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01

Novel Advances in the Management of Squamous Cell Carcinoma of the Head and NeckRobert Haddad, MDDisease Center Leader, Head and Neck Oncology Program, Dana-Farber Cancer Institute, Harvard Medical SchoolBoston, MA

02

Disclosures

• Research Funding: BMS, Merck, VentiRx, Boehringer Ingelheim, Celgene, Bayer

• Consultant: Merck, Eisai, Bayer, BI

• NCCN: Member—Head and Neck Committee

• NCCN: Chair—Thyroid Committee

03

Head and Neck Cancer

• Introduction– Epidemiology, HPV, Clinical Features, Prevention,

Treatment Modalities, Clinical Trials

• Concurrent Chemoradiotherapy

• Sequential Chemoradiotherapy

• Recurrent/Metastatic Disease

• Conclusion

04

Head and Neck Cancer Primary Disease Sites

• Oral Cavity

• Pharynx

• Larynx

• Nasal Cavity

• Paranasal Sinuses

Source: Maxwell V. Blum Cancer Resource Room.

05

Epidemiology

• Incidence:– US: 48,000 new cases per year– Central and South America: ≈43,000 per year

• 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

06

Circular 8 kB dsDNA GenomesOnly One Coding Strand

Infect Epithelial Cells≈200 HPV types

≈30 Mucosal HPVsLow-Risk: Genital Warts

High-Risk: Lesions That Progress to Cancer

HPV E6/E7 OncoproteinsSmall, 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

Münger K, et al. J Virol. 2004;78:11451-114560.

Human Papillomavirus (HPV)

07

Human Papillomavirus (HPV)-PositiveHead and Neck Cancer

• 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

• Favourable prognosis

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

08

HPV Testing in Tumours

• In situ hybridisation

• p16 immunohistochemistry

• PCR

09

PFS in overall population

Rising Incidence of HPV-Associated Cancers

Chaturvedi AK, et al. J Clin Oncol. 2008;26:612-619.

Smoking related

HPV- related

010

Survival Outcomes by HPV Status in Oropharyngeal Cancer in RTOG 0129Ang et al. N Engl J Med. 2010.

011

RTOG 0129 Phase III Trial: Concomitant CRT With Standard vs Accelerated Fractionation RT

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

tumour 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

RANDOMISE

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.

012PFS in overall population

RTOG 0129: OS and PFS by HPV Status

Ang KK, et al. N Engl J Med. 2010;363:24-35.

3-Year Outcomes HPV Positive (%) HPV Negative (%) P ValueOS 82.4 57.1 <0.001

PFS 73.7 43.4 <0.001

Locoregional failure 13.6 35.1 <0.001

Distant metastases 8.7 14.6 0.23

HR=0.38 (95% CI: 0.26-0.55); P<0.001 HR=0.40 (95% CI: 0.29-0.557); P<0.001

Ove

rall

Surv

ival

(%)

HPV negativeHPV positive

75

50

25

0

75

50

25

0Prog

ress

ion-

Free

Sur

viva

l (%

)

Overall Survival100

HPV negativeHPV positive

100PFS

013


Two Distinct HNSCC Entities

HPV positive HPV negative

Anatomic site Tonsil/base of tongue All sites

Histology Basaloid Keratinised

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 aetiology of head and neck cancer, the incidence of OPC rapidly increasing mostly in North America and Europe

Should we treat them the same?

014

E1308: A Phase II Trial of Induction Chemotherapy Followed by Cetuximab With Low Dose vs Standard Dose IMRT in Patients With HPV-Associated Resectable Squamous Cell Carcinoma of the OropharynxCmelak et al. ASCO 2014.

015

ECOG 1308: Phase II Schema

Cisplatin 75 mg/m2 d1Paclitaxel 90 mg/m2

d1, 8, 15Cetuximab 250 mg/m2

d1, 8, 15

q 21 days for 3 cycles

ER VE AS LP UO AN TS I E O

N

CLINICAL CR Low dose IMRT 54 Gy/27 fx + Cetuximab qWeek

CLINICAL PR/SDFull dose IMRT 69.3 Gy/33 fx+ Cetuximab qWeek

Induction Chemotherapy

Concurrent Chemoradiation

IMRT margins for primary: 1.0 to 1.5 cm around gross dzNodal margin: 1 cm margin minimum

Eligibility• OPSCC• Resectable• HPV ISH +

and/or p16+• Stage III, IVA

Cmelak et al. ASCO 2014.

016


Endpoint: 2-year PFS and OS

Cohort (n) 2-year PFS (90% CI) 2-year OS

All low dose pts (62) 0.80 (0.70, 0.88) 0.93 (0.85, 0.97)

T4a (7) 0.54 (0.19, 0.79) 0.86 (0.45, 0.97)

Non-T4a (55) 0.84 (0.73, 0.91) 0.94 (0.86, 0.98)

N2c (19) 0.77 (0.56, 0.89) 0.95 (0.76, 0.99)

Non-N2c (43) 0.82 (0.69, 0.90) 0.93 (0.82, 0.97)

Smoker >10 pk-years (22) 0.57 (0.35, 0.73) 0.86 (0.67, 0.94)

Smoker ≤10 pk-years (40) 0.92 (0.81, 0.97) 0.97 (0.87, 0.995)

Smoker ≤10 pk-years, <T4, N2c (27) 0.96 (0.82, 0.99) 0.96 (0.82, 0.99)

All high-dose pts (15)* 0.65 (0.41, 0.82) 0.87 (0.63. 0.96)

*3 high-dose pts did not go on to receive RT.Cmelak et al. ASCO 2014.

017


Overall survival by RT dose


Progression-free survival by RT dose

PFS and Survival: Dose

2-year = 80%

2-year = 65%

2-year = 87%

2-year = 93%

Cmelak et al. ASCO 2014.

018

Summary E1308

• Induction chemo followed by reduced-dose IMRT/cetuximab was feasible in a Cooperative Group setting

• CCR to induction was noted in 71% (52/80) and was well tolerated

• The 2-year PFS in 54 Gy IMRT patients was 80% (95% CI: 0.70, 0.88), and 2-year survival was 93%

• Best predictor of outcome: smoking history

• Best results of 54 Gy were in smokers <10 pk-years, non T-4 and non-N2c: 2-year PFS and 2-year survival of 96% (90% CI: 0.82, 0.99) (n=27)

• This approach remains investigational. Further studies are planned

019

RANDOMISE

A

Bolus cisplatin

XRT

RTOG 1016

STRATIFY

Weekly cetuximab

XRTB

Confirm p16

T1,2 vs T3,4

N0-2a vs N2b-3

PS 0,1 vs 2,3

>, <10 py

*Accrual Complete.

• Arm A (Control) RT + Cisplatin 100 mg/M2 on Days 1, 22 Concurrently with RT• Arm B (Investigational) RT + Weekly Cetuximab: 400 mg/m2 loading dose,

250 mg/m2 weekly + 1 week after RT• RT Accelerated IMRT, 70 Gy, 2 Gy Fx, in 6 Weeks

020

NRG HN002: A Randomised Phase II Trial for Patients With P16 Positive, Non-Smoking Associated, LocoregionallyAdvanced Oropharyngeal Cancer

Eligibility

• OP SCCA

• ≤10 pack-years

• T1-T2 N1-N2b

• T3 N0-N2b

60 Gy XRT (2 Gy/fx) in 6 weeks + cisplatin 40 mg/m2 weekly × 6 cycles

60 Gy XRT (2 Gy/fx) at 6 fractions/week for 5 weeks

R E G IS T E R

Central review

p16 + IHC

Declare IntentUnilat vs Bilat

Neck XRT

RANDOMISE

STRATIFY

021

Surgery: TORS, TLM, Other

022

ECOG-3311: HPV Positive

023

Evaluation and Staging

• Clinical exam of the head and neck• Endoscopy

– Fiberoptic flexible laryngopharyngoscopy– Exam under anaesthesia: laryngoscopy, oesophagoscopy,

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• Tumour-Node-Metastasis system applied

024

Treatment Approach

Disease Extent Treatment Options

T1N0-1 or T2N0 Surgery or RT

T2N1 or T3-4 or N2-3 Combined modality

Recurrent or M1

Surgery and/or RTCombined modalityChemotherapy

NCCN Clinical Practice Guidelines in Oncology. Head and Neck Cancers. V.2.2010. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp.

025

Treatment Approach




Recurrent or M1


026

Locoregionally Advanced

Surgery + RT ± Chemo

RT + ChemoSequential CRT

RT + ChemoSequential CRT

ComorbidityLow PS

CustomisedTreatment

Resectable

“Inoperable”

Unresectable

Locoregionally Advanced

027

Concurrent Chemoradiotherapy

028

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;355:949-955; 2. Monnerat C, et al. Ann Oncol. 2002;13:995-1006.

Design(No. of Studies/No. of Subjects)

Hazard Ratio(95% CI)

ChemotherapyEffect

(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 induction215 2487 5% 0.01

029

Concurrent Therapy: Standard of Care

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

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

• Potential approaches to improve on CRT:– Addition of induction chemotherapy– Accelerated fractionation of RT

030

RTOG 91-11 Induction Cisplatin/5-FU vs Concomitant Cisplatin vs RT Alone in Resectable SCC

Resectable stage III/IV SCC

• Glottic or supraglotticcancer

• Previously untreated

N=515

RANDOMISE

Cisplatin (100 mg/m2, d1)5-FU (1000 mg/m2/day, d1-5 C-I)

every 3 wks, 2 cycles

ICTRT (N=173)

CRT (N=171)

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)

LFS = laryngectomy-free survival.Forastiere AA, et al. N Engl J Med. 2003;349:2091-2098.

• Primary end point: larynx preservation

• Secondary end point: LFS

031

RTOG 91-11Larynx Preservation (LP) Trial

Arm Stomatitis*LP rate

(5 years)DFS

(5 years)OS

(5 years)

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%

*≥Grade 3.Forastiere AA, et al. N Engl J Med. 2003;349:2091-2098.

032

Forastiere AA, et al. J Clin Oncol. 2013;31:845-852.©2013 by American Society of Clinical Oncology.

38.8%

27.5%

Primary Endpoint LFS

os

Ten-year Update on RTOG-91-11

033PFS in overall population

Phase III Trial: Cetuximab + RT for SCC

Grade 3-5 ToxicityRT Alone (N=212)

RT + Cetuximab (N=208) P-value

Mucositis 52% 56% 0.44

Acneiform Rash 1% 17% <0.001

Infusion Reaction 0% 3% 0.01

Anaemia 6% 1% 0.006

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

Advanced SCC• Stage III/IV• N=424

RT*+

Cetuximab (400 mg/m2, then 250 mg/m2/wk)

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

RANDOMISE

034

PFS in overall populationPFS in overall population

Phase III: Cetuximab + RT for SCC: Results

47% vs 34% at 3 yearsP<0.01 at 3 years

55% vs 45% at 3 yearsP=0.05 at 3 years

Locoregional Control OS

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

035

Sequential Chemoradiotherapy

036

TAX 324: Sequential Combined Modality TherapyTPF vs PF Followed by Chemoradiotherapy

RANDOMISE

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 × 3 PF: Cisplatin 100 D1 + 5-FU 1000 CI-D1-5 Q 3 weeks × 3

Surgery as

Needed

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

037

Patient Characteristics: TPF vs PFIntent-to-Treat Population


038

PFS in overall populationPFS in overall population

TAX 324: Results

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

TPF 62%PF 48%

TPF 67%PF 54%

Log-rank P=0.0058HR=0.70

TPF 53%PF 42% TPF 49%

PF 37%

Log-rank P=0.004HR=0.701

Survival PFS

Time (mo)

Surv

ival

Pro

babi

lity

(%)

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 (mo)PF

S Pr

obab

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)


039


TAX 324 Phase III Trial: Docetaxel/Cisplatin/5-FU vs Cisplatin/ 5-FU Sequential Therapy in Advanced SCCHN—Toxicity

Grade 3/4 Toxicity TPF PFStomatitis 21% 27%

Nausea 14% 14%

Lethargy 5% 10%

Vomiting 8% 10%

Diarrhoea 7% 3%

Anorexia 12% 12%

Neutropaenia 83% 56%

Febrile neutropaenia 12% 7%

Neutropaenic infection 12% 8%Stomatitis 37% 38%

Dysphagia 23% 24%

Mouth, nose dryness 5% 4%

Nausea 6% 6%

Rash/itch 5% 2%

During ICTN=251 TPF,

243 PF

During CRTN=203 TPF,

184 PF


040


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;357:1695-1704.2. Hitt R, et al. J Clin Oncol. 2005;23:8636-8645.

041

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, thrombocytopaenia, and lethargy in the

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

TPF arm

042

Impact of Induction Chemotherapy (CT):Opposing Views and Ongoing Controversy

• Pro: Allows time to optimise patient medical status; Possible customisation 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

043

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

044

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 centres

choose 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;28:166-175.Ong SC, et al. J Nucl Med. 2008;49:532-540.

045

Treatment Approach




Recurrent or M1


046

Palliative Chemotherapy

047

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– Randomised 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.

048

EXTREME: Study Design

5-FU 1000 mg/m2 d1-4withCisplatin 100 mg/m2 d1orCarboplatin AUC 5 d1plusCetuximab 250 mg/m2/week*q 3 weeks

*Loading dose of 400 mg/m2 on week 1.Vermorken JB, et al. N Engl J Med. 2008;359:1116-1127.

RANDOMISE

N=442

5-FU 1000 mg/m2 d1-4withCisplatin 100 mg/m2 d1orCarboplatin AUC 5 d1

No treatment

6 cycles maximum

POD ortoxicity

Cetuximab POD ortoxicity

049


EXTREME: First-Line Platinum/5-FU ± Cetuximab in Recurrent/Metastatic SCC: Survival

10.1 mos7.4 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

Surv

ival

Pro

babi

lity

0.00.10.20.30.40.50.60.70.80.91.0

0 3 6 9 12 15 18 21 24

OSRR

18%35%

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

050

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

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

051

Phase II Trial: Cetuximab Monotherapy in Platinum-Refractory Recurrent/Metastatic SCC

Platinum-refractory SCC• Stage III/IV recurrent and/or

metastatic SCC not suitable for local therapy

• Documented PD within 30 days of cisplatin- or carboplatin-based chemotherapy (≥2 and ≤6 cycles)

• Tumour tissue available for IHC of EGFR expression

• No nasopharyngeal carcinoma• No nonplatinum chemotherapy

or RT within past 3 wks• No prior/concomitant surgery

within 30 days of enrollment

N=103

CR, PR, or SDContinue cetuximab until PD

PDOptional: cisplatin or

carboplatin + cetuximab N = 53

Monotherapy (continued if CR, PR, SD)

Vermorken JB, et al. N Engl J Med. 2008;359:1116-1127.Trigo J, et al. Presented at: American Society of Clinical Oncology 2004 Annual Meeting. Abstract 5502. Published as Trigo J, et al. J Clin Oncol. 2004;22:5502.

Cetuximab(400 mg/m2 then by

250 mg/m2/wk)≥6 wks

052

Phase II: Cetuximab Monotherapy in Platinum-Refractory Recurrent/Metastatic SCC: Results

Monotherapy Phase (95% CI); N=103

Combined Therapy Phase* (95% CI); N=53

ITT; N=103 IRC-PD; N=66 ITT IRC-PDCR 0% 0% 0% 0%PR 13% 12% 0% 0%SD 33% 33% 26% 27%PD 37% 35% 26% 24%ORR 13% (7-21) 12% (5-22) 0% (0-7) 0% (0-10)

DCR 46% (36-56) 45% (33-58) 26% (15-40) 27% (14-44)

Median Time to Response 49 days 50 daysNR

Median DOR 5.9 mos 4.2 mosMedian TTP 2.3 mos 2.1 mos 1.6 mos NRMedian Survival 5.9 mos 5.5 mos NR

*53 patients progressing while receiving cetuximab monotherapy continued with combined therapy (cetuximab plus cisplatin or carboplatin).DCR = disease control rate; DOR = duration of response; IRC-PD = ITT patients with PD determined by Independent Review Committee; ITT = intention to treat; TTP = time to progression.Vermorken JB, et al. N Engl J Med. 2008;359:1116-1127.Trigo J, et al. Presented at: American Society of Clinical Oncology 2004 Annual Meeting. Abstract 5502. Published as Trigo J, et al. J Clin Oncol. 2004;22:5502.

053

Afatinib vs CetuximabRandomised Open-label Phase II

HNSCC = head and neck squamous cell carcinoma; IV = intravenous; PD = progressive disease; CT = computed tomography scan; MRI = magnetic resonance imaging; R/M = recurrent/metastatic.Seiwert TY, et al. Ann Oncol. 2014;25:1813-1820.

Afatinib is approved in a number of markets, including the EU, Japan, Taiwan and Canada under the brand name GIOTRIF® and in the U.S. under the brand name GILOTRIF® for use in patients with distinct types of EGFR mutation-positive NSCLC. Registration conditions differ internationally, please refer to locally approved prescribing information. Afatinib is under regulatory review by health authorities in other countries worldwide. Afatinibis not approved in other indications.

054

Response to Therapy (Randomised Set) Stage 1Afatinib vs Cetuximab Open-label Phase II

Stage 1 TreatmentAfatinib

n=62Cetuximab

n=62P value

Disease control (CR, PR, SD)

50.0% 56.5% 0.48

Objective response (CR, PR) 16.1% 6.5% 0.09

Confirmation was made per protocol after 8 wks.Evaluable patients are those with at least 1 post-baseline image (afatinib = 52 and cetuximab = 57).

Per investigator assessment

Seiwert TY, et al. Ann Oncol. 2014;25:1813-1820.

055

Stage 2 Disease Control Rate: Afatinib vs Cetuximab

Seiwert TY, et al. Ann Oncol. 2014;25:1813-1820.

Cetuximab (after prior Afatinib) n=3219%

Afatinib (after prior Cetuximab) n=3633%

056

0

10

20

30

40

50

60

70

80

90

Patie

nts

(%)

All Adverse Events in ≥5% (All Grades)

Afatinib

Cetuximab

*Rash, dermatitis acneiform, dry skin, skin fissures, acne, dermatitis, nail disorders, hand-foot syndrome, pruritus, skin reaction, xeroderma. Safety data include treated patients only (1 randomised patient in the afatinib group and 2 randomised patients in the cetuximab group were not treated).Image courtesy of Seiwert et al, 2012.

057

Trial Design End Points Study Sites

Phase III, Randomised, Open-Label

Primary: PFS Key Secondary: OS; HR 0.73

Global

R/M HNSCC • Failing Platinum-Based CT for R/M HNSCC

• Documented PD• PS = 0–1• Max 1 CT Regimen for R/M HNSCC

• No Prior EGFR TKIs

RANDOMISE

2:1

Afatinib 40 mg qdp.o.

N=316

MTX 40 mg/m2 qw i.v.

N=158

LUX: HNC 1 (1200.43) Afatinib vs MTX in Second-Line R/M HNSCC

Treatment Until PD

N=483

Stratified by: ECOG PS, previous EGFR-targeted mAb for recurrent or metastatic disease

Machiels JP, et al. Lancet Oncol. 2015;16:583-594.

058

Trial Design Afatinib Methotrexate P-value

N=483 N=332 N=161

Median PFS (primary EP) 2.6 months 1.7 months 0.03

Median OS 6.8 months 6 months ns

Disease Control Rate 49.1% 38.5% 0.035

Overall Response Rate 10.2% 5.6% 0.10

LUX: HNC 1 (1200.43) Afatinib vs MTX in Second-Line R/M HNSCC Results


059

Afatinib vs Methotrexate as 2nd-Line Treatment (LUX-H/N1)

Time (months)

0

0.2

0.4

0.6

0.8

1.0

0 3 6 9 12

Estim

ated

PFS

Pro

babi

lity

15 18

No. of patientsAfatinib 322 93 26 9 3 1 0MTX 161 28 6 2 0 0 0

Afatinib(n=322)

MTX(n=161)

PFS event, n (%) 275 (85.4) 135 (83.9)

Median PFS (months) 2.6 1.7

HR (95% CI) 0.80 (0.65–0.98)

Log-rank test p-value 0.03042.8%

30.5%


060Factors Number of

patients HR (95% CI)

Total 483 0.80 (0.65–0.98)

Baseline ECOG PS 01

131352

0.730.77

(0.49–1.10)(0.60–0.98)

Prior use of EGFR-targeted antibody for R/M HNSCC

NoYes

196287

0.630.91

(0.45–0.88)(0.70–1.19)

Gender MaleFemale

41271

0.740.95

(0.59–0.92)(0.55–1.64)

Age <65 years≥65 years

355128

0.790.68

(0.62–1.01)(0.45–1.03)

RegionAsiaEuropeNorth/Latin American

4336960

0.620.820.41

(0.32–1.20)(0.64–1.04)(0.21–0.79)

Smoking pack-years <10 pack years≥10 pack years

87381

1.050.71

(0.66–1.70)(0.56–0.90)

Alcohol consumption ≤7 units/week>7 units/week

37491

0.790.73

(0.62–1.00)(0.46–1.14)

Primary tumour site

Oral cavityOropharynxHypopharynxLarynx

13615393

101

0.690.990.780.59

(0.46–1.04)(0.68–1.44)(0.48–1.25)(0.38–0.92)

Recurrence or metastasesRecurrentMetastaticBoth

16764

241

0.591.180.81

(0.42–0.84)(0.65–2.14)(0.60–1.10)

p16 PositiveNegative

49208

0.950.69

(0.51–1.75)(0.50–0.96)

Response to prior platinum therapy for R/M HNSCC

CR/PR/SDPD

261146

0.820.66

(0.62–1.09)(0.45–0.96)

PFS Subgroup Analysis

Favours Afatinib1/4 11/16 4 16

Favours Methotrexate Machiels JP, et al. Lancet Oncol. 2015;16:583-594.

061

FactorsNumber of

patientsAdjusted mean

difference (95% CI)

Pain HN35 (Q1–Q4 from QLQ-HN35) 382 –4.4 (–8.3, –0.4)

Pain in mouth (Q1) 380 –3.7 (–9.2, 1.7)

Pain in jaw (Q2) 380 –7.5 (–12.5, –2.5)

Soreness in mouth (Q3) 380 –2.5 (–8.0, 2.9)

Painful throat (Q4) 382 –4.3 (–9.2, 0.6)

Swallowing scale (Q5–Q8 from QLQ-HN35) 369 –0.1 (–4.3, 4.2)

Problem swallowing liquid (Q5) 373 –2.5 (–8.3, 3.2)

Problem swallowing pureed food (Q6) 365 –1.1 (–6.6, 4.4)

Problem swallowing solid food (Q7) 364 0.0 (–5.8, 5.8)

Choked when swallowing (Q8) 361 2.5 (–2.9, 7.9)

Global health status (Q8–Q9 from QLQ-C30) 384 –0.6 (–4.4, 3.3)

Overall health rate (Q29) 384 –0.5 (–4.5, 3.5)

Quality of life rate (Q30) 378 –0.3 (–4.5, 3.9)

Changes in Patient-reported Outcomes Over Time

– 10 0–20 2010Favours Afatinib Favours Methotrexate Machiels JP, et al. Lancet Oncol. 2015;16:583-594.

062

Afatinib Clinical Programme in HNSCC

LUX-Head & Neck 12nd line R/MPublished2

LUX-Head & Neck 2 Adjuvant, LA

Recruiting

Afatinib vs CetuximabPhase II PoC

Published1

LUX-Head & Neck 32nd line R/MRecruiting

LUX-Head & Neck 4Adjuvant, LA

Recruiting

Asian Bridging Trials (Ph III)

1. Seiwert TY, et al. Ann Oncol. 2014;25:1813-1820; 2. Machiels JP, et al. Lancet Oncol. 2015;16:583-594; 3. ClinicalTrials.gov Identifiers: NCT01345669 (LHN2), NCT 01856478 (LHN3), NCT 02131155 (LHN4), NCT 01427478 (BIBW2992ORL).

Pivotal Phase III Trials

Recurrent/Metastatic

Locally advanced

BIBW2992ORL

Maintenance, LARecruiting

063

Conclusions

• Afatinib significantly improved PFS vs methotrexate

• Tumour shrinkage was greater, response rate higher and DCR significantly higher compared to methotrexate

• Patient-reported outcomes favoured afatinib over methotrexate

• OS was not significantly different between afatinib and methotrexate

• Overall AE profiles were as expected– Fewer treatment-related dose reductions, discontinuations and fatal

events with afatinib compared to methotrexate

• Afatinib has shown efficacy and improved patient-reported outcomes in a Phase III trial in this setting

• Investigations with adjuvant afatinib in LA HNSCC following CRT are ongoing

064

KEYNOTE-012 – Study Design

• Multicenter, non-randomised Phase Ib HNSCC expansion cohort

• Multi-cohort trial* HNSCC cohort

*Additional cohorts included: Bladder Cancer, Triple Negative Breast Cancer, Gastric Cancer.Presented by: Tanguy Seiwert

065

Phase Ib Study of Pembrolizumab (MK-3475) in Patients With HPV-negative and HPV-positive HNSCC: Efficacy Waterfall Plot

Seiwert T, et al. ASCO 2014. Abstract 6011.

51% (26/51) of patients had decreased tumour burden

HPV (+)HPV (-)

Subjects–100

–80

–60

–40

–20

0

20

40

60

80

100

Cha

nge

From

Bas

elin

e, %

56 pts evaluable for response Total Head/Neck N=56†

HPV (+)N=20

HPV (-)N=36§

Response Evaluation n (%) n (%) n (%) Best Overall Response

(Complete + Partial)‡ 11 (19.6) 4 (20.0) 7 (19.4)

066

Best Overall Response

• PD-L1 expression correlates with Response

• Using a Youden-Index derived, preliminary PD-L1 cut point:– Above cutpoint: 45.5% (5/11) RR– Below cutpoint: 11.4% (5/44) RR

56 pts evaluable for response

Total Head/neck N=56*

HPV (+)N=20

HPV (-)N=36§

Response Evaluation n (%) 95% CI† n (%) 95% CI† n (%) 95% CI†

Complete Response 1 (1.8) (0.0, 9.6) 1 (5.0) (0.1, 24.9) 0 (0.0) (0.0, 9.7)

Partial Response 10 (17.9) (8.9, 30.4) 3 (15.0) (3.2, 37.9) 7 (19.4) (8.2, 36.0)

Best Overall Response (Complete + Partial)‡ 11 (19.6) (10.2, 32.4) 4 (20.0) (5.7, 43.7) 7 (19.4) (8.2, 36.0)

Stable Disease 16 (28.6) (17.3, 42.2) 8 (40.0) (19.1, 63.9) 8 (22.2) (10.1, 39.2)

Progressive Disease 25 (44.6) (31.3, 58.5) 7 (35.0) (15.4, 59.2) 18 (50.0) (32.9, 67.1)

No Assessment 4 (7.1) (2.0, 17.3) 1 (5.0) (0.1, 24.9) 3 (8.3) (1.8, 22.5)

Based on RECIST 1.1 Per site assessment; includes confirmed and unconfirmed responses.*61 patients eligible for treatment; 60 patients dosed; 56 patients eligible for pre-defined full analysis set. †Based on binomial exact confidence interval method.‡A single patient with PD followed by PR on treatment was classified as PR.§Includes 2 patients for whom HPV data were unavailable.Slide courtesy of Tanguy Seiwert.

067

Presente

068

Segal et al, ASCO 2014

Baseline Day 28

Slide courtesy of Neil Segal.

96-year-old female, previously progressed on cetuximab, HPV negative, PD-L1 positive

069

Trial Design End Points Study Sites

Phase III, Open-label Randomised

Primary: PFS, OS Secondary: ORR

Global

R/M HNSCC • PS = 0–1• Progression within 6 months of last platinum chemotherapy

RANDOMISE

2:1

Nivolumab 3 mg/kg IV q 2 weeks until PD

Cetuximab or MTX or docetaxeluntil PD

Nivolumab vs Investigator’s Choice Chemotherapy in R/M HNSCC

N=180

ClinicalTrials.gov Identifier: NCT02105636

070

Comprehensive Genomic Characterisation of Squamous Cell Carcinoma of the Head and Neck

January 2015

071

The Genetic Wiring of HNSCCs

TCGA Network. Nature. 2015.

072Lung squamous cell carcinoma (358)HPV-negative head and neck cancer (244)HPV-positive head and neck cancer (35)Cervical cancer (114)

SCNA in Head and Neck Squamous Cell Carcinomas Compared to Lung and Cervical Squamous Cell Carcinomas

TCGA Network. Nature. 2015.

073

Candidate Therapeutic Targets

TCGA. Nature. 2015.

074

Response to Pazopanib in a Patient With a FGFR2 Mutation

2 weeks pazopanib

FGFR2 P253R

Liao et al. 2013.

075ABL1 AKT1 AKT2 AKT3 ALK ALOX12B APC AR ARAF ARID1A ASXL1 ATM ATRX AURKA AURKB AXL B2M BAP1 BCL2 BCL2L12 BCL6 BCOR BCORL1 BLM BMPR1A BRAF BRCA1 BRCA2 BRD4 BRIP1

BUB1B CARD11 CBL CBLB CCND1 CCND2 CCND3 CCNE1 CD274 CD58 CD79B CDC73 CDH1 CDK1 CDK2 CDK4 CDK5 CDK6 CDK9 CDKN2A CDKN2B CDKN2C CEBPA CHEK2 CIITA CREBBP CRKL CRLF2 CRTC1 CRTC2

CTNNB1 CUX1 CYLD DDB2 DDR2 DICER1 DIS3 DMD DNMT3A EED EGFR EP300 EPHA3 EPHA5 EPHA7 ERBB2 ERBB3 ERBB4 ERCC2 ERCC3 ERCC4 ERCC5 ESR1 ETV1 ETV4 ETV5 ETV6 EWSR1 EXT1 EXT2

EZH2 FAM46C FANCA FANCC FANCD2 FANCE FANCF FANCG FAS FBXW7 FGFR1 FGFR2 FGFR3 FGFR4 FH FKBP9 FLCN FLT1 FLT3 FLT4 FUS GATA3 GATA4 GATA6 GLI1 GLI2 GLI3 GNA11 GNAQ GNAS

GPC3 GSTM5 H3F3A HNF1A HRAS ID3 IDH1 IDH2 IGF1R IGH@ IgK@ IgL@ IKZF1 IKZF3 JAK2 JAK3 KDM6B KDR KIT KRAS LMO1 MAP2K1 MCL1 MDM2 MDM4 MECOM MEF2B MEN1 MET MITF

MLH1 MLL MLL2 MPL MSH2 MSH6 MTOR MUTYH MYB MYBL1 MYC MYCL1 MYCN MYD88 NBN NF1 NF2 NFE2L2 NFKBIA NFKBIZ NKX2-1 NOTCH1 NOTCH2 NPM1 NRAS NTRK3 PALB2 PARK2 PAX5 PDCD1LG2

PDGFRA PDGFRB PHF6 PHOX2B PIK3C2B PIK3CA PIK3R1 PIM1 PMS1 PMS2 PNRC1 PRAME PRDM1 PRF1 PRKAR1A PRKCI PRKDC PRPF40B PRPF8 PSMD13 PTCH1 PTEN PTK2 PTPN11 RAD21 RAF1 RARA RB1 RBL2 RECQL4

REL RET RFWD2 RHPN2 ROS1 RPL26 RUNX1 SBDS SDHAF2 SDHB SDHC SDHD SETBP1 SF1 SF3B1 SH2B3 SMAD2 SMAD4 SMARCA4 SMARCB1 SMC1A SMC3 SMO SOCS1 SOX2 SRC SRSF2 STAG1 STAG2 STAT3

STK11 SUFU SUZ12 SYK TCF3 TERC TERT TET2 TNFAIP3 TP53 TRA@ TRB@ TRG@ TSC1 TSC2 U2AF1 VHL WRN WT1 XPA XPC XPO1 ZNF708 ZRSR2

Illumina HiSeq

Neal Lindeman – Director; Center for Advanced Molecular Diagnostics

Oncopanel – DFCI/BWH Targeted Next Generation Sequencing – Launched Summer 2013

076

Patient offered anti-HER2 therapy

59M HPV+ BOT Disease With Recurrence After TPF Induction Plus Chemo-RT

077

Beyond EGFR

Adapted from Chong. Janne Nature Rev. 2013.

BKM120BYL-719

PF-05212384

RAD001

078

Genomic Alterations in the Clinic

Commercial NGS DFHCC/BWH Profile NGS

079

Examples of Clinical Trials for R/M HNSCC at DFCI Employing Targeted Approaches

EGFR & ErbB Family2nd generation EGFR TKI

EGFR-Antibody Drug Conjugate

HPV– or CCND1 CDK4/6i

FGFR alteration FGFRi

P53, tumour suppressor P53 modulator, SINE

PD-1/L1, CTLA4 Anti-PD1/L1, Anti-CTLA-4

Rec

urre

nt/M

etas

tatic

HN

SCC

PI3Ki or mTORi or PI3K/mTORiHPV+ or PIK3CA+

080

Conclusions: Treatment of SCCHN in 2015

• Multiple options available – Concurrent chemoRT– Sequential therapy: TPF is the standard induction

regimen – Targeted therapy: Cetuximab/RT

• 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 research question

novel advances in the management of squamous cell ... · novel advances in the management of...

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