DISCLAIMERDISCLAIMERThis slide deck in its original and unaltered format is for educational purposes and is

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diagnosis, or treatment. The use of any information provided is solely at your own risk,and readers should verify the prescribing information and all data before treating

patients or employing any therapeutic products described in this educational activity.

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DISCLAIMERDISCLAIMERParticipants have an implied responsibility to use the newly acquired information

to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for

patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by

clinicians without evaluation of their patients’ conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s

product information, and comparison with recommendations of other authorities.

DISCLOSURE OF UNLABELED USEDISCLOSURE OF UNLABELED USEThis activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. PIM and IMER do not recommend the

use of any agent outside of the labeled indications.  

The opinions expressed in the activity are those of the faculty and do not necessarily represent the views of PIM and IMER. Please refer to the official

prescribing information for each product for discussion of approved indications, contraindications, and warnings.

Disclosure of Conflicts of InterestDisclosure of Conflicts of InterestMarshall R. Posner, MDMarshall R. Posner, MD

Reported a financial interest/relationship or affiliation in the form of: Consultant, Eisai, Inc., GlaxoSmithKline plc., Novartis Pharmaceuticals Corporation, Oxigene, Inc.

Learning ObjectivesLearning ObjectivesUpon completion of this activity, Upon completion of this activity,

participants should be better able to:participants should be better able to:

Review the clinical, pathologic, and molecular characteristics of patients with HNC

Appraise the importance of multidisciplinary collaboration in early screening and detection

Enumerate the role of HPV status in optimal treatment selection

Review current guidelines and emerging chemotherapy-based curative treatments, including combination therapies

Evaluate the impact of targeted therapies in the treatment of metastatic HNC

Integrate effective multidisciplinary rehabilitation therapy and survivorship care for patients with HNC

Provide accurate and appropriate counsel as part of the treatment team

Activity AgendaActivity Agenda Activity Overview (5 minutes)

Molecular and Biological Considerations (10 minutes)

Chemotherapy-Based Curative Treatment (10 minutes)

Individualized Treatment: Rationale for Emerging Targets (30 minutes)

Questions & Answers (5 minutes)

Molecular and Biological Molecular and Biological Considerations Considerations

Molecular and Biological Events in Molecular and Biological Events in Head and Neck Cancer (HNC)Head and Neck Cancer (HNC)

HPV-Related Cancers Caused by high-risk HPV

– HPV 16

– Driven by viral oncogenes

Restricted to oropharynx

Distinct molecular markers

“Good” prognosis

Young, good general health

Environment-Related Cancers Caused by environmental

mutagens

– Smoking, alcohol

Throughout oral mucosa

Distinct molecular markers

“Poor” prognosis, comorbidity

Second cancers

HNC Can Now Be Divided Into 2 Large and Distinct Subtypes

HPV = human papillomavirus.Goon et al, 2009; Rodriguez et al, 2010.

Chaturvedi et al, 2011.

Change in HPV Rates and Incidence Change in HPV Rates and Incidence Over Time: Over Time: UnitedUnited States States

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)Human Papillomavirus (HPV)

Münger et al, 2004.

Münger et al, 2004.

Mechanisms of HPV-Associated Mechanisms of HPV-Associated CarcinogenesisCarcinogenesis

HPV E6 And E7 Oncoproteins Associate With and Reprogram Cellular Enzymes

HPV E6 and E7 Oncoproteins Target Associated Cellular Tumor Suppressors for Degradation

E6

E6-AP

p53 Ubn

UbS

HPV16 E6 Retargets the Cellular Ubiquitin Ligase E6AP to the P53

Tumor Suppressor Protein

HPV16 E7 Retargets the Cellular Cullin 2 Ubiquitin Ligase Complex

to the Retinoblastoma Tumor Suppressor Protein, pRB

E7pRB

Rbx1

Cul2

EloB

EloC

NEDD8

E2

Ubn

UbS

RTOG 0129: A Randomized Phase III Trial RTOG 0129: A Randomized Phase III Trial of Chemoradiotherapy With 2 Schedulesof Chemoradiotherapy With 2 Schedules

RANDOMI ZE

P: 100 mg/m2

XRT

XRT

P: 100 mg/m2

Trial Completed Accrual in 6/05

P = platinum; XRT = fractionated radiotherapy.Ang et al, 2010.

743 Patients Randomized

P16+ P16–

HPV+ 192 (96%) 7 (4%)*

HPV– 22 (19%)* 94 (81%)

Kappa = 0.80: 95% CI 0.73–0.87

CI = confidence interval.Gillison et al, 2009.

Results of HPV Analysis: RTOG 0129Results of HPV Analysis: RTOG 0129

433/721 (60%) Oropharynx Primary

323/433 (75%) HPV Determination

206/323 (64%) HPV+

198/206 (96%) HPV16+

Sequential Combined Modality Therapy Sequential Combined Modality Therapy A Phase III Study: TAX 324 TPF Vs. PF A Phase III Study: TAX 324 TPF Vs. PF

Followed by ChemoradiotherapyFollowed by Chemoradiotherapy

RANDOMI ZE

P

P

F

F

Carboplatinum: AUC 1.5 Wkly

Daily Radiotherapy

EUA

T

Surgery

TPF: Docetaxel 75D1 + Cisplatin 100D1 + 5-FU 1,000 CI: D1–4 q3wks x 3 PF: Cisplatin 100 D1 + 5-FU 1,000 CI: D1–5 q3wks x 3

AUC = area under the curve; EUA = examination under anesthesia.Posner et al, 2007.

TAX 324: Demographics by HPV Status TAX 324: Demographics by HPV Status

HPV+N = 56 (50%)

HPV– N = 55 (50%) p Value

Treatment TPFPF

28 (50%)28 (50%)

26 (47%)29 (53%)

.85

Age YrsMedian (Range) 54 (39–71) 58 (41–78) .02

Nodal StageN0–N1N2–N3

13 (23%)43 (77%)

18 (33%)37 (67%)

.30

T stageT1–T2T3–T4

28 (50%)28 (50%)

11 (20%)44 (80%)

.001

PS WHO01

43 (77%)13 (23%)

27 (49%)28 (51%)

.003

PS = performance status; WHO = World Health Organization. Posner et al, 2011.

TAX 324: Survival and HPV StatusTAX 324: Survival and HPV Status

Posner et al, 2011.

Su

rviv

al O

rop

har

ynx

Can

cer

HPV+HPV–

p < .0001

TAX 324: Survival, PFS, and Site TAX 324: Survival, PFS, and Site of Failure By HPV Status of Failure By HPV Status

HPV+N = 56

HPV– N = 55

p Value

Median Follow-UpMonths (95% CI) 83 (77–93) 82 (68–86) NS

Survival Status– Alive– Dead

44 (79%)12 (21%)

17 (31%)38 (69%)

< .0001

PFS Status– No Progression/Death– Progression/Death

41 (73%)15 (27%)

16 (29%)39 (71%)

< .0001

Local-Regional Failure 7 (13%) 23 (42%) .0006Distant Metastases 3 (5%) 6 (11%) NS

Both 1 (2%) 2 (4%) NSTotal Disease Failures 9 (16%) 27 (49%) .0002Died Without Recurrence 5 (9%) 12 (22%) .07

PFS = progression-free survival; NS = not significant.Posner et al, 2011.

RTOG 1016: A Randomized Phase III Trial of RTOG 1016: A Randomized Phase III Trial of Chemoradiotherapy With Cisplatinum or Cetuximab Chemoradiotherapy With Cisplatinum or Cetuximab

in P16+ Oropharynx Cancerin P16+ Oropharynx Cancer

RANDOMIZE

IMRT 70Gy/35 fxs

Cetuximab400/250

mg/m2 qwk

Cisplatin100 mg/m2/q21d

Stratify: HPV, smoking, stage

Cetuximab loading dose = 400 mg/m2 on Day 1 of Cycle1 with induction

ELIGIBILITY

Stage

III, IVA, B

Resectable

P16+

Oropharynx

Cancer

IMRT 70Gy/35 fxs

IMRT = intensity-modulated radiation therapy.ClinicalTrials.gov.

Cisplatin

Cetuximab

E

SURGERY AND CRT

9 wks

Paclitaxel

Daily Radiotherapy 5400 cGy

CLINICAL

PR/CR

CLINICAL NR

ECOG 1308: P16+ Oropharynx Phase II:ECOG 1308: P16+ Oropharynx Phase II:Reduced Dose CRT for Reduced Dose CRT for ResectableResectable Oropharynx Oropharynx

Assess Response

Trial Accrual CompletedCRT = chemoradiotherapy; PR = partial response; CR = complete response; NR = no response.ClinicalTrials.gov.

Reduced 25%

C/E

Daily Radiotherapy 7000 cGy

3 Cycles

Daily Radiotherapy 5600 cGy

C

CLINICAL and PET PR/CR

CLINICAL and PET SD/NR

HPV+ Oropharynx Phase III:HPV+ Oropharynx Phase III:Reduced Dose Chemoradiotherapy for Induction PR/CRReduced Dose Chemoradiotherapy for Induction PR/CR

The Quarterback TrialThe Quarterback Trial

Assess Response

Primary End Points 1. 3-yr LRC, PFS 2. Toxicity/Function 3. Patterns of Failure

Stage IV, HPV 16, P16+Stratify: < 20 pack yrs smoking

RandomizeRandomize2:12:1

Reduced 20%

Cisplatin

5-FU

Docetaxel

SD = stable disease; LRC = local-regional control.

HPV+ Oropharynx Cancer in 2012: HPV+ Oropharynx Cancer in 2012: SummarySummary

HPV+ oropharynx cancer is increasing rapidly in North America and Europe

– > 20,000 cases/yr in 2015

The population is different

– More non-smokers, younger, healthier

The prognosis is better in advanced disease

– > 75% patients alive at 3 yrs

– Surgery, radiotherapy, and chemotherapy are all effective

HPV+ oropharynx patients will survive for decades

– Morbidity from therapy is considerable and studies to reduce morbidity are under way using surgery and chemotherapy to reduce radiotherapy impact

Molecular and Biological Events in HNCMolecular and Biological Events in HNC

Genetic integrity

– p53 pathway

Survival, metabolism

– PI3K pathway (AKT, mTor, PTEN)

– EGFr, MET

Proliferation

– Rb, p16 Pathway

– MET

Differentiation

– Notch, p63 pathway

Molecular Changes in HNC Are Organized Into Categories Based on Systems Biology Approach

There Are Distinct Pathways That Are Altered in HNC

Signaling Pathways in HNCSignaling Pathways in HNC

Image courtesy of Aaron Tward, MD, PhD.

Drivers Vs. SuppressorsDrivers Vs. Suppressors

Many genetic alterations in cancer are divided into driver (oncogene addiction) or loss of suppressor events

– Drivers: Activating mutations – creates critical drug targets

• NSCLC: EGFR, ALK-4; Melanoma: BRAF

• HNC: MET, PI3K

– Suppressors: Releasing mutations – loss of function – down stream targets

• How do you restore function?

• HNC: p53 (50%), p16 (60%), PTEN

Molecular and Biological Events in HNCMolecular and Biological Events in HNC

NSCLC = non-small cell lung cancer; EGFR = epidermal growth factor receptor.

The Multi-Fold Impact of Inactivating Suppressor GenesThe Multi-Fold Impact of Inactivating Suppressor Genes

p53

Image courtesy of Christine Chung, MD.

Key TakeawaysKey TakeawaysMolecular and Biological Events in HNCMolecular and Biological Events in HNC

The most important molecular biomarker in HNC is HPV status

Single-gene driver mutations are rare in HNC and loss of suppressor events are common

Single-agent targeted therapy is challenging in HNC

Multiple targets within signaling pathways are being identified

Chemotherapy and Surgery-Based Chemotherapy and Surgery-Based

Curative TreatmentCurative Treatment

The Current State of Curative TherapyThe Current State of Curative Therapy

Multidisciplinary decision making prior to definitive care is key

– Working together to establish and coordinate the combined modality treatment plan

• Determine stage/extent

• Establish prognostic/predictive factors

• Identify and coordinate a complex treatment plan

• Monitor response and toxicity: Modify therapy based on response/prognosis

• Long-term follow-up for toxicity, recurrence, and second primary

The Current State of Curative The Current State of Curative Therapy (cont.)Therapy (cont.)

Surgery

Postoperative chemoradiotherapy

Concurrent chemoradiotherapy

Sequential therapy

Surgical Technology Has Changed Surgical Technology Has Changed Significantly in the Last Decade Significantly in the Last Decade

Transoral approaches

– Transoral Laser Microsurgical (TLM) resection

– TransOral Robotic Surgery (TORS)

– Much better exposure

Lessened morbidity

– Much less bystander tissue damage, trauma

– Quick recovery

– More tumors resectable – oropharynx, larynx, pyriform

Who is a candidate?

– Is surgery biologically rational? Does it improve function, reduce late morbidity, impact on subsequent therapy

– HPV+ oropharynx

Transoral Robotic Surgery (TORS)Transoral Robotic Surgery (TORS)

Images courtesy of Marshall Posner, MD.

Surgical Technology Has Changed Surgical Technology Has Changed Significantly in the Last Decade (cont.) Significantly in the Last Decade (cont.)

Who is a candidate?

– Is surgery biologically rational?

– Does it improve function, reduce late morbidity?

– Does surgery impact on subsequent therapy?

HPV+ oropharynx

– Can we eliminate or reduce post-operative radiotherapy?

E3311 Trial DesignE3311 Trial Design Phase II trial of HPV+ (P16+) OPSCC patients will be randomized to

either low-dose (50 Gy) or standard-dose RT (60 Gy)

Patients with T1-T2N0-N1 will be observed (Arm A)

Patients with clear/close margins, ≤ 1 mm ECS, PNI/LVI, and/or 2–3 metastatic LN will be randomized to 50 Gy vs. 60 Gy (Arms B & C)

Patients with positive margins, ≥ 4 metastatic LN, and/or > 1 mm ECS will be treated with standard-dose RT + cisplatin (Arm D)

Primary objective is to evaluate the 2-yr PFS in HPV+ SCC patients treated with cetuximab plus low-dose RT (assume 85% per arm)

Secondary end points: Early & late toxicities, swallowing function, QOL, OS, and serum/tissue biomarkers in predicting clinical outcomes

Stopping rules for excessive recurrence or bleeding

RT = radiotherapy; QOL = quality of life; OS = overall survival.

INTERMEDIATE:Clear margins

≤ 1 mm ECS2–3 metastatic LN

PNILVI

HIGH RISK:Positive Margins> 1 mm ECS or

≥ 4 metastatic LN

Radiation TherapyIMRT 60 Gy/30 Fx +

Evaluate for 2-yr PFSLocal-Regional

Recurrence, Functional Outcomes/QOL

Transoral Resection (any approach)

with neck dissection

Radiation TherapyIMRT 50Gy/25 Fx

ECOG 3311 P16+ Trial – Low Risk OPSCC:ECOG 3311 P16+ Trial – Low Risk OPSCC:Personalized Adjuvant Therapy Based on Pathologic Personalized Adjuvant Therapy Based on Pathologic

Staging of Surgically Excised HPV+ Oropharynx CancerStaging of Surgically Excised HPV+ Oropharynx Cancer

Assess Eligibility:HPV (p16)+

SCC oropharynx

Stage III-IV: cT1-3, N1-2b

(no T1N1)

Baseline Functional/

QOL Assessment

Observation

RANDOMIZE

Radiation TherapyIMRT 66 Gy/33 Fx +CDDP 40 mg/m2 wkly

LOW RISK:T1-T2N0-N1

negative margins

RANDOMIZE

CisplatinCisplatin100 mg/m100 mg/m22 d 1, 22, 43 d 1, 22, 43

XRTXRT

XRTXRT

Cooper et al, 2004; Bernier et al, 2004.

SURGERY

RTOG 95-01RTOG 95-01459 patients459 patients

EORTC 22931EORTC 22931 334 patients334 patients

EORTC (66 Gy over 6 EORTC (66 Gy over 6 ½½ wks) wks)RTOG (60–66 Gy over 6-6 RTOG (60–66 Gy over 6-6 ½½ wks) wks)

Postoperative ChemoradiotherapyPostoperative Chemoradiotherapy

Images courtesy of Jay Cooper, MD.

Survival/Local Regional Control RTOG: Survival/Local Regional Control RTOG: 95-01 Median Follow-Up 9.4 Yrs95-01 Median Follow-Up 9.4 Yrs

p = 0.10p = 0.31

Patients at Risk

RT 208 170 119 92 75 68 60 53 44 33 26

RT + CT

202 158 129 111 95 85 75 64 55 48 37

Patients at Risk

RT 208 142 106 84 71 66 57 51 44 33 26

RT + CT

202 146 121 108 91 83 74 63 54 47 36

Survival/Local Regional Control RTOG:Survival/Local Regional Control RTOG:95-01 ECE or Positive Margin Median Follow-Up 9.4 Yrs95-01 ECE or Positive Margin Median Follow-Up 9.4 Yrs

Ove

rall

Surv

ival

(%)

0

25

50

75

100

Years after Randomization0 1 2 3 4 5 6 7 8 9 10

Patients at RiskRTRT+CT

Patients at Risk115127

Patients at Risk8897

Patients at Risk5377

Patients at Risk3765

Patients at Risk3152

Patients at Risk2848

Patients at Risk2345

Patients at Risk2137

Patients at Risk1632

Patients at Risk1328

Patients at Risk1123

RTRT+CT

Loca

l-Reg

iona

l Con

trol (

%)

0

25

50

75

100

Years after Randomization0 1 2 3 4 5 6 7 8 9 10

Patients at RiskRTRT+CT

Patients at Risk115127

Patients at Risk7193

Patients at Risk4872

Patients at Risk3464

Patients at Risk2950

Patients at Risk2747

Patients at Risk2145

Patients at Risk2037

Patients at Risk1632

Patients at Risk1328

Patients at Risk1123

RTRT+CT

p = 0.02 p = 0.07

Images courtesy of Jay Cooper, MD.

Patients at Risk

RT 115 88 53 37 31 28 23 21 16 13 11

RT + CT

127 97 77 65 52 48 45 37 32 28 23

Patients at Risk

RT 115 71 48 34 29 27 21 20 16 13 11

RT + CT

127 93 72 64 50 47 45 37 32 28 23

Postoperative ChemoradiotherapyPostoperative Chemoradiotherapy

Indicated for ECE, positive margin

– Relative indication for LVI, PNI

Cisplatin bolus therapy

– Replace with weekly cisplatin 40 mg/m2 based on data from nasopharynx cancer trials

No indication for weekly cetuximab or extended therapy as adjuvant

Multiple adjuvant trials ongoing

– Lapatinib, afatinib

Concurrent ChemoradiotherapyConcurrent ChemoradiotherapyRTOG 0129: A Phase III Trial Comparing RTOG 0129: A Phase III Trial Comparing

Acerbated Therapy to Standard RadiotherapyAcerbated Therapy to Standard Radiotherapy

RANDOMIZE

P: 100 mg/m2

XRT

XRT

P: 100 mg/m2

Trial Completed Accrual in 6/05

Ang et al, 2010.

743 Patients Randomized

RTOG 0129: Outcome End PointsRTOG 0129: Outcome End Points

Ang et al, 2010.

RTOG 0129: Secondary AnalysesRTOG 0129: Secondary AnalysesMultivariate Analysis With Therapy VariablesMultivariate Analysis With Therapy Variables

Parameters HR (95% CI)

OS PF Survival LR Relapse Distant Metastasis

HPV (ISH- vs. ISH+) 2.7 (1.90–3.92) 2.3 (1.68–3.08) 2.6 (1.72–3.84) 2.0 (1.19–3.49)

Smoking (> 10 vs. ≤ 10 PY) 1.8 (1.28–2.65) 2.0 (1.43–2.74) 2.0 (1.34–3.08) 1.6 (0.94–2.85)

T-Stage (T4 vs. T2-3) 1.6 (1.23–2.08) 1.3 (1.00–1.62) 1.4 (1.07–1.95) 1.0 (0.60–1.56)

N-Stage (N2b-3 vs. N0-2a) 1.6 (1.20–2.02) 1.5 (1.20–1.92) 1.3 (0.98–1.77) 2.2 (1.37–3.46)

Zubrod PS (1 vs. 0) 1.6 (1.21–2.03) 1.6 (1.25–1.99) 1.6 (1.20–2.17) 1.4 (0.92–2.19)

Cisplatin Cycles (1 vs. 3) 2.1 (1.35–3.32) 1.8 (1.19–2.82) 1.9 (1.07–3.34) 1.5 (0.67–3.41)

Cisplatin Cycles (2 vs. 3) 1.2 (0.84–1.59) 1.3 (0.98–1.76) 1.7 (1.20–2.54) 1.0 (0.57–1.66)

RT Dose (64-76 Gy, cont.) 1.08 (0.99–1.19) 1.03 (0.94–1.12) 1.02 (0.92–1.14) 1.04 (0.88–1.23)

RT Wks (7 vs. 6) 1.4 (0.88–2.15) 0.9 (0.64–1.32) 0.9 (0.55–1.35) 1.3 (0.59–2.62)

RT Wks (8–9 vs. 6–7) 2.2 (1.33–3.46) 1.4 (0.94–2.06) 1.5 (0.89–2.34) 1.7 (0.76–3.76)

HR = hazard ratio.Ang et al, 2010.

Concurrent ChemoradiotherapyConcurrent ChemoradiotherapyRTOG 0522: A Phase III Trial of Cisplatin CRT RTOG 0522: A Phase III Trial of Cisplatin CRT

With or Without CetuximabWith or Without Cetuximab

RANDOMIZE

P: 100 mg/m2

XRT

XRT

Cetuximab 400/250 mg

P: 100 mg/m2

Stratify: XRT as Standard or IMRT on

DAHANCA Ang et al, 2011.

GORTEC 99-02: Chemoradiotherapy Vs. Accelerated GORTEC 99-02: Chemoradiotherapy Vs. Accelerated Radiotherapy With or Without ChemotherapyRadiotherapy With or Without Chemotherapy

RANDOMIZE

XRT

XRT

Carboplatin/5-FU

XRT

Carboplatin/5-FU

Bourhis et al, 2012.

GORTEC 99-02GORTEC 99-02

Standard chemoradiotherapy was better in all parameters compared to accelerated therapy

There was a trend for standard fraction CRT to be better than ACB CRT in all parameters

Bourhis et al, 2012.

The Cetuximab/Radiotherapy Phase III Trial The Cetuximab/Radiotherapy Phase III Trial

RANDOMIZE

ERB

XRT

XRT

Surgery

Surgery

Bonner et al, 2006.

QD, BID or ACB Allowed

Stratify by Karnofsky score:

90–100 vs. 60–80 Regional Nodes:

Negative vs. Positive

Tumor stage:AJCC T1–3 vs. T4

RT fractionation:Concomitant boostvs. once dailyvs. twice daily

OS By Treatment: OS By Treatment: Median Follow-Up 60 MonthsMedian Follow-Up 60 Months

1.01.0

0.90.9

0.80.8

0.70.7

0.60.6

0.50.5

0.40.4

0.30.3

0.20.2

0.10.1

0.00.0

00 1010 2020 3030 4040 5050 6060 7070

Time (months)

OS

(%

)

Stratified Log Rank p = .018, HR = 0.73 (0.56–0.95)

Treatment Total Death Alive Median

Radiation AloneRadiation Alone 213213 130130 8383 29.329.3RT + CetuximabRT + Cetuximab 211211 110110 101101 49.049.0

Bonner et al, 2006.

Chemoradiotherapy for Locally Chemoradiotherapy for Locally Advanced HNCAdvanced HNC

Chemoradiotherapy improves survival compared to radiotherapy alone for locally advanced HNC

Standard fraction CRT is preferred over ACB CRT with reduced chemotherapy

There is no role for reducing chemotherapy during CRT

– 3 doses of cisplatin are better then 2 doses (RT0G 01-29, GORTEC 99-02)

CRT with platinum containing regimens remains the standard for CRT – carboplatin/FU or cisplatin

TAX 323: TPF VS. PF Followed by RadiotherapyTAX 323: TPF VS. PF Followed by Radiotherapy A Phase III Study in Unresectable SCCHN A Phase III Study in Unresectable SCCHN

RANDOMIZE

P

P

F

F

Daily Radiotherapy

EUA

T

Surgery

TPF: Docetaxel 75D1 + Cisplatin 75D1 + 5-FU 750 CI: D1–5 q3wks x4 PF: Cisplatin 100D1 + 5-FU 1000CI: D1–5 q3wks x 4

Vermorken et al, 2007.

PF TPF

Median PFS 14.5 m 18.8 m

OS Rate: 5 Yrs 19% 28%

HR 0.75 [0.60;0.95]

Adjusted p Value .015

TAX 323 Update: 2011TAX 323 Update: 2011

Vermorken et al, 2011.

Sequential Combined Modality Therapy Sequential Combined Modality Therapy A Phase III Study: TAX 324 TPF Vs. PF A Phase III Study: TAX 324 TPF Vs. PF

Followed by ChemoradiotherapyFollowed by Chemoradiotherapy

RANDOMIZE

P

P

F

F

Carboplatinum: AUC 1.5 Wkly

Daily Radiotherapy

EUA

T

Surgery

TPF: Docetaxel 75D1 + Cisplatin 100D1 + 5-FU 1000CI: D1–4 q3wks x 3 PF: Cisplatin 100D1 + 5-FU 1000CI: D1–5 q3wks x 3

Posner et al, 2007.

TAX 324: 5-Yr Follow-Up – OS TAX 324: 5-Yr Follow-Up – OS

Sustained Survival Advantage At 5 Yrs For Patients Receiving TPF Vs. PF Median OS 71 Vs. 30 Mos (HR 0.74, p = .0129)

HR 0.74 (.058–.094)p = .013

TPF 52%PF 42%

Lorch et al, 2011.

Sequential ChemotherapySequential Chemotherapy

Induction chemotherapy and sequential therapy improve local regional control and OS

Sequential therapy is a standard curative treatment for advanced disease and organ preservation

Sequential therapy requires and experienced team

StudyPopulation N

PrimaryEnd Point Regimen

SignificantOutcomes

TAX 323 Inoperable 358 PFS PF vs. TPF Better PFS, OS p < .01

TAX 324 Locally Advanced 501 Survival PF/CRT vs.TPF/CRT

BetterPFS, OS, LFS p = 0.01 and 0.3

GORTEC 2000-01Resectable Larynx/Hypopharynx

213 Larynx Preservation

PF vs. TPF Better LFS p < .04

LFS = laryngectomy-free survival. Vermorken et al, 2007; Lorch et al, 2011; Pointreau et al, 2010.

Individualized Treatment: Individualized Treatment: Rationale for Emerging Targets Rationale for Emerging Targets

New Targets and Therapies in HNCNew Targets and Therapies in HNC

Small Molecules

– EGFR

• Afatinib, Lapatinib

– Met

• ARQ 197, XL 184, XL 880

– PI3K Pathway

• BKM120

– mTOR

• Everolimus

– VEGFR

• Bevacizumab

Complex Biologics

– Virolytics

• Rheovirus

– Vaccines

• Dendritic Cell

• Long HPV Peptides

– Immune Modulators

• Ipilimumab, PD-1

Group ACetuximab 400 mg/m2 initial dose

then 250 mg/m2 wkly + EITHER carboplatin (AUC 5, D1) OR cisplatin (100 mg/m2 IV, D1)+ 5-FU (1,000 mg/m2 IV, D1–4):

3-wk cycles

Group BEITHER carboplatin (AUC 5, D1) OR cisplatin (100 mg/m2 IV, D1) + 5-FU (1,000 mg/m2 IV, D1–4):

3-wk cycles

No TreatmentCetuximab

Randomized

Progressive Disease or Unacceptable Toxicity

6 Chemotherapy Cycles Maximum

The EXTREME TrialThe EXTREME Trial

Vermorken et al, 2008.

EXTREME Trial: OSEXTREME Trial: OS

Vermorken et al, 2008.

10.1 months

7.4 months

~ 10%

Survival Time, Months

Afatinib: An ErbB Family SMIAfatinib: An ErbB Family SMI

Has demonstrated preclinical activity on Erbb1 (EGFR/HER1), Erbb2 (HER2), and Erbb4 (HER4)

Has shown clinical activity in solid tumors (eg, lung and breast cancer)

Side effects associated with afatinib treatment are manageable and reversible

Eskens et al, 2008; Li et al, 2008; Yamamoto et al, 2011. Image courtesy of Marshall Posner, MD.

In vitro Molecular Potency

nM

ErbB1 0.5

ErbB2 14

ErbB4 1

Afatinib Randomized Phase IIAfatinib Randomized 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.

Stage 1 Stage 2

CetuximabCetuximab

AfatinibAfatinib

Continue until PD or undue

AEs

AfatinibAfatinib

CetuximabCetuximab

CT/MRI q8wks

Afatinib

Afatinib

Cetuximab

Cetuximab

50 mg po

daily

400/250mg/m2 IV wkly

50 mg po daily

400/250 mg/m2 IV wkly

N = 124(62 per arm)

R

A

N

D

O

M

I

Z

E

Metastaticrecurrent HNSCC

Stratum: No. Prior Chemotherapies for R/M

Disease (0 or 1)

Continue until PD or undue

AEs

Response to Therapy (Randomized Set)Response to Therapy (Randomized Set)

Afatinib Cetuximab

Total randomized, n (%) 62 (100.0) 62 (100.0)

Disease control (CR, PR, SD), n (%) 31 (50.0) 35 (56.5)

95% CI 37.0%, 63.0% 43.3%, 69.0%

p Value 0.48

Objective response (CR, PR), n (%)(confirmed in randomized patients)

10 (16.1) 4 (6.5)

95% CI 8.0%, 27.7% 1.8%, 15.7%

p Value 0.09

Objective response (CR, PR), %(confirmed in evaluable patients)

19.2 7.3

Partial response, n (%) 10 (16.1) 2 (3.2)

Stable disease, n (%) 21 (33.9) 31 (50.0)

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

Seiwert et al, 2012.

All Adverse Events in ≥ 5% (All Grades) All Adverse Events in ≥ 5% (All Grades)

AfatinibCetuximab

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

Trial Design End Points Study Sites

Phase III, Randomized, Open-Label

Primary: PFS Key Secondary: OS; HR 0.73

Global

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

• Documented PD• PS = 0–1

• Max 1 CT Regimen for R/M HNSCC• No Prior EGFR TKIs

RANDOMIZE

Afatinib 40 mg qdN = 316

MTX, 40 mg/m2/qwN = 158

2

1

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

Treatment Until PD

Trial Design End Points Study Sites

Phase III,Randomized, Placebo Controlled

Primary: DFS HR 0.72Secondary: DFS Rate 2 Yrs, OS, Safety

Global

Locally Advanced HNSCC• Unresected

• Stage III–IVb• Previous CRT

• Exclude non-smokers with OP cancer• PS 0–1

• NED After CRT

RANDOMIZE

Afatinib 40 mg qdN = 446

Placebo qdN = 223

2

1

LUX: HNC 2 (1200.131) Adjuvant Afatinib LUX: HNC 2 (1200.131) Adjuvant Afatinib

in Locally Advanced HNSCCin Locally Advanced HNSCC

NED = no evidence of disease.

Treatment for 18 months/ recurrence

The PI3K/mTOR PathwayThe PI3K/mTOR Pathway

Clarke et al, 2011.

MTD = maximum tolerated dose. Voliva et al, 2010; Maira et al, 2010; Bendell et al, 2011; Graña-Suárez et al, 2011.

BKM120: A Potent Oral Pan-PI3K BKM120: A Potent Oral Pan-PI3K InhibitorInhibitor

BKM120 is a potent oral pan-class I PI3K inhibitor that selectively inhibits all four class I PI3K isoforms (α,β,γ,δ)

BKM120 demonstrates anti-proliferative activity in a variety of human tumor cell lines with dysregulated PI3K pathways

BKM120 has shown potent anti-tumor activity in tumor xenograft models

The MTD of oral BKM120 on a continuous daily schedule was determined as 100 mg

BKM120 is now in phase II development

E1305 SchemaE1305 Schema

PhysicianPhysician’’s choice of s choice of chemotherapy regimenchemotherapy regimen

RANDOMIZATIONRANDOMIZATION

ARM AARM A

Cisplatin-doublet Cisplatin-doublet q21days until q21days until progressionprogression

ARM BARM B

Cisplatin-doublet plus Cisplatin-doublet plus bevacizumab q21days bevacizumab q21days

until progressionuntil progression

Option to discontinue Option to discontinue chemotherapy after 6 cycles if chemotherapy after 6 cycles if maximum response reachedmaximum response reached

Option to discontinue Option to discontinue chemotherapy after 6 cycles if chemotherapy after 6 cycles if maximum response reached. maximum response reached.

Bevacizumab will continue until Bevacizumab will continue until progression.progression.

Cisplatin + Docetaxel Cisplatin + Docetaxel

Cisplatin + 5-FUCisplatin + 5-FU

ClinicalTrials.gov

Shinomiya et al, 2003.

c-MET Signaling Pathwayc-MET Signaling Pathway

Survival

Progression

Angiogenesis

Motility Proliferation

What Can Activate MET?What Can Activate MET?

Amplification

Mutation

HGF

Non-amplified overexpression

– Secondary induction of transcription

– Secondary activation

– Promotor mutation

– Altered degradation

Expression: MET IHCExpression: MET IHC

Normal tissue - N=24

21%

58%

21%

0%

0+ 1+ 2+ 3+

Dysplasia - N=10

20%

50%

30%

0%

0+ 1+ 2+ 3+

Cancer - N=97

1%15%

64%

20%

0+ 1+ 2+ 3+

Seiwert et al, 2009.

CancerDysplasia“Normal”

(Adjacent Tissue)

Expression: HGF IHCExpression: HGF IHC

Seiwert et al, 2009.

Compound Company Mechanism Phase

AMG102 Amgen Anti-HGF Ab I/II

ARQ197 Arqule MET inhibitor I / II (HNSCC)

BMS-777607 BMS MET inhibitor I / II

INCB-28060 Incyte MET inhibitor I

JNJ-38877605 Johnson & Johnson MET inhibitor I

MetMAb Genentech Anti-MET Ab I / II

MGCD-265 Methylgene MET, Ron, Tek, VEGFR1/2/3 I

MK-2461 Merck MET inhibitor I / II

PF02341066 Pfizer MET, ALK I

PF4217903 Pfizer MET inhibitor I

SGX523 SGX MET inhibitor Discontinued

XL184 Exelixis / BMS MET, VEGFR2, RET I / II

XL880 (GSK1363089) Exelixis / GSK MET, VEGFR2 I / II (HNSCC)

Anti-MET/HGF CompoundsAnti-MET/HGF Compounds

CTLA-4(CD152)

Adapted from Keir et al, 2008.

(*PD-Ligand are expressed on cancer cells)

*Anti-PD-1 mAb (MDX-1106, IgG4)

Anti-CTLA-4 mAb (MDX-010, IgG1)

PD-1 (Programmed Death-1) and CTLA-4 PD-1 (Programmed Death-1) and CTLA-4

Blocking Inhibitory Receptors to Blocking Inhibitory Receptors to Reactivate Cancer CellsReactivate Cancer Cells

Hodi et al, 2010; Robert et al, 2011.

Randomize

StageIII–IVA OPSCCTumor/Blood

CollectionP16 IHC

Arm A: Cetuximab/Radiotherapy Plus Low-Dose IpilimumabRT 66 Gy with 200 cGy daily fractions in 6.5 wksCetuximab wkly at a dose of 250 mg/m2 during radiation* Ipilimumab 3 mg/kg q21days

SCHEMA

*After loading dose of 400 mg/m2 on Cycle 1, Day 1Ipilumumab will be continued at indicated dose for additional 2 cycles

Phase Ib/II Trial of Concurrent Cetuximab/IMRT With Phase Ib/II Trial of Concurrent Cetuximab/IMRT With Ipilimumab, Plus Biomarker Correlatives, in Locally Ipilimumab, Plus Biomarker Correlatives, in Locally

Advanced P16+ (HPV+) Oropharynx Cancer Advanced P16+ (HPV+) Oropharynx Cancer

New Targets and Therapies in HNCNew Targets and Therapies in HNC There are many new agents directed at important

signaling pathways in HNC

– Survival, metabolism: EGFR, MET

– Cell death: PI3K, PTEN, MTOR

– Vascular support: Bevacizumab

– Differentiation?

Biomarkers are potentially available for some agents, but aside from HPV as a prognostic marker, predictive markers are not ready for prime time

Personalized cancer therapeutics are close to becoming a reality in HNC

Case Study 1: HPV16+ Oropharynx CancerCase Study 1: HPV16+ Oropharynx Cancer

A 72-yr-old retired man, executive notes a lump in his right neck

– Asymptomatic, non-smoker, single glass of wine on weekend nights, no exposures

– No significant comorbidities

– CT reveals base of tongue mass and pathologic lymph node

– FNA of lymph node: SCC, P16+, HPV16+

– EUA reveals infitrative mass in the base of tongue, approaching midline

– A PET scan was performed

Case Study 1: HPV16+ Oropharynx CancerCase Study 1: HPV16+ Oropharynx CancerClinical Implications of T2N1 or T2N2bClinical Implications of T2N1 or T2N2b

Case Study 1: Clinical Decision Case Study 1: Clinical Decision Question 1Question 1

What is your choice of therapy?

1) Surgery plus post-operative chemoradiotherapy

2) Chemoradiotherapy

3) Sequential therapy

4) A diagnostic procedure

Your choices are:

– Surgery plus post-operative chemoradiotherapy

• No change in therapy, bilateral neck irradiation, margins

• Proper staging

– Chemoradiotherapy

• Long-term sequelae, extent of fields (lower neck)

– Sequential therapy

• Only indicated if lower neck node positive

– A diagnostic procedure

• Lower, lymph node biopsy/FNA or neck dissection

Case Study 1: HPV16+ Oropharynx CancerCase Study 1: HPV16+ Oropharynx CancerClinical Implications of T2N1 or T2N2bClinical Implications of T2N1 or T2N2b

What is your treatment choice now?

1) Surgery plus PORT

2) CRT

3) Sequential therapy

Lower, lymph node biopsy/FNA

– Negative

Case Study 1: HPV16+ Oropharynx CancerCase Study 1: HPV16+ Oropharynx Cancer

Case Study 1: Clinical Decision Question 2Case Study 1: Clinical Decision Question 2

Case Study 2: HPV – Base of Tongue CancerCase Study 2: HPV – Base of Tongue Cancer

A 57-yr-old man presents with dysarthria and bilateral neck masses

– No alcohol, smoked 2–3 ppd for 20 yrs, quit 20 yrs ago

– No comorbidities

FNA and biopsy positive for SCC

– T4 right base of tongue, bilateral extensive adenopathy staged T4N2c, stage 4a

– P16-, HPV-

Primary Tumor

What is your choice of therapy?

1) Surgery plus post-operative chemoradiotherapy

2) Chemoradiotherapy

3) Sequential therapy

4) Palliative therapy

Case Study 2: Clinical Decision QuestionCase Study 2: Clinical Decision Question

Your choices are:

– Surgery plus post-operative chemoradiotherapy

• Total glossopharyngectomy and reconstruction

– Chemoradiotherapy

• Bolus cisplatin or carboplatin/5-FU

• Cetuximab

– Sequential therapy

• TPF followed by CRT

– Palliative therapy

• Afatinib randomized trial, MET+ cetuximab, etc.

Case Study 2: Case Study 2: HPV16- Oropharynx Cancer: T4N2c, Stage 4aHPV16- Oropharynx Cancer: T4N2c, Stage 4a