1. Melanoma: Overview and Early Stage Care This program is supported by educational grants from In association with

2. clinicaloptions.com/oncology A Unique Physician, Nurse, and Patient Seminar Series About These Slides  Users are encouraged to use these slides in their own noncommercial presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent  These slides may not be published or posted online without permission from Clinical Care Options (email permissions@clinicaloptions.com) Disclaimer The materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.

3. clinicaloptions.com/oncology A Unique Physician, Nurse, and Patient Seminar Series Faculty Jeffrey S. Weber, MD, PhD Senior Member and Director Comprehensive Melanoma Research Center H. Lee Moffitt Cancer Center Tampa, Florida Jeffrey S. Weber, MD, PhD, has disclosed that he has received consulting fees from Bristol-Myers Squibb, Genentech, GlaxoSmithKline, Merck, and Prometheus and funds for research support from Bristol-Myers Squibb.

4. clinicaloptions.com/oncology A Unique Physician, Nurse, and Patient Seminar Series Melanoma 2013 ACS Incidence Predictions  137,990 new cases of melanoma in the US predicted for 2013 – 61,300 noninvasive cases (melanoma in situ) – 76,690 invasive cases – 5330 cases predicted for Florida  9480 deaths predicted for 2013  Second leading adult cancer in yrs of life lost Siegel R, et al. CA Cancer J Clin. 2013;63:11-30.

5. clinicaloptions.com/oncology A Unique Physician, Nurse, and Patient Seminar Series 10 Leading Cancer Types for the Estimated New Cancer Cases by Sex, 2013  Men –Prostate: 238590 –Lung and bronchus: 118080 –CRC: 73680 –Urinary/bladder: 54610 –Melanoma: 45060 –Kidney/renal pelvis: 40430 –NHL: 37600 –Oral cavity/pharynx: 29620 –Leukemia: 27880 –Pancreas: 22740  Women –Breast: 232340 –Lung and bronchus: 110110 –CRC: 69140 –Uterine corpus: 49560 –Thyroid: 45310 –NHL: 32140 –Melanoma: 31630 –Kidney/renal pelvis: 24720 –Pancreas: 22480 –Ovary: 22240 Siegel R, et al. CA Cancer J Clin. 2013;63:11-30.

6. clinicaloptions.com/oncology A Unique Physician, Nurse, and Patient Seminar Series Risk Factors for Melanoma Genetic  Hair color (red, RR: 3; blond, RR: 1.6)  More than 20 nevi (RR: 3.4)  Race(white vs black/Asians, RR: 5- 10)  Skin color (fair, RR: 2.1)  Burns easily and does not tan  Previous history of melanoma (RR: 900)  Familial cases (4% to 10%) of cases in the US) –First-degree relatives with sporadic disease –B-K dysplastic nevus syndrome –DNA repair abnormalities (xeroderma pigmentosum) Environmental  Sunlight, especially UVB  Areas close to the equator  First sunburn at a young age Others  Age (80% cases in 50 yrs of age or older)  Sex (male = female)  UVA  Tanning lamps  High socioeconomic class  Immunosuppressive states  Fluorescent lights?  Halogenated compound?  Alcohol, tobacco, coffee, tea? Linette GP. In: Cancer principles and practice of oncology. 9th edition. Lippincott Williams & Wilkins; 2012. p. 375-382.

7. clinicaloptions.com/oncology A Unique Physician, Nurse, and Patient Seminar Series Sunlight and Ultraviolet Erythema (Sunburn)  Types of UV light –UV: 200-400 nm –UVA: 320-400 nm (high skin penetration) –UVB: 290-320 nm (intermediate skin penetration) –UVC: 200-290 nm (poor skin penetration) Maverakis E, et al. J Autoimmunity. 2010;34:J247-J257.

8. clinicaloptions.com/oncology A Unique Physician, Nurse, and Patient Seminar Series Diagnosing Melanoma: What to Look for Change in Color  Especially multiple shades of dark brown or black; red, white, and blue; spread of color from the edge of the lesion into surrouning skin Change in Size  Especially sudden or continuous enlargement Change in Shape  Especially development of irregular margins Change in Elevation  Especially sudden elevation of previously macular pigmented lesion Change in Surface  Especially scaliness, erosion, oozing, crusting, ulceration, bleeding Change in Surrounding Skin  Especially redness, swelling, satellite pigmentations Change in Sensation  Especially itching, tenderness, pain Change in Consistency  Especially softening or friability

9. clinicaloptions.com/oncology A Unique Physician, Nurse, and Patient Seminar Series ThicknessUlceration Status/Mitoses T1≤ 1.0 mma: without + mitosis < 1/mm 2, b: with or mitoses ≥ 1/mm 2 T21.01- 2 mma: without, b: with T32.01- 4 mma: without, b: with T4>4.0 mma: without, b: with Met. Nodes, nNodal Met. Mass N11 nodea: micro, b: macro N22-3 nodesa: micro, b: macro, c: in-transit/satellites without metastatic nodes N3≥ 4, matted nodes, or in-transit or satellite(s) with metastatic nodes SiteLDH M1aDistant skin, SQ, or nodal metastasesNormal M1bLung metastasesNormal M1cAll other visceral metastasesNormal Any distant metastasesElevated Balch CM, et al. J Clin Oncol. 2009;27:6199-206. AJCC Staging System for Cutaneous Melanoma

10. clinicaloptions.com/oncology A Unique Physician, Nurse, and Patient Seminar Series 012345678 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 Yrs Proportion Surviving 9101113121415 Stage I (n = 9175) Stage II (n = 5739) Stage III (n =1 528) Stage IV (n = 1158) Survival in Melanoma by Stage Balch CM, et al. J Clin Oncol. 2001;19:3635-3648.

11. clinicaloptions.com/oncology A Unique Physician, Nurse, and Patient Seminar Series Pathologic Reporting of Malignant Melanoma Prognostic Parameters  Breslow depth  Ulceration  Clark level  Angiolymphatic invasion  Mitotic rate  Regression  Growth phase  Unusual subtypes NCCN. Clinical practice guidelines in oncology: melanoma. v.1.2014.

12. clinicaloptions.com/oncology A Unique Physician, Nurse, and Patient Seminar Series  SLN remains the least invasive method of determining the most important predictor of OS, SLN status (positive or negative)  SLN status is the most significant clinicopathologic prognostic factor in determining overall patient survival  Informed patient: prognostic information can then be discussed with the patient with relatively accurate estimates of an individual patients mortality risk given Disease-Free Survival by SLN Status Gershenwald JE, et al. J Clin Oncol. 1999;17:976-983. Prognosis in Melanoma Negative Positive P <.0001 1.0 0.8 0.6 0.4 0.2 0 Proportion Disease Free Mos 01224364860728496

13. clinicaloptions.com/oncology A Unique Physician, Nurse, and Patient Seminar Series Management of Early-Stage Disease Tumor  MIS  ≤ 1 mm  1.01-2.00 mm  2.01-4.00 mm  > 4 mm  Any positive nodes, including sentinel nodes Surgical margin  0.5-1.0 cm, no SLNB  1 cm, no SLNB  1-2 cm, SLNB*  2 cm, SLNB  Complete LND *Selected patients 0.76-1.00 mm (young age or “high-risk histology”) should be considered for SLN biopsy. NCCN. Clinical practice guidelines in oncology: melanoma. v.1.2014.

14. clinicaloptions.com/oncology A Unique Physician, Nurse, and Patient Seminar Series Benefits of Sentinel Lymph Node Biopsy  Early therapeutic node dissection survival benefit (will be minimal) regional control  Careful pathologic scrutiny –Node-negative pts spared toxicity –Node-positive pts offered treatment  Critical prognostic information –Stratification criteria for clinical trials  17% of pts (overall) will have a positive sentinel node [1]  Identification of “unexpected” drainage patterns in 5% to 8% of pts [2,3] –In up to 3% of pts “interval” or “in-transit” nodes will be the site of a positive sentinel node [4] 1. Rousseau DL, et al. Ann Surg Oncol. 2003;10:569-574. 2. Sumner WE, et al. Cancer. 2002;95:354-360. 3. Steen St, et al. J Am Coll Surg. 2011;213:180-186. 4. McMasters KM, et al. Arch Surg. 2002;137:543-547.

15. clinicaloptions.com/oncology A Unique Physician, Nurse, and Patient Seminar Series Stage I/II MelanomaStage III Melanoma Balch CM, et al. J Clin Oncol. 2009;27:6199-6206. Survival of Patients With High-Risk Melanoma Yrs 02.57.512.517.520.0 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Proportion of Survival Rate 15.010.05.0 IA (n = 9452) IB (n = 8918) IIA (n = 4644) IIB (n = 3228) IIC (n = 1397) Yrs 02.57.512.517.520.0 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Proportion of Survival Rate 15.010.05.0 IIIA (n = 1196) IIIB (n = 1391) IIIC (n = 720) High-Risk Patients: Higher recurrence rate and relatively poor survival

16. clinicaloptions.com/oncology A Unique Physician, Nurse, and Patient Seminar Series Adjuvant Radiotherapy vs Observation After Lymphadenectomy: Efficacy  Adjuvant RT reduced the incidence of LNF relapse as first relapse by 48% compared with observation (P =.023) –Cumulative incidence of LNF relapse at 5 yrs (18% vs 33% for adjuvant RT and observation, respectively)  No significant difference in RFS or OS outcomes (n = 217)  Significant prognostic factors for OS: extranodal spread, number of positive nodes, sex –Extent of extranodal spread without RT use predictive of increased risk of LNF relapse 5-Yr Survival, %ARTObsHRP Value RFS34280.89.51 OS40451.27.21 Henderson MA, et al. ASCO 2013. Abstract 9001.

17. clinicaloptions.com/oncology A Unique Physician, Nurse, and Patient Seminar Series Historical Data: Summary  IFN alfa-2b has been the only agent to show success in randomized trials  All other adjuvant therapy trials to date with vaccines, chemotherapy, and other immunotherapy agents have been negative  Adjuvant RT improves local control but not distant relapse

18. clinicaloptions.com/oncology A Unique Physician, Nurse, and Patient Seminar Series  Adjuvant treatment with LDI did not improve outcome in trials of patients with high-risk, node-positive melanoma (stage IIb/III) Randomized TrialStageNDoseDuration, Yrs Outcome vs Observation WHO-16 [1] III4443 MU SC TIW 3OS, RFS (P = NS) UKCCCR [2] IIB, III6743 MU SCTIW 2OS, RFS (P = NS) ECOG-1690 [3] (HDI vs LDI vs observation) IIB, III6423 MU SC TIW 2OS, RFS (P = NS) 1. Cascinelli N, et al. Lancet. 2001;358:866-869. 2. Hancock BW, et al. J Clin Oncol. 2004;22:53-61. 3. Kirkwood JM, et al. Clin Cancer Res. 2004;10:1670-1677. LDI alfa for High-Risk Melanoma

19. clinicaloptions.com/oncology A Unique Physician, Nurse, and Patient Seminar Series StudyEligibilityN Treatment Agent/Dosage/DurationEffect on RFSOS ECOG 1684 [1] T4, N1287 IFN alfa-2b 20 MU/m 2 /day IV x 1 mo 10 MU/m 2 SC TIW x 11 mos ++ at 6.9-12.6 yrs ECOG 1690 [2] T4, N1642IFN alfa-2b 20 MU/m 2 /day IV x 1 mo 10 MU/m 2 SC TIW x 11 mos vs 3 MU/day SC TIW x 2 yrs +– at 4.3-6.6 yrs ECOG 1694 [3] T4, N1 880 IFN alfa-2b 20 MU/m 2 /day IV x 1 mo 10 MU/m 2 SC TIW x 11 mos vs GMK vaccine x 96 wks ++ at 1.3-2.1 yrs NCCTG 837052 [4] T3, T4, N1262 IFN alfa-2a 20 MU/m 2 /day IM TIW x 3 mos –– at ~7 yrs 1. Kirkwood JM, et al. J Clin Oncol. 1996;14:7-17. 2. Kirkwood JM, et al. J Clin Oncol. 2000;18:2444- 2458. 3. Kirkwood JM, et al. J Clin Oncol. 2001;19:1430-1436. 4. Creagan ET, et al. J Clin Oncol. 1996;13:2776-2783. HDI alfa-2b Trials for AJCC Stage IIB/III Melanoma

20. clinicaloptions.com/oncology A Unique Physician, Nurse, and Patient Seminar Series 3 Meta-analyses of All Trials of IFN-alfa Confirm RFS, OS Impact Meta-analysisRCT, nRFSOSComment Ives [1] 18+-/+Did not include E1694 ↑ benefit with ↑ IFN dose Wheatley [2] 13+ OR: 0.87 (95% CI: 0.81- 0.93; P =.00006) + OR: 0.9 (95% CI: 0.84- 0.97; P =.008) OS translates into absolute benefit of 3% (CI: 1% to 5%) at 5 yrs Mocellin [3] 14+ HR: 0.82 (95% CI: 0.77- 0.87; P <.001) + HR: 0.89 (95% CI: 0.83-0.96; P =.002) 18% risk reduction in DFS 11% risk reduction in OS 1. Ives NJ, et al. J Clin Oncol. 2007;25:5426-5434. 2. Wheatley K, et al. ASCO 2007. Abstract 8526. 3. Mocellin S, et al. J Natl Cancer Inst. 2010;102:493-501.

21. clinicaloptions.com/oncology A Unique Physician, Nurse, and Patient Seminar Series Median RFS, Yrs (95% CI) Observation (n = 481): 7.8 (5.8-9.8) IFN (n = 494): 7.3 (7.0-9.5) P =.690* *Stratified log-rank test. Agarwala SS, et al. ASCO 2011. Abstract 8505. HDI alfa-2b For 1 Month vs Observation in T3 Melanoma (E1697): RFS Yrs 0234812 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Probability 191011765 Treatment IFN Observation Total 494 481 Failed 133 130 Censored 361 351 Median 7.4 7.8

22. clinicaloptions.com/oncology A Unique Physician, Nurse, and Patient Seminar Series 2007 Evaluation 2011 Evaluation Eggermont AM, et al. ASCO 2011. Abstract 8506b. Eggermont AMM, et al. J Clin Oncol. 2012;30:3810-3818. HR: 0.82 (95% CI: 0.71-0.96; P =.01) HR: 0.87 (95% CI: 0.76-1.00; P =.055) Phase III EORTC 18991 Study of Adjuvant PegIFN alfa-2b in Stage III Melanoma: RFS Yrs 0246810 0 20 30 40 50 60 70 80 90 100 RFS (%) Patients at Risk, nON 368 328 629 627 311 346 76 8500 Observation PegIFN alfa Yrs 0246810 0 20 30 40 50 60 70 80 90 100 RFS (%) Patients at Risk, nON 406 384 629 627 317 349 238 283 205 233 63 94 Observation PegIFN alfa

23. clinicaloptions.com/oncology A Unique Physician, Nurse, and Patient Seminar Series Yrs Observation PegIFN alfa-2b ON 116181 108192 ON 5990 4596 Eggermont AM, et al. ASCO 2011. Abstract 8506b. Eggermont AMM, et al. J Clin Oncol. 2012;30:3810-3818. 0123456 012345 6 0 10 20 30 40 50 60 70 80 90 100 UlcerationUlceration and N1 HR: 0.77 (95% CI: 0.55-1.09; P =.05) HR: 0.59 (95% CI: 0.35-0.98; P =.006) EORTC 18991 Study of Adj PegIFN alfa-2b in Stage III Melanoma: RFS With Ulceration 0 10 20 30 40 50 60 70 80 90 100 RFS (%) Observation PegIFN alfa-2b

24. clinicaloptions.com/oncology A Unique Physician, Nurse, and Patient Seminar Series Practice Considerations  High-risk melanoma is defined as T4N0 and T (any), N+  Although OS benefit of adjuvant therapy is not consistent, RFS is a “bridge”  IFN alfa-2b is the only approved agent (HDI for 1 yr or pegIFN for up to 5 yrs)  1-mo induction alone is not effective  Certain subsets of patients may benefit more than others, but this needs confirmation in randomized studies  Results from randomized trial of ipilimumab vs placebo due soon

25. Go Online for More CCO Coverage of Melanoma! Interactive Case Challenges to compare your management decisions to those of the expert faculty Downloadable slides for your own noncommercial presentations or use as a self-study resource clinicaloptions.com/oncology