ASCO Highlights Head and Neck Cancer Anne S. Tsao, M.D. Director, - - PowerPoint PPT Presentation

Department of Thoracic/Head & Neck Medical Oncology

ASCO Highlights Head and Neck Cancer

Anne S. Tsao, M.D.

Assistant Professor July 11, 2009 The Univers rsit ity y of Texas MD AN ANDER ERSON SON CA CANCE CER R CE CENTER ER Director, Mesothelioma Program

HPV

Abstract 6001 HPV and tobacco Abstract 6002 HPV RTOG0129 Abstract 6004 HPV/p16 phase III

Outline

EGFR Biomarkers

Abstract 6005 EXTREME / EGFR FISH Abstract 6000 Mass Spectrometry

ChemoXRT

Abstract 6007 Darbepoetin alpha Abstract 6003 Phase II Braf mutations and sorafenib

Thyroid

Abstract 6009 Phase III CRT vs neoadjuvant chemo-CRT (PF, TPF)

Neoadjuvant

Abstract 6001: tobacco and HPV outcomes

• Retrospective review of tumor tissue from 124 pts with stage III/IV
• ropharynx cancer from 2 phase II chemoXRT trials.
• Objectives:

1) Evaluate association of HPV status and long-term outcomes 2) Evaluate effect of tobacco use on long-term outcomes in HPV positive patients UMMC 0221 UMMC 9921

Worden et al. Abstract #6001, ASCO 2009

Definitions

• HPV analysis: pre-treatment biopsies tested for

HPV DNA by multiplex pCR/mass spect analysis (detects 15 subtypes) (Sequenome)

• Smoking status: determined by chart review and

self-reporting

• Never tobacco: < 100 cigarettes per lifetime, never

used any chewing tobacco/cigars/pipes

• Current smoker: present, including those who quit < 1

year prior to diagnosis

• Former smoker: Quit > 1 year prior to diagnosis

Worden et al. Abstract #6001, ASCO 2009

Patient characteristics

Characteristic N=124 Male 83% Age 57 HPV (+) 82% HPV (+) never tobacco 27% HPV (+) any tobacco 56% HPV (-) never tobacco 0% HPV (-) any tobacco 18% Primary oropharynx site: BOT Tonsil

• ther

50% 46% 4% Stage III Stage IVA Stage IVB 14% 74% 12% Tobacco status HPV (+) N=102 HPV (-) N=22 Never (n=33) 32% 0% Former (n=52) 45% 28% Current (n=39) 23% 72%

Worden et al. Abstract #6001, ASCO 2009

Efficacy by HPV status

Worden et al. Abstract #6001, ASCO 2009

OS by HPV status and Treatment DFS by HPV status and Treatment TTR by HPV status and Treatment

HPV (+) status leads to improved DFS, OS, and time to disease recurrence regardless of treatment.

HPV status by tobacco usage

Worden et al. Abstract #6001, ASCO 2009

Time to recurrence In HPV (+) pts by tobacco usage

Risk of recurrence in HPV (+) patients HR P-value Current vs never 5.2 0.038 Former vs never 2.9 0.18 Current vs Former 1.8 0.24

P=0.063 for overall effect of tobacco

Smoking while HPV (+) leads to a worse time to recurrence.

Disease specific survival (DSS)

Worden et al. Abstract #6001, ASCO 2009

DSS in HPV (+) pts HR P-value Current vs never 7.2 0.07 Former vs never 3.6 0.24 Current vs Former 1.99 0.22

P=0.064 for overall effect of tobacco Disease specific survival by tobacco usage

Smoking while HPV (+) leads to a worse DSS.

Summary Abstract 6001

• In this retrospective analysis, HPV (+)

tumors have better OS and DSS and less risk of recurrence than HPV (-) tumors.

• Patients with HPV (+) disease and current

tobacco users have an increased risk of disease recurrence compared to HPV (+) never tobacco users.

Worden et al. Abstract #6001, ASCO 2009

Abstract #3 Survival outcomes by HPV status in

• ropharynx cancer patients in RTOG 0129

Gillison et al. Abstract #6003, ASCO 2009

Lab methodology: HPV 16 in situ hybridization (ISH) HPV 16 negative – wide spectrum ISH

(HPV18, 31, 33, 35, 39, 45, 52, 56. 59, 68)

P16 IHC Primary endpoint: Correlate HPV to OS, PFS

Baseline Lab analysis

P16 positive P16 negative HPV positive 192 (96%) 7 (4%) HPV negative 22 (19%) 94 (81%) Characteristic HPV + HPV - P-value Treatment 51.5% 50.4% 0.86 Age 53.5 57 0.02 Caucasian 92.2% 75.2% <0.001 PS 68.4% 56.4% 0.03 Stage IV 87.9% 83.8% 0.3 T stage 75.2% 60.7% 0.008 N stage 30.1% 38.5% 0.14 Pack years < 20 51% 22.2% <0.001 323 patients had oropharynx primary and HPV determination 206 (64%) were HPV-positive, 96% of which were HPV-16

Gillison et al. Abstract #6003, ASCO 2009

Overall Survival by HPV Status

Variable at 2 years HPV + HPV - P-value OS rate 87.9% 65.8% <0.001 PFS rate 71.8% 50.4% <0.001 Local-regional control 13.6% 24.8% 0.004 Distant mets 9.7% 12.9% 0.26 Second primary 3.9% 11.1% 0.01 Aerodigestive SPT 2.9% 7.7% 0.04

Gillison et al. Abstract #6003, ASCO 2009

OS by HPV and Pack Years

OS HR 95% CI HPV +, < 20 pack years 1

• HPV +, > 20 pack years

1.91 1.2-3.05 HPV-, < 20 pack years 2.25 1.44-3.5 HPV-, > 20 pack years 4.3 2.3-7.71

Gillison et al. Abstract #6003, ASCO 2009

Survival outcomes by HPV or p16 status

Overall Survival HR 95% CI HPV-positive tumor 0.44 0.29-0.69 p16 positive tumor 0.35 0.23-0.54 Progression-free survival HR 95% CI HPV-positive tumor 0.58 0.39-0.87 P16-positive tumor 0.46 0.31-0.68

Gillison et al. Abstract #6003, ASCO 2009

Summary Abstract #6003

• Positive tumor HPV status predicts for improved

OS and PFS in patients with oropharynx cancer, with less local-regional recurrence rates (but not distant recurrence).

• P16 IHC correlates with HPV tumor status and is

a reasonable surrogate.

• Tobacco use modifies biological behavior of

HPV positive tumors and leads to a worse

• utcome.
• Future trials in oropharyngeal HNSCC need to

stratify patients by HPV status or p16 IHC.

Gillison et al. Abstract #6003, ASCO 2009

Abstract 6004 p16/HPV in phase III

Rischin et al. Abstract #6004, ASCO 2009

• Retrospective review of tumor tissue from pts with stage III/IV
• ropharynx cancer from Phase III HeadSTART trial.
• HeadSTART showed no survival benefit to adding tirapazamine to

cisplatin-XRT but major XRT violations were reported.

• Objectives:

1) Determine the prognostic significance of HPV and p16 in

• ropharyngeal patients from an international phase III trial

Lab correlates

• HPV16/18 ISH (DAKO

Genpoint Tyamide Signal Amplification System) using biotinylated probes for HPV16/18

• p16 IHC (DAKO autostainer

using p16INK4a (Clone 16PO4) mouse monoclonal antibody. Nuclear and cytoplasmic staining intensity of tumor cells scored as grade 0-3 with grades 2-3 as positive.

Rischin et al. Abstract #6004, ASCO 2009

Patient characteristics

Characteristic HPV (+) n=55 HPV (-) N=140 P16 (+) N=108 P16 (-) N=78 Male 91% 83% 87% 81% Median Age 55 56 54 58 T stage 3-4 74% 75% 63% 84% N stage 2-3 87% 73% 86% 65% PS 0 76% 65% 79% 57% Current smoker 15% 37% 15% 45%

HPV and p16 positive patients have higher N-stage, are less likely to be current smokers, and had an improved PS compared to HPV/p16 negative patients (p<0.05)

Rischin et al. Abstract #6004, ASCO 2009

Overall Survival by HPV status

HPV positive patients had improved OS. HPV (-) patients who received TPZ had a slight improvement in OS when compared to HPV (-) patients who received cisplatin alone.

Rischin et al. Abstract #6004, ASCO 2009

HPV and p16

• HPV (-) but p16 (+) found in 33% cases
• Possible explanation:
• some cases may be due to other HPV subtypes.
• lack of sensitivity of HPV ISH assay (PCR analysis underway)

Failure-free survival by p16

Rischin et al. Abstract #6004, ASCO 2009

LRF by HPV/p16 status

Time to Locoregional failure by treatment Patterns of Failure

HPV or p16 (+) pts had improved LRF. HPV or p16 (-) patients who received TPZ had an improvement in LRF when compared to HPV/p16 (-) patients who received cisplatin alone; suggesting a benefit to modifying hypoxia with tirapazamine in these patients.

Rischin et al. Abstract #6004, ASCO 2009

Overall Survival – multi-variate analysis

Factor Overall survival HR P-value HPV (+) vs (-) 0.27 0.031 p16 (+) vs (-) 0.37 0.01 Stage III vs IV 0.34 0.28 PS 0 vs 1 0.57 0.12 Hgb high vs low 0.45 0.037

Rischin et al. Abstract #6004, ASCO 2009

Summary Abstract 6004

• HPV (+) oropharynx patients have an

improved prognosis.

• p16 IHC may identify more patients than

HPV ISH.

• Future trials need to stratify patients by

HPV and p16 status

• The optimal treatment for HPV (+) patients

is unknown but they should be treated differently than HPV (-) patients.

Rischin et al. Abstract #6004, ASCO 2009

HPV

Abstract 6001 HPV and tobacco Abstract 6002 HPV RTOG0129 Abstract 6004 HPV/p16 phase III

Outline

EGFR Biomarkers

Abstract 6005 EXTREME / EGFR FISH Abstract 6000 Mass Spectrometry

ChemoXRT

Abstract 6007 Darbepoetin alpha Abstract 6003 Phase II Braf mutations and sorafenib

Thyroid

Abstract 6009 Phase III CRT vs neoadjuvant chemo-CRT (PF, TPF)

Neoadjuvant

Q3 weeks Cisplatin 100 mg/m2 d1 or Carboplatin AUC 5 d1 5-FU 1000 mg/m2 d1-4 Weekly Cetuximab loading dose 400 mg/m2 IV times one followed by weekly infusions at 250 mg/m2

Metastatic or recurrent HNSCC excluding NP No prior chemo unless

• ver 8 months

prior for definitive therapy PS 0-2

Phase III EXTREME Trial

Vermorken et al. NEJM 359:1116-1127, 2008

Platinum 5-FU Platinum 5-FU Cetuximab Cetuximab Stratified by prior chemo, KPS (<80 vs > 80) R A N D O M I Z E Primary endpoint : OS Maximum 6 chemo cycles No crossover allowed

EXTREME Response Rate

Vermorken et al. NEJM 359:1116-1127, 2008

EXTREME PFS

Vermorken et al. NEJM 359:1116-1127, 2008

Platinum/5-FU Platinum/5-FU/C225 platinum/5-FU/C225 platinum/5-FU Median OS 10.1 months 7.4 months HR 0.797 p=0.0362

EXTREME Overall Survival

Vermorken et al. NEJM 359:1116-1127, 2008

Summary EXTREME Trial

• Adding cetuximab to platinum/5-FU improved overall

survival over platinum/5-FU in patients with metastatic HNSCC.

• This is the first systemic regimen in 25 years to show a

benefit over platinum-based chemotherapy in HNSCC

• However, quality of life needs to be considered in these
• patients. There was more vomiting, infusion rxn, rash with

cetuximab.

• Also, the optimal sequencing of agents remains unclear.

Identifying a biomarker to predict for treatment response is critical for optimizing treatment.

Vermorken et al. NEJM 359:1116-1127, 2008

Potential Ways of Assessing EGFR

• EGF Receptor (IHC)
• Gene Amplification (FISH)
• EGFR Mutation
• Downstream Signals / Events

(eg, K-ras, B-raf, MAPKinase)

Pao and Miller. JCO. 2005;23:2556-2568

Abstract #6005 Biomarker potential of EGFR FISH in the phase III EXTREME study

• Retrospective analysis of FISH and cellular EGFR and

CEP7 signals (Dakocytomation probe mix)

• 312 tumors of 442 patients evaluable (71% ITT)
• Baseline expression of EGFR and CEP7 were equal

amongst the two arms

Licitra et al. Abstract #6005, ASCO 2009

Colorado FISH+ definitions

• > 40% of cells displayed as > 4 EGFR counts
• r
• Gene amplification is present
• Presence of loose or tight EGFR gene clusters with > 4 copies
• EGFR gene to CEP7 ratio > 2
• Or 15 copies of EGFR per cell in >10% of cells

Licitra et al. Abstract #6005, ASCO 2009

EXTREME: Chemo + cetuximab patients

Colorado FISH status was not predictive for benefit to Cetuximab Did not influence OS, PFS, nor RR

Licitra et al. Abstract #6005, ASCO 2009

EXTREME: Chemo alone patients

Colorado FISH status was not prognostic Did not influence OS, PFS, nor RR

Licitra et al. Abstract #6005, ASCO 2009

FISH+ by Enrichment Model

Licitra et al. Abstract #6005, ASCO 2009

None of the Enrichment Models had correlation of FISH score with PFS

Example Enrichment Model B and FISH Score Each star is a patient by PFS

Licitra et al. Abstract #6005, ASCO 2009

None of the Enrichment Models had correlation of FISH score with OS

Example Enrichment Model B and FISH Score Each star is a patient by OS

Licitra et al. Abstract #6005, ASCO 2009

Summary Abstract #6005

• EGFR copy number by FISH was not

predictive for response or survival to cetuximab-chemotherapy treatment.

• Additional studies for alternative

biomarkers are needed:

• K-ras mutations are negative predictors in

colorectal cancer (CRYSTAL trial), but in HNSCC the incidence of K-ras mutations is < 3%. Also, HNSCC do not carry EGFR

• mutations. Other biomarkers are needed.

Abstract 6000: Mass spectrometry profiling after EGFR inhibitor therapy

Chung et al. Abstract #6000, ASCO 2009; Taguchi et al JNCI, 2007

MALDI is a proteomic profiling tool in serum and plasma. In NSCLC, a signature was developed that predicted for OS after EGFR TKI therapy. This profile called VeriStratR contains 8 distinguishing mass spectrometry peaks. Theory: MS profile is reflective of EGFR dependency of the tumor regardless

• f histology and may predict OS in HNSCC.

Population Evaluated

Control Cohorts N=78 HNSCC – surgery N=34 HNSCC from 2 phase II trials treated with docetaxel/bortezomib

• r docetaxel/irinotecan

EGFR Treated Cohorts N=55 Phase II gefitinib 250 mg daily N=32 Phase II erlotinib 150 mg po daily and bevacizumab 15 mg/kg every 3 wks N=21 cetuximab 400 mg/m2 LD then 250 mg/m2 weekly

Chung et al. Abstract #6000, ASCO 2009

Patient Demographics

Characteristic Gefitinib N=55 Erlotinib Bev N=34 C225 N=21 Control surgery N=78 Control No EGFRI N=34 Median Age 58 58 53 62.1 57 Male 45 27 16 55 26 Caucasian 49 9 20 72 NR PS 0 13 17 NR NR 7 Smoker 31 24 12 NR 27 Best response CR PR SD PD NE 20 31 4 1 4 20 9 NR NR NR

Chung et al. Abstract #6000, ASCO 2009

MALDI MS classification

Cohorts Gefitinib N=55 Erlotinib Bev N=34 C225 N=21 Control surgery N=78 Control No EGFRI N=34 Good 56% 75% 76% 99% 65% Poor 42% 19% 24% 1% 35% Undefined 2% 3% 0% 0% 0% Failed MS 0% 3% 0% 0% 0%

Chung et al. Abstract #6000, ASCO 2009

Overall Survival – MS Profile

Chung et al. Abstract #6000, ASCO 2009

Overall Survival – MS Profile

Chung et al. Abstract #6000, ASCO 2009

Summary Abstract #6000

• Preliminary studies suggest that MALDI-

MS (VeriStratR) has predictive ability for OS in HNSCC patients treated with EGFR

• inhibitors. This is consistent with the

group’s prior NSCLC data.

• Profile is predictive for both EGFR TKI and

monoclonal antibody work.

Chung et al. Abstract #6000, ASCO 2009

Outline

HPV

Abstract 6001 HPV and tobacco Abstract 6002 HPV RTOG0129 Abstract 6004 HPV/p16 phase III

EGFR Biomarkers

Abstract 6005 EXTREME / EGFR FISH Abstract 6000 Mass Spectrometry

ChemoXRT

Abstract 6007 Darbepoetin alpha Abstract 6003 Phase II Braf mutations and sorafenib

Thyroid

Abstract 6009 Phase III CRT vs neoadjuvant chemo-CRT (PF, TPF)

Neoadjuvant

Abstract 6007

Overgaard et al. Abstract #6007, ASCO 2009

Primary endpoint: LRC Secondary endpoint: Local control, DFS, OS, Hgb levels, early/late morbidity, compliance Stats: 80% power to detect 12% increase in LRC (n=600); interim analysis after 150 events; Due to planned interim analysis, trial stopped in Oct 2006 with 522 pts. HNSCC, no NP Hgb < 9 mmol/l (14.5 g/dl) within 10 days of Tx PS 0-2

Abstract 6007 DAHANCA 10

Overgaard et al. Abstract #6007, ASCO 2009

Radiotherapy + Darbepoetin Alpha

Darbepoetin alpha Effect during XRT

SAE Darbepoetin (n=260) Control (n=262) Thrombo-embolic 3% 1% Other 3% 2%

Overgaard et al. Abstract #6007, ASCO 2009

Darbepoetin alpha

Efficacy

LRC OS

Aranesp led to a worse LRC and OS results.

Overgaard et al. Abstract #6007, ASCO 2009

Darbepoetin alpha

Darbepoetin

Efficacy: DFS, cancer/non-cancer related Deaths

Deaths from cancer Darbepoetin led to worse DFS and more deaths from cancer. There was no difference in non-cancer related deaths. Non-cancer Related deaths DFS

Overgaard et al. Abstract #6007, ASCO 2009

Darbepoetin alpha

Darbepoetin alpha

Subgroup analysis LRC

There was no subgroup that benefited from darbepoetin

Overgaard et al. Abstract #6007, ASCO 2009

Summary Abstract 6007

• Darbepoetin alpha should not be used

concurrently with XRT in HNSCC patients – it leads to a worse outcome and poorer tumor control.

• The reason remains unknown at this time.

Overgaard et al. Abstract #6007, ASCO 2009

Outline

HPV

Abstract 6001 HPV and tobacco Abstract 6002 HPV RTOG0129 Abstract 6004 HPV/p16 phase III

EGFR Biomarkers

Abstract 6005 EXTREME / EGFR FISH Abstract 6000 Mass Spectrometry

ChemoXRT

Abstract 6007 Darbepoetin alpha Abstract 6003 Phase II Braf mutations and sorafenib

Thyroid

Abstract 6009 Phase III CRT vs neoadjuvant chemo-CRT (PF, TPF)

Neoadjuvant

Induction Chemo HNSCC Trials

Trial N Therapy Outcome

TAX 323/EORTC 24971

NEJM 2007

358 TPF vs. PF OS benefit p=0.02 TAX 324

NEJM 2007

539 TPF vs. PF OS benefit P=0.006 Hitt, Madrid

JCO 2005

382 Paclitaxel-PF

• vs. PF

OS benefit P=0.06 GORTEC

Calais 2006

220 TPF vs. PF Larynx preservation 73% vs. 63%

Paccagnella et al. ASCO 2008 abstract #6000: Induction chemo with chemoXRT versus chemoXRT alone.

ASCO 2009 Abstract 6009 Phase III

Primary endpoint: TTF Secondary endpoint: LRC, TTP, OS, safety Stats: 80% power to detect 50% increase in median TTF ChemoXRT Cisplatin 100 mg/m2 days 1, 22, 43 XRT to tumor 66-70 Gy once daily XRT to LN 60 Gy once daily Neoadjuvant therapy x 3 Q3 wk Cisplatin 100 mg/m2 day 1 5-FU 1000 mg/m2 days 1-5 Cisplatin 75 mg/m2 day 1 Docetaxel 75 mg/m2 day 1 5-FU 750 mg/m2 days 1-5 G-CSF primary prophylaxis Unresectable LAHNC No NP PS 0-1 Stage III or IV

Hitt et al. Abstract #6009, ASCO 2009

Patient Demographics

Characteristics CRT

(n=128)

PF + CRT

(n=156)

TPF + CRT

(n=155)

Median age 56 57 58 Male 80% 93% 94% PS 0/1 26%/74% 31%/66% 29%/70% Primary tumor site Oropharynx Hypopharynx Larynx Oral cavity 42% 18% 20% 20% 43% 18% 17% 22% 43% 17% 19% 21% T4 stage 74% 80% 76%

Hitt et al. Abstract #6009, ASCO 2009

Compliance

Characteristics CRT

(n=128)

PF + CRT

(n=156)

TPF + CRT

(n=155)

% received 3 cycles neoadjuvant chemo

• 76%

68% Median cycles of chemo during CRT 3 2 2 % receiving protocol XRT 80% 68% 62%

Hitt et al. Abstract #6009, ASCO 2009

Adverse Events Grade 3/4

Toxicity CRT

(n=119)

PF + CRT

(n=156)

TPF + CRT

(n=153)

Neutropenia 20% 38% 34% Febrile neutropenia* 1% 3% 18% Thrombocytopenia 4% 10% 10% Asthenia 3% 9% 14% Mucositis 31% 4% 42% XRT dermatitis 8% 11% 3%

*Before GCSF amendment, 22% febrile neutropenia. After GCSF amendment, Incidence of febrile neutropenia was 11%. No GI, neuro, or renal toxicity reported.

Hitt et al. Abstract #6009, ASCO 2009

TTF

Hitt et al. Abstract #6009, ASCO 2009

TTP

Hitt et al. Abstract #6009, ASCO 2009

LCR

Hitt et al. Abstract #6009, ASCO 2009

Rate of surgery in CRT 50% and 25% in neoadjuvant chemo-CRT

Efficacy

Efficacy CRT

(n=119)

PF + CRT

(n=123)

TPF + CRT

(n=111)

Total neoadj chemo (n=234) Median TTF (months) 5 12.3 13.4 12.5

HR 0.57

Median TTP (months) 13.1 18.5 20.4 18.5

HR 0.79

Median OS (months) 27.1 33.6 37.2 37.1

HR 0.85

Deaths during neoadj chemo

• 2 pts

5 pts* 7 pts Deaths during CRT 2 pts 2 pts 2 pts* 4 pts

*After GCSF amendment, only 1 pt treated on TPF arm died

Hitt et al. Abstract #6009, ASCO 2009

Summary Abstract #6009

• Neoadjuvant chemotherapy prior to chemoradiation is feasible and

improves local-regional control.

• Although neoadjuvant chemo is becoming more popular, this trial does

not definitive set neoadjuvant therapy as the new standard because of problems with the trial:

• No report on radiation quality or compliance.
• High rate of drop out rate from efficacy analysis (33, 44 pts missing! from

neoadjuvant chemo arms). ITT analysis needs to be done.

• Incomplete toxicity report
• Efficacy report given during interim 2006 analysis reported that TPF was

better than PF and CRT but now this is not the case and only 2 arms were reported on in this analysis.

• Higher rate of deaths with chemo-CRT. Emphasizes the need for

patient selection and supportive therapy.

• A treatment benefit was seen in both neoadjuvant regimens -

supports the point that it is not necessary to use TPF as neoadjuvant therapy.

• ther options: cisplatin (75 mg/m2) + docetaxel (75 mg/m2)

platinum + 5-FU or platinum + taxane

• Choice of population to treat with TPF remains to be decided.

Hitt et al. Abstract #6009, ASCO 2009

Outline

Abstract 6003 Phase II Braf mutations and sorafenib

Thyroid HPV

Abstract 6001 HPV and tobacco Abstract 6002 HPV RTOG0129 Abstract 6004 HPV/p16 phase III

EGFR Biomarkers

Abstract 6005 EXTREME / EGFR FISH Abstract 6000 Mass Spectrometry

ChemoXRT

Abstract 6007 Darbepoetin alpha Abstract 6009 Phase III CRT vs neoadjuvant chemo-CRT (PF, TPF)

Neoadjuvant

Brose et al. Abstract #6002, ASCO 2009

Primary endpoint: overall response rate Secondary endpoints: survival, safety, duration of response, PK, genetic correlates

UPCC 03305: Phase II single center trial of single-agent sorafenib in patients with thyroid cancer

Sorafenib: VEGFR, PDGFR-b, BRAF, c-Kit, RET Eligibility Criteria Metastatic thyroid cancer N=55 Sorafenib Continuous 28- day dosing 400 mg po BID

Thyroid cancer: 44% PTC have BRAF V600E gene mutations 0% FTC have BRAF V600E gene mutations

UPCC 03305 Patient Demographics

Brose et al. Abstract #6002, ASCO 2009

Characteristics (n=55) % pts Male 51% Histology Papillary thyroid FTC/Hurthle cell variant Medullary thyroid Anaplastic Poorly differentiated 47% 35% 4% 7% 5%

UPCC03305 Grade 3+ Toxicity (n=30)

Brose et al. Abstract #6002, ASCO 2009

Adverse event % pts Atrial fibrillation 3% Hand foot syndrome 7% Rash 7% Anxiety 3% Pruritis/skin discomfort 7% HTN 10% Vomiting 3% Diarrhea 7% LFT elevation (grade 5) 3%

UPCC 03305: Efficacy (n=46)

Brose et al. Abstract #6002, ASCO 2009

Efficacy % pts PR 36% SD 46% Median PFS 63 wks Median OS – DTC only 84 wks Median OS – first 30 pts only 140 wks

UPCC 03305 BRAF V600E mutation PFS (n=22)

Brose et al. Abstract #6002, ASCO 2009

There was a trend towards improved PFS in patients with BRAF V600E mutation but it was not statistically significant.

Summary Abstract #6002

• Sorafenib has clinical activity in iodine

refractory metastatic differentiated thyroid cancer.

• Patients with BRAFV600E mutations may

have a trend towards improved PFS.

Brose et al. Abstract #6002, ASCO 2009

ASCO 2009 HNSCC Conclusions - Biomarkers

• HPV or p16 positive oropharynx HNSCC is a unique

entity with an improved prognosis and may not need as aggressive treatment as HPV/p16 negative disease.

• Tobacco use and hypoxia may have an influential role in

HPV/p16 positive disease.

• Currently, there are no tumor biomarkers available for

predictive use in HNSCC with regard to EGFR inhibitors. (EGFR FISH in the EXTREME trial) Mass spectrometry proteomic profiling in plasma may be promising.

• In thyroid cancer, sorafenib has preliminary efficacy and

may be especially beneficial in BRAF V600E mutation patients.

ASCO 2009 HNSCC Conclusions – Concurrent and Neoadjuvant therapy

• Darbepoetin alpha use during concurrent chemoradiation

is contraindicated.

• Although neoadjuvant chemotherapy is commonly being

used, the phase III Hitt et al. trial had some flaws and did not establish this treatment strategy as a standard of care practice. However, additional studies are underway to elucidate this issue.

Neoadjuvant therapy is becoming accepted in standard practice. However, the optimal regimen in the specific patient population remains unknown. Induction TPF followed by weekly platinum with XRT is reasonable however, it is not always necessary to use TPF, platinum-doublets can be utilized in the appropriate patient. Low N stage - Chemoradiation may be sufficient as distant disease recurrence is modest High T stage and/or High N stage – May need induction chemo but not high dose chemo-XRT. N2C disease should probably receive induction chemo. N2B if large and bulky should also be considered. Optimal induction chemo regimen remains to be seen. Would avoid induction TPF then concurrent high dose cisplatin-XRT [in SWOG 0216, this was toxic with deaths and had a poor compliance (68%)]. Cetuximab with TPF or with platinum-docetaxel is under investigation.

HNSCC Tsao’s Neoadjuvant Recommendations