a multidisciplinary approach to personalizing the treatment of head & neck cancers
Post on 15-Jan-2015
1.948 Views
Preview:
DESCRIPTION
TRANSCRIPT
DISCLAIMERDISCLAIMERThis slide deck in its original and unaltered format is for educational purposes and is
current as of April 2012. All materials contained herein reflect the views of thefaculty, and not those of IMER, the CME provider, or the commercial supporter. Thesematerials may discuss therapeutic products that have not been approved by the US
Food and Drug Administration and off-label uses of approved products. Readersshould not rely on this information as a substitute for professional medical advice,
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.
Usage RightsUsage RightsThis slide deck is provided for educational purposes and individual slides may be
used for personal, non-commercial presentations only if the content and referencesremain unchanged. No part of this slide deck may be published in print or
electronically as a promotional or certified educational activity without prior writtenpermission from IMER. Additional terms may apply. See Terms of Service on
IMERonline.com for details.
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
top related