DISCLAIMER This slide deck in its original and unaltered format is for educational purposes and is     current as of May 2...
DISCLAIMER Participants have an implied responsibility to use the newly acquired information      to enhance patient outco...
Disclosure of Conflicts of Interest   Peg Esper, MSN, MSA, RN, APRN-BC, AOCN®, reported a    financial interest/relations...
Learning Objectives              L           Upon completion of this activity, participants                   should be be...
Activity OverviewPeg Esper, MSN, MSA, RN, ANP-BC, AOCN®  University of Michigan Comprehensive              Cancer Center
Introduction to Faculty Panel   Peg Esper, MSN, MSA, RN, ANP-BC, AOCN® (Chairperson)    – Nurse Practitioner, Medical Onc...
Activity Agenda6:30 – 6:35 AM     Welcome and Activity Overview6:35 – 6:50 AM     Clinical Update: What’s New in Melanoma ...
Treatment Update inAdvanced Melanoma  Evan M. Hersh, MD Arizona Cancer Center  University of Arizona
2012 Overview of Melanoma            Fastest rising incidence of any cancer over the             last 3 decades          ...
Melanoma: Incidence, Mortality,                   and Survival by Stage                         Incidence                 ...
Systemic Therapy for Metastatic                Melanoma: Prior History            Surgery (metastasectomy)            Da...
Ipilimumab Is a Member of a Novel Class         of Immunotherapeutic Antibodies        1) Co-stimulation via CD28         ...
Ipilimumab Registration Trials            Second-line MDX010-20 trial HLA-A2 positive (N = 650)                – 3 arms 3...
MDX010-20: Study Design                           Ipilimumab + gp100    (n = 403)                      R                  ...
Kaplan-Meier Analysis of Survival                                          Ipilimumab + gp100 (A)                         ...
Ipilimumab Plus DTIC Vs. DTIC Alone                     (Study 024): Design                Screening                      ...
Ipilimumab Plus DTIC Vs. DTIC: OSCI = confidence interval.Wolchok et al, 2011.
Study 024: Select AEs       Select AEs are shown, regardless of attributionGI = gastrointestinal; AEs = adverse events.Wo...
Study 024: Select AEs (cont.)     Select AEs are shown, regardless of attribution1 (0.4%) hypophysitis in a patient on ma...
Ipilimumab Patterns of Response                  Baseline (Day 0)                        Week 12 (Day 84)                 ...
Targeted MAPK Pathway: BRAF          cKIT mutations: 3% of all           melanomas – almost exclusively           acral l...
Phase III First-Line BRIM3                             Study Design                                                       ...
Best Tumor Response by Individual Patient                        Vemurafenib: 48.4% response                       Dacarba...
Progression-Free Survival                                  (12/30/10 cutoff)                        100                   ...
PET Scans at Baseline                 and Day 15 After Vemurafenib                                #69 MDACC               ...
Survival in BRAF V600-Mutant Advanced          Melanoma Treated With Vemurafenib            Phase II study in 132 previou...
Phase III of HD IL-2 +/- Vaccine      Study population (eligible for HD IL-2)            – Stage IV or unresectable stage...
Phase III of HD IL-2 +/- Vaccine (cont.)       Outcome                               IL-2, No. (%)   IL-2 + Vaccine, No. (...
nab-Paclitaxel Plus Bevacizumab                   in Melanoma  Patient Characteristics                                    ...
nab-Paclitaxel Plus Bevacizumab                          in Melanoma (cont.)                                    RR (RECIST...
New Treatment Algorithm for                         Stage IV Melanoma         Clinical trial         Treatment naïve    ...
Evolution of Response Criteria:                      mWHO to irRCWHO = World Health Organization; irRC = immune-related re...
Monitoring Disease Response in              Patients Receiving Ipilimumab           Analysis of 5 clinical trials (N = 26...
Key Takeaways:Treatment of Advanced Melanoma   Melanoma is increasing dramatically in incidence   2 new therapies have b...
The Workshop: Nursing    Management Strategies forPatients With Advanced Melanoma   Peg Esper, MSN, MSA, RN, ANP-BC, AOCN®...
Nursing Management:                        Ipilimumab Administration            Ipilimumab (FDA approved 3/25/11)        ...
Nursing Management:                     Vemurafenib Administration       Vemurafenib (240 mg tablets; approved 8/17/11)  ...
Additional Regimens        HD IL-2           – 600,000 IU/kg administered as IV bolus over 15 mins q8hrs up             t...
IL-2 Toxicities         Significant immune-mediated toxicity profile         Dose related and schedule dependent        ...
IL-2 Side-Effect Monitoring and TreatmentTLC = triple lumen catheter; PRN = as needed; NSAIDs = non-steroidal anti-inflamm...
Ipilimumab: The “ITIS Syndromes”      The most frequent target organ effects of ipilimumab include            –    Skin (...
Ipilimumab Boxed Warning            Severe and fatal immune-mediated adverse reactions due to T-cell             activati...
New Agent Side-Effect Profile:                          Vemurafenib           Arthralgia           Rash           Nause...
Managing Toxicities of Treatment                                                     GRADE OF TOXICITY        GRADE 1     ...
Managing New Agent Toxicities         Dermatologic            – Rash            – Vitiligo            – Pruritis         ...
Rash                                       •   Use of emollient       IPILIMUMAB                          creams          ...
NCI-CTCAE v4.03: Grading of Rash        Grading is based on percent of BSA covered by macules/papules       Definition: A...
HFSR (Palmar-Plantar Dysesthesia): Vemurafenib      Thickened skin with patchy       hyperkeratodermia seen       primari...
GI Adverse Effects (AEs)       Diarrhea – Primarily ipilimumab, but may be seen with vemurafenib       Can rapidly progr...
Progression to Colitis: Ipilimumab        7+ stools/day over baseline, fever, ileus, peritoneal signs        Dehydration...
More Immune-RelatedAdverse Events (IRAEs)       Ipilimumab
Autoimmune Hepatitis            Transaminitis reported in up to 20% of patients treated with             anti-CTLA-4 anti...
Endocrinopathies          Seen in 15% of phase III study participants          Hypothyroidism             – Elevated TSH...
Hypophysitis          Inflammation of the pituitary gland          Symptoms include: Fatigue, headache, loss of libido, ...
Hypophysitis (cont.)          Management includes             – Replacement of deficient               hormones          ...
Additional AEs             Ocular (seen with both ipilimumab and vemurafenib)                – Uveitis (decreased visual ...
Labs and Evaluations           IPILIMUMAB                                                                      VEMURAFENIB...
Drug-Drug Interactions          Ipilimumab             – No known drug-drug interactions          Vemurafenib           ...
When to Discontinue Ipilimumab    Permanently discontinue ipilimumab for any of the following:    Persistentmoderate adve...
Dose Modification Information:                       Vemurafenib        Grade (CTC-AE)*                                Rec...
Patient Education: General   Assess for both patient and family (or significant other)     – Knowledge of therapy and dis...
Patient Education: Challenges        Ipilimumab           – Effect of treatment is on the immune system, not directly    ...
Patient Education: Challenges (cont.)   Vemurafenib    – What is BRAF?    – Do I have genetic mutations?    – Yes, it is ...
Putting the Workshop Into  Practice: RoundtableDiscussions on Metastatic Melanoma Case StudiesKrista M. Rubin, MS, RN, FNP...
Putting the Workshop Into                 Practice Please   assign a moderator for your table You   have 10 minutes to d...
Case Study 1
Case Study 1: History            30-yr-old man with a history of a 2.3 mm, non-ulcerated             nodular, melanoma of...
Case Study 1: History (cont.)             Repeat imaging 1 wk later revealed an increase in size              of known tu...
Case Study 1: Questions What treatment options would be discussed with this patient? What   would be recommended and why?
Case Study 1: Treatment Options        Clinical trials               − None available for first-line therapy at the time ...
Case Study 1: Treatment Options (cont.)         Given rapid progression of disease, obtaining tissue for BRAF          an...
Case Study 1: Monitoring and Response          Tolerated first infusion well: No issues          F/U labs notable for in...
Case Study 1: Monitoring and                     Response (cont.)           Fourth infusion              – Labs all norma...
Case Study 2
Case Study 2: History            PL is a 50-yr-old man            PMH: HTN, anxiety            SH: Married, 2 adult chi...
Case Study 2 (cont.)        Presents to local dermatologist with a bleeding and         changing mole. Biopsy demonstrate...
Case Study 2: Questions What treatment options would be discussed with this patient? What   would be recommended and why?
Case Study 2: Treatment Options       Treatment           options for stage IIA melanoma               – Observation     ...
Case Study 2: Treatment Course         Patient chose participation in E1697: An          intergroup trial of 1 month of I...
Case Study 2: Monitoring            2 yrs later, patient noted a non-tender lump in (L) axilla               – Upon exami...
Case Study 3
Case Study 3: History   30-yr-old man with a history of a 2.3 mm, non-ulcerated nodular,    melanoma of (R) forearm [T3aN...
Case Study 3: Monitoring and               Response   Tolerated first infusion well (no issues)   F/U labs notable for i...
Case Study 3 (cont.)   Tolerated 4 doses (induction) ipilimumab no issues   Repeat scans 6 wks later showed further resp...
Case Study 3: Clinical Question What   treatment options are recommended?  – Recall     • Patient is BRAF WT     • Now ha...
Case Study 3: Treatment Course          CNS: Decision made to proceed with stereotactic           radiosurgery (SRS)     ...
Case Study 3: Treatment Course                           (cont.)          1 wk after SRS, he received his first dose of r...
Case Study 3: Clinical Question        What are the treatment recommendations for         this patient at your facility? ...
Case Study 4
Case Study 4: History   PL is a 50-yr-old man   PMH: HTN, anxiety   SH: Married, supportive wife, 2 children, respirato...
Case Study 4: Follow-Up         2 yrs later, patient noted a nontender lump in (L) axilla.          Exam: 2-cm rubbery mo...
Case Study 4: Follow-Up (cont.)             1 month after XRT completed, patient called to report low back pain “pulled  ...
Case Study 4: Clinical Question   What would be the next step at your institution?   What other services may be offered?
Case Study 4: Treatment Options        CNS options: WB-XRT vs. SRS        Systemic options: Chemotherapy, immunoRx, BSC ...
Case Study 4 (cont.) Patient  received his first dose of ipilimumab  at the time of this writing Remains    on 4 mg po d...
Metastatic Melanoma: An Oncology Nurse Workshop on Novel Treatments, Adverse Event Management, and Patient Education
Metastatic Melanoma: An Oncology Nurse Workshop on Novel Treatments, Adverse Event Management, and Patient Education
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Metastatic Melanoma: An Oncology Nurse Workshop on Novel Treatments, Adverse Event Management, and Patient Education

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In 2011, the treatment armamentarium dramatically expanded with the approval of the anti-CTLA4 antibody ipilimumab and the BRAF inhibitor vemurafenib. Oncology nurses who care for patients with melanoma are beginning to administer these new agents and have numerous questions regarding their efficacy, different response patterns, unique toxicity profiles, how they may be integrated into current treatment regimens, and how to educate patients on their benefits and risks.

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Review a downloadable slide deck by Peg Esper, MSN, MSA, RN, APN-BC, AOCN®, covering the most clinically relevant new data reported from Metastatic Melanoma: An Oncology Nurse Workshop on Novel Treatments, Adverse Event Management, and Patient Education.

Target Audience
This activity has been designed to meet the educational needs of oncology nurses involved in the treatment of patients with advanced melanoma.

Slide Deck Disclaimer
This slide deck in its original and unaltered format is for educational purposes and is current as of May 2012. All materials contained herein reflect the views of the faculty, and not those of IMER, the CE 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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  • Figure adapted from Fong et al, 2008
  • A phase III, randomized, double-blind, multicenter study comparing monotherapy with ipilimumab or gp100 peptide vaccine and the combination in patients with previously treated, unresectable stage III or IV melanoma - Study MDX010-20
  • Graph adapted from Hodi et al, 2010.
  • Maint was offered but protocol doesn ’t test necessity Phase 3 randomized study of ipilimumab (IPI) plus dacarbazine (DTIC) vs DTIC alone as first line treatment in patients with unresectable stage III or IV melanoma - Jedd Wolchok 1 , Luc Thomas 2 , Igor Bondarenko 3 , Steven O ’Day 4 , Jeffrey Weber 5 , Claus Garbe 6 , Stephen Francis 7 , Ramy Ibrahim 8 , Axel Hoos 8 , Caroline Robert 9
  • Graph adapted from Wolchok et al, 2011.
  • Presented with permission, Copyright 2011 by C. Lovly, L. Horn, and W. Pao. Lovly, C., L. Horn, and W. Pao. 2012. BRAF. My Cancer Genome http://www.mycancergenome.org/mutation.php?dz=gist&gene=BRAF&code=BRAF-WT (Accessed April 5). Image taken form website: http://www.mycancergenome.org/mutation.php?dz=gist&gene=BRAF&code=BRAF-WT
  • Graphs need permission from Chapman et al, 2011
  • Graph adapted from Chapman et al, 2011
  • Clinical Trial is always a first therapeutic consideration in treatment options for patients , this slide presents a step wise presentation of choices and potential and sound order for selection of potential treatments for patients who are treatment naïve, who are previously treated, pts who have rapidly progressive disease, and potential multi line therapies. Patients who have a lower volume of tumor burden are better candidates for immunotherapy, for they have the time for the immune system to create an immune response. Conversely, those patients with rapidly progressive disease, should be considered for clinical trial, use of targeted agents such as a braf inhibitor (if V600 mutated) or possibly a chemotherapeutic approach in an attempt to control the progression of disease.
  • Monitoring for disease response in patients on CTLA-4 antibodies is a challenge in that responses may be delayed. Trials demonstrate a therapeutic peak response between 12-24 weeks, and yet some patients have experienced disease progression before regression and others, a delayed response. While no set guideline for monitoring exists, practice should be based on objective response data indicated in the slide and subjective response of the patient. Monitoring should continue beyond disease monitoring criteria. In the NEJM study by Hodi et al. (2010), disease was monitored as follows: at baseline, and all patients who did not have documented early disease progression and who had stable disease or better at week 12 had confirmatory scans at weeks 16 and 24 and every 3 months thereafter.
  • Eggermont AMM. (2010). Advances in systemic treatment of melanoma. Annals of Oncology, 21(7), 339-344. Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbé C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010 Aug 19;363(8):711-23.
  • Zelboraf, PI, 2012.
  • Mier, 2011
  • Boyle, GM. (2011). Therapy for metastatic melanoma: an overview and update. Expert Rev. Anticancer Ther. 11(5), 725-737. Esper, P. Immune Modulation in Melanoma and Advanced Cancer Therapy: Anti-Cytotoxic T Lymphocyte-Associated Antigen 4 (CTLA4) Monoclonal Antibodies. Clin J Onc Nsg, 13(5), 547-554, 2009. Mansfield AS, Markovic SN. (2009). Novel therapeutics for the treatment of metastatic melanoma. Future Oncology 5(4):543-557.
  • Puzanov, I. et al., Biological challenges of BRAF inhibitor therapy, Molecular Oncology (2010), doi:10.1016/j.molonc.2011.01.005 Lacouture, M.E., McArthur, G.A., Chapman, P.B., Ribas, K., Flaherty, K.T., Lee, R.J., et al., 2010. PLX4032 (RG7204), a selective mutant RAF inhibitor: clinical and histologic characteristics of therapy-associated cutaneous neoplasms in a Phase I trial. J. Clin. Oncol. 28 (15 Suppl.) (Abstract No. 8592).
  • NCI-Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0
  • Lin et al, 2008 Lemech, C., & Arkenau, H. T. (2012). Novel treatments for metastatic cutaneous melanoma and the management of emergent toxicities. Clinical Medicine Insights.Oncology, 6, 53-66. doi:10.4137/CMO.S5855
  • NCI, 2011.
  • Thumar JR, Kluger HM. (2011). Ipilimumab: A promising immunotherapy for melanoma. Oncololgy, 24(14), January. http://www.cancernetwork.comdisplay/article/10165/1771398
  • Weber, J. (2009). Ipilimumab: controversies in its development, utility and autoimmune adverse events. Cancer Immunol Immunother. May;58(5):823-30. Ledezma B. (2009). Ipilimumab for advanced melanoma: a nursing perspective. Onc Nurs Forum, 36(1), 97-104. Thumar JR, Kluger HM. (2011). Ipilimumab: A promising immunotherapy for melanoma. Oncololgy, 24(14), January. http://www.cancernetwork.comdisplay/article/10165/1771398 Lemech, C., & Arkenau, H. T. (2012). Novel treatments for metastatic cutaneous melanoma and the management of emergent toxicities. Clinical Medicine Insights.Oncology, 6, 53-66. doi:10.4137/CMO.S5855
  • Kaehler, K. C., Sondak, V. K., Schadendorf, D., & Hauschild, A. (2009). Pegylated interferons: Prospects for the use in the adjuvant and palliative therapy of metastatic melanoma. European Journal of Cancer (Oxford, England : 1990), 46 (1), 41-46. doi:10.1016/j.ejca.2009.10.004
  • Figure 8. Hypophysitis with thickened pituitary gland and stalk.
  • Product information – Zelboraf & Yervoy
  • Metastatic Melanoma: An Oncology Nurse Workshop on Novel Treatments, Adverse Event Management, and Patient Education

    1. 1. DISCLAIMER This slide deck in its original and unaltered format is for educational purposes and is current as of May 2012. All materials contained herein reflect the views of thefaculty, and not those of IMER, the CME provider, or the commercial supporter. These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. Readers should not rely on this information as a substitute for professional medical advice,diagnosis, or treatment. The use of any information provided is solely at your own risk, and readers should verify the prescribing information and all data before treating patients or employing any therapeutic products described in this educational activity. Usage Rights This slide deck is provided for educational purposes and individual slides may be used for personal, non-commercial presentations only if the content and references remain unchanged. No part of this slide deck may be published in print or electronically as a promotional or certified educational activity without prior written permission from IMER. Additional terms may apply. See Terms of Service on IMERonline.com for details.
    2. 2. DISCLAIMER Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients’ conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities. DISCLOSURE OF UNLABELED USE This activity may contain discussion of published and/or investigational uses ofagents that are not indicated by the FDA. IMER does 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 IMER. Please refer to the official prescribing information foreach product for discussion of approved indications, contraindications, and warnings.
    3. 3. Disclosure of Conflicts of Interest Peg Esper, MSN, MSA, RN, APRN-BC, AOCN®, reported a financial interest/relationship or affiliation in the form of: Speakers Bureau, Novartis Pharmaceuticals Corporation, Pfizer, Inc., Prometheus. Evan M. Hersh, MD, reported a financial interest/relationship or affiliation in the form of: Speakers Bureau, Bristol-Myers Squibb Company, Pfizer and Glaxo Smith Kline and consultant to Genentech and Pfizer. Krista M. Rubin, MS, RN, FNP-BC, reported a financial interest/relationship or affiliation in the form of: Consultant, Bristol- Myers Squibb Company, Genentech, Inc., Merck & Co., Inc.
    4. 4. Learning Objectives L Upon completion of this activity, participants should be better able to: Identify the emerging role of novel therapies in the treatment of advanced melanoma Implement strategies for the safe administration of novel therapies Apply evidence-based or best practice supportive care to manage side effects and optimize therapeutic outcomes of patients with melanoma receiving novel therapies Provide accurate and health-literate responses to melanoma patients’ questions regarding their disease, treatment guidelines, and side effects
    5. 5. Activity OverviewPeg Esper, MSN, MSA, RN, ANP-BC, AOCN® University of Michigan Comprehensive Cancer Center
    6. 6. Introduction to Faculty Panel Peg Esper, MSN, MSA, RN, ANP-BC, AOCN® (Chairperson) – Nurse Practitioner, Medical Oncology – University of Michigan Comprehensive Cancer Center Evan M. Hersh, MD – Professor of Medicine, Microbiology and Immunology – Arizona Cancer Center, University of Arizona Krista M. Rubin, MS, RN, FNP-BC – Nurse Practitioner, Center for Melanoma – Massachusetts General Hospital
    7. 7. Activity Agenda6:30 – 6:35 AM Welcome and Activity Overview6:35 – 6:50 AM Clinical Update: What’s New in Melanoma Therapy?6:50 – 7:10 AM The Workshop: Nursing Management Strategies for Patients With Advanced Melanoma7:10 – 7:55 AM Putting the Workshop Into Practice: Roundtable Discussions on Metastatic Melanoma Case Studies7:55 – 8:00 AM Audience Questions and Answers
    8. 8. Treatment Update inAdvanced Melanoma Evan M. Hersh, MD Arizona Cancer Center University of Arizona
    9. 9. 2012 Overview of Melanoma  Fastest rising incidence of any cancer over the last 3 decades – 76,250 cases in 2012  Median age at diagnosis: 60 yrs  Early metastatic potential  Early and common CNS seeding  Historic lack of effective systemic therapies until recently – Mortality 9,180 cases in 2012CNS = central nervous system.Weber, 2008; ACS, 2011.
    10. 10. Melanoma: Incidence, Mortality, and Survival by Stage Incidence Survival Curves by AJCC Stage 1.0 0.9 Stage I (n = 18,370) 0.8 0.7 0.6 Stage II (n = 9,269) 0.5 Stage III (n = 3,307) 0.4 0.3 0.2 Stage IV (n = 7,972) 0.1 0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0 0.0 Survival, Years  20-yr survival curves for patients with melanoma by stage. The differences between the curves are  Age adjusted incidence rates of all ages, highly significant (p < .0001). all races, both male and female, 1975–2008AJCC = American Joint Committee on Cancer.Howlader et al, 2010; Edge et al, 2010.
    11. 11. Systemic Therapy for Metastatic Melanoma: Prior History  Surgery (metastasectomy)  Dacarbazinea (DTIC)1  High-dose bolus IL-22  Biochemotherapy with IL-2  Carboplatin/paclitaxel  Temozolomide (US)  Fotemustine (Europe)FDA approved: 11970s, 21998.aOS = overall survival; IL-2 = interleukin-2.Middleton et al, 2000; Agarwala, 2009; Serrone et al, 2000; Gonzalez-Larriba et al, 2010; Flaherty et al, 2010; Seront et al, 2010.
    12. 12. Ipilimumab Is a Member of a Novel Class of Immunotherapeutic Antibodies 1) Co-stimulation via CD28 2) CTLA-4 ligation on 3) Blocking CTLA-4 ligation ligation transduces T-cell activated T cells down- enhances T-cell responses activating signals regulates T-cell responses T-cell activation T-cell inactivation T-cell activation T cell CTLA-4 T cell T cell CTLA-4 TCR TCR TCR CTLA-4 MHC CD28 MHC CD28 CD28 B7 MHC B7 B7 Ipilimumab APC APC APCCTLA-4 = cytotoxic T-lymphocyte antigen-4; MHC = major histocompatibility complex;TCR = T-cell receptor; APC = antigen presenting cell.Fong et al, 2008.
    13. 13. Ipilimumab Registration Trials  Second-line MDX010-20 trial HLA-A2 positive (N = 650) – 3 arms 3:1:1 (ipilimumab/gp100 vaccine, ipilimumab alone, gp100 alone) – First study in metastatic melanoma to demonstrate OS benefit in large randomized placebo-controlled trial  First-line CA184-024 trial, randomized placebo control (N = 500) – Ipilimumab/DTIC vs. placebo/DTIC – Reported as having positive OS (ipilimumab/DTIC combination vs. DTIC)HLA-A2 = human leukocyte antigen-alpha 2.Hodi et al, 2010; Wolchok et al, 2011.
    14. 14. MDX010-20: Study Design Ipilimumab + gp100 (n = 403) R A Pre-treated N metastatic D melanoma O Ipilimumab + placebo (n = 137) (N = 676) M I Z E gp100 + placebo (n = 136)Hodi et al, 2010.
    15. 15. Kaplan-Meier Analysis of Survival Ipilimumab + gp100 (A) Ipilimumab alone (B) gp100 alone (C) Comparison HR p Value Arms A vs. C 0.68 .0004 Arms B vs. C 0.66 .0026 1 2 3 4 Time (yrs)HR = hazard ratio.Hodi et al, 2010.
    16. 16. Ipilimumab Plus DTIC Vs. DTIC Alone (Study 024): Design Screening Induction Maintenancea Ipilimumab 10 mg/kg Ipilimumab 10 mg/kg Previously q3wks x 4 q12wks Untreated Metastatic DTIC 850 mg/m2 R q3wks x 8 Melanoma (N = 502) Placebo Placebo q3wks x 4 q12wks DTIC 850 mg/m2 R = blinded q3wks x 8 randomization (1:1) Wk 1 Wk 12 Wk 24 Baseline First Scheduled Tumor Assessment Tumor AssessmentIn absence of progression.aWolchok et al, 2011.
    17. 17. Ipilimumab Plus DTIC Vs. DTIC: OSCI = confidence interval.Wolchok et al, 2011.
    18. 18. Study 024: Select AEs  Select AEs are shown, regardless of attributionGI = gastrointestinal; AEs = adverse events.Wolchok et al, 2011.
    19. 19. Study 024: Select AEs (cont.)  Select AEs are shown, regardless of attribution1 (0.4%) hypophysitis in a patient on maintenance was reported on Day 364.aALT = alanine aminotransferase; AST = aspartate aminotransferase.Wolchok et al, 2011.
    20. 20. Ipilimumab Patterns of Response Baseline (Day 0) Week 12 (Day 84) Week 16 (Day 112) Week 72 (Day 503)Hoos et al, 2010; Images courtesy of K. Harmankaya, MD.
    21. 21. Targeted MAPK Pathway: BRAF  cKIT mutations: 3% of all melanomas – almost exclusively acral letiginous, mucosal, or chronic sun damaged skin  BRAF mutations: 50% cutaneous melanomas – intermittent sun exposed skinMAPK = mitogen activated protein kinase; BRAF = serine/threonine protein kinase.Curtin et al, 2006; Presented with permission, Copyright 2011 by C Lovly, L Horn, & W Pao, 2012.
    22. 22. Phase III First-Line BRIM3 Study Design Vemurafenib Screening 960 mg po bid (n = 337) BRAFV600E mutation Randomization Stratification • Stage N = 675 • ECOG PS (0 vs. 1) • LDH level (↑ vs. nL) Dacarbazine • Geographic region 1,000 mg/m2 IV q3wks (n = 338)ECOG PS = Eastern Cooperative Oncology Group performance status; LDH = lactate dehydrogenase level; IV= intravenous; po = oral; bid = twice daily.Chapman et al, 2011.
    23. 23. Best Tumor Response by Individual Patient Vemurafenib: 48.4% response Dacarbazine: 5.5% responseChapman et al, 2011.
    24. 24. Progression-Free Survival (12/30/10 cutoff) 100 HR 0.26 90 (95% CI; 0.20–0.33) Vemurafenib (N = 275) 80 Log-rank p < .001 70 Dacarbazine PFS (%) 60 (N = 274) 50 40 Median 5.3 mos 30 Median 20 1.6 mos 10 0 0 1 2 3 4 5 6 7 8 9 10 11 12 No. Patients in Follow-Up Time (mos) Dacarbazine 274 213 85 48 28 16 10 6 3 0 Vemurafenib 275 268 211 122 105 50 35 16 4 3Chapman et al, 2011.
    25. 25. PET Scans at Baseline and Day 15 After Vemurafenib #69 MDACC #63 MSKCCPET = positron emission tomography; MDACC = The University of Texas M. D. Anderson Cancer Center;MSKCC = Memorial Sloan-Kettering Cancer Center.Chapman, 2009.
    26. 26. Survival in BRAF V600-Mutant Advanced Melanoma Treated With Vemurafenib  Phase II study in 132 previously-treated patients  Response Rate: 53% – 6% CR, 47% PR  DOR: 6.7 mos  PFS: 6.8 mos (CI 5.6-8.1)  OS: 15.9 mos (CI 11.6–18.3 mos)  Comparison – DTIC OS 6–8 mos – Phase II chemotherapy survival: 6.3 mosCR = complete response; PR = partial response; DOR = duration of response; PFS = progression-free survival.Sosman et al, 2012.
    27. 27. Phase III of HD IL-2 +/- Vaccine  Study population (eligible for HD IL-2) – Stage IV or unresectable stage III melanoma – HLA-A0201 positive – No brain metastases – No previous HD IL-2  1:1 randomization – 1) HD IL-2 q8hrs x 12 doses q3wks – 2) IL-2 + gp100 vaccine  179 evaluable patients accrued (93 IL-2/86 Vac) – 21 centers, 2000–2007HD = high-dose.Schwartzentruber et al, 2011.
    28. 28. Phase III of HD IL-2 +/- Vaccine (cont.) Outcome IL-2, No. (%) IL-2 + Vaccine, No. (%) p Value No. patients 93 85 CR (investigator) 2 (2) 9 (11) .02 CR + PR (investigator) 9 (10) 17 (20) .05 CR + PRa 6 (6) 14 (16) .03 (central, primary end point) PFS (median) 1.6 m 2.2 m .008 OS (median) 11.1 m 17.8 m .06Most of RR difference due to responses in M1b/lung met.aRR = response rate.Schwartzentruber et al, 2011.
    29. 29. nab-Paclitaxel Plus Bevacizumab in Melanoma Patient Characteristics Toxicity # M/F 32 / 18 26 grade 3 events related to study drug Stage # (%) Neutropenia 10 IIIC 2 (4) Neuropathy 7 IV:M1a 4 (8) Mucositis 4 IV:M1b 11 (22) Fatigue 3 IV:M1c 34 (66) Proteinuria 1 LDH HFS 1 Normal 30 (60) No study drug-related grade 4 toxicity Elevated 20 (40)HFS = hand-foot syndrome; M/F= masculine/feminine.Boasberg et al, 2011.
    30. 30. nab-Paclitaxel Plus Bevacizumab in Melanoma (cont.) RR (RECIST) # (%) CR 2 (4) PR 16 (32) SD 22 (44) PD 10 (20) Clinical benefit (CR + PR + SD) 40 (80) PFS PFS at 4 mos 73% Median PFS 7.63 mos Median duration of follow-up 41.6 mos OS 1-yr survival 62% 2-yr survival 30% Median survival 16.8 mosRECIST = Response Evaluation Criteria In Solid Tumors; SD = stable disease; PD = progressive disease.Boasberg et al, 2011.
    31. 31. New Treatment Algorithm for Stage IV Melanoma  Clinical trial  Treatment naïve – HD IL-2 if eligible – High priority protocol if eligible – Vemurafenib (V600) or imatinib (c-kit) if tumor mutated – Ipilimumab alone or with other drugs if not mutated  Previously treated – High priority protocol if eligible – HD IL-2, ipilimumab, vemurafenib, or imatinib if appropriate – nab-Paclitaxel plus bevacizumab off label therapy – Standard therapy, or phase I or II protocol  Low tumor burden: ImmunoRx; High burden: BRAF inhibitor  Chemotherapy options include – Dacarbazine, temozolomide, dacarbazine- or temozolomide-based combination chemotherapy/biochemotherapy, paclitaxel, paclitaxel/cisplatin, paclitaxel/carboplatinRx = prescription.NCCN, 2012a.
    32. 32. Evolution of Response Criteria: mWHO to irRCWHO = World Health Organization; irRC = immune-related response criteria; SPD = sum of perpendicular diameters.Wolchok et al, 2009.
    33. 33. Monitoring Disease Response in Patients Receiving Ipilimumab  Analysis of 5 clinical trials (N = 269) – CR 10–106 wks after treatment initiation – PR 5–62 wks after treatment initiation – Therapeutic responses peak between 12–24 wks, slow responses up to and beyond 12 mos – DOR 6–187+ wks  Clinical trial monitoring (Hodi et al, 2010) – Baseline – 12 wks – 16, 20, 24 wks if no early PD and SD or better at Wk 12 – q3mos thereafterCallahan et al, 2010; Hamid et al, 2007; Boasberg et al, 2010; Hodi et al, 2010.
    34. 34. Key Takeaways:Treatment of Advanced Melanoma Melanoma is increasing dramatically in incidence 2 new therapies have been approved recently – Ipilimumab – Vemurafenib 2 other therapies are promising – HD IL-2 + peptide vaccine (vaccine experimental) – nab-Paclitaxel plus bevacizumab (off label) A new treatment paradigm for melanoma is at hand
    35. 35. The Workshop: Nursing Management Strategies forPatients With Advanced Melanoma Peg Esper, MSN, MSA, RN, ANP-BC, AOCN®University of Michigan Comprehensive Cancer Center
    36. 36. Nursing Management: Ipilimumab Administration  Ipilimumab (FDA approved 3/25/11) – 3 mg/kg IV over 90 mins q3wks for a total of 4 doses – Available as • 50 mg / 10 mL • 200 mg / 40 mL – Store the diluted solution for no more than 24 hrs under refrigeration (2–8°C, 36–46°F) or at room temperature (20–25°C, 68–77°F) – Compatible with 0.9% NaCl or D5W – Discard partially used vials or empty vials of ipilimumabNaCl = sodium chloride; D5W = 5% dextrose injection.Yervoy™ prescribing information, 2012.
    37. 37. Nursing Management: Vemurafenib Administration  Vemurafenib (240 mg tablets; approved 8/17/11) – Recommended dose: 960 mg (four 240-mg tablets) bid – The first dose should be taken in the morning and the second dose approximately 12 hrs later – Swallow whole with a glass of water, either with or without a meal – Should not be crushed or chewed – If a dose is missed, it can be taken up to 4 hrs prior to the next dose; both doses should not be taken at the same timeZelboraf® prescribing information, 2012.
    38. 38. Additional Regimens  HD IL-2 – 600,000 IU/kg administered as IV bolus over 15 mins q8hrs up to 14 doses – 1-wk break period and then repeat  Chemotherapy regimens include – DTIC 1,000 mg/m2 IV q3wks – Carboplatin and paclitaxel q3wks – Temozolomide 200 mg/m2 daily x 5 days (q3wks); 75 mg/m2 x 42 days on 14 days offProleukin® prescribing information, 2012; Temodar® prescribing information, 2012; Sosman, 2011.
    39. 39. IL-2 Toxicities  Significant immune-mediated toxicity profile  Dose related and schedule dependent  Toxicities, while acute, reverse after completion of therapy  Common toxicities related to IL-2 therapy include – Fever and rigors – Hypotension – N/V/D – Mental status changes – Oliguria, ↑ creatinine – Respiratory dysfunction – Hematologic toxicity – Dry skin, desquamation – Infections – Skin rashes/pruritis – Weight gain during treatment  Most severe toxicities (grade 3/4) observed with IL-2 therapy are associated with CLS  Rare – Cardiac related deathsN/V/D = nausea, vomiting, diarrhea; CLS = capillary leak syndrome.Proleukin® prescribing information, 2012; Schwartz et al, 2002.
    40. 40. IL-2 Side-Effect Monitoring and TreatmentTLC = triple lumen catheter; PRN = as needed; NSAIDs = non-steroidal anti-inflammatory drugs.Proleukin® prescribing information, 2012; Schwartz et al, 2002.
    41. 41. Ipilimumab: The “ITIS Syndromes”  The most frequent target organ effects of ipilimumab include – Skin (dermatitis) – GI tract (enterocolitis) – Hepatic system (hepatitis) – Neurologic system (neuritis) – Endocrine system (hypophysitis, thyroiditis) – Additionally: Nephritis, pneumonitis, meningitis, pericarditis, uveitis, iritis, and vasculitis (smaller percent)  Most commonly observed adverse reactions (≥ 5%, any grade) – Diarrhea – Rash – Fatigue – Pruritis – ColitisYervoy™ prescribing information, 2012.
    42. 42. Ipilimumab Boxed Warning  Severe and fatal immune-mediated adverse reactions due to T-cell activation and proliferation can occur and may involve any organ system  The most common adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy  Most adverse reactions are initially manifested during treatment; however, a minority occurred weeks to months after discontinuation of ipilimumab  Permanently discontinue and initiate systemic high-dose corticosteroid therapy for severe immune-mediated reactions  Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy and evaluate clinical chemistries including liver function tests and thyroid function tests at baseline and before each doseYervoy™ prescribing information, 2012.
    43. 43. New Agent Side-Effect Profile: Vemurafenib  Arthralgia  Rash  Nausea  Photosensitivity  Fatigue  Pruritus  HFSR / palmar-plantar dysesthesia  Development of SCC, keratoacanthoma typeHFSR = hand foot skin reaction; SCC = squamous cell carcinoma.Puzanov et al, 2010; Lacouture et al, 2010.
    44. 44. Managing Toxicities of Treatment GRADE OF TOXICITY GRADE 1 Asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated GRADE 2 Minimal, local, or noninvasive intervention indicated; limiting age- appropriate instrumental ADLs GRADE 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADLs GRADE 4 Life-threatening consequences; urgent intervention indicated GRADE 5 DeathADLs = activities of daily living.NCI-(CTC-AE) v4.0, 2010.
    45. 45. Managing New Agent Toxicities  Dermatologic – Rash – Vitiligo – Pruritis – HFSR – PhotosensitivityPuzanov et al, 2010; Photos courtesy of Peg Esper, MSN, MSA, RN, ANP-BC, AOCN®.
    46. 46. Rash • Use of emollient IPILIMUMAB creams VEMURAFENIB • Antipruritic agents • Immune-mediated • Steroid creams if • Use of IRAE indicated minocycline for • Avoid hot showers • papular/pustular Loose clothing • Corticosteroid use • rashes Avoid changing more common detergents, softeners, • Frequent skin etc. • Can progress to • evaluations to Limit sun exposure and Stevens-Johnson use sunscreen check for SCC syndrome in rare • Dermatologist cases referral PRN • Hold or discontinue • Hold or PRN discontinue PRNLemech et al, 2012; Lacouture, 2011.
    47. 47. NCI-CTCAE v4.03: Grading of Rash  Grading is based on percent of BSA covered by macules/papules Definition: A disorder characterized by the presence of macules (flat) and papules (elevated). Also known as morbilliform rash, it is one of the most common cutaneous adverse events, frequently affecting the upper trunk, spreading centripetally and associated with pruritus..BSA = body surface area.NCI-CTCAE v4.03, 2010.
    48. 48. HFSR (Palmar-Plantar Dysesthesia): Vemurafenib  Thickened skin with patchy hyperkeratodermia seen primarily over high pressure areas  Believed to be related to affects of agents on keratinocyte differentiation  Discomfort can be severe and prevent ambulation  Use of gel inserts for shoes  Podiatrist evaluation pre-Tx  Urea based creams  Foot soaksChoi et al, 2011; Photos courtesy of Peg Esper, MSN, MSA, RN, ANP-BC, AOCN®.
    49. 49. GI Adverse Effects (AEs)  Diarrhea – Primarily ipilimumab, but may be seen with vemurafenib  Can rapidly progress to colitis if not treated – Grade 1 (2 or < episodes in 24 hrs) • Antidiarrheals with close follow-up • Consider need for stool evaluation (clostridium) – Grade 2 (3–6 episodes in 24 hrs) • Oral budesonide (9 mg/d) along with antidiarrheals • Urgent sigmoidoscopy – Grade 3 (7+ episodes in 24 hrs) • Oral corticosteroids – Prednisone, methylprednisolone, dexamethasone  Symptomatic treatment of diarrhea/colitis has been required up to 2 yrs in some reportsThumar et al, 2011; Hodi, 2010.
    50. 50. Progression to Colitis: Ipilimumab  7+ stools/day over baseline, fever, ileus, peritoneal signs  Dehydration or bleeding (colitis on sigmoidoscopy) – Inpatient admission – IV corticosteroids – Possible infliximab, 5 mg/kg for corticosteroid-resistant or refractory cases – Bowel rest – Possible TPN for prolonged diarrhea  Severe unrelenting cases – Tacrolimus or sirolimus may be added – Diverting ileostomy or partial/total colectomy may be considered  Discontinuation of therapy recommended for patients with severe enterocolitisTPN = total parenteral nutrition.Thumar et al, 2011; Weber, 2009; Ledezma, 2009; Greenstein, 2008, Lemech et al, 2012.
    51. 51. More Immune-RelatedAdverse Events (IRAEs) Ipilimumab
    52. 52. Autoimmune Hepatitis  Transaminitis reported in up to 20% of patients treated with anti-CTLA-4 antibodies  Severe autoimmune hepatitis reported 2%  Liver biopsies have revealed diffuse lymphocytic infiltrates  Discontinue treatment for grade 3 or higher elevations  Oral corticosteroids for 30 days+ may be needed  Elevations of grade 4 level require hospitalization and IV corticosteroids  LFTs/bilirubin must be checked prior to every dose  Observe for symptoms of increased fatigue, N/V, or mental status changesLFTs = liver function tests.Thumar et al, 2011; Lemech et al, 2012.
    53. 53. Endocrinopathies  Seen in 15% of phase III study participants  Hypothyroidism – Elevated TSH – Symptoms of fatigue, hair thinning, constipation, weight gain – Replacement thyroid hormone is indicated – Ongoing monitoring of thyroid hormone levels (baseline, prior to each cycle and as clinically indicated) – Some patients may ultimately be able to taper off thyroid supplement therapy  Hyperthyroidism was also seenTSH = thyroid stimulating hormone.Weber, 2009; Lemech et al, 2012.
    54. 54. Hypophysitis  Inflammation of the pituitary gland  Symptoms include: Fatigue, headache, loss of libido, pressure behind eyes, nausea, diminished visual fields  Laboratory data – Decreased cortisol – Decreased testosterone – Decreased ACTH  Radiographic studies – MRI scan of brain with attention to the sella region with diffuse enlargement of the pituitary glandACTH = adrenocorticotrophic hormone; MRI = magnetic resonance imaging.Weber, 2009; Kaehler et al, 2010; Thumar et al, 2011.
    55. 55. Hypophysitis (cont.)  Management includes – Replacement of deficient hormones • Cortisol (hydrocortisone, initial dexamethasone/prednisone) • Thyroid replacement therapy • Testosterone – Consider endocrinology consult – Patients may ultimately be able to taper off replacement therapyThumar et al, 2011; Weber, 2009; Image adapted from Kaehler et al, 2010.
    56. 56. Additional AEs  Ocular (seen with both ipilimumab and vemurafenib) – Uveitis (decreased visual acuity, photophobia, tearing) – Conjunctivitis  Neurologic (ipilimumab) – Myopathies (weakness, altered sensory function, paresthesias) – 1 case of fatal Guillian-Barre and 1 case of grade 3 peripheral motor neuropathy seen in investigational studies  General (ipilimumab and vemurafenib) – Fatigue – Anorexia – Cough – Anemia – HeadacheThumar et al, 2011; Yervoy® prescribing information, 2012; Zelboraf® prescribing information, 2012; Lemech et al, 2012.
    57. 57. Labs and Evaluations IPILIMUMAB VEMURAFENIB • Labs to be • Molecular testing to rechecked prior to Baseline labs to confirm BRAF each cycle of mutation include CBC, LFTs, treatment Lytes • LFTs to be checked • Monitor thyroid at least monthly and function and as clinically indicated chemistry panel prior to each cycle of • EKG 15 days into Tx, treatment then monthly x 3, then q3mosCBC = complete blood count; Lytes = electrolytes; EKG = electrocardiogram.Yervoy® prescribing information, 2012; Zelboraf® prescribing information, 2012.
    58. 58. Drug-Drug Interactions  Ipilimumab – No known drug-drug interactions  Vemurafenib – CYP substrates: Concomitant use of vemurafenib with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP1A2, or CYP2D6 is not recommended. If co- administration cannot be avoided, exercise caution and consider a dose reduction of the concomitant CYP1A2 or CYP2D6 substrate drug. – May increase exposure to concomitantly administered warfarin. Exercise caution and consider additional INR monitoring when used concomitantly with warfarin.INR = international normalized ratio; CYP = cytochrome P450.Yervoy® prescribing information, 2012; Zelboraf® prescribing information, 2012.
    59. 59. When to Discontinue Ipilimumab Permanently discontinue ipilimumab for any of the following: Persistentmoderate adverse reactions or inability to reduce corticosteroid dose to 7.5 mg prednisone or equivalent per day Failure to complete full treatment course within 16 wks from administration of first dose Severe or life-threatening adverse reactions, including any of the following: – Colitis with abdominal pain, fever, ileus, or peritoneal signs; increase in stool frequency (7 or more over baseline) – Stool incontinence – Need for IV hydration for > 24 hrs – Gl hemorrhage and Gl perforation AST or ALT > 5 times ULN or total bilirubin > 3 times ULN Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations Severe motor or sensory neuropathy, Guillain-Barré syndrome, or myasthenia gravis Severe immune-mediated reactions involving any organ system (eg, nephritis, pneumonitis, pancreatitis, non-infectious myocarditis) Immune-mediated ocular disease that is unresponsive to topical immunosuppressive therapyULN = upper limit of normal.Yervoy® prescribing information, 2012.
    60. 60. Dose Modification Information: Vemurafenib Grade (CTC-AE)* Recommended Vemurafenib Dose Modification Grade 1 or Grade 2 (tolerable) Maintain vemurafenib at dose of 960 mg bid Grade 2 (intolerable) or Grade 3 1st Appearance Interrupt treatment until Grade 0–1 Resume dosing at 720 mg bid 2nd Appearance Interrupt treatment until Grade 0–1 Resume dosing at 480 mg bid 3rd Appearance Discontinue permanently Grade 4 1st Appearance Discontinue permanently or interrupt vemurafenib treatment until Grade 0–1 Resume dosing at 480 mg bid 2nd Appearance Discontinue permanently*The intensity of clinical AEs graded by the CTC-AE.Zelboraf® prescribing information, 2012.
    61. 61. Patient Education: General Assess for both patient and family (or significant other) – Knowledge of therapy and disease process – Educational level – Preferred learning methods Develop a plan Implement teaching, using a wide variety of materials and methods Evaluate patient and family for continued educational needs related to the therapy and disease process Contact – Who to call – Why to call – When to call – Where to call (must have 24/7 clinician availability)
    62. 62. Patient Education: Challenges  Ipilimumab – Effect of treatment is on the immune system, not directly targeting the tumor – Vast side-effect profile, when to notify clinician – Variability in response to treatment – Four treatments in the FDA approved therapyLedezma, 2009.
    63. 63. Patient Education: Challenges (cont.) Vemurafenib – What is BRAF? – Do I have genetic mutations? – Yes, it is 4 pills bid! – You treat 1 skin cancer, but develop another type of skin cancer? – Does this cure my cancer?
    64. 64. Putting the Workshop Into Practice: RoundtableDiscussions on Metastatic Melanoma Case StudiesKrista M. Rubin, MS, RN, FNP-BCMassachusetts General Hospital
    65. 65. Putting the Workshop Into Practice Please assign a moderator for your table You have 10 minutes to discuss the case Moderators: – Please record all group responses on the “Moderator Handout” – Leave this handout on your table; this will be collected at the end of the presentation by IMER staff
    66. 66. Case Study 1
    67. 67. Case Study 1: History  30-yr-old man with a history of a 2.3 mm, non-ulcerated nodular, melanoma of (R) forearm s/p wide excision and negative sentinel node biopsy [T3aN0MX: Stage IIA]. No adjuvant Rx recommended. Followed accordingly.  2 yrs later, develops SOB playing basketball. Presents to ER: CXR showed large (L) pleural effusion. – Rx: Thoracentesis (therapeutic and diagnostic) for ~ 1 L bloody fluid – Cytology → IHC: MART–1, HMB45, S100 all (+) c/w metastatic melanoma – Imaging studies: Large subcarinal LN and multiple (L) pleural masses. Brain MRI(-). Pleurodesis with symptomatic improvements in dyspnea.SOB = shortnes of breath; ER = emergency room; CXR = chest X-ray; IHC = immunohistochemistry;MART-1, HMB45, and S100 = IHC markers of melanocytic tumors; LN = lymph node; PMH = patient medical history.
    68. 68. Case Study 1: History (cont.)  Repeat imaging 1 wk later revealed an increase in size of known tumor and new bilateral pleural masses, diffuse LAN in the prevascular and anterior mediastinum.  PMH notable controlled asthma  Meds: Fluticasone 110 mcg INH, 2 puffs bid (albuterol inhaler prn)  Allergies: NKA  FH: Negative for melanoma  SH: Married, 2-yr old twins, works in investment banking. Non-smoker and social drinker.FH = family history; SH = social history.
    69. 69. Case Study 1: Questions What treatment options would be discussed with this patient? What would be recommended and why?
    70. 70. Case Study 1: Treatment Options  Clinical trials − None available for first-line therapy at the time of diagnosis  Immunotherapy − Ipilimumab − HD IL-2  Targeted therapy − BRAF inhibitor if BRAF mutation identified  Chemotherapy − DTIC − Temozolomide (off-label) − Carbo/paclitaxel (off-label)  Best Supportive Care (BSC)NCCN, 2012a.
    71. 71. Case Study 1: Treatment Options (cont.)  Given rapid progression of disease, obtaining tissue for BRAF analysis felt to be crucial to treatment recommendations  Biopsy of plural met obtained – no mutation identified (BRAF WT)  Recommendation for ipilimumab − Given his otherwise good health − BRAF WT − Concern for asthma exacerbation off inhaled corticosteroids and pulmonary toxicity from IL-2 − Best chance of durable response  Began Rx 1 wk later after insurance approvals obtainedWT = wild-type.NCCN, 2012a.
    72. 72. Case Study 1: Monitoring and Response  Tolerated first infusion well: No issues  F/U labs notable for increased LFTs: Grade 1  Second infusion – Pre-Rx labs unremarkable – Increasing dyspnea: O2 sats 92%–93%, mild intermittent pruritus – Labs stable – Fatigue worsening  Third infusion – Grade 1 elevation of amylase/lipase, LFTs normal – No abdominal complaints – Dyspnea stable to slightly improved – Pruritus improved with moisturizers – Fatigue stableF/U = follow-up.
    73. 73. Case Study 1: Monitoring and Response (cont.)  Fourth infusion – Labs all normal – Dyspnea improved: Sats increased at 96% – Erythematous papules on chest and abdomen- (+) pruritus – Fatigue much improved  CT scans (full body) obtained 4 wks from the time of the last dose showed minor regression of adenopathy, no new lesions  Repeat scans 6 wks later showed further response: No new lesions – patient continues to have slow, but clear clinical response with improved symptoms, now 5 mos from his last doseCT = computed tomography.
    74. 74. Case Study 2
    75. 75. Case Study 2: History  PL is a 50-yr-old man  PMH: HTN, anxiety  SH: Married, 2 adult children, respiratory therapist. Non-smoker and social drinker.  FH: Negative for melanoma or pancreatic cancer  Medications: Venlafaxine 75 mg po qd, olmesartan medoxomil/HCTZ 20/12.5 mg po qd  ALL: ASA → active systemic anaphylaxisHTN = hypertension; HCTZ = hydrochlorothiazide.
    76. 76. Case Study 2 (cont.)  Presents to local dermatologist with a bleeding and changing mole. Biopsy demonstrated a 2.0 mm, ulcerated, SSM of the (L) lateral trunk, 8 mitoses/mm2.  He underwent wide excision and sentinel node evaluation: Drained to both (L) groin and (L) axilla. Final path – 0 nodes involved. No residual melanoma.  T2bN0Mx – Stage IIA diseaseSSM = superficial spreading melanoma.NCCN, 2012a.
    77. 77. Case Study 2: Questions What treatment options would be discussed with this patient? What would be recommended and why?
    78. 78. Case Study 2: Treatment Options  Treatment options for stage IIA melanoma – Observation – Clinical trialNCCN, 2012a.
    79. 79. Case Study 2: Treatment Course  Patient chose participation in E1697: An intergroup trial of 1 month of IFN vs. observation for patients with lower risk for recurrence  He was randomized to IFN arm – Wk 2: Experienced Grade 3 nausea prompting holding 2 doses, nausea improved, restarted with 33% DR as per protocol – Completed the full course of induction receiving all 20 doses – Followed q3mos with H&P and CXRIFN = interferon; DR = dose reduction; H&P = history and physical examination.ClinicalTrials.gov
    80. 80. Case Study 2: Monitoring  2 yrs later, patient noted a non-tender lump in (L) axilla – Upon examination – 2 cm rubbery mobile node, no other palpable nodes. Location was concerning, but texture not. – Plan: Re-evaluate in 1 month  1 month later is 3 cm – FNA obtained same day- (+) for metastatic melanoma  PET-CT and brain MRI: NED other than FDG avid, enlarged (L) axillary node  Axillary node dissection was performed  Path → met melanoma in 1/15 nodes, with the metastasis measured at 4.0 cm and ECE noted  Since he had already received IFN, post-operative XRT was recommended to (L) axillaFNA = fine needle aspiration; NED = no evidence of disease; FDG = fluorodeoxiglucose avidity;XRT = radiotherapy; ECE = extracapsular extension.NCCN, 2012a.
    81. 81. Case Study 3
    82. 82. Case Study 3: History 30-yr-old man with a history of a 2.3 mm, non-ulcerated nodular, melanoma of (R) forearm [T3aN0MX: Stage IIA] 2 yrs later: Presents to ER and CXR showed large (L) pleural effusion Due to rapid progression of disease, tissue was obtained for BRAF analysis: No mutation identified (BRAF WT) Ipilimumab recommended – Given his otherwise good health – BRAF WT – Concern for asthma exacerbation off inhaled corticosteroids and pulmonary toxicity from IL-2 – Best chance of durable response Therapy started 1 wk later after insurance approvals were obtained
    83. 83. Case Study 3: Monitoring and Response Tolerated first infusion well (no issues) F/U labs notable for increased LFTs (Grade 1) Second infusion: Increasing dyspnea, labs stable, fatigue worsening Third infusion: Dyspnea stable to slightly improved, pruritus improved with moisturizers, fatigue stable Fourth infusion: Dyspnea improved, erythematous papules on chest and abdomen- (+) pruritus, fatigue much improved CT scans (full body) obtained 4 wks from the time of the last dose showed minor regression of adenopathy, no new lesions
    84. 84. Case Study 3 (cont.) Tolerated 4 doses (induction) ipilimumab no issues Repeat scans 6 wks later showed further response – No new lesions: Patient continues to have slow, but clear clinical response with improved symptoms, now 5 mos from his last dose Repeat imaging 8 wks later demonstrated small, but clear progression of pleura based nodules, and brain MRI demonstrated a 4 mm cerebellar metastasis There was no edema, patient remained asymptomatic from a neurologic standpoint. Slight increase in cough, but overall, respiratory status was stable from last evaluation.
    85. 85. Case Study 3: Clinical Question What treatment options are recommended? – Recall • Patient is BRAF WT • Now has a new brain metastasis • He is young • No other comorbidities
    86. 86. Case Study 3: Treatment Course  CNS: Decision made to proceed with stereotactic radiosurgery (SRS)  Systemic disease – Given his initial response to ipilimumab before progression, data supports re-induction with another 4 cycles  SRS was administered in a single session: Given the small size of the met, there was little risk of seizure or edema, thus neither anti-seizure medications nor steroids were recommended. A 6-wk F/U brain MRI was scheduled.NCCN, 2012b.
    87. 87. Case Study 3: Treatment Course (cont.)  1 wk after SRS, he received his first dose of re-induction which he tolerated without adverse event, but his fatigue was moderate to severe (Grade 2–3)  Second dose of ipilimumab was held for Grade 3 amylase/lipase, but without pancreatitis. Labs were repeated bwkly and did resolve to Grade 1 prior to the third infusion.  6-wk F/U MRI showed response to SRS and no new lesions  He received his fourth dose of induction without further toxicity. Fatigue stable, cough worse.  Given worsening cough, CTs obtained 1 wk later, demonstrated stable disease, no new lesionsNCCN, 2012b.
    88. 88. Case Study 3: Clinical Question  What are the treatment recommendations for this patient at your facility? – Chemotherapy • CVD + IL-2/IFN (biochemotherapy) • Carbo/paclitaxel (combination) • DTIC or temozolomide (single-agent) – Observation (repeat scans again in some designated time period: 6, 8, 10, or 12 wks) – HospiceNCCN, 2012a.
    89. 89. Case Study 4
    90. 90. Case Study 4: History PL is a 50-yr-old man PMH: HTN, anxiety SH: Married, supportive wife, 2 children, respiratory therapist. Non-smoker and social drinker. FH: Negative for melanoma or pancreatic cancer Medications: Venlafaxine 75 mg po qd, olmesartan medoxomil/HCTZ 20/12.5 mg po qd ALL: ASA → active systemic anaphylaxis T2bN0Mx – Stage IIA melanoma, patient chose a clinical trial: E1697: Randomized to IFN for 1 month
    91. 91. Case Study 4: Follow-Up  2 yrs later, patient noted a nontender lump in (L) axilla. Exam: 2-cm rubbery mobile node, no other palpable nodes. Location was concerning, but texture not. Plan: Re-evaluate in 1 month.  1 month later, the node is 3 cm. FNA obtained same day- (+) for metastatic melanoma.  PET-CT and brain MRI: NED other than FDG avid, enlarged (L) axillary node  Axillary node dissection was performed  Path → met melanoma in 1/15 nodes, with the metastasis measured at 4.0 cm and ECE noted  Since he received IFN, post-operative XRT was recommended to (L) axillaNCCN, 2012a.
    92. 92. Case Study 4: Follow-Up (cont.)  1 month after XRT completed, patient called to report low back pain “pulled a muscle”; endorsed severe pain making it difficult to walk – MRI L-spine: Diffuse bony metastatic disease with destruction of the L4 vertebral body with pathological fracture and extensive surrounding edema and enhancement. – CT: Splenic lesion, 2 small liver lesions – possibly perfusion anomalies vs. mets. New multiple bilateral pulmonary nodules, the largest in the RLL, ~ 1.3 cm. – Brain MRI: NED  Palliative XRT to (L) spine planned, and at the same time, BRAF status was to be obtained  BRAF mutation status returned V600E mutant: Difficulty obtaining drug d/t insurance issues  Patient did again require admission for intractable pain and nausea  Started vemurafenib while in-house  Ultimately required kyphoplasty X2 to stabilize fractures and subsequently had placement of intrathecal infusion pump  Remained on vemurafenib for ~ 3 mos. An interval scan showed stable disease, but repeat imaging demonstrated progression with new brain mets.  Brain MRI: Multiple new small brain mets – largest being 6 mmRLL = right lower lobe.NCCN, 2012a.
    93. 93. Case Study 4: Clinical Question What would be the next step at your institution? What other services may be offered?
    94. 94. Case Study 4: Treatment Options  CNS options: WB-XRT vs. SRS  Systemic options: Chemotherapy, immunoRx, BSC  After much discussion, a treatment plan was established to pursue ipilimumab for the following reasons – CNS disease was small, patient was asymptomatic – Given multiple sites, WB-XRT would be recommended vs. multiple SRS – Data supporting CNS effect with ipilimumabWB-XRT = whole brain radiotherapy.NCCN, 2012b; Margolin et al, 2012.
    95. 95. Case Study 4 (cont.) Patient received his first dose of ipilimumab at the time of this writing Remains on 4 mg po dexamethasone for nausea – Discussion points: • Dexamethasone and ipilimumab • Plans for CNS progression • Plans for systemic progression

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