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1 Supplementary Online Ctent Devji T, Levine O, Neupane B, Beyene J, Xie F. Systemic therapy for previously untreated advanced -mutated melanoma: a systematic review and network meta-analysis of randomized clinical trials. JAMA Oncol. Published line October 27, doi: /jamacol etable 1. Literature Search Strategy (April 29th, 2016) etable 2. Study and patient populati characteristics of included studies etable 3. Surface under the cumulating ranking curve (SUCRA) data for all outcomes etable 4. Serious Adverse Events etable 5. Pooled estimates for all possible treatment effects for adverse events efigure 1. Study Flow Diagram efigure 2. Network diagram for each outcome efigure 3. Risk of Bias assessment of included studies efigure 4. The SUCRA (all in e) plot of each treatment to be the best overall This supplementary material has been provided by the authors to give readers additial informati about their work.

2 FIGURES AND TABLES etable 1. Literature Search Strategy (April 29 th, 2016) etable 2. Study and patient populati characteristics of included studies etable 3. Surface under the cumulating ranking curve (SUCRA) data for all outcomes etable 4. Serious Adverse Events etable 5. Pooled estimates for all possible treatment effects for adverse events efigure 1: Study Flow Diagram efigure 2. Network diagram for each outcome efigure 3. Risk of Bias assessment of included studies efigure 4. The SUCRA (all in e) plot of each treatment to be the best overall

3 etable 1. Literature Search Strategy (April 29 th, 2016) MEDLINE EMBASE CENTRAL 1. melanoma/ 2. ((unresect* or advance*) adj3 melanoma).mp. 3. metastatic melanoma.mp. 4. or/ (dabrafenib or tafinlar).mp. 6. (trametinib or mekinist).mp. 7. (vemurafenib or zelboraf).mp. 8. cobimetinib.mp. 9. inhibit*.mp. 10. MEK inhibit*.mp. 11. targeted therap*.mp. 12. Immunotherapy/ 13. Immunotherap*.mp. 14. Immune checkpoint inhibit*.mp. 15. (ipilimumab or yervoy).mp. 16. (nivolumab or opdivo).mp. 17. (pembrolizumab or keytruda).mp. 18. or/ and randomized ctrolled trial.pt. 21. randomized.mp. 22. placebo.mp. 23. or/ and limit 24 to animals 26. limit 25 to humans not not melanoma/ 2. ((unresect* or advance*) adj3 melanoma).mp. 3. metastatic melanoma.mp. 4. or/ (dabrafenib or tafinlar).mp. 6. (trametinib or mekinist).mp. 7. (vemurafenib or zelboraf).mp. 8. cobimetinib.mp. 9. inhibit*.mp. 10. MEK inhibit*.mp. 11. targeted therap*.mp. 12. Immunotherapy/ 13. Immunotherap*.mp. 14. Immune checkpoint inhibit*.mp. 15. (ipilimumab or yervoy).mp. 16. (nivolumab or opdivo).mp. 17. (pembrolizumab or keytruda).mp 18. or/ and random:.tw. 21. placebo:.mp. 22. double-blind:.tw. 23. or/ and limit 24 to animals 26. limit 25 to humans not not melanoma/ 2. ((unresect* or advance*) adj3 melanoma).mp. 3. metastatic melanoma.mp. 4. or/ (dabrafenib or tafinlar).mp. 6. (trametinib or mekinist).mp. 7. (vemurafenib or zelboraf).mp. 8. cobimetinib.mp. 9. inhibit*.mp. 10. MEK inhibit*.mp. 11. targeted therap*.mp. 12. Immunotherapy/ 13. Immunotherap*.mp. 14. Immune checkpoint inhibit*.mp. 15. (ipilimumab or yervoy).mp. 16. (nivolumab or opdivo).mp. 17. (pembrolizumab or keytruda).mp 18. or/ and 18

5 etable 2. Study and patient populati characteristics of included studies Author/y Interventi Ctrol ear Samp le size (n) McArthu r, Vemurafeni b 960 mg orally twice daily Hauschil d, Dabrafenib 150 mg orally twice daily Dabrafenib /MEK Lg, mg orally twice daily, Trametinib 2 mg orally ce daily Larkin, 495 Vemurafeni b 960 mg orally twice daily, Cobimetini e 1000 mg/m 2 IV e 1000 mg/m 2 IV Dabrafenib 150 mg orally twice daily Vemurafen ib 960 mg orally twice daily Mutati status V600E V600E V600E /K V600E /K Medi an age Ma le (%) Stud y Desi gn Phas Phas Phas Phas Metastasis stage M 0 (%) Acti ve Ctr ol History of Brain Metastasis Acti ve Ctr ol LDH>ULN (%) Acti ve Ctr ol Outco mes 6 4 NR NR PFS 3 2 NA NA PFS 2 5 NR NR PFS PFS

6 b 60 mg orally ce daily for 21 days of a 28-day cycle Robert, 2015a Dabrafenib 150 mg orally twice daily, Trametinib 2 mg orally ce daily MEK Kirkwoo 200 Selumetinib d, mg orally twice daily in 28 day cycles MEK/Chemotherapy Gupta, 83 Selumetinib mg orally twice daily, Docetaxel 75 mg/m 2 ce day 1 of a 21- day cycle Vemurafen ib 960 mg orally twice daily Temozolo mide 200 mg/m 2 ce daily for 5 days of a 28-day cycle Docetaxel 75 mg/m 2 ce day 1 of a 21-day cycle (max of 6 cycles) V600E /K Wildtype and V600 Wildtype Phas 57* 60 Phas e II Phas e II 4 7 NR NR PFS 3 3 NR NR PFS NR NR NR NR PFS

7 (max of 6 cycles) Robert, Selumetinib 75 mg orally twice daily, e 1000 mg/m 2 day 1 of every 21- day cycle PD-1 Robert, 418 Nivolumab 2015b 46 3 mg/kg IV every 2 Robert, 2015c Pembrolizu mab 10 mg/kg every 2 Pembrolizu mab 10 mg/kg e 1000 mg/m 2 day 1 of every 21- day cycle e 1000 mg/m 2 IV Ipilumuma b 3 mg/kg for 4 doses Wildtype Wildtype and V Phas e II Phas Phas 0 0 NR NR PFS NR NR PFS PFS

8 CTLA-4 Ribas, Tremelimu mab 15 mg/kg IV ce every 90 days for up to 4 cycles Nivolumab PD-1/CTLA-4 Postow, mg/kg, Ipilimumab 3 mg/kg ce every 3 for 4 doses, followed by Nivolumab 3 mg/kg every 2 maintenanc e e 1000 mg/m 2 IV day 1 of a 21-day cycle; OR Temozolo mide 200 mg/m 2 orally days 1 to 5 of a 28-day cycle Ipilimumab 3 mg/kg ce every 3 for 4 doses NR 57* 57 Phas Wildtype and V Phas e II 6 4 NA NA PFS** * PFS

9 Larkin, Nivolumab 1 mg/kg, Ipilimumab 3 mg/kg ce every 3 for 4 doses, followed by Nivolumab 3 mg/kg every 2 maintenanc e CTLA-4/Chemotherapy Robert, 502 Ipilimumab mg/kg for 4 cycles, e 850 mg/m 2 administere d at 1,4,7, and Nivolumab 3 mg/kg every 2 Ipilimumab 3 mg/kg for 4 doses e 850 mg/m 2 administere d at 1,4,7, and 10, followed by e ale Wildtype and V600 Wildtype and V600 60* 65 Phas 57* 60 Phas NR NR PFS NR NA NA PFS **

10 Ipilimumab 10, followed by e ale through week 22 CTLA-4/GM- CSF Hodi, mg/kg IV for 4 doses then every 12, Sargramosti m 250 μg subcutaneo usly days 1-14 of 21 day cycles through week 22 Ipilimumab 10mg/kg IV for 4 doses then every 12 NR Phas e II NA NA PFS * Abbreviatis: IV=intravenous, M 0 = No detectable evidence of distant metastases, =Overall survival, PFS=Progressi-free survival, =Objective respse rate, =Serious averse events, NR=Not reported *mean Trial has 3 treatment arms ULN 2xULN

11 Study reports for entire study populati but not for treatment-naïve subgroup **Updated reported in lg-term follow-up publicati (Maio et al ) ***Hazard ratio for PFS was not reported. Insufficient reporting precluded accurate estimati of PFS

12 etable 3. Surface under the cumulating ranking curve (SUCRA) data for all outcomes a. SUCRA rankings for overall survival /MEK 91.6 PD CTLA-4/GM-CSF 67.1 CTLA-4/CHEMO CTLA MEK CHEMO 20.8 CHEMO 19.5 MEK 2.6 b. SUCRA rankings for progressi-free survival /MEK 99.8 PD-1/CTLA PD MEK/CHEMO 46.2 CTLA-4/CHEMO 38.1 CTLA CTLA-4/GM-CSF 30.4 CHEMO 10.3 MEK 7.5 c. SUCRA rankings for objective respse /MEK PD-1/CTLA PD MEK/CHEMO 47.5 CTLA-4/CHEMO 36.5 CTLA CHEMO 14.1 MEK 4.5 d. SUCRA rankings for adverse events CHEMO 92.9 PD CTLA /MEK 38.0 MEK/CHEMO 34.0 PD-1/CTLA CTLA-4/CHEMO

13 Abbreviatis: SUCRA=Surface under cumulative ranking curve, CHEMO=Chemotherapy

14 etable 4. Serious Adverse Events Treatment # Trials # Randomized # Events Percentage /MEK CHEMO CTLA CTLA-4/CHEMO MEK/CHEMO PD PD-1/CTLA Serious adverse events were defined as grade three according to the Natial Cancer Institute Comm Terminology Criteria for Adverse Events

15 etable 5. Pooled estimates for all possible treatment effects for adverse events BRA F 0 84 (0 66, 1 06) 0 52 (0 34, 0 80) 0 95 (0 57, 1 58) 0 85 (0 34, 2 19) 0 28 (0 18, 0 45) 0 85 (0 51, 1 42) 0 28 (0 20, 0 40) /ME K 0 62 (0 38, 1 01) 1 13 (0 65, 1 98) 1 01 (0 39, 2 67) 0 34 (0 21, 0 57) 1 02 (0 58, 1 78) 0 34 (0 22, 0 51) CTL A (1 14, 2 89) 1 63 (0 66, 4 12) 0 55 (0 42, 0 72) 1 63 (1 19, 2 26) 0 54 (0 42, 0 71) CTLA- 4/CHEM O 0 89 (0 35, 2 34) 0 30 (0 19, 0 49) 0 90 (0 53, 1 53) 0 30 (0 21, 0 43) MEK/CHE MO 0 34 (0 13, 0 83) 1 00 (0 38, 2 58) 0 34 (0 14, 0 79) PD (2 1 8, 4 12 ) 1 00 (0 7 4, 1 34 PD1/CTL A (0 23, 0 49) CHEM O ) Effect estimates reflect comparis of the treatment in the row heading being compared to the column heading. Effect estimates are presented as odds ratios and numbers in parentheses are 95% credible intervals. Abbreviatis: Chemo = chemotherapy

efigure 1: Study Flow Diagram Identificati 2546 Records identified through MEDLINE, EMBASE, CENTRAL (OVID Interface) 698 Duplicate records excluded Screening 1848 Records screened 1750 Records

16 efigure 1: Study Flow Diagram Identificati 2546 Records identified through MEDLINE, EMBASE, CENTRAL (OVID Interface) 698 Duplicate records excluded Screening 1848 Records screened 1750 Records excluded after title and abstract screening Eligibility 98 Full-text articles assessed for eligibility 1 Article included through manual search of references Included 16 articles (including 15 randomized ctrolled trials) included in meta-analysis 83 Articles excluded 59 Cference abstract 4 Not an RCT 15 Secd line treatment 3 No relevant outcome 2 Preliminary data of a RCT subsequently published with lgterm follow-up

17 efigure 2. Network diagram for each outcome The number of trials in which any two treatments were compared head to head is displayed alg the gray line (edge) cnecting those two treatments. The radius of a node (vertex) is proportial to the number of patients assigned to the correspding treatment in the entire network of all trials; therefore, a larger node size means larger number of total patients were randomized to that treatment. Abbreviatis: Chemo = chemotherapy

18 efigure 3. Risk of bias assessment of included studies

19 efigure 4. The SUCRA (all in e) plot of each treatment to be the best overall A. Overall survival B. Progressi-free survival C. Objective respse rate D. Serious adverse events Abbreviatis: SUCRA=Surface under cumulative ranking curve, CHEMO=Chemotherapy

Melanoma: From Chemotherapy to Targeted Therapy and Immunotherapy. What every patient needs to know. James Larkin

Melanoma: From Chemotherapy to Targeted Therapy and Immunotherapy What every patient needs to know James Larkin Melanoma Therapy 1846-2017 Surgery 1846 Cytotoxic Chemotherapy 1946 Checkpoint Inhibitors