Ezra W Cohen University of California, San Diego - PowerPoint Presentation

Ezra W CohenUniversity of California, San Diego RTP ON DEMAND: Thyroid Cancer

Thyroid CancerNewly Detected 2015 (n = 62,450)Cancer Facts & Figures 2015. Hürthle

Five- and 10-Year Cumulative Incidences of Death Among Patients with Thyroid Cancer Yang L et al.  J Clin Oncol   2013;31(4):468-74. Characteristic Cumulative incidence of death resulting from thyroid cancer 5 years (%)10 years (%)p-value*All patients1.93.0—Age at diagnosis, years  <0.001 <450.30.5 45-641.93.5 65-746.810.3 ≥7512.216.0Histologic subtype  <0.001 Papillary1.32.2 Follicular2.64.8 Medullary9.39.3 Anaplastic77.878.9 Other27.429.3 * Gray's test

Five- and 10-Year Cumulative Incidences of Death Among Patients with Thyroid Cancer by Age Yang L et al.  J Clin Oncol   2013;31(4):468-74. Characteristic Cumulative incidence of death resulting from thyroid cancer 5 years (%)10 years (%)p-value*All patients1.93.0—Age at diagnosis, years  <0.001 <450.30.5 45-641.93.5 65-746.810.3 ≥7512.216.0 Other27.429.3<0.001

Radioactive Iodine-Refractory Differentiated Thyroid Cancer: Molecular Pathways and Drug Targets Adapted from Dadu R, Cabanillas ME. Minerva Endocrinol 2012;37(4):335-56.

Selected Agents in Thyroid Cancer and Some of Their Kinase Targets — Are These “Actionable”? Colevas AD et al. Proc ASCO 2014;Discussant. Agent FGFR VEGFR PDGFRBRAFCKITFLT3CMETTIE2EGFRRETSorafenibXXXXXSunitinibXXXXXCabozantinibXXXXXXVandetanibXXXLenvatinibXXXXXLenalidomideXAxitinibXXMotesanibXXXXPazopanibXXXVemurafenibX

Agent ORR (RECIST) mPFS Axitinib 1,2 30%-35% 16.1-18.1 months Lenvatinib 3 50%12.6 monthsMotesanib414%40 weeksPazopanib549%11.7 monthsSorafenib6,7,815%-23%16 months – not reachedSunitinib9,1018%-31%12.8 months – not reachedVEGFRi in Thyroid Cancer — Phase II Trials1 Cohen EE et al. J Clin Oncol 2008;26(29):4708-13; 2 Locati LD et al. Cancer 2014;120(17):2694-703; 3 Sherman SI et al. ASCO 2011;Abstract 5503; 4 Sherman SI et al. N Engl J Med 2008;359(1):31-42; 5 Bible KC et al. Lancet Oncol 2010;11(10):962-72; 6 Gupta-Abramson V et al. J Clin Oncol 2008;26(29):4714-9; 7 Kloos RT et al. J Clin Oncol 2009;27(10):1675-84; 8 Ahmed M et al. Eur J Endocrinol 2011;165(2):315-22; 9 Carr LL et al. Clin Cancer Res 2010;16(21):5260-8; 10 Cohen EE et al. WCTC 2011.

Cohen EE et al.  J Clin Oncol  2008;26(29):4708-13. Investigator-Assessed Response to Treatment in a Phase II Study of Axitinib Response (n = 60) No.%Complete response00Partial response1830Stable disease2338Progressive disease47Indeterminate*813Missing712Objective response rate 1830 95% CI18.9 to 43.2CI = confidence interval* Includes 8 patients who did not meet any response criteria and 7 patients without postbaseline scans

Efficacy of Pazopanib in a Phase II Study in Progressive, Radioiodine-Refractory, Metastatic Differentiated Thyroid Cancer Bible KC et al. Lancet Oncol   2010;11(10):962-72.  Response (n = 37 evaluable patients) No. (%) Complete response 0 (0)Partial response18 (49) Follicular (n = 11)8 (73) Hürthle cell (n = 11)5 (45) Papillary (n = 15)5 (33)

Vandetanib in Locally Advanced or Metastatic Differentiated Thyroid Cancer: Progression-Free Survival in a Randomised, Double-Blind, Phase II Trial Leboulleux S et al. Lancet Oncol  2012;13(9):897-905.   Vandetanib (n = 72) Placebo(n = 73)Hazard ratio(95% CI)p-valueMedian progression-free survival11.1 mo5.9 mo0.63(0.54-0.74)0.008CI = confidence interval

Phase III Trials of Lenvatinib and Sorafenib in Radioiodine-Refractory Differentiated Thyroid CancerSELECT1 DECISION2 EndpointLenvatinib(n = 261)Placebo(n = 131)Sorafenib(n = 207)Placebo(n = 210)Response rate64.8%1.5%12.2%0.5%Median PFS18.3 mo3.6 mo10.8 mo5.8 mo1 Schlumberger M et al. N Engl J Med 2015;372(7):621-30; 2 Brose MS et al. Lancet 2014;384(9940):319-28.

Phase III DECISION Study Design Brose MS et al. BMC Cancer 2011;11:349; www.clinicaltrials.gov , NCT00984282. R 417 patients Locally advanced or metastatic RAI-refractory DTCProgression (RECIST) within the previous 14 monthsNo prior chemotherapy, targeted therapy or thalidomideSorafenib 400 mg orally twice dailyPlacebo Orally twice dailyRandomization 1:1Primary endpointProgression-free survivalStratified byGeographical region (North America or Europe or Asia)Age (<60 or 60 years) Progression assessed every 8 weeks (independent central review)Patients were allowed to receive open-label sorafenib after progressionSecondary endpoints:Overall survival Response rateSafetyTime to progressionDisease control rateDuration of responseSorafenib exposure (AUC 0-12 hours)

DECISION Study: Response, Survival and AEs Endpoint Sorafenib (n = 207) Placebo (n = 210) Hazard ratio p-value Median PFS 10.8 mo5.8 mo0.59<0.0001Median TTP11.1 mo5.7 mo0.56<0.0001Median OS*NRNR0.800.14Median OS corrected for crossover† ——0.69—ORR12.2%0.5%—<0.0001Disease control rate54.1%33.8%—<0.0001* 71.4% of patients receiving placebo crossed over at progressionMost AEs were Grade 1 or 2Most frequent sorafenib-associated AEsHand-foot skin reaction: 76.3%Diarrhea: 68.6%Alopecia: 67.1%Rash or desquamation: 50.2%Brose MS et al. Lancet 2014;384(9940):319-28; † Brose MS et al. Proc ASCO 2014;Abstract 6060.

SELECT: Phase III Trial of Lenvatinib versus Placebo in Radioiodine-Refractory Thyroid Cancer Schlumberger M et al. N Engl J Med 2015;372(7):621-30. Stratification Geographic region (Europe, North America, other) Prior VEGF/VEGFR-targeted therapy (0, 1)Age (≤65 years, >65 years)2:1Patients with DTC (N = 392)IRR evidence of progression within previous 13 months131I-refractory diseaseMeasurable diseaseUp to 1 prior VEGF- or VEGFR-targeted therapyRLenvatinib (n = 261)24 mg daily POPrimary endpointPFS Secondary endpointsORROSSafetyLenvatinib(optional, open label)Treatment until disease progression confirmed by IRR (RECIST v1.1)Placebo (n = 131)24 mg daily PO

SELECT: Patient Characteristics Schlumberger M et al. N Engl J Med  2015;372(7):621-30. Variable Lenvatinib (N = 261) Placebo (N = 131) Median age — y6461Male sex — no. (%) 125 (47.9) 75 (57.3)Region — no. (%) Europe North America Other 131 (50.2)77 (29.5) 53 (20.3) 64 (48.9)39 (29.8)28 (21.4) ECOG performance status — no. (%) 0 or 1 2 or 3 248 (95.0) 13 (5.0)129 (98.5) 2 (1.5)One prior treatment regimen with a tyrosine kinase inhibitor — no. (%) 66 (25.3) 27 (20.6) Histologic subtype of differentiated thyroid cancer — no. (%) Papillary Poorly differentiated Follicular, not Hürthle cell Hürthle cell132 (50.6) 28 (10.7) 53 (20.3) 48 (18.4) 68 (51.9) 19 (14.5) 22 (16.8) 22 (16.8) Metastatic lesions — no. (%) With bony metastases With pulmonary metastases 104 (39.8) 226 (86.6) 48 (36.6)124 (94.7)

SELECT: Kaplan-Meier Estimate of PFS From The New England Journal of Medicine , Martin Schlumberger , Makoto Tahara, Lori J Wirth, et al, Lenvatinib versus Placebo in Radioiodine-Refractory Thyroid Cancer, 372, 621-30. Copyright © 2015 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

SELECT: Progression-Free Survival by Previous VEGF-Targeted Therapy Schlumberger M et al. N Engl J Med  2015;372(7):621-30. Median progression-free survival   Lenvatinib PlaceboHazard ratio(95% CI)p-valueTKI naïve (n = 299) 18.7 mo 3.6 mo 0.20(0.14-0.27) <0.0001One prior TKI regimen (n = 93)15.1 mo3.6 mo0.22 (0.12-0.41)<0.0001CI = confidence interval

Schlumberger M et al. N Engl J Med 2015;372(7):621-30. Events/N Median (months) Lenvatinib PlaceboHR (95% CI)LenvatinibPlaceboTarget tumor size at baseline (mm)≤3514/6521/280.14 (0.06, 0.33)NE5.635-6031/7231/320.19 (0.10, 0.36)16.43.761-9231/6331/340.24 (0.13, 0.43)14.83.6>9231/6130/370.21 (0.11, 0.42)13.92.4HistologyPapillary58/13258/680.30 (0.20, 0.44)16.43.5Poorly differentiated14/2818/190.21 (0.08, 0.56)14.82.1Follicular20/53 20/22 0.07 (0.03, 0.21) 18.8 2.4 Hürthle cell 15/48 17/22 0.22 (0.10, 0.51) NE 5.3 Bone metastasis No 60/157 74/83 0.18 (0.12, 0.27) 20.2 3.7 Yes 47/104 39/48 0.26 (0.16, 0.42) 14.8 2.1 Lung metastasis No 17/35 7/7 0.24 (0.08, 0.77) 14.8 2.4 Yes 90/226 106/124 0.21 (0.15, 0.29) 18.7 3.6 SELECT: Progression-Free Survival Subgroup Analysis NE = not evaluable/estimable (not reached)

SELECT: Response Rates Schlumberger M et al. N Engl J Med   2015;372(7):621-30. Lenvatinib (N = 261) Placebo(N = 131)Odds ratio (95% CI) Response rate — no. (%)* 169 (64.8) 2 (1.5) 28.87 (12.46–66.86)† Complete response 4 (1.5) 0Partial response 165 (63.2) 2 (1.5) Stable disease 60 (23.0) 71 (54.2) Durable stable disease ≥23 wk 40 (15.3) 39 (29.8) Progressive disease 18 (6.9) 52 (39.7) Could not be evaluated 14 (5.4) 6 (4.6) Median time to first objective response — mo (95% CI) 2.0 (1.9–3.5) 5.6 (1.8–9.4) * Tumor responses were assessed with the use of Response Criteria in Solid Tumors (RECIST), version 1.1, and were confirmed by independent centralized radiologic review.† p < 0.001 for the comparison between the two groups

SELECT: Best Tumor Response From The New England Journal of Medicine , Martin Schlumberger , Makoto Tahara, Lori J Wirth, et al, Lenvatinib versus Placebo in Radioiodine-Refractory Thyroid Cancer, 372, 621-30. Copyright © 2015 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.Best Overall Response (n = 245)CR (n = 4) PR (n = 165)SD (n = 60)PD (n = 16)Best Overall Response (n = 126)PR (n = 2)SD (n = 71)PD (n = 51)NE (n = 2)Treatment group: PlaceboTreatment group: LenvatinibPercent Change From Baseline at NadirPercent Change From Baseline at Nadir CR = complete response; NE = not evaluable/estimable (ie, not reached); PD = progressive disease; PR = partial response; SD = stable disease

Schlumberger M et al. N Engl J Med 2015;372(7):621-30. SELECT: Overall Survival, ITT Population Lenvatinib(n = 261)Placebo(n = 131)Hazard ratio(95% CI)p-valueMedian overall survivalNRNR0.73(0.50-1.07)0.1032No significant difference was observed in RPSFT-adjusted overall survival (p = 0.051), which was used to correct for a potential crossover effect in the placebo arm.

SELECT: Effect of Age and Lenvatinib Treatment on Overall Survival Brose MS et al. Proc ASCO   2015;Abstract 6048. Patients stratified by: Age: Younger (≤ 65 y) vs Older (>65 y)RegionPrior VEGF-targeted therapyMedian OS was not reached in any subgroup except for older patients in placebo group.Older patients in the placebo group had worse OS than younger patientsThe impact of age was mitigated by lenvatinib treatmentNo difference in OS between younger and older patients in lenvatinib group

SELECT: Treatment-Related Adverse Events of Special Interest Schlumberger M et al. N Engl J Med   2015;372(7):621-30. Effect (%)Lenvatinib (N = 261) Placebo (N = 131) All grades Grade ≥3 All grades Grade ≥3 Hypertension 67.8 41.8 9.2 2.3Diarrhea 59.4 8.08.40Fatigue or asthenia 59.0 9.2 27.5 2.3Decreased appetite 50.2 5.4 11.50Decreased weight 46.4 9.6 9.20Nausea 41.02.313.70.8Stomatitis 35.64.23.80Palmar–plantar erythrodysesthesia syndrome 31.83.40.80Proteinuria 31.010.01.50

Phase II Trials of Everolimus C ombined with Sorafenib in Refractory Thyroid CancerEndpoint NCT012639511 (n = 33)NCT011413092(n = 38)Complete response (CR)0%NRPartial response (PR)3%55%Stable disease (SD)55%37%Clinical benefit (CR + PR + SD ≥6 mo)58%NRDisease progressionNR8%Median PFS13.7 moNR 1 Brose MS et al. Proc ASCO 2015;Abstract 6072; 2 Sherman EJ et al. Proc ASCO 2015;Abstract 6069.NR = not reported

Kim KB et al. Thyroid 2013;23(10):1277-83. Clinical Responses to Vemurafenib in Patients with Metastatic Papillary Thyroid Cancer Harboring BRAF V600E Mutation 3 subjects treated 1 PR (31% reduction in pulmonary target lesion)2 SDTTP = 11.4 to 13.2 months

VemurafenibPhase I study1/3 thyroid cancer with response; other 2 with stable diseasePhase II study in thyroid cancer completed Recurrent, unresectable or metastatic papillary thyroid cancer BRAF V600 mutation-positive by cobas Radioactive iodine refractory Evidence of progressionwithin 14 months   VemurafenibBrose MS et al. ECCO/ESMO 2013;Abstract 28. VEGFR2i naïve(n = 26)Vemurafenib 960 mg BID until disease progression or unacceptable toxicityVEGFR2i pretreated(n = 25)

Vemurafenib Response Rate Brose MS et al. ESMO/ ECC 2013 ;Abstract 28. VEGFR2i naïve VEGFR2i pretreated Complete response 0 0 Partial response 35%26%Stable disease 6 mo 23%10%Clinical benefit rate58%36%Median PFS15.6 months6.8 months

Single-Institution, Single-Arm Pilot Study Investigating the Potential for the BRAF Inhibitor Dabrafenib to Induce Radioiodine Uptake in BRAF-Mutant, Radioiodine-Refractory PTC Primary endpoint: Increased radioiodine uptake by 4mCi 131-I whole body scan. All 7 patients on study had negative 131-I scans within 14 months of enrollment.6/10 evaluable patients demonstrated new radioiodine uptake on whole body scan after treatment with dabrafenib. 2 patients had partial responses and 4 patients had stable disease on standard radiographic restaging at 3 months.Thyroglobulin decreased in 4 of 6 patients who received treatment. Rothenberg SM et al. Clin Cancer Res 2015;21(5):1028-35.

Selumetinib Response Rate All number (%) Evaluable number (%) BRAF V600E number (%) Total number 393212Complete response 0 (0%) 0 (0%) 0 (0%) Partial response1 (3%)1 (3%)1 (8%)Stable disease 21 (54%) 21 (66%) 9 (75%) Progression 11 (28%) 10 (31%) 2 (17%) No data on response 6 (15%) Hayes DN et al. Clin Cancer Res 2012;18(7):2056-65.

Impact of Selumetinib on 124I Incorporation Ho AL et al. N Engl J Med 2013;368(7):623-32. N = 20 Patients with new/increased 124I incorporation after selumetinib 12/20Patients who went on to receive therapeutic RAI 8/20Tumor genotypePatients with increased lesional iodine incorporation after selumetinib (fraction of total)Patients who received RAI (fraction of total)BRAF4/91/9NRAS5/55/5RET/PTC2/31/3Wild type1/31/3Total12/208/20

Ho AL et al. N Engl J Med 2013;368(7):623-32. Response to Iodine-131 Therapy with Selumetinib Treatment Patient numberGenotypeResponseSerum thyroglobulin values (ng/mL)   Before selumetinib (wk 1)After selumetinib (wk 5)1 mo after radioiodine2 mo after radioiodine6 mo after radioiodine1RET/PTCSD6507802402007402WTSD3608802702101943NRASPR2,7003,2003,7007404804NRASPR5101,300NA31225NRASPR220530 11.3 0.4 <0.2 6 NRAS SD 840 570 46 31 100 7 NRAS PR 6,500 1,070 170 66 57 8 BRAF PR 82 650 NA 23 14 SD = stable disease ; WT = wild type; PR = partial response ; NA = not available

A Phase I/II Study of Cediranib (CED) and Lenalidomide (LEN) in Patients with Advanced Differentiated Thyroid Cancers Brown RL et al. The Endocrine Society’s 94 th Annual Meeting and Expo 2012;Abstract SUN-281. PHASE I PHASE II Dose escalation of CED and LEN Cohort A: CED 30 mgCohort B: CED + LEN at MTDProgression-free survival Determine maximum tolerated dose (MTD) of combined therapy

RET10q11.23 functional domainsGenotype-phenotype correlationsSignals through multiple pathways to regulate survival, cell growth, differentiation N-terminal signal sequence Cadherin-like domain Cysteine-rich domain Transmembrane domain Tyrosine kinase domain MEN 2A/FMTC FMTC MEN 2BAlternative 3 splice sitesCOOH

Phase III ZETA Study Design Vandetanib 300 mg/day n = 231 Follow for progression Follow for progression Optional open-label vandetanib 300 mg/day Follow for survivalPatients with unresectable locally advanced or metastatic hereditary or sporadic MTC (N = 331)Placebon = 100 2:1 randomizationDiscontinue blinded treatment at progression**Progression as assessed by the site investigatorwww.clinicaltrials.gov, NCT00410761.

Phase III ZETA Study: PFS by Central Independent Review 0 Vandetanib 300 mg Placebo Time (months) 231 196 169 140 40101007157451300No. at risk Vandetanib 300 mgPlacebo 0.6 0.8 Progression-Free Survival (proportion) 0.9 0 0.1 0.2 0.3 0.4 0.5 0.7 1.0 6 12 18 24 30 36 Wells, SA Jr et al: J Clin Oncol 30 (2), 2012: 134-41. Reprinted with permission. © 2012 American Society of Clinical Oncology . All rights reserved .

ZETA Study: Other Notable FeaturesSignificantly higher objective response rate45% versus 13%; odds ratio = 5.48, 95% CI: 2.99-10.79, p < 0.001 12 of 13 responses in the placebo arm were seen during treatment with open-label vandetanib Objective responses were durable Biochemical response rateCalcitonin (69% versus 3%; odds ratio = 72.9, 95% CI: 26.2-303.2, p < 0.001)CEA (52% versus 2%; odds ratio = 52.0, 95% CI: 16.0-320.3, p < 0.001)Statistically significant delay in time to worsening of pain with vandetanib versus placebo (hazard ratio = 0.61; p = 0.006)Median overall survival: Not yet reached Wells SA Jr et al. J Clin Oncol 2012;30(2):134-41.

CabozantinibA potent oral targeted therapy that inhibits MET, VEGFR2 and RET1Clinical activity observed in MTC patients in a Phase I study229% objective response rate per RECIST 68% disease control rate Stable disease for >6 months or confirmed partial response 1 Yakes FM et al. Mol Cancer Ther 2011;10(12):2298-308; 2 Kurzrock R et al. J Clin Oncol 2011;29(19):2660-6.

Trial design Endpoints Study sites Phase III, randomized, placebo controlled Primary: PFS Secondary: OS, ORR per RECIST Global EXAM: Phase III Trial of Cabozantinib in Medullary Thyroid Carcinoma with RECIST Progression at Baseline21RMedullary thyroid carcinomaUnresectable locally advanced or metastatic diseaseDocumented RECIST progression within 14 moNo limit to prior therapiesCabozantinib 140 mg qdN = 219Placebo qdN = 111 ProgressionNo crossover allowed.Schlumberger M et al. Proc ASCO 2015;Abstract 6012.Survival follow-up

EXAM Study: Survival, Response and AEs Endpoint Cabozantinib Placebo Hazard ratio p -valueMedian PFS11.2 mo 4.0 mo 0.28<0.001ORR (all partial responses)*28%0%—<0.001* ORR for RET mutation-positive and negative subgroups receiving cabozantinib was 32% and 25%, respectivelyNinety-four percent (170 of 180) of patients with measurable disease at baseline and at least one postbaseline assessment who received cabozantinib had a detectable decrease in target lesion size compared to 27% (24 of 89) of patients in the placebo group. Elisei R et al. J Clin Oncol 2013;31(29):3639-46.Common Grade ≥3 cabozantinib-related AEsDiarrhea:15.9%Palmar-plantar erythrodysesthesia:12.6%Decreased weight:4.7%Decreased appetite:4.7%Nausea:1.4%Fatigue:9.3%Treatment discontinuation in 16% of cabozantinib and 8% placebo

EXAM: Response and Survival According to RET M918T Status Endpoint RET M918T Positive RET M918T Negative Cabozantinib (n = 81) Placebo (n = 45) Cabozantinib (n = 75) Placebo(n = 32)ORR34%0%20%0%Median OS (mo)44.318.920.2 mo21.5moOS HR (95% CI)0.60 (0.38-0.95)1.12 (0.70-1.82)p-value0.02600.6308Median PFS (mo)13.94.05.75.4PFS HR (95% CI)0.15 (0.08-0.28)0.67 (0.37-1.23)p-value<0.00010.1875ORR = objective response rate; OS = overall survival; PFS = progression-free survival; HR = hazard ratioSchlumberger M et al. Proc ASCO 2015;Abstract 6012.

Genomic Landscape of Anaplastic Thyroid Cancer (ATC) Capdevila J et al. Proc ASCO   2015;Abstract 6033. Exome-seq on 13 cases of ATC including 2 cases of concomitant papillary thyroid cancer (PTC) and ATC in the same patient, showed:Mutations related with ATC include TP53 (30%); RAS (29%), PIK3CA (23%), STAT (23%), BRAF (15%) and mutations in genes involved in SWI/SNF (15%), CDK (15%) and hedgehog (15%) pathwaysSignificantly different genomic background with few common root mutations between PTC and ATCSubclonal oncogenic BRAF and NRAS mutations enriched in PTC but decreased in ATCDriver mutations TP53, PI3KCA, STAT and PDGFR detectable only in ATC

Ezra W CohenUniversity of California, San Diego RTP ON DEMAND: Head and Neck Cancer

Anatomic Sites of Head and Neck CancerHeterogeneous group of cancers; varying primary sites Squamous histology in 95% of cases Anatomic sites Oral cavity Nasopharynx /oropharynx/ hypopharynx LarynxOther anatomic sitesParanasal sinusesLip Salivary glands Adapted from SEER training modules, head & neck cancer. National Institutes of Health, National Cancer Institute. Oral CavityLipBuccal mucosaAlveolar ridgeRetromolar trigoneFloor of mouthHard palateOral tongue (anterior two thirds) LarynxSupraglottisGlottisSubglottisNasal CavityTongueEsophagusJawNasopharynx OropharynxBase of tongueSoft palateTonsillar pillar and fossa Hypopharynx Pharynx

Two Distinct SCCHN Entities HPV+ HPV- Anatomic slide Tonsil/base of tongue All sites Histology Basaloid Keratinized AgeYoungerOlderGender3:1 men3:1 men Risk factors Sexual behavior Alcohol/tobacco Incidence Rising Declining Survival Improved Worse Molecular PI3K pathway alterations p53, p16, CCDN1, FAT1 Population-level incidence of HPV-positive oropharyngeal cancers increased by 225% (95% CI, 208% to 242%) from 1988 to 2004 (from 0.8 per 100,000 to 2.6 per 100,000), and incidence for HPV-negative cancers declined by 50% (95% CI, 47% to 53%; from 2.0 per 100,000 to 1.0 per 100,000) . 1 1 Chaturvedi AK et al. J Clin Oncol 2011;29(32):4294-301.

Subtype Proportion Key characteristics Basal 31% Expression patterns in basal layer of human airway epithelium; low levels of SOX2 relative to TP63 Mesenchymal27%Expression markers of epithelial to mesenchymal transformation including VIM, DES, TWIST1, PDGFRA/BAtypical24%Includes all HPV+; little evidence for chromosome 7 amplificationClassical18%Heaviest smoking histories; elevation expression levels of oxidative stress response genes, including NFE2L2Gene Expression Subtypes of SCCHNThe Cancer Genome Atlas Network. Nature 2015;517:576-82

ObservationBest supportive careTreatment Algorithm for Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma Fit with aggressive symptomatic disease Good performance status with active disease Frail or indolent asymptomatic disease Cisplatin/carboplatin+ 5-FU + cetuximab Platinum doublet* Cisplatin/paclitaxel Carboplatin/paclitaxel Cisplatin/docetaxel+/- cetuximabSingle-agent therapy: Paclitaxel/docetaxel Cetuximab* Capecitabine Vinorelbine MethotrexateR/M HNSCC Locally recurrent or distant metastases* Consider if platinum resistantPrice KA, Cohen EE. Curr Treat Options Oncol 2012;13(1):35-46.

Single-Agent Response Rates of EGFR-Targeted mAbs and TKIs in SCCHN - Drug Phase Reference RR Cetuximab II Vermorken et al, 200713%ErlotinibIISoulieres et al, 20044%GefitinibIICohen et al, 200311%IICohen et al, 20052%IIIStewart et al, 20098%LapatinibIIAbidoye et al, 2006 (ASCO)0%ZalutumumabIIIMachiels et al, 2010 (ASCO)6%Vermorken JB et al. J Clin Oncol 2007;25(16):2171-7; Soulieres D et al. J Clin Oncol 2004;22(1):77-85; Cohen EE et al. J Clin Oncol 2003;21(10):1980-7; Cohen EE et al. Clin Cancer Res 2005;11(23):8418-24; Kirby AM et al. Br J Cancer 2006;94(5):631-6; Stewart JS et al. J Clin Oncol 2009;27(11):1864-71; Abidoye OO et al. Proc ASCO 2006;Abstract 5568; Machiels JH et al. Proc ASCO 2010;Abstract LBA5506; Seiwert TY et al. ESMO 2010;Abstract 1010PD.

EXTREME Study Design R Group A Cetuximab 400 mg/m 2 initial dose then 250 mg/m 2 weekly + EITHER carboplatin (AUC 5, d1) OR cisplatin (100 mg/m2 IV, d1)+ 5-FU (1,000 mg/m2 IV, d1-4): 3-week cyclesGroup BEITHER carboplatin (AUC 5, d1) OR cisplatin (100 mg/m2 IV, d1) + 5-FU (1,000 mg/m2 IV, d1-4):3-week cyclesCetuximabNo treatmentProgressive disease or unacceptable toxicity6 chemotherapy cycles maximumVermorken JB et al. N Engl J Med 2008;359(11):1116-27.

EXTREME Study: Overall Survival Vermorken JB et al. N Engl J Med 2008;359(11):1116-27.   Cetuximab + platinum/fluorouracil(n = 222)Platinum/fluorouracil alone (n = 220)Hazard ratio(95% CI)p-valueMedian overall survival10.1 mo7.4 mo0.80(0.64-0.99)0.04

Phase II Trial of Dacomitinib : Response, Survival and Grade 3/4 AEs Response (n = 63) n (%) Complete response (CR) 0 (0) Partial response (PR) 8 (12.7) Stable disease (SD) ≥24 weeks <24 weeks36 (57.1)9 (14.3)27 (42.9)Progressive disease17 (27)Indeterminate2 (3.2)Objective response rate (CR + PR)8 (12.7)Clinical benefit rate (CR + PR + SD ≥24 weeks)17 (27.0)Abdul Razak AR et al. Ann Oncol 2013;24(3):761-9.Most common Grade ≥3 AEsDiarrhea: 15.9%Acneiform dermatitis: 8.7%Fatigue: 8.7%Survival (n = 69) Median progression-free survival12.1 weeksMedian overall survival34.6 weeks

Eligibility criteria:Locoregionally recurrent or metastatic SCCHN PS 0 or 1 Primary endpoint: Progression-free survival PD Trial ID: NCT01836029 Estimated enrollment: 175 (open) www.clinicaltrials.gov; Accessed April 2015.ACTIVE8: Phase II Trial of Chemotherapy and Cetuximab in Combination with VTX-2337 in Recurrent or Metastatic SCCHN1:1RChemotherapy + cetuximab + VTX-2337Up to 6 cyclesChemotherapy + cetuximab + placeboUp to 6 cyclesCetuximabCetuximab

Vermorken JB et al. Lancet Oncol 2013;14(8):697-710. SPECTRUM: Cisplatin + 5-FU ± Panitumumab in Recurrent/Metastatic SCCHNOpen-label, randomized Phase III trial Patients with distant metastatic and/or locally recurrent SCCHN, ECOG PS ≤1(N = 657)Stratified by previous treatment, primary tumor site, ECOG PSOptional panitumumab maintenance q3wkPanitumumab 9 mg/kg day 1Cisplatin 100 mg/m2 day 15-FU 1,000 mg/m2 days 1-4(n = 327)Cisplatin 100 mg/m2 day 15-FU 1,000 mg/m2 days 1-4(n = 330)Max six 3-wk cyclesPrimary endpoint: OSSecondary endpoints: PFS, ORR, DOR, TTR, safety

SPECTRUM Study: Overall SurvivalVermorken JB et al. Lancet Oncol 2013;14(8):697-710.   Cisplatin /5-FU + panitumumab(n = 327)Cisplatin/5-FU (n = 330)Hazard ratio(95% CI)p-valueMedian overall survival11.1 mo9.0 mo0.873(0.729-1.046)0.1403

Chen LF et al. Clin Cancer Res 2010;16:2489-2495 Mechanisms of Resistance to EGFRi

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 CT/MRI q8wk Phase II Study of Afatinib versus CetuximabMetastatic recurrent HNSCCN = 124 (62 per arm)RAfatinib50 mg po dailyCetuximab400/250 mg/m2 IV weeklyContinue until PD or undue AEsContinue until PD or undue AEsCetuximab400/250 mg/m2 IV weeklyAfatinib50 mg po dailyStratum: No. prior chemotherapies for R/M disease (0 or ≥1)Seiwert TY et al. Ann Oncol 2014;25(9):1813-20.

Phase II Study of Afatinib versus Cetuximab: Maximum Tumor Shrinkage in Target Lesions Seiwert TY et al. Ann Oncol 2014;25(9):1813-20. Investigator review Independent central review AfatinibCetuximabAfatinibCetuximabTotal randomized, n62626262ORR (CR, PR), n (%) 95% CI10 (16.1)8.0-27.74 (6.5)1.8-15.75 (8.1)2.7-17.86 (9.7)3.6-19.9 p-value0.090.78

Phase II Study of Afatinib versus Cetuximab: Progression-Free and Overall Survival Seiwert TY et al. Ann Oncol 2014;25(9):1813-20. Stage 1   Afatinib(n = 62)Cetuximab (n = 62)Hazard ratio(95% CI)p-valueMedian progression-free survival13.0 wk15.0 wk0.93(0.62-1.38)0.71Stage 2 Afatinib(n = 36)Cetuximab (n = 32)Hazard ratio (95% CI)p-valueMedian progression-free survival9.3 wk5.7 wk0.64 (0.38-1.05)0.08Stage 1 and Stage 2 Afatinib (n = 62)Cetuximab (n = 62)Hazard ratio (95% CI)p-valueMedian overall survival35.9 wk47.1 wk1.06 (0.70-1.62)0.78

Phase II Study of Afatinib versus Cetuximab: Tumor Shrinkage in Stage 2 Seiwert TY et al. Ann Oncol 2014;25(9):1813-20.   Afatinib after prior cetuximab in Stage 1, nCetuximab after prior afatinib in Stage 1, nMaximum % tumor shrinkage ≥20%611 ≥0% and <20%127 >-30% and <0%117 ≤30%11

Phase II Study of Afatinib versus Cetuximab: Treatment-Related Adverse Events in ≥10% of Patients (Stage 1) Afatinib (n = 61) Cetuximab (n = 60) All grades Grade 3-4 All grades Grade 3-4Total, n (%)59 (96.7)32 (52.5)51 (85.0)11 (18.4)Rash/acne48 (78.7)11 (18.0)46 (76.7)5 (8.3)Diarrhea48 (78.7)9 (14.8)12 (20.0)0Stomatitis21 (34.4)7 (11.5)14 (23.3)0Fatigue20 (32.8)3 (4.9)13 (21.7)1 (1.7)Nausea17 (27.9)1 (1.6)12 (20.0)1 (1.7)Vomiting10 (16.4)1 (1.6)8 (13.3)0Dry skin9 (14.8)015 (25.0)0Dehydration8 (13.1)5 (8.2)1 (1.7)0Decreased appetite5 (8.2)3 (4.9)8 (13.3)0Nail effects4 (6.6)06 (10.0)1 (1.7)Ocular effects4 (6.6)06 (10.0)1 (1.7)Constipation 2 (3.3) 0 7 (11.7) 0 Seiwert TY et al. Ann Oncol 2014;25(9):1813-20.

Trial design Endpoints Study sites Phase III, randomized , open-label Primary: PFS Key secondary: OSGlobal21LUX-Head & Neck 1: Second-Line Afatinib versus Methotrexate in Recurrent and/or Metastatic Squamous Cell Carcinoma of the Head and Neck Progressing After Platinum-Based TherapyRRelapsed/metastatic squamous cell carcinomaFailure of platinum-based chemotherapy for relapsed/metastatic diseaseDocumented PDPS 0-1Maximum of 1 chemotherapy regimen for relapsed/metastatic diseaseNo prior EGFR TKIsAfatinib 40 mg qdN = 316Methotrexate 40 mg/m2 qwkN = 158Treatment until PD Machiels J et al. ESMO 2014;Abstract LBA29_PR.PFS = progression-free survival; OS = overall survival; PD = progressive disease

LUX-Head & Neck 1: Efficacy Endpoint Afatinib (n = 322) Methotrexate (n = 161) Hazard ratio p -value Progression-free survival2.6 mo1.7 mo0.800.03Overall survival6.8 mo6.0 mo0.96NSDisease control rate49.1%38.5%—0.04Overall response rate10.2%5.6%—0.10Machiels J et al. ESMO 2014;Abstract LBA29_PR.Afatinib delayed deterioration of global health status, pain and swallowing (all p ≤0.03) and provided improvement in pain (p = 0.03)Most frequent Grade 3/4 drug-related AEsAfatinib: Rash/acne (9.7%), diarrhea (9.4%)Methotrexate: Leukopenia (15.6%), stomatitis (8.1%)Fewer treatment-related dose reductions, discontinuations and fatal events with afatinib

LUX-Head & Neck 1: Select Drug-Related Adverse EventsMachiels J et al. ESMO 2014;Abstract LBA29_PR. Afatinib (n = 320) Methotrexate (n = 160) All grades Grade 3 Grade 4 All grades Grade 3Grade 4 More frequent with afatinibRash/acne74100800Diarrhea 72911220Paronychia1410000Decreased appetite13301310Vomiting131<1900Dry skin1100000More frequent with methotrexate Stomatitis 39 6 <1 43 8 0 Fatigue 25 6 0 32 3 0 Nausea 20 2 0 23 1 0 Neutropenia <1 <1 0 19 6 1 Anemia 7 1 0 19 5 1

Trial design Endpoints Study sites Phase III, randomized, placebo controlled Primary: DFS Secondary: 2-year DFS rate, OS, safety Global LUX-Head & Neck 2: Adjuvant Afatinib in Locally Advanced Squamous Cell Carcinoma of the Head and NeckNED = no evidence of disease21RLocally advanced squamous cell carcinoma of the head and neckUnresectedStage III–IVbPrevious chemoradiation therapyExcludes nonsmokers with oropharyngeal cancerPS 0-1NED after chemoradiation therapyAfatinib 40 mg qdN = 446Placebo qdN = 223 Treatment for 18 months/ until recurrence

Basis for Immunotherapy — Immune Escape Adapted from Seiwert TY et al. Proc ASCO 2014;Abstract 6011; Melero I et al. Clin Cancer Res 2013;19(5):997-1008. Expression of PD-L1 on tumor cells and macrophages can suppress immune surveillance.In mouse models antibodies blocking PD-1/PD-L1 interaction lead to tumor rejection.Clinical prognosis correlates with presence of TILs and PD-L1 expression in multiple cancers.

KEYNOTE-012: Multicenter, Nonrandomized, Phase Ib Squamous Cell Carcinoma of the Head and Neck Expansion Cohort Seiwert TY et al. Proc ASCO 2014;Abstract 6011. Recurrent or metastatic head and neck cancer PD-L1-positive Investigator- assessed HPV statusHPV-negative cohortHPV-positivecohortTreat until PD** Treatment beyond initial PD allowed; radiation therapy to progressive lesion allowedPD = progressive diseasePembrolizumab10 mg/kg q2wkPembrolizumab10 mg/kg q2wk

KEYNOTE-012: Best Overall Response Seiwert TY et al. Proc ASCO 2014;Abstract 6011. Total head/neck N = 56 HPV (+)N = 20HPV (-)N = 36*Response evaluationn (%) 95% CI n (%) 95% CIn (%) 95% CI Complete response (CR)1 (1.8) 0.0, 9.6 1 (5.0) 0.1, 24.9 0 (0.0)0.0, 9.7 Partial response (PR)10 (17.9) 8.9, 30.4 3 (15.0)3.2, 37.9 7 (19.4)8.2, 36.0 Best overall response (CR + PR)† 11 (19.6) 10.2, 32.4 4 (20.0) 5.7, 43.7 7 (19.4)8.2, 36.0 Stable disease16 (28.6) 17.3, 42.2 8 (40.0) 19.1, 63.9 8 (22.2)10.1, 39.2 Progressive disease25 (44.6) 31.3, 58.5 7 (35.0) 15.4, 59.2 18 (50.0)32.9, 67.1 No assessment4 (7.1) 2.0, 17.3 1 (5.0) 0.1, 24.9 3 (8.3)1.8, 22.5PD-L1 expression correlates with responseUsing a Youden-Index derived, preliminary PD-L1 cut point:Above cut point: 45.5% (5/11) RRBelow cut point: 11.4% (5/44) RRBased on RECIST 1.1 per site assessment; includes confirmed and unconfirmed responses* Includes 2 patients for whom HPV data were unavailable.† A single patient with PD followed by PR on treatment was classified as PR.

KEYNOTE-012: PD-L1 Screening Results 104 patients screened:   PD-L1 staining in tumors of screened patients (N = 104)Staining (%)01-1011-2021-3031-4041-5051-6061-7071-8081-9091-100n26*248932243221* Three patients with tumor (-) but stroma (+) by IHCPD-L1-positive: 78% (81)Study eligible n = 61*HPV (-) n = 36HPV (+) n = 23HPV (na) n = 2PD-L1-negative: 22% (23)Seiwert TY et al. Proc ASCO 2014;Abstract 6011.

Clinical endpoint Overall (n = 117) HPV (+) (n = 34) HPV (-) (n = 81)ORR, n (%)29 (24.8)7 (20.6)22 (27.2) Complete response1 (0.9)1 (2.9)0 (0) Partial response28 (23.9)6 (17.6)22 (27.2)KEYNOTE-012: Efficacy by HPV StatusSeiwert TY et al. Proc ASCO 2015;Abstract LBA6008.

KEYNOTE-012: Select Drug-Related Adverse Events Seiwert TY et al. Proc ASCO 2014;Abstract 6011. All grades Grades 3-5  n %n %Any drug-related event3558.31016.7 Fatigue 10 16.7 0 0.0 Pruritus 6 10.0 0 0.0 Rash 5 8.3 2 3.3 Nausea 4 6.7 0 0.0 Decreased appetite 3 5.0 0 0.0 Myalgia 3 5.0 0 0.0

Phase I Study of MEDI4736 in Recurrent/Metastatic SCCHN: Results SummaryEfficacy outcomes29 SCCHN patients evaluable7 patients had radiographic shrinkage of target tumor lesions ranging from 7% to 76%5 of 7 have been followed for at least 12 weeks4 patients have partial responses0 patients have evidence of objective progression Safety outcomes 50 patients evaluable39 % had treatment-related AEs (TRAEs) Most frequent were nausea, diarrhea, rash and dizzinessNo pneumonitis observedNo TRAE led to treatment discontinuation Fury M et al. Proc ESMO 2014;Abstract 988PD.

Role for Induction Chemotherapy (IC) in Locally Advanced Head and Neck Cancer Prior to Concomitant Chemoradiation Therapy (CCRT)Meta-analysis of randomized controlled trials showed with IC:No significant effect on OS or PFSAdvantage in complete response and disease control Trend to improved overall survival Selected patients may benefit from the addition of IC to CCRT Future studies are warranted to evaluate role of IC in subpopulations of patients with locally advanced head and neck cancer Popovtzer A et al. ASCO 2015;Abstract 6068.

NCT00193765: Phase III Trial of Elective Neck Dissection versus Watch and Wait Policy (Therapeutic Neck Dissection) Elective Neck Dissection (n=243) Watch & Wait / Therapeutic Neck Dissection (n=253)D’Cruz AK et al. Proc ASCO 2015;Abstract LBA3.TreatmentPhysical ExamPhysical Exam + UltrasonographyFollow-UpR1R2Histologically proven SCC cT1/T2N0 oral cavity squamous cell cancersAmenable to per-oral excisionTreatment naive

Survival: Elective versus Therapeutic Neck Dissection Endpoint Elective neck dissection (n = 243) Therapeutic neck dissection (n = 253) Hazard ratio p -value Three-year overall survival80%67.5%0.640.014Three-year disease-free survival69.5%45.9%0.45<0.001D’Cruz AK et al. Proc ASCO 2015;Abstract LBA3.

Oropharyngeal , laryngeal, oral, hypopharyngeal or occult HNSCC Nodal metastases Stage N2 (a, b, or c) or N3 on CT/MRI Indication for curative radical concurrent CRT Suitable for ND 1 :1RPET-CT & assessment*CRTPET-NECK: A Phase III Trial Comparing PET-CT Guided Active Surveillance to Planned Neck Dissection (ND) for Locally Advanced Nodal Metastases in Patients with HNSCC Treated with Primary Radical Chemoradiation Therapy (CRT)PET-CT guided “active surveillance”(n = 282 )Standard treatment “planned ND”(n = 282)Mehanna H et al. ASCO 2015;Abstract 6009.CT & assessment** 9-13 wk after CRT completionND before or after CRT

PET-NECK Trial ConclusionsPET-CT guided surveillance resulted in equivalent OS to standard treatment of planned ND:Only 20% of patients received neck dissectionsFewer neck dissection complications Fewer serious adverse events Similar quality of life Surveillance arm was more cost-effective Mehanna H et al. ASCO 2015;Abstract 6009.