Community Oncology Clinical Debates: Advanced Melanoma


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Community Oncology Clinical Debates: Advanced Melanoma

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This educational activity has been designed to meet the unique learning needs of oncologists involved in the treatment of patients with advanced melanoma.

This slide deck in its original and unaltered format is for educational purposes and is current as of June 2012. All materials contained herein reflect the views of the faculty, 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.

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  • Adjuvant treatment: High dose interferon alpha 2b (Intron-A®) Pegylated interferon alpha 2b (Sylatron®) Metastatic melanoma: High dose IL-2 (Proleukin®) Ipilimumab (Yervoy®)
  • Chambers et al. Annu Rev Immunol 2001, Ribas et al. J Nucl Med 2010
  • Blank et al. Cancer Res 2004, Pardoll, Nature Rev Cancer 2012
  • Clinical activity and safety of anti-PD-1 (BMS-936558, MDX-1106) in patients with advanced melanoma (MEL). Abstract No: 8507 F. Stephen Hodi, MD   
  • Clinical activity and safety of anti-PD-1 (BMS-936558, MDX-1106) in patients with advanced melanoma (MEL). Abstract No: 8507 F. Stephen Hodi, MD   
  • Figure 1. Overall survival of patients receiving TILs with the chemotherapy preparative regimen alone (no TBI) or plus 2 or 12 Gy TBI.
  • Left figure: Constitutive mitogen-activated protein (MAP) kinase signaling in the RAS–RAF–MEK–ERK pathway drives the growth of melanoma cells through the up-regulation of cyclin D1 expression. Treatment with PLX4032 can result in the regression of melanomas harboring the BRAF V600E mutation because the drug blocks the activity of the mutant BRAF. Survival of melanoma cells and resistance to apoptosis are often mediated through the constitutive activity of phosphoinositide-3-kinase (PI3K) and the serine–threonine protein kinase AKT, which arises through multiple mechanisms, including loss of expression of the tumor suppressor phosphatase and tensin homologue (PTEN). Increased signaling through RAF1, possibly due to increased RAF1 expression or increased receptor tyrosine kinase activity, restores MEK and ERK activity and results in cyclin D1 expression. In addition, some melanomas harboring BRAF V600E mutations may al- ready have cyclin D1 amplification, whereas others may have lost PTEN expression; these melanomas may be particularly likely to manifest intrinsic resistance to BRAF-inhibitor therapy. Since resistance to BRAF inhibitors is associated with a continued reliance on the RAS– RAF–MEK–ERK pathway, MEK inhibitors will probably be useful in the management of acquired resistance to BRAF inhibitors. Right images: Multicenter, phase 1, dose-escalation trial of PLX4032 (also known as RG7204), an orally available inhibitor of mutated BRAF, followed by an extension phase involving the maximum dose that could be administered without adverse ef- fects (the recommended phase 2 dose). Patients received PLX4032 twice daily until they had disease progression. Pharmacokinetic analysis and tumor-response assess- ments were conducted in all patients. In selected patients, tumor biopsy was per- formed before and during treatment to validate BRAF inhibition. Representative Findings of the Effect of PLX4032 at the Recommended Phase 2 Dose in Study Patients with Melanoma That Carried the V600E Mutation. The recommended phase 2 dose was 960 mg twice daily. (hematoxylin and eosin) shows immunohisto- chemical analyses of the expression of phosphorylated extracellular signal-regulated kinase (ERK), cyclin D1, and Ki-67 in tumor-biopsy specimens obtained at base- line and on day 15 of treatment.
  • All metastatic melanoma patients should have BRAF testing at time of diagnosis as BRAF inhibitors have demonstrated overall survival benefit
  • Ribas A, Kim KB, Schuchter LM, et al. BRIM-2: an openlabel, multicenter phase II study of vemurafenib in previously treated patients with BRAF V600E mutation-positive metastatic melanoma. J Clin Oncol. 2011;29(suppl; abstr 8509). 2011 ASCO Annual Meeting. Abstract 8509. Presented June 4, 2011.
  • BRIM2 ASCO 2011
  • N Engl J Med. 2011 Jun 30;364(26):2507-16. 
  • The NCCN guidelines help delineate sound guidance in accordance with evidence based practice and clinical expertise a rationale approach to choices in a patients therapeutic approach. First evaluating any available clinical trial, evaluate BRAF mutational status and the pace in which the patients disease is moving. Immunotherapy is most appropriate when a patient has no immune system contraindications, is BRAF wild type, has failed a BRAF inhibitor, and has a relatively low level symptoms. The immune response with anti-CTLA4 can be delayed, and patients who are very symptomatic may require a more aggressive treatment plan up front.
  • Community Oncology Clinical Debates: Advanced Melanoma

    1. 1. DISCLAIMER This slide deck in its original and unaltered format is for educational purposes and is current as of June 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 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 InterestD A Antoni Ribas, MD, PhD Reported a financial interest/relationship or affiliation in the form of: Consultant, Amgen, Inc., Celgene Corporation, Genentech BioOncology, GlaxoSmithKline plc., Millennium Pharmaceuticals, Inc.
    4. 4. Introduction Antoni Ribas, MD, PhDUniversity of California, Los Angeles (UCLA)
    5. 5. Learning Objectives Upon completion of this activity, participants should be better able to: Assess the results of clinical studies evaluating the safety and efficacy of BRAF and CTLA4 inhibitors Identify the role of genetic testing in selecting treatment for frontline therapy Determine optimal treatment regimens for frontline therapy Discuss implications of frontline therapy selection for second- and third-line settings
    6. 6. Activity Agenda Introduction (10 mins) Clinical Debates: Interactive Thought Leader/Group Discussion (45 mins) – What is the optimal frontline treatment for patients who present with metastatic melanoma? • Should all patients get tested for BRAF mutations upfront? • How do you treat patients with BRAF mutations? • Should therapies be used in combination? • What affect does the choice of first-line treatment have on subsequent treatment? Questions and Answers (5 mins)
    7. 7. Therapeutic Targets in Melanoma Kit inhibitors cKit NRAS BRAF inhibitors BRAF MEK inhibitors MEK ERK IL-2 IFN-a Anti-CD40 Anti-CD137 Anti-OX40 Antitumor immune Oncogenic cell response proliferation Anti-CTLA4 and survival Anti-PD1MEK = MAPK/ERK kinase; CTLA4 = cytotoxic T-lymphocyte antigen-4; PD1 = programmed death-1;IL-2 = interleukin-2; IFN-a = interferon alfa-2b.Adapted from Fecher et al, 2007; Xing, 2010.
    8. 8. Relevance of Immunotherapy for the Treatment of Melanoma  FDA-approved immunotherapies for melanoma – Adjuvant treatment • High-dose IFN-a • Pegylated IFN-a – Metastatic melanoma • High-dose IL-2 • Ipilimumab  Immunotherapy has been demonstrated to reproducibly result in long-term responses (not immediate) in (few) patients with metastatic melanomaYervoyTM prescribing information, 2012; Proleukin® prescribing information, 2012; Sylatron® prescribing information, 2012;Intron-A® prescribing information, 2012; NCCN, 2012.
    9. 9. Active and Passive Immunotherapy Peptide vaccine CD40 DC vaccine Genetic vaccine CD137 IL-2 OX40 IFN IL-15 IL-21 CTLA4 PD1 Active immunotherapy Passive immunotherapy TCR or CAR T-cell cloning genetic engineeringTCR = T-cell receptor; CAR = chimeric antigen receptor.Courtesy of Antoni Ribas, MD, PhD.
    10. 10. CTLA4 Blockade T-cell T-cell T-cell activation inactivation activation CTLA-4 CTLA-4 T cell T cell T cell TCR CD28 HLA B7 APC APC APCHLA = human leukocyte antigen; APC = antigen presenting cell.Adapted from Weber, 2009.
    11. 11. Phase III Trial of Ipilimumab ± gp100 Vaccine Vs. gp100 Vaccine Alone: MDX010-20 Ipilimumab + gp100 R (n = 403) A Pretreated N Metastatic D Ipilimumab + Placebo Melanoma O (n = 137) (N = 676) M I gp100 + Placebo Z (n = 136) E  Primary end point: OS  Secondary end points: ORR, DOR, PFSOS = overall survival; ORR = overall response rater; DOR = duration of response;gp100 = glycoprotein 100; PFS = progression-free survival.Hodi et al, 2010.
    12. 12. Phase III Trial of Ipilimumab Plus Dacarbazine Vs. Dacarbazine Alone: Study 024 Ipilimumab 10 mg/kg R q3wks x 4 Ipilimumab A Dacarbazine 850 mg/m2 10 mg/kg Previously N q3wks x 8 q12wks Untreated D (n = 250) Metastatic O Melanoma M (N = 502) I Dacarbazine 850 mg/m2 Z E q3wks x 8 Placebo Placebo q12wks (n = 252)  Scheduled tumor assessments at baseline, 12 wks, and 24 wks  Primary end point: OSRobert et al, 2011.
    13. 13. Improved Survival With Ipilimumab 10 mg/kg x 4 doses q3wks, 3 mg/kg x 4 doses q3wks then q3mos + dacarbazine with or without gp100Hodi et al, 2010; Robert et al, 2011.
    14. 14. Objective Response to Ipilimumab After Significant Progression With Tumor Volume Increase Screening Week 12: Progression Week 20: Regression Week 36: Still RegressingReproduced with permission from Wolchok et al, 2008.
    15. 15. Unique Kinetics of Response in Patients Treated With Ipilimumab Week 12: Swelling Screening and Progression Week 12: Improved Week 16: Continued Week 72: Complete Week 108: Complete Improvement Remission RemissionImages courtesy of Jedd D. Wolchok, MD.
    16. 16. Mechanism of the Differential Kinetics of Tumor Response With Ipilimumab Tumor Response by Immunotherapy WHO or RECIST Progression The patterns of tumor response with ipilimumab are different from responses to cytotoxic therapies due to the immune Cancer Cell Lymphocyte mechanism of action Macrophage irRC? Tumor responses usually take time (1–4 months) to declare, and may go through a period of uncertainty about response or progressionWHO = World Health Organization.Wolchok et al, 2009; Ribas et al, 2009.
    17. 17. Ipilimumab Treatment and irAEs  Blockade of CTLA-4 can lead to the development of irAEs  Treatment results in T cells losing tolerance to self-antigens  Preclinical melanoma tumor models utilizing CTLA-4 blockade have demonstrated enhanced immune-mediated tumor rejection and irAEs such as depigmentation  Common autoimmunities in patients treated with anti–CTLA-4 – Dermatitis – Enterocolitis – Endocrinopathies  Toxicity does not always equal response, but there does appear to be an associationAttia et al, 2005; Downey et al, 2007; Lutzky et al, 2009; van Elsas et al, 1999; Weber et al, 2008.
    18. 18. Gl irAEs: Overview  Diarrhea is a frequent irAE – Most cases are mild or moderate – May be severe (> 7 stools/day and hematochezia) – Biopsy demonstrates inflammatory colitis,T cell infiltrates – Most cases respond to either symptomatic treatment or steroids, may need anti-TNF Rx – Can rarely lead to GI perforation (< 1%) requiring surgeryGI = gastrointestinal.Attia et al, 2005; Beck et al, 2006.
    19. 19. Endocrinopathies: IrAEs (Overview)  Symptoms: Fatigue, weakness, nausea, amenorrhea, impotence, hypotension, hyponatremia, hypoglycemia, eosinophilia – If strong suspicion for adrenal crisis (dehydration, hypotension) start stress dose steroids  Laboratory evaluation: ACTH, cortisol, TSH – Closely follow; if grade 2 toxicity, continue ipilimumab – Hormone replacement; consider trial of high-dose steroids prn – If suspect hypophysitis, head MRI with pituitary cuts; visual field testingBeck et al, 2006.
    20. 20. Management of irAEs  Patient education for early recognition of irAEs  Aggressive work-up and management for moderate/severe events  Non-specific complaints might reflect endocrine (eg, pituitary) toxicity  Corticosteroids might be effective  Algorithms established for the management of irAEsBeck et al, 2006; Agarwala, 2009; Weber, 2009.
    21. 21. Other Combinations With Anti-CTLA4 AntibodiesmAb = monoclonal antibody; CR = complete response; PR = partial response; OR = objective response.Maker et al, 2005; Ribas et al, 2009; Tarhini et al, 2012.
    22. 22. Immune Effects of VEGF hypoxia Immunosuppressive mechanisms COX-2 HIF-1 CXCL12 arginase PGE2 MDSC VEGF VEGF Foxp3+ T cell IL-17 + macrophage Stat3 IL-6 angiogenesis + VEGF bFGF 23VEGF = vascular endothelial growth factor.Tartour et al, 2011.
    23. 23. Immune Cell Infiltration in Tumors With Ipilimumab + BevacizumabPre-Treatment CD3 CD8 CD4 CD163Post-Treatment 24Hodi et al, 2011.
    24. 24. Differences Between Blocking CTLA4/B7 and Blocking PD-1/PD-L1 T cell MHC TCR Dendritic cell CD28 B7 CTLA4Ribas, 2012.
    25. 25. Differences Between Blocking CTLA4/B7 and Blocking PD-1/PD-L1 (cont.) T cell MHC TCR Dendritic cell B7 CD28 CTLA4Ribas, 2012.
    26. 26. Differences Between Blocking CTLA4/B7 and Blocking PD-1/PD-L1 (cont.) T cell TCR MHC Melanoma cell PD-1 PD-L1 (B7-H1)Ribas, 2012.
    27. 27. Differences Between Blocking CTLA4/B7 and Blocking PD-1/PD-L1 T cell TCR MHC Melanoma cell PD-1Ribas, 2012.
    28. 28. Induced Expression of PD-L1 (B7-H1) on Melanoma Cells by Infiltrating T Cells Induction of the B7- H1/PD-1 pathway may represent an adaptive immune resistance mechanism exerted by tumor cells in response to endogenous antitumor activity and may explain how melanomas escape immune destruction despite endogenous antitumor immune responsesTaube et al, 2012.
    29. 29. Differences Between Blocking CTLA4/B7 and Blocking PD-1/PD-L1Ribas, 2012.
    30. 30. Clinical Activity and Safety of Anti-PD-1 (BMS-936558, MDX-1106) in Patients With Advanced Melanoma  Grade 3/4 drug-related AEs – 20% of patients – Most common lymphopenia, fatigue, diarrhea, abdominal pain, and lipase  Among 94 evaluable patients – 20%–40% objective responses – Approximately 2/3 being durable responses (> 1 year)  The durable responses compares favorably to prior melanoma immunotherapies with HD IL-2, anti-CTLA4, dendritic cell vaccines, etc.Hodi et al, 2012; Ribas, 2012.
    31. 31. Changes in Target Lesions Over Time in Melanoma Patients 1 mg/kg 10 mg/kg  Of 26 patients with OR – 18 were treated ≥ 1 year (before 2/24/12) and 13 had responses of ≥ 1 year – 8 were treated < 1 year and 6 had responses ranging from 1.9–5.6 monthsHodi et al, 2012.
    32. 32. Summary of ACT Therapies for Melanoma  ACT of TIL results in Survival of Patients With reproducible and durable Metastatic Melanoma Treated clinical responses in ~ 20% of With Autologous TILs and IL-2 patients refractory to other therapies  ACT of cloned peripheral blood T cells can result in responses in patients  ACT of TCR engineered lymphocytes can result in responses in patients Survival Time (months)ACT = adoptive cell therapy; TILs = tumor infiltrating lymphocytes.Rosenberg et al, 2011; Hunder et al, 2008; Morgan et al, 2006; Johnson et al, 2009.
    33. 33. Melanoma Molecular Profiling: Driver Oncogenic Mutations Define Clinically Relevant Melanoma Molecular Subsets Usually mutually exclusive Noted in ~70% of melanomas < 5% melanomas (mucosal, acral) Kit inhibitors: imatinib, nilotinib, dasatinib cKit 20% melanomas (> age) NRAS 50% melanomas (< age) BRAF BRAF inhibitors: vemurafenib, dabrafenib MEK MEK inhibitors ERK Oncogenic cell proliferation and survivalAdapted from Fecher et al, 2007; Xing, 2010; Curtin et al, 2005, 2006; Van Raamsdonk et al, 2010.
    34. 34. Key Takeaways: FDA Approvals for the Treatment of Metastatic Melanoma  2 therapies approved based on OS improvement in randomized trials – Ipilimumab (2011) – Vemurafenib (2011)  2 therapies approved based on RR in single arm trials – Dacarbazine (1975) – IL-2 (1998)RR = response rate.YervoyTM prescribing information, 2012; Zelboraf® prescribing information, 2012; NCCN, 2012; Bhatia et al, 2009.
    35. 35. Clinical Debates: Interactive ThoughtLeader/Group Discussion
    36. 36. Clinical Debates:What Is the Optimal FrontlineTreatment for Patients Who Present With Metastatic Melanoma?
    37. 37. Treatment of Advanced Melanoma in 2012 V600 V600 BRAF + BRAF Negative SOC Experimental SOC Experimental Vemurafenib GSK BRAFi+MEKi Ipilimumab Anti-PD1 Ipilimumab Anti-PD1 HD IL-2 TIL ACT HD IL-2 TIL ACT Open Questions Special Considerations - Immunotherapy vs. BRAFi first-line? - Uncommon BRAF mutations - Immunotherapy + BRAFi? - NRAS mutants with MAPK dependency - Treatment of BRAFi resistance? - Prevention of BRAFi resistance? - Role of MTKis? - Role of chemotherapy?GSK = GlaxoSmithKline; BRAFi = BRAF inhibitor; MEKi = MEK inhibitor; SOC = standard of care.NCCN, 2012; US NIH, 2012a–g.
    38. 38. Different Clinical Benefits of Immunotherapy and Targeted Therapy for Metastatic Melanoma Immunotherapy Targeted Therapy Percent Alive Percent Alive 0 1 2 3 0 1 2 3 Time (yrs) Time (yrs)Chapman et al, 2011; Hodi et al, 2010.Adapted from Ribas et al, 2012.
    39. 39. ORR by Pre-Defined Subgroups in BRIM2 80 70 60ORR (%) 50 40 30 20 Overall ORR of 53% (IRC) 10 RR (size proportional to the number of patients in the subgroup) 95% CI 0 All < 65 ≥ 65 F M 0 1 M1a/ M1c 1 >1 Yes No Normal 1.0–1.5x >1.5x treated M1b ULN ULN Age Sex ECOG PS # prior Previous IL-2 patients Stage therapies LDH at enrollment Baseline characteristicsECOG PS = Eastern Cooperative Oncology Group performance status; LDH = lactate dehydrogenase;ORR = overall response rate; CI = confidence interval; ULN = upper limit of normal.Ribas et al, 2011.
    40. 40. Subgroup Analyses for OS With Vemurafenib (BRIM3)Chapman et al, 2011.
    41. 41. Subgroup Analyses for OS With IpilimumabHodi et al, 2010.
    42. 42. Subgroup Analyses for OS With IpilimumabRobert et al, 2011.
    43. 43. Clinical Debates:Should All Patients Get Tested for BRAF Mutations Upfront? How Do You Treat Patients With BRAF Mutations?
    44. 44. BRAF Inhibitors, Targeted Therapy to Block the Driver Oncogenic Signaling BRAF MEK ERK Cancer growth andAdapted from Fecher et al, 2007; Xing, 2010; Weber, 2011. survival
    45. 45. Inhibition of MAPK Signaling in Biopsies of BRAFV600 Melanoma From Patients Treated With Vemurafenib GF Baseline Day 15 RTK V600 BRAF Y-P Y-P pERK Ras GTP PLX4032 MEK P ERK P cyclin D Cyclin D Cell cycle (Ki67) Ki67MAPK = mitogen-activated protein kinase;pERK = phosphorylated extracellurar signal-regulated kinase.Adapted from Smalley et al, 2010; Flaherty et al, 2010b.
    46. 46. Flaherty et al, 2010; Chapman et al, 2011; Sosman et al, 2012.
    47. 47. Comparison of Maximum Response With Vemurafenib and Dabrafenib > 100 BRIM3 Vemurafenib Chapman et al, 2011 5 0 0 -5 0 -10 0 BREAK3 Dabrafenib Hauschild et al, 2012Chapman et al, 2011; Hauschild et al, 2012.
    48. 48. Early Analysis of the Phase III Trial Comparing Vemurafenib and Dacarbazine OS: HR = 0.37 Screening Vemurafenib 960 mg po bid PFS: HR = 0.26 BRAFV600E mutation (n = 337) Stratification: Randomization • Stage N = 675 • ECOG PS (0 vs. 1) Dacarbazine • LDH (elevated vs. normal) 1,000 mg/m2 iv q3w • Geographic region (n = 338)Chapman et al, 2011.
    49. 49. Improved Survival With VemurafenibChapman et al, 2011.
    50. 50. Update of the Overall Survival in BRIM3 (not censored at crossover) 100 Vemurafenib (n = 337) 90 Median F/U 12.5 months Overall Survival (%) 80 HR 0.76 70 (95% CI: 0.63–0.93) 60 p < .01 (post-hoc) 50 Dacarbazine (n = 338) 40 Median F/U 9.5 months 30 20 10 10.3 13.6 0 0 6 12 18 24 Time (months) No. at risk Dacarbazine 338 255 211 173 136 81 34 6 0 Vemurafenib 337 326 280 231 178 109 44 7 1Chapman et al, 2012.
    51. 51. BREAK-3: Comparison of PFS With Dabrafenib and Dacarbazine Screened Dabrafenib N = 733 150 mg bid n = 187 3:1 randomization Cross over allowed at Dabrafenib Enrolled DTIC radiological PD 150 mg bid n = 250 1,000 mg/m2 IV n = 28 q3w Proportion Alive Without Progression (%) (68% of PD n = 63 patients) 1.0 0.9 0.8 0.7 PFS HR 0.30 0.6 Dabrafenib median PFS 5.1 months 0.5 0.4 DTIC: 0.3 median PFS 2.7 months 0.2 0.1 0.0 0 1 2 3 4 5 6 7 8 9 Time from Randomization (Months) At risk 187 184 173 113 100 41 31 5 3 0 63 53 31 14 11 6 4 2 0 0Hauschild et al, 2012.
    52. 52. Two-Cohort Open-Label Study of Dabrafenib in Patients With Brain Metastases Screened (N = 325) Enrolled (n = 172) Cohort A (n = 89) (no prior brain treatment) Metastatic melanoma Dabrafenib Centrally confirmed BRAF V600E/K mutation 150 mg bid Asymptomatic brain metastases Cohort B (n = 83) No prior treatment with MEK or BRAF (prior brain treatment) inhibitors No prior brain treatment: Cohort A Prior brain treatment: Cohort B OIRR: 39% OIRR: 31% ORR: 38% ORR: 31% Maximum percent change frombaseline intracranial measurement Maximum percent change from baseline intracranial measurement Intracranial DCR: 81% Intracranial DCR: 89% Overall DCR: 80% Overall DCR: 83% Kirkwood et al, 2012.
    53. 53. Examples of Brain Metastases Responses to Dabrafenib Baseline Week 8 Baseline Week 32Kirkwood et al, 2012.
    54. 54. BRIM2: Toxicities With Vemurafenib Includes AEs reported in ≥ 20 patients All grades Grade 3 Grade 4 n (%) n (%) n (%) Overall 130 (99) 79 (60) 5 (4)† Arthralgia 78 (59) 8 (6) – Rash 69 (52) 9 (7) – Photosensitivity reaction 69 (52) 4 (3) – 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)¶†One patient with 2 grade 4 AEs.‡Cases of cuSCC/KA were managed with simple excision and did not require dose modification.§Managed with dose reduction; one removed from study.¶Led to discontinuation of therapy.cuSCC = cutaneous squamous cell carcinoma; KA = keratoacanthomas; AEs = adverse events.Ribas et al, 2011.
    55. 55. cuSCC/KAs With Vemurafenib Median 0 5 10 15 20 25 30 35 40 Time on Vemurafenib (wks)  cuSCCs – Incidence: 26% – Median time: 8 wks (2–36) – Median number of cuSCC/KAs per patient: 1 (range 1–7) – Each dot represents wks to development of first cuSCC/KA lesionRibas et al, 2011.
    56. 56. Acquired Resistance to Vemurafenib: Time to Response and Progression Time on study Time to response Progressive disease Continued response 0 2 4 6 8 10 12 14 16 Approx timing Time (mos) of CT assessments Median DOR = 6.7 mos (95% CI 5.6, 9.8; range 1.3–12.7)CT = computed tomography.Ribas et al, 2011.
    57. 57. Phase III Trial Comparing Trametinib (MEK inhibitor) and Dacarbazine in Metastatic Melanoma METRIC PFS – Primary Efficacy Population 1.0 Events Median HR (95%CI) n (%) (months) p Value Screened 0.9 (N = 1,059) Trametinib 96 (54) 4.8 0.44 (0.31, 0.64) Proportion Alive and Progression-Free 0.8 < .0001 Chemotherapy 68 (72) 1.4 V600E/K 0.7 mutation (n = 322) 0.6 Trametinib 0.5 Chemotherapy 2 mg QD (n = 108) 0.4 (n = 214) 0.3 PFS Cross-over* INV – Trametinib 0.2 IRC – Trametinib Trametinib FSFV: Dec 0.1 INV – Chemotherapy 2 mg QD 2010, LSFV: 0.0 IRC – Chemotherapy July 2011 0 1 2 3 4 5 6 7 8 9 Time From Randomization (Months) Number at risk INV – INV – Trametinib 178 170 130 79 69 22 18 4 0 0 Chemotherapy 95 77 38 20 17 8 5 1 0 0 Conclusion: Trametinib is the first MEKi to show statistically significant PFS, RR, and OS benefit in a randomized trial compared to chemotherapyRobert et al, 2012; Flaherty et al, 2012.
    58. 58. Clinical Debates:Should Therapies Be Used in Combination?
    59. 59. Mechanisms of Resistance to BRAF Inhibitors PDGFRb or IGF1R NRASQ61 BRAF inh PI3K CRAF PI3Ki or AKTi COT BRAFV600E AKT MEK-independent MEK progression PMEKi MEK-dependent progression ERK P SurvivalAdapted from Poulikakos et al, 2011; Shi et al, 2012; Nazarian et al, 2010;Villanueva et al, 2010; Johannessen et al, 2010; Wagle et al, 2011.
    60. 60. Treating Resistance to BRAFi Occasional prolonged BRAFi Local Tx + BRAFi responses (Kim et al, 2011) BRAFi MEKi No activity (Kim et al, 2011) BRAFi BRAFi ORR 19% MEKi (Flaherty et al, 2011) BRAFi ORR 50%–74%, increased PFS? (Infante et al, 2011) MEKi Progression of melanomaBRAFi = vemurafenib, dabrafenib (GSK2118436); MEKi = trametinib (GSK1120212).
    61. 61. Dabrafenib + Trametinib Study Design and Objectives Objective/s • Trametinib effects on Part A Drug–drug interaction dabrafenib PK Dose escalation N = 77 BRAFi-naïve • Safety/tolerability melanoma • Determine phase II dose patients • Steady-state PK Part B across 4 • Clinical activity Expansion cohorts dose levels • Clinical activity Colorectal BRAF+ Prior BRAF inhibitor • Clinical activity (RR, PFS) of combo vs. dabrafenib vs dabrafenib • Assess safety/tolerability Part C Randomized Phase II trial phase • Safety/tolerability • Characterize PK of dabrafenib Bridging Study study Part D dabrafenib (HPMC) + HPMC capsules trametinibWeber et al, 2012.PFS = progression-free survival; PK = pharmacokinetics; HPMC = hydroxypropyl methylcellulose.
    62. 62. Investigator-Assessed Maximum Tumor Reduction Part B BRAFi-Naïve Melanoma Patients (N = 77) RR 44%–67% Median DOR 11.3 months (95% CI: 9.2, NR) Dose level: dabrafenib/trametinib (mg bid/mg QD) Median PFS 7.4 months, PFS at the highest dose 10.8 months 75/1 150/1 150/1.5 150/2 KK K K K KK = BRAFV600K mutation-positive patients.Weber et al, 2012.
    63. 63. Best Confirmed Response Rate Part B BRAFi-Naïve Melanoma Patients (N = 77) Median DOR 11.3 months (95% CI: 9.2, NR) CR+PR CR+PR+SD Response Rate (%) 67% 64% 63% 57% 44% 18% CR 8% CR 8% CR 75/1 150/1 150/1.5 150/2 All doses (n = 6) (n = 22) (n = 25) (n = 24) (n = 77) Dose-Level of Dabrafenib/TrametinibWeber et al, 2012.
    64. 64. Treatment Duration Part B BRAFi-Naïve Melanoma Patients (N = 77) Median Duration of Treatment = 10.7 months 38% of patients are ongoing Ongoing Discontinued/progressed Treatment Duration (months)Weber et al, 2012.
    65. 65. Combining Immunotherapy and Targeted Therapy for Melanoma? Immunotherapy Targeted Therapy Combination? Percent Alive Percent Alive Percent Alive 0 1 2 3 0 1 2 3 0 1 2 3 Time (yrs) Time (yrs) Time (yrs)Chapman et al, 2011; Hodi et al, 2010.Adapted from Ribas et al, 2012.
    66. 66. Can BRAF Inhibitors Be Combined With Tumor Immunotherapy? Author Title Journal Comin-Anduix et al, 2010 The Oncogenic BRAF Kinase Inhibitor Clinical PLX4032/RG7204 Does Not Affect Cancer the Viability or Function of Human Research Lymphocytes across a Wide Range of Concentrations Boni et al, 2010 Selective BRAFV600E Inhibition Enhances Cancer T-Cell Recognition of Melanoma Without Research Affecting Lymphocyte Function Wilmott et al, 2012 Selective BRAF Inhibitors Induce Marked Clinical T-cell Infiltration Into Human Metastatic Cancer Melanoma ResearchComin-Anduix et al, 2010; Boni et al, 2010; Wilmott et al, 2011.
    67. 67. Clinical Debates:What Effect Does the Choiceof First-Line Treatment Have on Subsequent Treatment?
    68. 68. Systemic Therapies for Advanced or Metastatic Melanoma  Clinical trial  Ipilimumab, HD IL-2, vemurafenib (BRAFV600E)  Paclitaxel, carboplatin, cisplatin  Dacarbazine, temozolomide Patients who progress after initial therapy may be offered subsequent therapy if they maintain ECOG PS 0–2 or Karnofsky score ≥ 60NCCN, 2012.
    69. 69. Guidance in Therapy Decisions  Recommendation for first-line systemic therapy of melanoma based on: – BRAF mutation status – Tempo of disease – Presence or absence of cancer-related symptoms  Patients with low-volume, asymptomatic metastatic melanoma may be good candidates for immunotherapy (ipilimumab or IL-2; unless contraindicated) – May be time for an antitumor immune response  Patients with BRAF-mutant melanoma who have symptomatic disease or who have progressed despite immunotherapy should be considered for vemurafenib  Clinical trials underway to address unanswered questions regarding optimal sequencing and/or combination  Patients who are intolerant to, or relapsing after first-line systemic therapy, additional systemic therapy may be indicated if the patient has ECOG PS 0–2 or Karnofsky score ≥ 60  Options for second-line therapy include clinical trial (preferred) or treatment with a different agent from the list of first-line optionsNCCN, 2012.
    70. 70. Case Study 1 65-yr-old woman with BRAFV600 positive metastatic melanoma Progression on prior experimental therapy with a dendritic cell vaccine M1a – Metastases to lymph nodes to the axilla and subpectoral area – LDH within normal limits
    71. 71. Case Study 1 (cont.) Should this patient receive: – Ipilimumab 3 mg/kg x 4 doses – Vemurafenib 960 mg po BID – Clinical trial – Surgery
    72. 72. Case Study 1 (cont.) Thepatient received vemurafenib 960 mg po BID within the PLX4032 phase I trial (BRIM1) and continues with a sustained tumor response over 2 yrs later
    73. 73. Case Study 2 64-yr-old with a BRAFV600 negative metastatic melanoma Progression on prior therapy with: – Dacarbazine – nab-Paclitaxel – Intra-lesional IL-2 injections M1c – Metastases to liver, spleen, and lymph nodes – LDH ~ 2x ULN
    74. 74. Case Study 2 (cont.) Should this patient receive: – Ipilimumab 3 mg/kg x 4 doses – Ipilimumab 10 mg/kg in combination with dacarbazine – Clinical trial – Hospice care
    75. 75. Metastatic Melanoma Response to Ipilimumab Before Ipilimumab After Ipilimumab 04/22/11 08/05/11Case by Antoni Ribas, MD, PhD.
    76. 76. Key Takeaways Patients with metastatic melanoma should have molecular testing, at least for the BRAFV600 mutation – Vemurafenib is a selective BRAFV600E kinase inhibitor Immunotherapy has demonstrated long-term responses in patients with metastatic melanoma Ipilimumab and vemurafenib have demonstrated improvements in OS for the treatment of metastatic melanoma The choice of frontline or follow-up therapy in patients with BRAFV600 mutant melanoma includes – Vemurafenib – Ipilimumab – High-dose IL-2 – Dacarbazine – Clinical trials: BRAF+MEK inhibitors, anti-PD1