A Multidisciplinary Approach to Personalizing the Treatment of Head & Neck Cancers

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This activity has been designed to meet the educational needs of medical oncologists, radiation oncologists, surgical oncologists, APNs, RNs, pharmacists, managed care pharmacy directors, pathologists, medical directors, allied health professionals, and other physicians affiliated with medical facilities treating patients with head and neck cancers (HNC).

HNC are challenging to treat due to the complex and aggressive nature of these cancers. Timely diagnosis and referral to the appropriate specialist is imperative as early diagnosis can lead to reduced mortality. Clinical advances are evolving regarding the use of molecularly targeted therapies such as EGFR inhibitors and anti-angiogenic agents into the multidisciplinary treatment of HNC. Optimal disease management, rehabilitation, and survivorship care depend on access to a multidisciplinary team comprised of a spectrum of specialists and support services. As research advances, clinicians need to remain aware of this new evidence to understand the multidisciplinary clinical practice implications that can affect patient care. This series of live grand rounds, webinars, and enduring curriculum include a didactic presentation, case illustrations, and clinical resources and tools.

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A Multidisciplinary Approach to Personalizing the Treatment of Head & Neck Cancers

  1. 1. DISCLAIMER This 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. These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. Readers should 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 Rights This slide deck is provided for educational purposes and individual slides may be used for personal, non-commercial presentations only if the content and references remain unchanged. No part of this slide deck may be published in print or electronically as a promotional or certified educational activity without prior written permission from IMER. Additional terms may apply. See Terms of Service on IMERonline.com for details.
  2. 2. DISCLAIMERParticipants 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 forpatient 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 USE This 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.
  3. 3. Disclosure of Conflicts of Interest Marshall R. Posner, MD Reported a financial interest/relationship or affiliation in the form of: Consultant, Eisai, Inc., GlaxoSmithKline plc., Novartis Pharmaceuticals Corporation, Oxigene, Inc.
  4. 4. Learning Objectives L Upon completion of this activity, 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
  5. 5. Activity 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)
  6. 6. Molecular and Biological Considerations
  7. 7. Molecular and Biological Events in Head and Neck Cancer (HNC) HNC Can Now Be Divided Into 2 Large and Distinct Subtypes HPV-Related Cancers Environment-Related Cancers  Caused by high-risk HPV  Caused by environmental – HPV 16 mutagens – Driven by viral oncogenes – Smoking, alcohol  Restricted to oropharynx  Throughout oral mucosa  Distinct molecular markers  Distinct molecular markers  “Good” prognosis  “Poor” prognosis, comorbidity  Young, good general health  Second cancersHPV = human papillomavirus.Goon et al, 2009; Rodriguez et al, 2010.
  8. 8. Change in HPV Rates and Incidence Over Time: United StatesChaturvedi et al, 2011.
  9. 9. Human Papillomavirus (HPV) HPV-Associated Cancers > 99% of Cervical Carcinoma ~ 90% Anal Carcinomas ~ 40% Vulvar and Vaginal Carcinomas ~ 60% of Oropharynx Cancers HPV GENOME INTEGRATION LCR E6 E7 Frequent Event During Malignant Progression Terminates Viral Life Cycle Circular 8 kB dsDNA Genomes Expression of E6 and E7 Is Retained Only One Coding Strand Infect Epithelial Cells HPV E6/E7 Oncoproteins ~ 200 HPV types Small, Non-Enzymatic Proteins ~ 30 Mucosal HPVs (~ 150aa E6; ~ 100aa E7) Low-Risk: Genital Warts Associate With and Functionally Modify High-Risk: Lesions That Progress to Cancer Host Cellular Protein ComplexesMünger et al, 2004.
  10. 10. Mechanisms of HPV-Associated Carcinogenesis HPV E6 And E7 Oncoproteins Associate With and Reprogram Cellular Enzymes E2 S Ub Rbx1 S Ub NEDD8 E6-AP Cul2 pRB Ubn E6 Ubn E7 p53 EloC EloB HPV16 E6 Retargets the Cellular HPV16 E7 Retargets the Cellular Ubiquitin Ligase E6AP to the P53 Cullin 2 Ubiquitin Ligase Complex Tumor Suppressor Protein to the Retinoblastoma Tumor Suppressor Protein, pRB HPV E6 and E7 Oncoproteins Target Associated Cellular Tumor Suppressors for DegradationMünger et al, 2004.
  11. 11. RTOG 0129: A Randomized Phase III Trial of Chemoradiotherapy With 2 Schedules P: 100 mg/m2 R A XRT N D Trial Completed Accrual in 6/05 O M P: 100 mg/m2 I Z XRT E 743 Patients RandomizedP = platinum; XRT = fractionated radiotherapy.Ang et al, 2010.
  12. 12. Results of HPV Analysis: RTOG 0129  433/721 (60%) Oropharynx Primary  323/433 (75%) HPV Determination  206/323 (64%) HPV+  198/206 (96%) HPV16+ P16+ P16– HPV+ 192 (96%) 7 (4%)* HPV– 22 (19%)* 94 (81%) Kappa = 0.80: 95% CI 0.73–0.87CI = confidence interval.Gillison et al, 2009.
  13. 13. Sequential Combined Modality Therapy A Phase III Study: TAX 324 TPF Vs. PF Followed by Chemoradiotherapy R T A P Carboplatinum: AUC 1.5 Wkly N D F O EUA Surgery M P Daily Radiotherapy I Z F E 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 3AUC = area under the curve; EUA = examination under anesthesia.Posner et al, 2007.
  14. 14. TAX 324: Demographics by HPV Status HPV+ HPV– N = 56 (50%) N = 55 (50%) p Value Treatment TPF 28 (50%) 26 (47%) .85 PF 28 (50%) 29 (53%) Age Yrs Median (Range) 54 (39–71) 58 (41–78) .02 Nodal Stage N0–N1 13 (23%) 18 (33%) .30 N2–N3 43 (77%) 37 (67%) T stage T1–T2 28 (50%) 11 (20%) .001 T3–T4 28 (50%) 44 (80%) PS WHO 0 43 (77%) 27 (49%) .003 1 13 (23%) 28 (51%)PS = performance status; WHO = World Health Organization.Posner et al, 2011.
  15. 15. TAX 324: Survival and HPV Status Survival Oropharynx Cancer p < .0001 HPV+ HPV–Posner et al, 2011.
  16. 16. TAX 324: Survival, PFS, and Site of Failure By HPV Status HPV+ HPV– p Value N = 56 N = 55 Median Follow-Up Months (95% CI) 83 (77–93) 82 (68–86) NS Survival Status – Alive 44 (79%) 17 (31%) < .0001 – Dead 12 (21%) 38 (69%) PFS Status – No Progression/Death 41 (73%) 16 (29%) < .0001 – Progression/Death 15 (27%) 39 (71%) Local-Regional Failure 7 (13%) 23 (42%) .0006 Distant Metastases 3 (5%) 6 (11%) NS Both 1 (2%) 2 (4%) NS Total Disease Failures 9 (16%) 27 (49%) .0002 Died Without Recurrence 5 (9%) 12 (22%) .07PFS = progression-free survival; NS = not significant.Posner et al, 2011.
  17. 17. RTOG 1016: A Randomized Phase III Trial of Chemoradiotherapy With Cisplatinum or Cetuximab in P16+ Oropharynx Cancer R Cisplatin A 100 mg/m2/q21d ELIGIBILITY N IMRT Stage D 70Gy/35 fxs III, IVA, B O Resectable M P16+ I Cetuximab Oropharynx 400/250 Z mg/m2 qwk Cancer E IMRT 70Gy/35 fxs Stratify: HPV, smoking, stage Cetuximab loading dose = 400 mg/m2 on Day 1 of Cycle1 with inductionIMRT = intensity-modulated radiation therapy.ClinicalTrials.gov.
  18. 18. ECOG 1308: P16+ Oropharynx Phase II: Reduced Dose CRT for Resectable Oropharynx E Paclitaxel CLINICAL PR/CR Cisplatin Daily Radiotherapy 5400 cGy Cetuximab Assess Response 9 wks CLINICAL NR SURGERY AND CRT Trial Accrual CompletedCRT = chemoradiotherapy; PR = partial response; CR = complete response; NR = no response.ClinicalTrials.gov.
  19. 19. HPV+ Oropharynx Phase III: Reduced Dose Chemoradiotherapy for Induction PR/CR The Quarterback Trial C/E Docetaxel CLINICAL and PET PR/CR Randomize Cisplatin 2:1 Daily Radiotherapy 5600 cGy Reduced Assess 20% 5-FU Reduced 25% Response 3 Cycles C CLINICAL and PET Primary End Points SD/NR 1. 3-yr LRC, PFS 2. Toxicity/Function Daily Radiotherapy 7000 cGy 3. Patterns of Failure Stage IV, HPV 16, P16+ Stratify: < 20 pack yrs smokingSD = stable disease; LRC = local-regional control.
  20. 20. HPV+ Oropharynx Cancer in 2012: Summary 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
  21. 21. Molecular and Biological Events in HNC Molecular Changes in HNC Are Organized Into Categories Based on Systems Biology Approach There Are Distinct Pathways That Are Altered in HNC Genetic integrity  Proliferation – p53 pathway – Rb, p16 Pathway Survival, metabolism – MET – PI3K pathway (AKT, mTor, PTEN)  Differentiation – EGFr, MET – Notch, p63 pathway
  22. 22. Signaling Pathways in HNCImage courtesy of Aaron Tward, MD, PhD.
  23. 23. Molecular and Biological Events in HNC Drivers 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%), PTENNSCLC = non-small cell lung cancer; EGFR = epidermal growth factor receptor.
  24. 24. The Multi-Fold Impact of Inactivating Suppressor Genes p53Image courtesy of Christine Chung, MD.
  25. 25. Key Takeaways Molecular and Biological Events in HNC Themost 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 Multipletargets within signaling pathways are being identified
  26. 26. Chemotherapy and Surgery-Based Curative Treatment
  27. 27. The 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
  28. 28. The Current State of Curative Therapy (cont.) Surgery Postoperative chemoradiotherapy Concurrent chemoradiotherapy Sequential therapy
  29. 29. Surgical Technology Has Changed 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
  30. 30. Transoral Robotic Surgery (TORS)Images courtesy of Marshall Posner, MD.
  31. 31. Surgical Technology Has ChangedSignificantly 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?
  32. 32. E3311 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 bleedingRT = radiotherapy; QOL = quality of life; OS = overall survival.
  33. 33. ECOG 3311 P16+ Trial – Low Risk OPSCC: Personalized Adjuvant Therapy Based on PathologicStaging of Surgically Excised HPV+ Oropharynx Cancer LOW RISK: T1-T2N0-N1 Observation Assess negative marginsEligibility:HPV (p16)+ Radiation Therapy SCC IMRT 50Gy/25 Fxoropharynx R A N INTERMEDIATE: Stage III-IV: Transoral Resection D Clear margins Evaluate for 2-yr PFScT1-3, N1-2b (any approach) ≤ 1 mm ECS Local-Regional O (no T1N1) with neck dissection 2–3 metastatic LN Recurrence, Functional M PNI Outcomes/QOL I Baseline Z LVIFunctional/ E Radiation Therapy QOL IMRT 60 Gy/30 Fx +Assessment HIGH RISK: Positive Margins > 1 mm ECS or Radiation Therapy ≥ 4 metastatic LN IMRT 66 Gy/33 Fx + CDDP 40 mg/m2 wkly
  34. 34. Postoperative Chemoradiotherapy RTOG 95-01 459 patients R XRT S A EORTC (66 Gy over 6 ½ wks) U RTOG (60–66 Gy over 6-6 ½ wks) N R D G O E M Cisplatin R 100 mg/m2 d 1, 22, 43 I Y Z XRT EORTC 22931 E 334 patientsCooper et al, 2004; Bernier et al, 2004.
  35. 35. Survival/Local Regional Control RTOG: 95-01 Median Follow-Up 9.4 Yrs 100 100 75 75 p = 0.31 Local-Regional Control (%) p = 0.10 Overall Survival (%) 50 50 25 25 RT RT 0 RT+CT 0 RT+CT 0 1 2 3 4 5 6 7 8 9 10 0 1 2 3 4 5 6 7 8 9 10 Years after Randomization Years after RandomizationPatients at Risk Risk Patients at Patients at Risk Risk Patients atRT 208 170 119 92 75 68 60 53 44 33 26 RT 208 142 106 84 71 66 57 51 44 33 26RT+CT 208 170 202 119 RT 158 129 92 111 75 95 68 85 7553 64 44 55 60 33 48 26 RT+CT 208 37 RT 142 202 106146 84 121 108 71 6691 83 57 74 6344 54 33 47 26 36 51 RT 202 158 129 111 95 85 75 64 55 48 37 RT 202 146 121 108 91 83 74 63 54 47 36 + + CT CTImages courtesy of Jay Cooper, MD.
  36. 36. Survival/Local Regional Control RTOG: 95-01 ECE or Positive Margin Median Follow-Up 9.4 Yrs 100 100 75 75 Local-Regional Control (%) Overall Survival (%) 50 p = 0.07 50 p = 0.02 25 25 RT RT 0 RT+CT 0 RT+CT 0 1 2 3 4 5 6 7 8 9 10 0 1 2 3 4 5 6 7 8 9 10 Years after Randomization Years after RandomizationPatients at Risk Risk Patients at Patientsatat Risk Patients RiskRT 115 88 53 37 31 28 23 21 16 13 11 RT 115 71 48 34 29 27 21 20 16 13 11RT+CT 115 88 12753 9737 77 31 65 RT 28 52 23 48 2145 37 16 32 13 28 11 23 RT+CT 115 71 RT 127 9334 72 29 64 48 27 50 47 21 45 20 37 3213 28 11 23 16RT 127 97 77 65 52 48 45 37 32 28 23 RT 127 93 72 64 50 47 45 37 32 28 23+ +CT CTImages courtesy of Jay Cooper, MD.
  37. 37. Postoperative 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
  38. 38. Concurrent Chemoradiotherapy RTOG 0129: A Phase III Trial Comparing Acerbated Therapy to Standard Radiotherapy P: 100 mg/m2 R A XRT N D Trial Completed Accrual in 6/05 O M P: 100 mg/m2 I Z XRT E 743 Patients RandomizedAng et al, 2010.
  39. 39. RTOG 0129: Outcome End PointsAng et al, 2010.
  40. 40. RTOG 0129: Secondary Analyses Multivariate 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.
  41. 41. Concurrent Chemoradiotherapy RTOG 0522: A Phase III Trial of Cisplatin CRT With or Without Cetuximab R P: 100 mg/m2 A N XRT D O Cetuximab 400/250 mg M I P: 100 mg/m2 Z E XRT Stratify: XRT asStandard or IMRT on DAHANCAAng et al, 2011.
  42. 42. GORTEC 99-02: Chemoradiotherapy Vs. Accelerated Radiotherapy With or Without Chemotherapy Carboplatin/5-FU R A XRT N D O Carboplatin/5-FU M XRT I Z E XRTBourhis et al, 2012.
  43. 43. GORTEC 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 parametersBourhis et al, 2012.
  44. 44. The Cetuximab/Radiotherapy Phase III Trial Stratify by R XRT Surgery  Karnofsky score: A 90–100 vs. 60–80 N  Regional Nodes: D QD, BID or Negative vs. Positive O ACB Allowed  Tumor stage: M AJCC T1–3 vs. T4 I  RT fractionation: Z ERB Concomitant boost vs. once daily E XRT Surgery vs. twice dailyBonner et al, 2006.
  45. 45. OS By Treatment: Median Follow-Up 60 Months 1.0 0.9 0.8 0.7 OS (%) 0.6 0.5 0.4 0.3 0.2 Stratified Log Rank p = .018, HR = 0.73 (0.56– 0.1 0.95) 0.0 0 10 20 30 40 50 60 70 Time (months) Treatment Total Death Alive Median Radiation Alone 213 130 83 29.3 RT + Cetuximab 211 110 101 49.0Bonner et al, 2006.
  46. 46. Chemoradiotherapy for Locally Advanced 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
  47. 47. TAX 323: TPF VS. PF Followed by Radiotherapy A Phase III Study in Unresectable SCCHN R T A N P D F O EUA Surgery M I P Daily Radiotherapy Z E F TPF: Docetaxel 75D1 + Cisplatin 75D1 + 5-FU 750 CI: D1–5 q3wks x4 PF: Cisplatin 100D1 + 5-FU 1000CI: D1–5 q3wks x 4Vermorken et al, 2007.
  48. 48. TAX 323 Update: 2011 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 .015Vermorken et al, 2011.
  49. 49. Sequential Combined Modality Therapy A Phase III Study: TAX 324 TPF Vs. PF Followed by Chemoradiotherapy T Carboplatinum: AUC 1.5 Wkly R P A N F D EUA Surgery O P Daily Radiotherapy M IZ F E TPF: Docetaxel 75D1 + Cisplatin 100D1 + 5-FU 1000CI: D1–4 q3wks x 3 PF: Cisplatin 100D1 + 5-FU 1000CI: D1–5 q3wks x 3Posner et al, 2007.
  50. 50. TAX 324: 5-Yr Follow-Up – OS HR 0.74 (.058–.094) p = .013 TPF 52% PF 42% Sustained Survival Advantage At 5 Yrs For Patients Receiving TPF Vs. PF Median OS 71 Vs. 30 Mos (HR 0.74, p = .0129)Lorch et al, 2011.
  51. 51. Sequential 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 teamStudy Primary SignificantPopulation N End Point Regimen OutcomesTAX 323 Inoperable 358 PFS PF vs. TPF Better PFS, OS p < .01TAX 324 Locally Advanced 501 Survival PF/CRT vs. Better TPF/CRT PFS, OS, LFS p = 0.01 and 0.3GORTEC 2000-01 213 Larynx PF vs. TPF Better LFSResectable Preservation p < .04Larynx/HypopharynxLFS = laryngectomy-free survival.Vermorken et al, 2007; Lorch et al, 2011; Pointreau et al, 2010.
  52. 52. Individualized Treatment:Rationale for Emerging Targets
  53. 53. New Targets and Therapies in HNC Small Molecules  Complex Biologics – EGFR – Virolytics • Afatinib, Lapatinib • Rheovirus – Met – Vaccines • ARQ 197, XL 184, XL 880 • Dendritic Cell – PI3K Pathway • Long HPV Peptides • BKM120 – Immune Modulators – mTOR • Ipilimumab, PD-1 • Everolimus – VEGFR • Bevacizumab
  54. 54. The EXTREME Trial Randomized Group A Group B Cetuximab 400 mg/m2 initial dose EITHER carboplatin (AUC 5, D1) then 250 mg/m2 wkly + OR cisplatin (100 mg/m2 IV, D1) EITHER carboplatin (AUC 5, D1) + 5-FU (1,000 mg/m2 IV, D1–4): OR cisplatin (100 mg/m2 IV, D1) 3-wk cycles + 5-FU (1,000 mg/m2 IV, D1–4): 3-wk cycles 6 Chemotherapy Cycles Maximum Cetuximab No Treatment Progressive Disease or Unacceptable ToxicityVermorken et al, 2008.
  55. 55. EXTREME Trial: OS ~ 10% 10.1 months 7.4 months Survival Time, MonthsVermorken et al, 2008.
  56. 56. Afatinib: 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) In vitro Molecular Potency  Side effects associated with nM afatinib treatment are ErbB1 0.5 manageable and reversible ErbB2 14 ErbB4 1Eskens et al, 2008; Li et al, 2008; Yamamoto et al, 2011.Image courtesy of Marshall Posner, MD.
  57. 57. Afatinib Randomized Phase II Afatinib Afatinib Cetuximab Cetuximab R 50 mg 400/250 A N po mg/m2 IV wkly Metastatic daily Continue Continue D recurrent O until PD or undue until PD or undue AEs AEs HNSCC M I N = 124 Z E (62 per arm) Cetuximab Cetuximab Afatinib Afatinib 400/250 mg/m2 50 mg po IV wkly daily Stratum: No. Prior Chemotherapies for R/M Disease (0 or 1) Stage 1 Stage 2 CT/MRI q8wksHNSCC = head and neck squamous cell carcinoma; IV = intravenous; PD = progressive disease;CT = computed tomography scan; MRI = magnetic resonance imaging; R/M = recurrent/metastatic.
  58. 58. 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 (%) 10 (16.1) 4 (6.5) (confirmed in randomized patients) 95% CI 8.0%, 27.7% 1.8%, 15.7% p Value 0.09 Objective response (CR, PR), % 19.2 7.3 (confirmed in evaluable patients) 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.
  59. 59. All Adverse Events in ≥ 5% (All Grades) Afatinib Cetuximab*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 werenot treated).Image courtesy of Seiwert et al, 2012.
  60. 60. LUX: HNC 1 (1200.43) Afatinib Vs. MTX in Second-Line R/M HNSCC Trial Design End Points Study Sites Phase III, Randomized, Primary: PFS Global Open-Label Key Secondary: OS; HR 0.73 R Afatinib 40 mg qd A N = 316 R/M SCC N 2• Failing Platinum-Based CT for R/M D • Documented PD Treatment O • PS = 0–1 Until PD M• Max 1 CT Regimen for R/M HNSCC 1 I • No Prior EGFR TKIs MTX, 40 mg/m2/qw Z E N = 158
  61. 61. LUX: HNC 2 (1200.131) Adjuvant Afatinib in Locally Advanced HNSCC Trial Design End Points Study Sites Phase III, Primary: DFS HR 0.72 Global Randomized, Placebo Controlled Secondary: DFS Rate 2 Yrs, OS, Safety R Afatinib 40 mg qd Locally Advanced HNSCC A N = 446 • Unresected N 2 • Stage III–IVb D Treatment for • Previous CRT O 18 months/ • Exclude non-smokers with OP cancer M recurrence • PS 0–1 I 1 • NED After CRT Z Placebo qd E N = 223NED = no evidence of disease.
  62. 62. The PI3K/mTOR PathwayClarke et al, 2011.
  63. 63. BKM120: A Potent Oral Pan-PI3K Inhibitor  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 developmentMTD = maximum tolerated dose.Voliva et al, 2010; Maira et al, 2010; Bendell et al, 2011; Graña-Suárez et al, 2011.
  64. 64. Treatment Schema: Cetuximab Plus Bevacizumab Recurrent orMetastatic SCCHN ECOG PS 0–2 Cetuximab 250 mg/m2 IV wklyNo Previous EGFR (after loading dose of 400 mg/m2)or VEGF Inhibitors Up to 1 Regimen Bevacizumab 15 mg/kg IV, q3wks for Recurrent orMetastatic Disease 1 Prior Curative Regimen Is Also Allowed
  65. 65. Efficacy Results: Best Objective Response (RECIST) Best Response N = 45 PR 8 (18%) SD 25 (55%) DCR (CR/PR/SD) 33 (73%) Progression 12 (27%)Argiris et al, 2011.
  66. 66. Cet/Bev Grade 3/4 Toxicities (n = 46) Toxicity Grade No. Patients (%) Proteinuria 4 1 (2%) Cardiac ischemia 4 1 (2%) Hyponatremia 3 3 (7%) Dysphagia 3 4 (9%) Rash 3 4 (9%) Fatigue 3 3 (7%) Pain 3 4 (9%) Hypertension 3 3 (7%) Infection 3 3 (7%) Hemorrhage 3 2 (4%) *Grade 2 hemorrhage was reported in 4 patients and grade 1 in 6. Two patients died of aspiration pneumonia, one with associated cardiac ischemia and another with acute renal failure; these events were considered unrelated to study drugs.Argiris et al, 2011.
  67. 67. E1305 Schema Physician’s choice of Cisplatin + Docetaxel chemotherapy regimen Cisplatin + 5-FU RANDOMIZATION ARM A ARM B Cisplatin-doublet Cisplatin-doublet plus q21days until bevacizumab q21days progression until progression 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 progression.ClinicalTrials.gov
  68. 68. Clinical Trial Design  Neoadjuvant bevacizumab dose flanked by novel imaging studies and tissue biopsy  Bevacizumab dose escalated with concurrent CRTClinicalTrials.gov
  69. 69. c-MET Signaling Pathway Motility Proliferation Progression Survival AngiogenesisShinomiya et al, 2003.
  70. 70. What Can Activate MET? Amplification Mutation HGF Non-amplified overexpression – Secondary induction of transcription – Secondary activation – Promotor mutation – Altered degradation
  71. 71. Expression: MET IHC “Normal” (Adjacent Tissue) Dysplasia Cancer Normal tissue - N=24 Dysplasia - N=10 Cancer - N=97 0% 0% 1% 20% 15% 21% 21% 20% 30% 58% 50% 64% 0+ 1+ 2+ 3+ 0+ 1+ 2+ 3+ 0+ 1+ 2+ 3+Seiwert et al, 2009.
  72. 72. Expression: HGF IHCSeiwert et al, 2009.
  73. 73. Anti-MET/HGF Compounds 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 / IIXL880 (GSK1363089) Exelixis / GSK MET, VEGFR2 I / II (HNSCC)
  74. 74. Phase II Study of XL880 (Foretinib) in HNSCC  Failed to meet primary end point (trial did not proceed to stage II) Evidence of minor activity; more specific anti-MET agents in clinical testing for HNCSeiwert et al, Epub.
  75. 75. Blocking Inhibitory Receptors to Reactivate Cancer Cells PD-1 (Programmed Death-1) and CTLA-4 Anti-CTLA-4 mAb (MDX-010, IgG1) * CTLA-4 Anti-PD-1 mAb (MDX-1106, IgG4) (CD152) (*PD-Ligand are expressed on cancer cells)Adapted from Keir et al, 2008.
  76. 76. Phase Ib/II Trial of Concurrent Cetuximab/IMRT With Ipilimumab, Plus Biomarker Correlatives, in Locally Advanced P16+ (HPV+) Oropharynx Cancer SCHEMA R Stage a III–IVA n Arm A: Cetuximab/Radiotherapy Plus Low-Dose Ipilimumab OPSCC d RT 66 Gy with 200 cGy daily fractions in 6.5 wks Tumor/ o Cetuximab wkly at a dose of 250 mg/m2 during radiation* Blood m Ipilimumab 3 mg/kg q21days Collection i P16 IHC z *After loading dose of 400 mg/m2 on Cycle 1, Day 1 e Ipilumumab will be continued at indicated dose for additional 2 cyclesHodi et al, 2010; Robert et al, 2011.
  77. 77. New 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
  78. 78. Case 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
  79. 79. Case Study 1: HPV16+ Oropharynx Cancer Clinical Implications of T2N1 or T2N2b
  80. 80. Case Study 1: Clinical Decision Question 1What is your choice of therapy? 1) Surgery plus post-operative chemoradiotherapy 2) Chemoradiotherapy 3) Sequential therapy 4) A diagnostic procedure
  81. 81. Case Study 1: HPV16+ Oropharynx Cancer Clinical Implications of T2N1 or T2N2b 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
  82. 82. Case Study 1: HPV16+ Oropharynx Cancer Lower, lymph node biopsy/FNA – NegativeCase Study 1: Clinical Decision Question 2 What is your treatment choice now? 1) Surgery plus PORT 2) CRT 3) Sequential therapy
  83. 83. Case 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, Primary quit 20 yrs ago Tumor – No comorbidities FNA and biopsy positive for SCC – T4 right base of tongue, bilateral extensive adenopathy staged T4N2c, stage 4a – P16-, HPV-
  84. 84. Case Study 2: Clinical Decision Question What is your choice of therapy? 1) Surgery plus post-operative chemoradiotherapy 2) Chemoradiotherapy 3) Sequential therapy 4) Palliative therapy
  85. 85. Case Study 2:HPV16- Oropharynx Cancer: T4N2c, Stage 4a 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.

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