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Please note, these are the actual video-recorded proceedings from the live CME event and may include the use of trade names and other raw, unedited content. Oncology Grand Rounds Melanoma Nurse and Physician Investigators Discuss New Agents, Novel Therapies and Actual Cases from Practice Saturday, April 30, 2016 6:00 AM – 7:30 AM Faculty Katherine Benchich, MSN, ANP, OCN Adil Daud, MD Rene Gonzalez, MD Jason J Luke, MD Kathleen Madden, MSN, FNP, AOCNP, APHN Moderator Neil Love, MD Oncology Grand Rounds Series Oncology Grand Rounds: Themes • New agents and treatment strategies: Benefits and risks • Counseling patients about side effects – Practical implementation • End-of-life care • Psychosocial issues in patient care • Supporting the supporters • Job satisfaction and burnout in oncology professionals • The oncology professional just entering practice • The bond that heals Courtesy of Christiana Care Health System Module 1: Overview of Melanoma; Surgery and Adjuvant Therapy for Localized Disease 60-Year-Old Man with In-Transit Metastatic Melanoma (Ms Madden) • 2013: Diagnosed with melanoma on his mid back • Wide-margin surgical excision • Sentinel lymph node biopsy: Negative • 2015: Biopsy/PET-CT — melanoma on right scapula – Wide excision of in-transit metastasis and splitthickness skin graft from the right thigh • Adjuvant ipilimumab – Gastrointestinal toxicity after the third dose • A pastor with many resources, but his sister and wife need much emotional support Case discussion points (Ms Madden) • How did the patient tolerate the surgical procedures that accompanied the original melanoma diagnosis? • How does this presentation compare to how most patients present with melanoma? Risk Factors for Melanoma • Sun exposure • Pigmentary characteristics • Multiple nevi • Family and personal history of melanoma • Immunosuppression • Environmental exposures PDQ Cancer Information Summaries 2002-2016 Feb 2 Ipilimumab: Mechanism of Action T-cell activation T cell T-cell inhibition T cell T cell CTLA4 TCR CD28 MHC B7 APC T-cell potentiation CTLA4 TCR TCR CD28 MHC APC CTLA4 X CD28 B7 CD28 MHC B7 IPILIMUMAB binds CTLA-4 APC TCR = T-cell receptor; MHC = major histocompatibility complex; APC = antigen presenting cell; CTLA-4 = cytotoxic T-lymphocyte associated antigen-4 Fong et al, 2008. Courtesy, Kathy Madden, MSN, FNP, AOCNP, APHN Module 2: Intralesional Therapy for Subcutaneous Dermal and Nodal Disease — Use of Talimogene Laherparepvec (T-VEC) Discussion Topics • Clinical spectrum of subcutaneous, dermal and nodal involvement of melanoma • Mechanism of action of T-VEC, an injectable herpes simplex virus 1-based oncolytic virus • Review of efficacy and safety data with T-VEC, including the pivotal trial that led to the recent FDA approval • Local and systemic effects of T-VEC; integration into the management of malignant melanoma Discussion Topics • Patient identification and selection for therapy with T-VEC: Contraindications, precautions and recommendations pertaining to concomitant antiviral therapy • Practical considerations for storage, handling, administration and dosing of T-VEC • Active trials of T-VEC and other investigational injectable agents, such as PV-10 and SCIB1 58-Year-Old Man with BRAF V600R-Mutant Metastatic Melanoma (Ms Benchich) • 2011: Primary melanoma on the scalp – Widely excised – Sentinel lymph node biopsy: Negative • 4/2015: Multiple bilateral pulmonary metastases – Fine needle aspiration of a scalp nodule was positive for melanoma with a BRAF V600R mutation • Clinical trial: Ipilimumab and T-VEC – 1 subcutaneous nodule on the scalp was injected, with initial clinical response, before ipilimumab was administered – Grade 3 diarrhea after the first ipilimumab infusion, which was treated with prednisone and infliximab • He lives alone and owns a business Determination of T-VEC Injection Volume Based on Lesion Size Lesion size (longest dimension) Injection volume >5 cm Up to 4 mL >2.5 cm to 5 cm Up to 2 mL >1.5 cm to 2.5 cm Up to 1 mL >0.5 cm to 1.5 cm Up to 0.5 mL ≤0.5 cm Up to 0.1 mL Talimogene laherparepvec package insert T-VEC: An HSV-1-Derived Oncolytic Immunotherapy Designed to Produce Local and Systemic Effects Local Effect: Virally-Induced Tumor Cell Lysis Selective viral replication in tumor tissue Tumor cells rupture for an oncolytic effect Systemic Effect: Tumor-Specific Immune Response Systemic tumor-specific immune response Courtesy, Jason J Luke, MD Death of distant cancer cells Kaufman et al. ASCO (2014);Abstract LBA9008 Talimogene Laherparepvec: Proposed Mechanism of Action for Systemic Immunologic Effect 1 Inside a healthy cell, the virus ( ) is unable to replicate, leaving the cell unharmed. 2 Inside a cancer cell, the virus replicates and secretes GM-CSF ( ) until the cells lyses, releasing more viruses, GM-CSF and antigens ( ). 3 GM-CSF attracts dendritic cells to the site, which process and present the antigens to T cells. The T cells are now “programmed” to identify and destroy cancer cells throughout the body. T cells destroy cancer cells throughout the body, including those not directly injected with the virus. T cells Dendritic cell T cells destroy noninjected cancer cells Adapted from Kaufman H et al. Ann Surg Oncol 2010;17(3):718-30. Recommended T-VEC Dose and Schedule Treatment interval Max. injection volume/vis it — Second All subsequent treatments Treatment Initial Dose strength Prioritization of lesions for injection 4 mL 106 PFU/mL • Largest lesion(s) first • Prioritize remaining lesions by size until max. injection volume reached or all lesions treated 3 wk after initial 4 mL 108 PFU/mL • New lesions since initial treatment • Prioritize remaining lesions as above 2 wk after previous 4 mL 108 PFU/mL • New lesions since previous treatment • Prioritize remaining lesions as above Talimogene laherparepvec package insert T-VEC Injection Procedure 1. Intralesional injection using a single insertion point, along multiple tracks as far as the radial reach of the needle allows. a. Multiple insertion points may be used if a lesion is larger than the needle’s radial reach. 2. Inject evenly and completely within the lesion by pulling the needle back without exiting the lesion. a. Redirect the needle as needed while injecting the remainder of the dose. b. Continue until the full dose is evenly and completely dispersed. 3. Withdraw the needle from the lesion slowly to avoid leakage at the insertion point. Talimogene laherparepvec package insert Practical Considerations for the Preparation and Handling of T-VEC • Pregnant or immunocompromised healthcare professionals should avoid exposure • Proper thawing and storage important • Biohazard precautions for preparation, administration and handling necessary – Personal protective equipment – Avoidance of accidental exposure – Proper disposal of materials (both for healthcare providers and patients) Talimogene laherparepvec package insert Locoregional Responses to T-VEC Baseline 12 months Andtbacka RHI et al. Proc ASCO 2013;Abstract LBA9008. Locoregional Responses to T-VEC Baseline Andtbacka RHI et al. Proc ASCO 2013;Abstract LBA9008. 1 year T-VEC Injection Sites 1 month Andtbacka RHI et al. Proc ASCO 2013;Abstract LBA9008. 12 months Phase III Trial of T-VEC versus GM-CSF Overall Survival (ITT) T-VEC 189/295 (64) 23.3 GM-CSF 101/141 (72) 18.9 Overall Survival (%) Events/n (%) Median (95% CI) OS in months Stage IIB, IIC, or IVM1a Log-rank P = .051 Hazard ratio, 0.79 Andtbacka RHI et al. J Clin Oncol 2015;33(25):2780-8. Treatment-naïve T-VEC 41.1 33.1 GM-CSF 21.5 17.0 Phase III Trial of T-VEC versus GM-CSF Duration of Response CR PR Censored Durable response rate T-VEC: 16.3% GM-CSF: 2.1% 15 12 9 6 3 0 3 6 9 12 Duration of Response (months) GM-CSF Andtbacka RHI et al. J Clin Oncol 2015;33(25):2780-8. Talimogene laherparepvec 15 T-VEC Side Effects Most Common AEs • Fatigue • Chills • Pyrexia Grade 3 or 4 AEs • Only cellulitis (2.1%) No fatal treatment-related AEs Andtbacka RHI et al. J Clin Oncol 2015;33(25):2780-8. Module 3: Management of Metastatic Disease (Part 1) — Use of BRAF and MEK Inhibitors Discussion Topics • Biologic rationale and current indications for combined BRAF and MEK inhibition in metastatic melanoma • Selection of a BRAF and MEK inhibitor combination for patients with metastatic melanoma: Dabrafenib/trametinib versus vemurafenib/cobimetinib • Incidence of photosensitivity reactions and dermatotoxicities with available BRAF inhibitors and combinations • Prevalence and management of pyrexia associated with dabrafenib/trametinib • Choosing between immunotherapy and anti-BRAF therapy for patients with BRAF tumor mutations Systemic Therapy for Metastatic Melanoma Historical Standards • Dacarbazine (DTIC) • Biochemotherapy with IL-2 • High-dose bolus IL-2 • Carboplatin/paclitaxel • Temozolomide Recently Approved — Immunotherapy Recent Approved — Targeted Therapy • Ipilimumab • Dabrafenib • Pembrolizumab • Vemurafenib • Nivolumab • Trametinib • Nivolumab-ipilimumab • Dabrafenib-trametinib • Vemurafenib-cobimetinib 52-Year-Old Woman with BRAF V600E-Mutant Metastatic Melanoma (Ms Madden) • Ulcerated melanoma on the right calf – Workup: BRAF V600E mutation-positive metastatic disease in the stomach, bowel and brain • 6/2014: Dabrafenib 150 mg BID and trametinib 2 mg daily – Complete clinical response with minimal tolerability issues – Remains on treatment • Works full time as a pediatric nurse • Married with 3 young children BRAF Inhibitor Mechanism of Action Webber, 2011 Courtesy, Kathy Madden, MSN, FNP, AOCNP, APHN “Best Practices” Patient Education and AE Management • Educational sessions – Review specific mechanisms of selected treatment – Pre-treatment and at each office visit/encounter • Assess patients ability to communicate symptoms – Language barrier – Access to phone; computer • Provide a calendar or treatment schedule – Follow-up visits – Important time points • Encourage patients to keep a treatment diary • Provide prescription medications and encourage having medications on hand for anticipated AEs Ledezma, 2009, Rubin 2012. Courtesy, Kathy Madden, MSN, FNP, AOCNP, APHN “Best Practices” Patient Education and AE Management (cont.) • Thorough physical assessment and evaluation of adverse effects – Baseline and at each office visit • Educate patients to contact provider at the onset of adverse effects or changes in condition from baseline • At each office visit review the relevant potential adverse effects of therapy • Provide support for patients experiencing the unique patterns of adverse events associated with new novel therapies Ledezma, 2009, Rubin 2012. Courtesy, Kathy Madden, MSN, FNP, AOCNP, APHN Dabrafenib/Trametinib in Untreated V600E or V600K BRAF-Mutant Metastatic Melanoma Overall survival (%) Similar rates of AEs between groups • Except less hyperkeratosis, cutaneous squamous cell carcinoma, new primary melanomas and noncutaneous treatment-emergent cancers for the combination Dabrafenib and trametinib Dabrafenib and placebo OS Dabrafenibtrametinib (n = 211) Dabrafenib (n = 212) Hazard ratio P-value 25.1 mo 18.7 mo 0.71 0.01 Time (months) Long GV et al. Lancet 2015;386:444-51. Select Adverse Events Associated with the Dabrafenib-Trametinib Combination Dabrafenib/trametinib (n = 209) Dabrafenib/placebo (n = 211) Any grade Grade 3 Any grade Grade 3 Pyrexia 52% 7% 25% 2% Fatigue 27% 2% 28% <1% AST (aspartate aminotransferase) increase 11% 3% 3% <1% Peripheral edema 11% 1% 2% 0 ALT (alanine aminotransferase) increase 10% 2% 3% 0 Adverse event Long GV et al. Lancet 2015;386:444-51. Survival Distribution Function (%) coBRIM: Updated Survival Analyses of Cobimetinib with Vemurafenib in BRAF-Mutated Advanced Melanoma ITT population PFS events, n (%) Median PFS, months HR* Cobi + vem n = 247 Pbo + vem n = 248 143 (57.9) 180 (72.6) 12.25 7.20 0.58 * Stratified HR + Cobimetinib + vemurafenib (n = 247) Placebo + vemurafenib (n = 248) Censored Time The final OS analysis demonstrated that cobimentib + vemurafenib reduced the risk of death by 30% compared to vemurafenib + placebo (median OS, 22.3 mo vs 17.4 mo). Larkin JMG et al. Proc ASCO 2015;Abstract 9006; Atkinson V et al. Abstract presented at the 12th International Congress of the Society of Melanoma Research. coBRIM: Select Adverse Events Associated with Cobimetinib/Vemurafenib Vemurafenib/cobimetinib (n = 254) Adverse event Vemurafenib/placebo (n = 239) Grade 1/2 Grade 3/4 Grade 1/2 Grade 3/4 Diarrhea 50% 6% 28% 0 Rash 33% 6% 30% 5% Photosensitivity reaction 26% 2% 15% 0 Pyrexia 24% 2% 22% 0 Hyperkeratosis 10% 0 27% 2% Larkin J et al. N Engl J Med 2014;371(20):1867-76. Module 4: Management of Metastatic Disease (Part 2) — Use of Checkpoint Inhibitors Discussion Topics • Biology of the immune system; mechanisms of action of various immunotherapy agents • Efficacy and tolerability/toxicity of anti-CTLA-4 antibodies, anti-PD-1/PD-L1 antibodies and the combination in melanoma: Current approved indications • Sequencing immunotherapy and other systemic therapies for patients with metastatic disease • Role of immunotherapeutic approaches for patients with underlying autoimmune disorders (eg, Crohn’s disease, rheumatoid arthritis) 63-Year-Old Woman with BRAF Wild-Type Metastatic Melanoma (Ms Benchich) • 2011: 2-cm thick desmoplastic melanoma on the scalp – Excision and postoperative radiation therapy – Sentinel lymph node biopsy: Negative • 2013: Multiple BRAF wild-type pulmonary nodules • Ipilimumab disease progression • Pembrolizumab with a complete response – Remains on treatment • Before her diagnosis her daughter died of metastatic melanoma KEYNOTE-006: OS with Pembrolizumab versus Ipilimumab in Advanced Melanoma Pembrolizumab Q3W Overall Survival (%) Pembrolizumab Q2W Ipilimumab 1-year survival Pembrolizumab q2wk Pembrolizumab q3wk Ipilimumab 74.1% 68.4% 58.2% Months Robert C et al. N Engl J Med 2015;372:2521-32. HR = 0.63, p<0.0005 HR = 0.69, p=0.0036 KEYNOTE-002: PFS with Pembrolizumab versus Chemotherapy for Ipilimumab-Refractory Melanoma Pembro 2mg/kg (n = 180) Pembro 10mg/kg (n = 181) Chemo (n = 179) HR (PFS) 0.57, p<0.0001 0.50, p<0.0001 Reference 6-month PFS 34% 38% 16% Months Ribas A et al. Lancet Oncol 2015;16:908-18. Nivolumab # ORR=32% ICC Patients (responders) CheckMate-037: Time to and Duration of Response with Nivolumab versus Chemotherapy in Advanced Melanoma ORR=11% Time (weeks) Weber JS et al. Lancet Oncol 2015;16(4):375-84. On treatment Off treatment First response Censored Death 69-Year-Old Woman with BRAF Wild-Type Metastatic Melanoma (Ms Benchich) • 2011: Diagnosed with primary melanoma • 6/2015: Lumbar mass, diagnosed with metastatic BRAF wild-type disease • Ipilimumab/nivolumab – Rapid clinical complete response – Adrenal insufficiency and hypothyroidism – Continues to receive single-agent nivolumab CheckMate-067: Nivolumab, Ipilimumab or the Combination in Untreated, Unresectable or Metastatic Melanoma Median tumor burden change = -51.9% Nivo alone = -34.5% Ipi alone = 5.9% Nivo/Ipi (n = 314) Nivolumab (n = 316) Ipilimumab (n = 315) Best ORR (all pts) 58% 44% 19% PD-L1+ 72% 58% 21% 11.5 mo 6.9 mo 2.9 mo 14 mo 14 mo 3.9 mo Median PFS (all pts) PD-L1+ Larkin J et al. N Engl J Med 2015;373:23-34.