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Targeted Therapy for the Treatment of Basal Cell Carcinoma and Melanoma

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This slidedeck presents an up-to-date disease overview of BCC, reviews current treatment options in BCC, explains the hedgehog signaling pathway and its role in BCC, review recent data of the …

This slidedeck presents an up-to-date disease overview of BCC, reviews current treatment options in BCC, explains the hedgehog signaling pathway and its role in BCC, review recent data of the first-in-class hedgehog inhibitor, vismodegib, and other novel agents in clinical trials. Faculty will also review recently approved novel agents in melanoma, to include treatment planning and managing adverse events. Case studies will demonstrate the practical application of current and emerging clinical evidence for the treatment of BCC and melanoma. During the panel discussion, faculty will discuss the importance of cross-communication in the treatment planning process and strategies to optimize the continuum of care for patients with BCC.

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  • More common than lung, breast, prostate, and colon cancer combined
  • SCC cumulative UV, BCC more short term, intermittent weekend
  • The pivotal molecular abnormality in BCC carcinogenesis is inappropriate activation of the hedgehog (HH) signaling pathway. Essentially all BCC tumors have an overactive HH signaling pathway, commonly occurring by mutational inactivation of the tumor suppressor Patched1 ( PTCH1 ) gene
  • The pivotal molecular abnormality in BCC carcinogenesis is inappropriate activation of the hedgehog (HH) signaling pathway [17]. Essentially all BCC tumors have an overactive HH signaling pathway, commonly occurring by mutational inactivation of the tumor suppressor Patched1 ( PTCH1 ) gene
  • BCNS pts and others with multiple BCCs need not just chemotherapy but chemo prevent of their BCCs. What as dermatologists can we recommend? Not sure – tell you what doesn ’ t work.
  • Figure 2
  • Multiple elements contribute to acquired resistance against SMO antagonists. In cases of medulloblastoma and basal cell carcinoma, loss of PTCH1 results in aberrant, ligand-independent activation of SMO, leading to hyperactivation of the Hh pathway and associated tumorigenesis. Inhibition of SMO in such contexts is thus an enticing therapeutic strategy, and a number of SMO antagonists are currently under investigation in clinical trials (listed above). Mutation of SMO, amplification of the downstream Hh signaling molecule GLI2, and amplification of the Hh target gene CCND1 have been identified as potential mechanisms leading to resistance against SMO antagonists. Another potential resistance mechanism is upregulation of the phosphoinositide 3-kinase (PI3K) pathway. The details of how PI3K pathway activation might contribute to the reemergence of disease after acquired resistance to SMO antagonists are not yet known, and the mechanism by which the PI3K pathway might be activated in the context of Hh-driven disease remains to be determined. Intriguingly, though, the IGFR ligand IGF2 is reportedly upregulated in response to Hh pathway activation and is required for progression of medulloblastoma in Ptch1 heterozygous mice
  • the duration of GDC-0449 therapy and best responses for the 33 patients in the study. Patients were assessed according to either Response Evaluation Criteria in Solid Tumors (RECIST) (mainly for patients with metastatic tumors) or clinical criteria (mainly for patients with locally advanced tumors). Patients 15 and 29 were the only ones with locally advanced disease who could be evaluated radiologically and were assessed according to RECIST. Patients with metastatic disease were evaluated with the use of RECIST, except for Patients 10 and 24, who did not have radiologically measurable disease and were evaluated with the use of clinical measures. Patient 20 was evaluated with the use of both RECIST and clinical measures. Clinical criteria consisted of physical examination for reepithelialization of ulcerated lesions, flattening of nodular lesions, or shrinkage of palpable tumor masses.
  • ERIVANCE BCC, the pivotal Phase 2 study included 2 tumor cohorts: Those with metastatic BCC (which had to be measurable by imaging) and those with locally advanced BCC. Patients were treated with vismodegib at 150mg daily until disease progression, intolerable toxicity or withdrawal from study for other reasons. Responses in the metastatic cohort were measured by imaging, using RECIST criteria and in laBCC cohort using a novel composite endpoint that included measurable diameter and ulceration of visible tumor as well as RECIST measures of the deeper tumor component when present. The term, “locally advanced BCC” in this study was defined as: a BCC tumor that was either inoperable or where surgery was inappropriate, with the tumors being over 1 cm in diameter and characterized by 2 or more recurrences after surgery, rendering curative resection unlikely and/or anticipated substantial morbidity and/or deformity from surgery.
  • The Metastatic cohort was roughly 1/3 of the total and the locally advanced cohort roughly 2/3 of the total. The average age of patients on the study was 61, with the oldest patient being 101. Some male predominance was seen and all patients were white. Of the patients with laBCC entered in the trial, 38.1% were characterized as inoperable and in 61.9% surgery was felt to be inappropriate for indicated reasons.
  • This waterfall plot depicts the change in lesion diameter for patients with laBCC. Similar to the waterfall plot in mBCC we see that majority of patients had some level of tumor shrinking. Patients labeled by IRF as responders are depicted in green.
  • Our results also indicate significant objective response rate of vismodegib in laBCC, measured at 43% by independent review facility and 60% by investigator. Another 38.1 % of patients had stable disease and progression was seen in 12.7% patients. Of relevance, the response rate observed by investigator in this study is identical to that observed by investigator in the Phase I study.
  • Our results indicate significant objective response rate of vismodegib in metasatatic BCC, measured at 30% by independent review facility and 46% by investigator. Another 64 % of patients had stable disease and progression as best response was seen in only 3% of patients.
  • Clinical response to vismodegib observed in responders frequently occurred in matter of weeks, as indicated by these ear photographs at baseline week 12.
  • Although this patient had basal cell nevus syndrome, this alone would not qualify him for our study. His locally advanced BCC qualifying target lesions were these larger medial canthal lesions presenting ocular risk and resection challenge. These photos demonstrated not only the target lesion improvement but his global facial response shown at week 48. At week 24 4/5 target lesion biopsies had no BCC
  • AAD Melanoma Guidelines
  • AAD Melanoma Guidelines
  • AAD Melanoma Guidelines
  • BRIM2
  • BREAK-2 trial
  • BRIM3
  • Cut off 12/30/10
  • Transcript

    • 1. 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.
    • 2. Disclosure of Conflicts of Interest Jean Y. Tang, MD, PhD, reported a financial interest/relationship or affiliation in the form of: Consultant, Genentech, Inc. Keith T. Flaherty, MD, reported a financial interest/relationship or affiliation in the form of: Consultant, Genentech, Inc. Vernon K. Sondak, MD, reported a financial interest/relationship or affiliation in the form of: Consultant, Merck & Co., Inc., Navieda Biopharmaceuticals; Speakers Bureau, Merck & Co., Inc.
    • 3. Learning Objectives Upon completion of this activity, participants should be better able to: Identify the patient symptoms and disease characteristics that influence the diagnosis and treatment strategy of BCC Describe the mechanism of action and emerging evidence supporting the clinical utility of hedgehog inhibitors in treating BCC Demonstrate the management of treatment-related side effects in patients with BCC taking hedgehog inhibitors Evaluate novel agents in ongoing clinical trials for the treatment of BCC and melanoma Describe molecular tests and patient characteristics that facilitate individual treatment planning for melanoma Evaluate newly approved treatment options for advanced/metastatic melanoma
    • 4. Introduction to Faculty Panel Jean Y. Tang, MD, PhD (Chairperson) – Stanford School of Medicine Keith T. Flaherty, MD – Harvard Medical School – Massachusetts General Hospital Cancer Center Vernon K. Sondak, MD – H. Lee Moffitt Cancer Center & Research Institute
    • 5. Activity Agenda Introduction (5 mins) – Jean Y. Tang, MD, PhD Overview of Basal Cell Carcinoma (5 mins) – Jean Y. Tang, MD, PhD Current Treatment Approaches in Basal Cell Carcinoma (15 mins) – Jean Y. Tang, MD, PhD Basal Cell Carcinoma Clinical Advances With Novel Targeted Agents (40 mins) – Keith T. Flaherty, MD Beyond Basal Cell Carcinoma: Novel Approaches to Treating Melanoma (40 mins) – Vernon K. Sondak, MD and Keith T. Flaherty, MD Panel Discussion: Multi-Disciplinary Perspectives in Basal Cell Carcinoma (10 mins) – All Faculty Activity Conclusion/Q&A (5 mins)
    • 6. Overview of Basal Cell Carcinoma Jean Y. Tang, MD, PhDStanford School of Medicine
    • 7. Types of Skin Cancer Approximately 3.6 Million Americans Will Be Diagnosed With Skin Cancer This Year BCC SCC MelanomaBCC = basal cell carcinoma; SCC = squamous cell carcinoma.Images courtesy of Jean Y. Tang, MD, PhD.Rogers et al, 2010; ACS, 2012.
    • 8. Basal Cell Carcinoma: Clinical Need  1 in 5 Caucasians  Treatment: Mainly surgery  Prevention: None  Cost: $5 billion per yearImages courtesy of Jean Y. Tang, MD, PhD.Goppner et al, 2011.
    • 9. Epidemiology of BCC  Estimated 1 million BCC cases per year in US – According to the ACS, 75% of all skin cancers are BCC  Rare risk of metastasis: 0.003%–0.5%  5th most costly cancer for Medicare  The age-adjusted incidence per 100,000 Caucasians – 475 cases in men – 250 cases in women  The estimated lifetime risk of BCC in Caucasian population is 33%–39% in men and 23%–28% in women  Risk of second BCC: 44% in 3 yearsACS = American Cancer Society.Ridky, 2007; ACS, 2012; Rubin et al, 2005; Housman et al, 2003; Christenson et al, 2005; Marcil et al, 2000.
    • 10. BCC Risk Factors*This syndrome is an autosomal dominant disorder, characterized by BCC, atrophoderma vermiculata, milia, hypotrichosis,trichoepithelioma, and peripheral vasodilatation.† This syndrome is an X-linked dominant disorder, characterized by BCC, follicular atrophoderma, hypotrichosis, and localized anhidrosis.‡ This syndrome is an autosomal dominant disorder, characterized by BCC, palmoplantar pits, odontogenic keratocysts, bifid ribs, frontalbossing, and central nervous system defects.Rubin et al, 2005.
    • 11. Subtypes of BCCImages courtesy of Jean Y. Tang, MD, PhD.
    • 12. High Risk for Recurrence (NCCN Guidelines)  Diameter – ≥ 20 mm on trunk/extremities – ≥ 10 mm on cheeks/forehead/neck – ≥ 6 mm anywhere else on face  Poor tumor borders  Immunosuppressed patient  Prior radiation  Subtype: Morphea, infiltrative, mixed  PerineuralNCCN = National Comprehensive Cancer Network.NCCN, 2012a.
    • 13. Key Takeaways BCC is the most common cancer in the US BCC incidence is increasing
    • 14. Current Treatment Approaches in Basal Cell Carcinoma Jean Y. Tang, MD, PhD Stanford School of Medicine
    • 15. Common Treatment Options for BCC (NCCN Guidelines)  Curettage and electrodesiccation  Surgical excision  Mohs micrographic surgery  Cryosurgery  Creams – Imiquimod – 5-FU  Radiation therapy  PDT5-FU = 5-fluoruracil; PDT = photodynamic therapy.NCCN, 2012a.
    • 16. Rationale for Treatment Selection  Location – Face (near critical structures) and scarring – Trunk  Size  Subtype  Patient age, comorbidities, and complianceNCCN, 2012a.
    • 17. Locally Advanced or Metastatic BCCImage courtesy of Jean Y. Tang, MD, PhD.
    • 18. Advanced BCC  Radiation therapy  Cisplatin and doxorubicin  EGFR inhibitors  Targeted therapies with Hedgehog pathway antagonistsEGFR = epidermal growth factor receptor.Ganti et al, 2011.
    • 19. BCC Have Mutations in Genes Involved in the Hedgehog Signaling Pathway ONImages courtesy of Jean Y. Tang, MD, PhD.Von Hoff et al, 2009.
    • 20. Vismodegib Is a Small Molecule Inhibitor of the Hedgehog Signaling Pathway Vismodegib OFFImages courtesy of Jean Y. Tang, MD, PhD.Von Hoff et al, 2009.
    • 21. Basal Cell Nevus Syndrome (BCNS) Patients Have Mutations in PTCH1 GeneImage courtesy of Jean Y. Tang, MD, PhD.
    • 22. No Effective Chemopreventive Agents for BCC  Oral retinoids in immunocompetent patients fail to prevent BCC  Selenium does not prevent  Field treatment with 5-FU, Imiquimod, PDTDe Graaf et al, 2004; Duffield-Lillico et al, 2003.
    • 23. Investigator-Initiated, Randomized, Double-Blinded Trial for 18 Months  Vismodegib at 150 mg pill vs. placebo (2:1)  41 patients with BCNS 3 clinical centers: September 2009 to December 2010  Primary end point: Prevention of new BCC  Secondary end point – Reduction in size of existing BCC – Safety/tolerabilityTang, 2011.
    • 24. Two Groups Are Similar at Baseline Vismodegib Placebo (N = 26) (N = 15) Age (years) 54 53 % female 30 40 Weight (lbs) 222 222 No. BCC at baseline 29 27 (median) Average follow-up (months) 9 7 2,000 existing BCCs 694 new BCCsTang, 2011.
    • 25. Baseline Month 9Images courtesy of Jean Y. Tang, MD, PhD.
    • 26. Baseline Baseline Month 5 Month 5 Month 5Images courtesy of Jean Y. Tang, MD, PhD.
    • 27. Vismodegib Prevents New BCCs Vismodegib PlaceboTang, 2011.
    • 28. Key Takeaways Curerate is excellent for most BCC with current surgical or topical therapies Limited therapeutic options for locally advanced or metastatic BCC Vismodegib works for BCC prevention in BCNS patients
    • 29. Basal Cell Carcinoma ClinicalAdvances With Novel Targeted Agents Keith T. Flaherty, MD Harvard Medical School Massachusetts General Hospital Cancer Center
    • 30. Systemic Chemotherapy for BCC  Cisplatin-based therapy was “standard-of care” based on case reports  Single-agent cisplatin – 1 complete and 1 partial response noted in a phase I trial of cisplatin (1978) – 1 complete response (1983)  Cisplatin and doxorubicin – 5 complete and 2 partial responses in 8 patients – 4 complete, 5 partial in 12 patientsSalem et al, 1978; Wieman et al, 1983; Guthrie et al, 1985, 1990.
    • 31. Targeted Therapy for BCC  EGFR highly expressed in 38% of BCC – Expression not a good marker of sensitivity to EGFR targeted therapy in lung or colon cancer – Case report: “Dramatic response” with cetuximab (EGFR antibody) – Case report: 2 cisplatin-refractory patients with stable disease with cetuximabKrahn et al, 2001; Muller et al, 2008; Caron et al, 2009.
    • 32. Hedgehog/Smoothened Signaling in BCC  Mutations in patched gene identified in Gorlin’s syndrome/BCNS (1996)  90% of sporadic BCC have patched mutations  10% of sporadic BCC have smoothened mutations (binding partners of patched)Johnson et al, 1996; Gailani et al, 1996; Caro et al, 2010.
    • 33. Patched/Smoothened Function vismodegib  Gli first identified as an amplified oncogene in glioblastomaImage adapted from Metcalfe et al, 2011; Kinzler et al, 1987.
    • 34. Small Molecule Smoothened Inhibitors in Clinical Development  GDC-0449 (vismodegib)  IPI-926  BMS-833923  LDE225  PF-04449913  LEQ506  TAK-441Metcalfe et al, 2011.
    • 35. Vismodegib Phase I Trial  33 BCC patients received – 150 mg QD (n = 17) – 270 mg QD (n = 15) – 540 mg QD (n = 1)QD = per day; CR = complete response;PR = partial response; SD = stable disease;PD = progressive disease.Von Hoff et al, 2009.
    • 36. ERIVANCE BCC: Pivotal Phase 2 Study in Advanced BCC Metastatic BCC RECIST (RECIST-measurable) REGISTRATION • Progression Vismodegib • Intolerable toxicity  laBCC • Withdrawal from • Inoperable Composite study • Surgery inappropriate end point Primary end point: Secondary end points: ORR per IRF ORR per investigator – Metastatic BCC: RECIST DOR – laBCC: Novel composite end PFS point Absence of residual BCC on Dose 150 mg QD biopsy (laBCC only)RECIST = Response Evaluation Criteria In Solid Tumors; laBCC = locally advanced basal cell carcinoma; ORR = objectiveresponse rate; IRF = independent review facility; DOR = duration of response; PFS = progression-free survival.Sekulic et al, 2011.
    • 37. ERIVANCE BCC: Demographics Efficacy Evaluable Patients Metastatic BCC laBCC (n = 33) (n = 63) Age Mean (SD) 61.6 (11.4) 61.4 (16.9) Median 62.0 62.0 (range) (38–92) (21–101) Sex Male, n (%) 24 (72.7) 35 (55.6) Female, n (%) 9 (27.3) 28 (44.4) Race White, n (%) 33 (100) 63 (100) IaBCC Inoperable, n (%) 24 (38.1) Surgery inappropriate, n (%) 39 (61.9) Multiple recurrence, n (%) 16 (25.4) Significant morbidity/deformity, n (%) 32 (50.8)Sekulic et al, 2011.
    • 38. Tumor Response Criteria  Tumor response – Metastatic BCC: ≥ 30% size reduction by CT (RECIST) – laBCC: Novel composite end point ∀ ≥ 30% size reduction (physical exam and/or CT) and/or • Complete resolution of ulceration  Progression ≥ 20% size increase – New lesions or new ulcerations  SD: Does not meet criteria for response or progressionCT = computed tomography.Sekulic et al, 2011.
    • 39. Maximum Decrease in Tumor Size by IRF Locally Advanced Cohort 100 Response Stable disease Progressive disease 50 Change in lesion diameter (%) 0 -50 -100Sekulic et al, 2011.
    • 40. Vismodegib Demonstrates a Significant ORR in Locally Advanced BCC laBCC (n = 63) Independent Investigator review assessment Responders, n (%) 27 (42.9) 38 (60.3) SD, n (%) 24 (38.1) 15 (23.8) PD, n (%) 8 (12.7) 6 (9.5) Unevaluable/missing, n (%) 4 (6.3) 4 (6.3) 95% CI for objective response (30.5–56.0) (47.2–71.7) p value (RR > 20%) < .0001 Median DOR (months) 7.6 7.6CI = confidence interval.Sekulic et al, 2011.
    • 41. Vismodegib Demonstrates a Significant ORR in Metastatic BCC Metastatic BCC (n = 33) Independent Investigator review assessment Responders, n (%) 10 (30.3) 15 (45.5) SD, n (%) 21 (63.6) 15 (45.5) PD, n (%) 1 (3.0) 2 (6.1) Unevaluable/missing, n (%) 1 (3.0) 1 (3.0) 95% CI for objective response (15.6–48.2) (28.1–62.2) p value (RR > 10%) .0011 Median DOR (months) 7.6 12.9Sekulic et al, 2011.
    • 42. Vismodegib in laBCC Baseline Week 12Sekulic et al, 2011.
    • 43. Vismodegib in laBCC (cont.) Baseline Week 8 Week 48 Week 24: 4 out of 5 target lesion biopsies no BCCSekulic et al, 2011.
    • 44. Most Common Adverse Events All Treated Patients (n = 104) All adverse Grade 1 Grade 2 Grade 3–4 Toxicity events mild moderate severe (%) (%) (%) (%) Muscle spasms 68 48 16 4 Alopecia 64 49 14 0 Dysgeusia 51 28 23 0 Weight 46 27 14 5 decreased Fatigue 36 27 5 4 Nausea 29 21 7 1 Decreased 23 14 6 3 appetite Diarrhea 22 16 5 1Sekulic et al, 2011.
    • 45. Vismodegib Toxicity Management  Starting dose is 150 mg orally daily – Supplied as 150 mg capsules  In phase I trials, discontinuation due to toxicity was uncommon  Intolerable toxicities managed with temporary dose interruptionVon Hoff et al, 2009; Erivedge® prescribing information, 2012.
    • 46. Case Study 1:Advanced BCC
    • 47. Case Study 68-year-oldwidower presents with enlarging, bleeding mass on right ear, and post- auricular scalp Extensive sun exposure history secondary to lifelong outdoor construction work Hasn’t seen a doctor in 25 years Biopsy reveals BCC
    • 48. ARS Question: Next StepsWhat would be your next step? 1) CT of the head and neck 2) Referral to plastic surgeon 3) Referral to radiation oncologist 4) Initiate cisplatin-based chemotherapy
    • 49. Further Evaluation After further consultation with a surgeon and radiation oncologist: – The patient is deemed unresectable – Radiation oncologist feels that radiation is likely to help reduce bleeding, but unlikely to provide significant regression or make him resectable
    • 50. ARS Question: Choosing TherapyWhat systemic therapies would yourecommend? 1) Cisplatin-based chemotherapy 2) Oral inhibitor of Hedgehog/Smoothened 3) EGFR inhibitor 4) No systemic therapy, supportive measures only
    • 51. Key Takeaways  Chemotherapy has some activity in advanced/metastatic BCC  Discovery of mutations in patched/smoothened created opportunity to target smoothened  ~ 80% of patients with advanced BCC have regression of disease (30%–60% have objective responses)  Possibility of using smoothened inhibitors as neoadjuvant therapy for locally advanced patients needs to be studied  On January 30, 2012, the FDA approved vismodegib for the treatment of adults with metastatic BCC, or with laBCC that has recurred following surgery or who are not candidates for surgery, and who are not candidates for radiation – Recommended dose is 150 mg taken orally once dailyErivedge® prescribing information, 2012.
    • 52. Beyond Basal Cell Carcinoma: Novel Approaches to Treating Melanoma Vernon K. Sondak, MDH. Lee Moffitt Cancer Center & Research Institute Keith T. Flaherty, MD Harvard Medical SchoolMassachusetts General Hospital Cancer Center
    • 53. Ten Leading Cancer Types for the Estimated New Cancer Cases by Sex, 2012 Estimated New Cases Prostate 241,740 29% Male Female Breast 226,870 29% Lung & bronchus 116,470 14% Lung & bronchus 109,690 14% Colon & rectum 73,420 9% Colon & rectum 70,040 9% Urinary bladder 55,600 7% Uterine corpus 47,130 6% #5 Melanoma of the skin 44,250 5% Thyroid 43,210 5% Kidney & renal pelvis 40,250 5% Melanoma of the skin #6 32,000 4% Non-Hodgkin lymphoma 38,160 4% Non-Hodgkin lymphoma 31,970 4% Oral cavity & pharynx 28,540 3% Kidney & renal pelvis 24,520 3% Leukemia 26,830 3% Ovary 22,280 3% Pancreas 22,090 3% Pancreas 21,830 3% All Sites 848,170 100% All Sites 790,740 100%Siegel et al, 2012.
    • 54. Annual Age-Adjusted Cancer Incidence Rates for Selected Cancers by Sex, 1975–2008Siegel et al, 2012.
    • 55. Ten Leading Cancer Types for the Estimated New Cancer Deaths by Sex, 2012 Estimated Deaths Lung & bronchus 87,750 29% Males Females Lung & bronchus 72,590 26% Prostate 28,170 9% Breast 39,510 14% Colon & rectum 26,470 9% Colon & rectum 25,220 9% Pancreas 18,850 6% Pancreas 18,540 7% Ovary 15,500 6% Liver & intrahepatic bile duct 13,980 5% Leukemia 10,040 4% Leukemia 13,500 4% Non-Hodgkin lymphoma 8,620 3% Esophagus 12,040 4% Uterine corpus 8,010 3% Urinary bladder 10,510 3% Liver & intrahepatic bile duct 6,570 2% Non-Hodgkin lymphoma 10,320 3% Brain & other nervous system 5,980 2% Kidney & renal pelvis 8,650 3% All Sites 275,370 100% All Sites 301,820 100%Siegel et al, 2012.
    • 56. Death Rate (per 100,000) Change Male 1990* 2007 Absolute % %Contribution† All malignant cancers 279.82 217.79 -62.03 -22.17 Decreasing Contribution of Lung & bronchus 90.56 65.23 -25.33 -27.97 38.5 Individual Cancer Prostate Colorectum 38.56 30.77 23.50 20.05 -15.06 -10.72 -39.06 -34.84 22.9 16.3 Sites to Change Stomach 8.86 5.01 -3.85 -43.45 5.9 Oral cavity & pharynx 5.61 3.85 -1.76 -31.37 2.7 in Male Cancer Non-Hodgkin lymphoma 9.97 8.29 -1.68 -16.85 2.6 Death Rates, Leukemia Larynx 10.71 2.97 9.44 2.05 -1.27 -0.92 -11.86 -30.98 1.9 1.4 1990–2007 Brain & other nervous system 5.97 5.10 -0.87 -14.57 1.3 Myeloma 4.83 4.39 -0.44 -9.11 0.7 Urinary bladder 7..97 7.56 -0.41 -5.14 0.6 Kidney & renal pelvis 6.16 5.79 -0.37 -6.01 0.6 Hodgkin lymphoma 0.85 0.50 -0.35 -41.18 0.5 Other decreasing 38.66 35.89 -2.77 -7.17 4.2 Total 262.45 196.65 -65.80 100.0 Increasing Liver & intrahepatic bile duct 5.27 7.92 2.65 50.28 Esophagus 7.16 7.67 0.51 7.12 Melanoma of the skin 3.80 3.98 0.18 4.74 Other increasing 0.84 1.29 0.45 53.57 Total 17.07 20.86 3.79 No change Bones & joints 0.55 0.55 0.00 0.00Siegel et al, 2011.
    • 57. Melanoma 2012 ACS Incidence Predictions  131,810 new cases of melanoma in the US predicted for 2012 – 55,560 noninvasive cases (melanoma in situ) – 76,250 invasive cases – 9,250 cases predicted for California – 5,450 cases predicted for Florida  9,180 deaths predicted for 2012Image courtesy of Vernon K. Sondak, MD.Siegel et al, 2012.
    • 58. Cutaneous Malignant Melanoma AJCC Staging System TUMOR NODES  T1 ≤ 1.00 mm*  N0 all nodes -ve  T2 1.01–2.00 mm  N1 1 +ve node  T3 2.01–4.00 mm  N2 2–3 +ve nodes  T4 > 4.00 mm  N3 ≥ 4 +ve nodes a) non-ulcerated a) microscopic b) ulcerated (*or mitoses b) macroscopic ≥ 1/mm2)AJCC, 2009.
    • 59. Cutaneous Malignant Melanoma 2012 Surgical Guidelines TUMOR SURGERY  < 1 mm  1 cm excision  1–2 mm  1–2 cm excision  > 2 mm  2 cm excision  Any positive nodes  Complete LN dissectionLN = lymph node.Bichakjian et al, 2011.
    • 60. Cutaneous Malignant Melanoma 2012 Surgical Guidelines (cont.) TUMOR SURGERY  < 1 mm  1 cm excision, no SLN Bx*  1–2 mm  1–2 cm excision, SLN Bx  > 2 mm  2 cm excision, SLN Bx  Any positive nodes  Complete LN dissection *Selected patients < 1 mm (young age or “high-risk histology”) should be considered for SLN Bx.Bx = biopsy; SLN = sentinel lymph node.Bichakjian et al, 2011.
    • 61. Sentinel Node Biopsy Update  Sentinel node status remains the most important predictor of melanoma-specific survival for thinner, intermediate, and thick melanomas  Sentinel node biopsy reliably detects nodal metastases which, if left in place, would result in clinical recurrence – 4%–5% of patients with negative sentinel nodes fail in the regional nodes (~ 15% of positive nodes are missed)  The evidence continues to indicate that patients with a positive node benefit from earlier lymphadenectomy both in terms of melanoma-specific survival (intermediate thickness subset) and with less lymphedema from node dissectionBichakjian et al, 2011.
    • 62. FDA Approved Drugs in Use for Melanoma (as of February 2011)  Dacarbazine, 1970s – RR: < 10% in unselected stage IV melanoma patients – No proven impact on survival – Temozolomide, carbo-taxol frequently used instead  High-dose IFN, 1995 – The only approved adjuvant therapy – Consistent benefit on relapse-free survival, controversial survival benefit  High-dose IL-2, 1998 – RR: 16% in highly selected stage IV melanoma patients – Durable responses: ~ 5% – Rarely used outside of a high-volume centersIFN = interferon; IL-2 = interleukin-2.Intron®A prescribing information, 2012; Proleukin® prescribing information, 2012; DTIC-Dome® prescribing information, 2012;Middleton et al, 2000; Mansfield et al, 2009; Fyfe et al, 1995; Kammula et al, 1998; Atkins et al, 2000.
    • 63. Drugs Approved for Melanoma by the FDA in 2011  Pegylated IFN-2b – Improved relapse-free survival in adjuvant therapy of stage III melanoma – No proven impact on survival – 5-year treatment regimen  Ipilimumab (anti-CTLA4 monoclonal antibody) – Immunotherapy for stage IV melanoma – Improved OS in 2 phase III trials  Vemurafenib (V600 mutant BRAF inhibitor) – For patients with BRAF V600 mutant melanoma – Rapid responses, rarely durable – Improved OS in a phase III trial compared to DTICCTLA4 = cytotoxic T-lymphocyte antigen 4; OS = overall survival.Zelboraf® prescribing information, 2012; Yervoy® prescribing information, 2012; Sylatron® prescribing information, 2012.
    • 64. Anti-CTLA4 Antibodies Vernon K. Sondak, MDH. Lee Moffitt Cancer Center & Research Institute
    • 65. Targeted Immunotherapy CTLA4 Blockade Taking the Brakes Off T-Cell Activation T-cell T-cell T-cell activation inactivation activation CTLA-4 CTLA-4 T cell T cell T cell TCR CD28 HLA B7 Ipilimumab APC APC APCTCR = T-cell receptor; APC = antigen presenting cell.Image adapted from Weber et al, 2008b.
    • 66. Targeting T Cells With Ipilimumab (anti-CTLA4 antibody) Leads to Durable Response Treatment SD = Ipilimumab Treatment, 10 mg/kg 100 PR 80 Tumor Size (%) 60 40 Response CR ongoing years 20 later with no new lesions 0 0 10 20 30 40 50 60 Post-Treatment Initiation (weeks)Weber, 2008a.
    • 67. Progression Followed by Response in Melanoma Patient Treated With Ipilimumab Screening Week 8: “Progression” Week 12: Improved Week 16: Continued Week 72: Complete Week 108: Still in Improvement Remission Complete RemissionImages courtesy of Jedd Wolchok, MD.Hoos et al, 2010; Maggon, 2011.
    • 68. Ipilimumab (3 mg/kg x 4) Improves OS in Previously Treated Stage IV Melanoma Ipilimumab + gp100 Ipilimumab alone gp100 alone 1 2 Years 3 4 Ipi + gp100 Ipi + pbo gp100 + pbo Survival Rate (N = 403) (N = 137) (N = 136) 1 year 44% 46% 25% 2 years 22% 24% 14%Hodi et al, 2010.
    • 69. Ipilimumab (10 mg/kg) + DTIC Improves OS in Previously Untreated Stage IV Melanoma No. of deaths: 196 vs. 218, HR 0.72 (0.59–0.87) p < .001 1-year survival 47.3% vs. 36.3% 2-year survival 28.5% vs. 17.9% 3-year survival 20.8% vs. 12.2%HR = hazard ratio.Robert et al, 2011.
    • 70. Randomized Phase 2 Trial of 3 Doses of Ipilimumab (0.3 mg/kg, 3.0 mg/kg, 10 mg/kg) in Stage IV Melanoma Dose 0.3 mg/kg 3 mg/kg 10 mg/kg RR (%) 0 4.2 11.1Wolchok et al, 2010.
    • 71. When Going Downhill With No Brakes, A Steering Wheel Is A Great Idea!Images courtesy of Vernon K. Sondak, MD.
    • 72. Ipilimumab Treatment and irAEs  Blockade of CTLA-4 frequently leads to the development of irAEs, due to T cells losing tolerance to self-antigens  Common autoimmune adverse events – Dermatitis – Hepatitis – Endocrinopathies/pituitary dysfunction – Enterocolitis  Diarrhea is often the first manifestation of autoimmune toxicity, and requires prompt and aggressive treatment – Antidiarrheal agents (loperamide or diphenoxylate/atropine) – Intravenous and/or oral corticosteroids – Oral budesonide – Infliximab (anti-TNFα antibody) – Surgery in extreme cases (< 1%)  Toxicity does not equal response, but there appears to be an associationirAEs = immune-related adverse events.Images courtesy of Vernon K. Sondak, MD.Yervoy® prescribing information, 2011; Thumar & Kluger, 2011; Hodi et al, 2010; Ledezma, 2009.
    • 73. The Future of Melanoma Immunotherapy PD1 Blockade Reviving Exhausted T Cells T-cell T-cell exhaustion reactivation T cell T cell TCR PD1 HLA PDL1 Anti-PD1 Tumor TumorImage adapted from Topalian et al, 2012.
    • 74. BRAF Inhibitors Keith T. Flaherty, MD Harvard Medical SchoolMassachusetts General Hospital Cancer Center
    • 75. Oncogenes in Melanoma Year Target Prevalence (%) Drug 1984 NRAS 20 – 2002 BRAF 50 Sorafenib, PD0325901, AZD6244, RAF-265, XL281, Vemurafenib, GSK2118436 2005 c-Kit 1 Imatinib, Dasatinib, Nilotinib 2008 GNAQ/GNA11 1a –80%–90% of uveal.aPadua et al, 1984; Davies et al, 2002; Willmore-Payne et al, 2005; Van Raamsdonk et al, 2009.
    • 76. Distribution of Commonly Mutated Oncogenes by Body Site of Primary Melanoma GNAQ 45% GNA11 32 % uveal BRAF 28% scalp/face NRAS 18% BRAF 57%NRAS 10% trunk/legs NRAS 18%BRAF 20%c-Kit 36% acral mu c os a l c-Kit 39% ac NRAS 10% ra l BRAF 5%
    • 77. Signaling Pathways Downstream of Melanoma Oncogenes c-kit BRAF CRAF NRAS GNA11 GNAQ PI3K MEK AKT PKC ERK mTORVan Raamsdonk et al, 2010; Curtin et al, 2006; Lee et al, 2011; Perez-Lorenzo et al, 2012.
    • 78. BRAF Mutation Testing Guidelines  As vemurafenib is FDA approved for the treatment of metastatic disease, testing for a BRAF mutation for metastatic patients is considered standard of care  For patients with high risk, resected melanoma physicians may consider ordering BRAF mutation testing based on the assumption that systemic therapy may be needed quickly upon recurrenceZelboraf® prescribing information, 2012.
    • 79. BRAF Mutation Testing  Visceral metastatic tissue or lymph node metastases are typically used as source serial for mutation testing  Testing can be performed either on formalin fixed, paraffin embedded tumors, or fresh tumor biopsies placed in formalin  The FDA has approved 1 BRAF mutation test: Cobas® 4800 BRAF V600 Mutation TestZelboraf® prescribing information, 2012.
    • 80. Phase 2 Study of Vemurafenib in Previously Treated Patients With Metastatic Melanoma Previously treated End Points V600 mutant Vemurafenib Primary: RR metastatic melanoma (960 mg PO bid) Secondary: DOR, (N = 132) PFS, OS, Safety Eligibility Criteria • PD after prior IL-2 or standard chemotherapy • ECOG PS 0 or 1 • Brain metastases allowed if treatment with stereotactic RT or surgery, and stable for > 3 mos Statistical Considerations • Target ORR 30% • Assume 10% ineligibility • Total of 90 patients needed to demonstrate the lower boundary of the exact 95% CI is ≥ 20%ECOG PS = Eastern Cooperative Oncology Group performance status; RT = radiotherapy.Sosman et al, 2010; Ribas et al, 2011.
    • 81. Patient Demographics N = 132 Patient/Disease Characteristics (%) %/% Sex, Female/Male 39 / 61 Race, Caucasian/Hispanic 98 / 2 Median age (years) 51.5 Age < 65/≥ 65 81 / 19 ECOG PS, 0/1 46 / 54 Stage at Diagnosis, M1a/M1b/M1c 25 / 14 / 61 Serum LDH, Normal/Elevated 51 / 49 Number Prior Therapies, 1/2/≥ 3 51 / 27 / 22 Previous IL-2, No/Yes 61 / 39 Previous Ipilimumab or Tremelimumab (No/Yes) 95 / 5LDH = lactate dehydrogenase.Sosman et al, 2010; Ribas et al, 2011.
    • 82. Tumor Regression in Approximately 90% of Patients 7 confirmed CRsCR = confirmed response.Ribas et al, 2011.
    • 83. PFS 100 Median PFS 6.7 months (95% CI: 5.5, 7.8 months) 90 PFS at 6 months 54% (95% CI: 45, 63%) Probability of PFS (%) 80 70 60 50 40 30 20 10 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 No. At Risk Time (months) 132 129 115 93 85 73 62 45 41 33 25 18 11 6 1Ribas et al, 2011.
    • 84. OS 100 90 Probability of OS (%) 80 70 60 50 Median OS Not Reached 40 OS at 6 months 77% (95% CI: 70, 85) 12 months 58% (95% CI: 49, 67) 30 20 10 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 No. At Risk Time (months) 132 131 128 122 118 109 97 90 83 78 71 55 34 19 7 0Ribas et al, 2011.
    • 85. Most Commonly Reported Drug-Related AEs Includes AEs Reported in ≥ 20 Patients All grades Grade 3 Grade 4 n (%) n (%) n (%) Arthralgia 78 (59) 8 (6) – Rash 69 (52) 9 (7) – Photosensitivity 69 (52) 4 (3) – Reaction Fatigue 56 (42) 2 (2) – Alopecia 48 (36) – – Pruritus 38 (29) 3 (2) – Skin Papilloma 38 (29) – – cuSCC (KA)* 34 (26) 34 (26) – Nausea 30 (23) 2 (2) – Elevated Liver Enzymes 23 (17) 8 (6) 4 (3)*Cases of cuSCC/KA were managed with simple excision and did not require dose modification.AE = adverse event; cuSCC/KA = cutaneous squamous cell carcinoma/keratoacanthomas.Ribas et al, 2011.
    • 86. AEs Leading to Drug Modifications, Interruptions, and Discontinuations n (%) Total dose modifications 59 (45) Dose reductions Reduction to 720 mg bid 37 Reduction to 480 mg bid 21 Reduction to < 480 mg bid 1 Dose interruptions 85 (64) Discontinuations 4 (3) Common AEs leading to dose modifications/interruptions were rash, arthralgia, LFT abnormalities, and photosensitivityLFT = live function test.Ribas et al, 2011.
    • 87. Phase 2 Trial of GSK2118436 in Patients With BRAF Mutation-Positive (V600E/K) Metastatic Melanoma • Single arm, phase II, open label • Green-Dahlberg 2-Stage: Ho: ORR ≤ 25% vs. Ha: ORR ≥ 40% Patients Screened Metastatic melanoma n = 211 Confirmed V600E n = 76 BRAFV600E/K GSK2118436 mutation 150 mg bid Enrolled until PD, death, Absence of brain n = 92 or unacceptable metastases AE V600K n = 16 No prior treatment with MEK or BRAF inhibitors Primary objective: RR in V600E mutatedTrefzer et al, 2011.
    • 88. Study Population Population Description N All Treated Subjects All subjects that received at least 1 92 dose of GSK2118436 V600E Subjects with a V600E mutation 76 V600K Subjects with a V600K mutation 16 M-status, n (%) M1 1 (1%) M1a 16 (17%) M1b 14 (14%) M1c 58 (63%) Missing 3 (3%)Trefzer et al, 2011.
    • 89. Most Common AEs AE N = 92 n (%) Arthralgia 30 (33%) Hyperkeratosis 25 (27%) Pyrexia 22 (24%) Fatigue 20 (22%) Headache 19 (21%) Nausea 18 (20%) SCC 8 (9%)Trefzer et al, 2011.
    • 90. Best Tumor Response: V600E Population M-Stage at screening M1 M1a M1b M1c MissingTrefzer et al, 2011.
    • 91. Best Tumor Response: V600K Population M-Stage at screening M1 M1a M1b M1c Missing Scans unavailable for 1 patientTrefzer et al, 2011.
    • 92. PFS V600E Median PFS (weeks): 27.4, Progressed: 40 (53%) V600K Median PFS (weeks): 19.7, Progressed: 13 (81%) 1.0 Estimated PFS Function (%) 0.8 0.6 0.4 0.2 0.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 Time Since First Dose (Weeks)Trefzer et al, 2011.
    • 93. Phase 3 Trial Comparing Vemurafenib to DTIC in Patients With V600 Mutated BRAF Melanoma BRAFV600 mutation Vemurafenib by Cobas® 4800 test 960 mg PO bid (n = 337) Randomization N = 675 Stratification DTIC • Stage 1,000 mg/m2 IV q3wks • ECOG PS (0 vs. 1) (n = 338) • LDH elevated vs. normal • Geographic regionDTIC = dacarbazine; IV = intravenous.Chapman et al, 2011.
    • 94. Patient Demographics Dacarbazine (n = 338) Vemurafenib (n = 337) Median age (years) 52.5 56.0 Male, no. (%) 181 (54) 200 (59) ECOG PS, no. (%) 0 108 (32) 108 (32) 1 230 (68) 229 (68) Stage, no. (%) Unresectable IIIc 13 (4) 20 (6) M1a 40 (12) 34 (10) M1b 65 (19) 62 (18) M1c 220 (65) 221 (66) LDH > ULN 142 (42) 142 (42)ULN = upper limit of normal.Chapman et al, 2011.
    • 95. OS 100 84% of patients alive at 6 months 90 Vemurafenib (n = 336) 80 70 64% of patients alive at 6 months OS (%) 60 50 Dacarbazine (n = 336) 40 30 HR 0.37 20 (95% CI: 0.26–0.55) 10 Log-rank p < .0001 0 0 1 2 3 4 5 6 7 8 9 10 11 12 Time (months) No. Patients in Follow-Up Dacarbazine 336 283 192 137 98 64 39 20 9 1 1 Vemurafenib 336 320 266 210 162 111 80 35 14 6 1Chapman et al, 2011.
    • 96. Efficacy Data From Vemurafenib Phase 3, Phase 2, and Phase 1: Cross Trial Comparison Study Phase 3 Phase 2 Phase 1 6-month OS (%) 84 77 87 1-year OS (%) Not yet reached 58 > 50 2-year OS (%) Not yet reached Not yet reached 37.5 Median OS (months) Not yet reached Not yet reached 14.9 Median PFS (months) 5.3 6.7 7.8 Confirmed 48 53 56 Response (%)Chapman et al, 2011; Ribas et al, 2011; Flaherty et al, 2010; Kim et al, 2011; McArthur et al, 2011.
    • 97. A Phase II Study of the MEK1/MEK2 Inhibitor GSK1120212 in Metastatic BRAF-V600E or K Mutant Cutaneous Melanoma Patients Previously Treated With or Without a BRAF Inhibitor < 3 CR/PR  Green-Dahlberg 2-Stage Stop due to futility Prior Patients BRAFi (Cohort A) Metastatic n = 30 n = 25 Cutaneous Melanoma Enroll, then GSK1120212 dosed at 2 mg qd BRAFV600E/K/D Stable Brain n = 30 n = 25 Metastases Prior Therapy, no BRAFi (Cohort B)Kim et al, 2011.
    • 98. Patient Characteristics Cohort A Cohort B Cohort A Cohort B Characteristic N = 40 N = 57 Characteristic N = 40 N = 57 (%) (%) (%) (%) Mean age, years 55.6 54.0 LDH > ULN 55 42 Gender, Male 63 75 Stage IIIc 0 2 ECOG 0 48 74 M1a 13 12 Prior brain 13 21 M1b 15 11 metastases M1c 73 75 BRAF mutation 83 81 Prior therapies V600E 10 14 1–2 50 87 V600K 3 2 ≥3 50 13 K601E 0 2 Chemotherapy 62 86 V600K/R1 3 2 Immunotherapy3 42 54 V600K/E1 3 0 Both chemo/immuno 33 40 Unknown2 1 Same tissue with different results in different assays. 2 BRAF mutation positive; details unknown. 3 3 patients in each cohort received prior ipilimumab; all 6 also received prior chemotherapy.Kim et al, 2011.
    • 99. Most Common Treatment-Related AEs ≥ 20% Events n = 97 (%)  Only one Grade 4 G1–2 G3 Total treatment-related event Skin-related toxicity1 76 10 87 – Pulmonary embolism Rash 45 6 52 Dermatitis acneiform 25 4 30  Dose reductions due to AEs in 15% of patients Diarrhea 47 4 52 – Most frequently for rash Peripheral edema 26 3 29 and dermatitis acneiform Fatigue 23 2 26  3% of patients Pruritis 26 1 27 permanently withdrew Nausea 30 0 30 GSK1120212 due to Dry skin 22 0 22 toxicity1 Skin-related toxicity includes multiple terms.Kim et al, 2011.
    • 100. Cohort A Tumor Response (n = 40) 266% 155% Unconfirmed Response Rate (RR): 5% (95% CI, 0.6, 16.9) 1 CR, 1 PR, 10 SD * Change at Maximum Reduction From Baseline Measurement (%) K K K K * K V600K * Discontinued prior BRAFi due to toxicity * M-Stage at screening M1a M1b M1c Scans unavailable for 5 patients: 2 died and 1 withdrew before first scan, 2 had incomplete scanKim et al, 2011.
    • 101. Cohort A PFS (n = 40) Median PFS 1.8 months (95% CI, 1.8, 2.0) 1.0 0.8 PFS (%) 0.6 0.4 0.2 0.0 0 1 2 3 4 5 6 7 8 9 Time (months)Kim et al, 2011.
    • 102. Cohort B Tumor Response (n = 57) Confirmed Response Rate (RR): 25% (95% CI, 14.1, 37.8) 256% 1 CR, 13 PR, 29 SD Unconfirmed RR: 35% (95% CI, 22.9, 48.9) Change at Maximum Reduction From 2 CR, 18 PR, 23 SD Baseline Measurement (%) Median DOR: 5.7 months * (95% CI 3.7, 9.2) * K * K * * * K * K K * * K * * * K K K V600K * Prior history of brain metastases M-Stage at screening M0 M1a M1b M1c Scans unavailable for 2 patients: 1 progressed before scan, 1 had incomplete scanKim et al, 2011.
    • 103. Cohort B PFS (n = 57) Median PFS 4.0 months (95% CI, 3.6, 5.6) 1.0 0.8 0.6 PFS (%) 0.4 0.2 0.0 0 50 100 150 200 250 300 350 400 Time (Days)Kim et al, 2011.
    • 104. Ongoing Targeted Therapy Trials BRAF mutated – Dabrafenib (GSK2118436) vs. DTIC (first-line) – Trametinib (GSK1120212) vs. DTIC or paclitaxel (first or second- line) CKIT mutated – Nilotinib phase II (first-line) – Imatinib phase II (first-line) – Dasatinib phase II (first-line) – Sunitinib phase II (second-line) GNAQ/GNA11 – AZD6244 vs. temozolomide randomized phase II
    • 105. Phase II Trial of imatinib in Patients With c-kit Genetic Aberrations: Patient Characteristics Patients (N = 35) Median age 56 (27–76) Gender (M/F) 17/18 Primary site 16:10:4:2:3 (Acral: Mucosal: CSD: NSD: MM) Previous regimen (0: 1: 2: 3) 4:17:13:1 Stage (M1a: M1b: M1c) 7:2:26 KIT status (Exon 9:11:13:17:18: amplif) 2:14:8:3:5:3CSD: Melanoma on skin with chronic sun-induced damage; Non-CSD: Melanoma on skin without chronic sun-induced damage;MM: Metastatic melanoma with unknown primary.Guo et al, 2010.
    • 106. Change in Tumor Size Compared to Baseline M1a M1b M1cGuo et al, 2010.
    • 107. Correlations of Response and KIT Aberrations KIT Status PR SD PR + SD KIT Amp 1/3 0/3 1/3 Exon11 2/12 8/12 10/12 70% Exon13 3/8 1/8 4/8 Exon17 0/3 1/3 1/3 Exon18 0/4 2/4 2/4 Multiple gene aberrations* 3/4 1/4 4/4*4 patients respectively harbored multiple KIT aberrations as following: (13)K642E+Amplification; (13) I817T(T2450C);(18)F848L(T2542C); (11)L576P+Amplification.Guo et al, 2010.
    • 108. Systemic Therapies for Advanced or Metastatic Melanoma: NCCN Guidelines  Clinical trial  Ipilimumab – Approved on 3/25/11 for unresectable or metastatic melanoma  Vemurafenib (BRAFV600E) – Approved on 8/17/11 for BRAFV600E mutation-positive metastatic melanoma  HD-IL2  Paclitaxel/carboplatin/cisplatin  Dacarbazine, temozolomideNCCN, 2012b; Zelboraf® prescribing information, 2012; Yervoy® prescribing information, 2012.
    • 109. Currently Accruing Clinical Trials in MelanomaAgent Trial Name PhaseNilotinib vs. DTIC NCT01028222 2TIL + IL-2 vs. observation NCT00200577 3AZD6244 NCT00866177 2DTIC vs. paclitaxel + cisplatin vs. treosulfan + cytarabine ChemoSensMM 3Ipilimumab vs. HD IFN-2b NCT01274338 3Masitinib vs. DTIC NCT01280565 3RO5185426 NCT01307397 3Ipilimumab 3 mg/kg vs. 10 mg/kg NCT01515189 3
    • 110. Case Study 2:First-Line Treatment Options for Stage IV Metastatic Melanoma
    • 111. Case Study A 28-year-old woman is diagnosed with metastatic melanoma in the lungs, liver, and bone 3 years after undergoing wide excision of an ulcerated 1.2 mm melanoma of the left upper arm Serum LDH is 3x the upper limit of normal and a brain MRI is negative The patient is severely symptomatic due to bone pain, although imaging studies have not shown any evidence of a pathologic fracture
    • 112. ARS Question: TestingWhat testing would be appropriate at this point? 1) None required 2) BRAF V600E 3) Fluorescence In Situ Hybridization (FISH) 4) ImmunoHistoChemisty (IHC) 5) KRAS
    • 113. Biopsy Results Mutation analysis performed on a core biopsy specimen from a lung nodule – Positive for BRAF V600E mutation
    • 114. ARS Question: Treatment OptionsAt this point, the treatment option associated with the bestchance of symptomatic relief and achieving objectiveresponse is: 1) Stereotactic radiosurgery to any symptomatic bone lesions without systemic therapy 2) Single-agent dacarbazine or temozolomide 3) HD IL-2 4) Ipilimumab 5) Vemurafenib
    • 115. Key Takeaways on the Management of Stage IV Melanoma If possible, resect all disease and consider an adjuvant therapy clinical trial For unresectable disease, consider high dose IL-2 first for patients with excellent performance status, few/no comorbidities and limited tumor burden For IL-2 failures or patients who are not candidates, ipilimumab if BRAF negative or BRAF V600 mutant with limited disease burden Vemurafenib has a high response rate, improved progression-free and overall survival compared to chemotherapy – Represents a new treatment option for patients with V600 mutations GSK2118436 (BRAF) and GSK1120212 (MEK) are emerging as promising agents as well for V600 mutation positive melanoma Always consider clinical trials
    • 116. Panel Discussion: Multi-DisciplinaryPerspectives in Basal Cell Carcinoma Jean Y. Tang, MD, PhD – Dermatologist Keith T. Flaherty, MD – Medical OncologistVernon K. Sondak, MD – Surgical Oncologist
    • 117. Topics for Discussion When are surgical options no longer appropriate? WhichBCC patients are best candidates for systemic therapy? When should dermatologists refer a patient to an oncologist? How to best manage patients in an era of targeted therapy?