard ratios (HRs)...

Chen et al : The Lancet Oncology Volume 13, Issue 2 2012 163 - 171

RESULTS

Neoadjuvant Chemotherapy Followed by Concurrent

Chemoradiotherapy Versus Concurrent Chemoradiotherapy Alone

in Locoregionally Advanced Nasopharyngeal Carcinoma

Ming-Yuan Chen

Sun Yat-sen University Cancer Center, Guangzhou, China

ASCO 2017

Baseline characteristics

Characteristic NACT+CCRT Arm (238)

No. of patients (%)

CCRT only Arm (238)

No. of patients (%)

Age, y

Median 44 42

Range 19-65 21-66

Sex

Men 173 (72.7) 190 (79.8)

Women 65 (27.3) 48 (20.2)

T classification

T1 4 (1.7) 1 (0.4)

T2 44 (18.5) 48 (20.2)

T3 108 (45.4) 107 (45.0)

T4 82 (34.5) 82 (34.5)

N classification

N0 12 (5.0) 8 (3.4)

N1 35 (14.7) 39 (16.4)

N2 145 (60.9) 164 (68.9)

N3 46 (19.3) 27 (11.3)

Staging

II 1 (0.4) 0 (0.0)

III 117 (49.2) 133 (55.9)

IV 120 (50.4) 105 (44.1)

Radiotherapy technique

2DRT 122 (51.3) 149 (62.6)

IMRT 116 (48.7) 89 (37.4)

Intention-to-treat Analyses

DFS DMFS

Induction Chemotherapy in NPC

1. TPF Followed by ChemoRT vs. ChemoRT

2. 480 Patients

3. Attenuated dose of TPF: 60/60/600

4. Primary endpoint: FFS

5. Median Follow up 45 months Lancet Oncol 2016

Kaplan-Meier survival curves for the two treatment groups(A) Failure-free survival, (B) overall survival, (C) distant failure-free

survival, and (D) locoregional failure-free survival, all from the start of treatment.

Induction Chemotherapy in NPC

Lancet Oncol 2016

Recurrent/Metastatic NPC

• Locoregional relapse and DM occur in >30%

• As in other R/M head and neck cancers, outcomes are

poor

• Salvage surgery preferred approach to LR relapse

• Palliative chemotherapy is available to most patients

• OS typically 9-12 months

• Responses frequently short-lived

Trial design – Randomized, open-label, multi-center, phase III

Patients

◆Pathologically

confirmed recurrent or

metastatic NPC

◆At least one measurable

lesions per RESIST 1.1

◆PS 0-1 (ECOG)

GP group

G: 1000mg/m2,d1,d8, ivdrip

P: 80mg/m2, d1, ivdrip

q3w for 4-6 cycles

FP group

F: 1000mg/m2/day, civ=96h

P: 80mg/m2, d1, ivdrip

q3w for 4-6 cycles;

Primary Endpoint

◆PFS

Secondary Endpoints

◆ORR

◆OS

◆Safety

R

NPC, nasopharyngeal carcinoma; RESIST, Response Evaluation Criteria In Solid Tumors; PS, performance status; ECOG,

Eastern Cooperative Oncology Group; G, gemzar; P, cisplatin; F, 5-FU; civ, continuous infusion; PFS, progression-free survival;

OS, overall survival; ORR, objective response rate.

1:1

Lancet 2016: Li Zhang et al

Primary End Point: PFS by independent imaging-review committee

Intent-to-Treat Population (N=362)

Risk of progression or death decreased by 45% with GP vs. FP

Pro

gre

ssio

n-f

ree

Su

rviv

al

Months Since Randomization

GP

(N=181)

FP

(N=181)

Events – n (%) 156 (86.2) 173 (95.6)

Median PFS - months 7.0 5.6

HR for GP vs. FP (95% CI) 0.55 (0.44 to 0.68)

Two-sided P value

Conclusions: Treatment of SCCHN in 2018

• Multiple options available – Concurrent chemoRT

– Sequential therapy: TPF is the standard induction regimen

– Targeted therapy : Cetuximab/RT

– PD-1 inhibitors : Clear activity shown in platinum resistant disease .

• Patient selection is important– Stage, patient characteristics, PS, and primary site

• HPV-related oropharynx disease is a major public health problem– HPV-positive and HPV-negative disease are distinct entities

• Pts with HPV-positive disease demonstrate improved responses to therapy and better Survival

• De-intensification is a relevant and important research question

head and neck cancer · dissection . final pathology report c/w t2n2b disease (stage 4): primary...

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