Efficacy Outcomes in the Phase 3 COMBI-AD Study of Adjuvant Dabrafenib Plus Trametinib vs Placebo in Patients With Stage III BRAF V600E/K–Mutant Melanoma Georgina V. Long,1 Axel Hauschild,2 Mario Santinami,3 Victoria Atkinson,4 Mario Mandalà,5 Vanna Chiarion-Sileni,6 James Larkin,7 Marta Nyakas,8 Caroline Dutriaux,9 Andrew Haydon,10 Caroline Robert,11 Laurent Mortier,12 Jacob Schachter,13 Dirk Schadendorf,14 Thierry Lesimple,15 Ruth Plummer,16 Ran Ji,17 Pingkuan Zhang,17 Bijoyesh Mookerjee,17 Jeff Legos,17 Richard Kefford,18 Reinhard Dummer,19 John M. Kirkwood20 1Melanoma Institute Australia, The University of Sydney, Royal North Shore and Mater Hospitals, Sydney, NSW, Australia; 2University Hospital Schleswig-Holstein, Kiel, Germany; 3Fondazione Istituto Nazionale Tumori, Milano, Italy; 4Princess Alexandra Hospital, Gallipoli Medical Research Foundation, University of Queensland, QLD, Australia; 5Papa Giovanni XXIII Cancer Center Hospital, Bergamo, Italy; 6Melanoma Oncology Unit, Veneto Oncology Institute, Gattamelata, Padova, Italy; 7Royal Marsden NHS Foundation Trust, London, United Kingdom; 8Oslo University Hospital, Oslo, Norway; 9Centre Hospitalier Universitaire de Bordeaux, Hôpital Saint- André, Bordeaux, France; 10The Alfred Hospital, Melbourne, VIC, Australia; 11Institute Gustave Roussy, Paris, France; 12Université de Lille, INSERM U 1189, CHRU Lille, France; 13Ella Institute for Melanoma, Sheba Medical Center, Tel Hashomer, Israel; 14University Hospital Essen, Essen, Germany, and German Cancer Consortium, Heidelberg, Germany; 15Medical Oncology Department, Centre Eugène Marquis, Rennes, France; 16Northern Centre for Cancer Care, Freeman Hospital, Newcastle upon Tyne, United Kingdom; 17Novartis Pharmaceuticals Corporation, East Hanover, NJ, United States; 18Macquarie University, Melanoma Institute Australia, Westmead Hospital, and University of Sydney, NSW, Australia; 19University Hospital Zürich Skin Cancer Center, Zürich, Switzerland; 20Melanoma Program, Hillman UPMC Cancer Center, University of Pittsburgh, Pittsburgh, PA, United States Introduction • Surgery alone is often curative for patients with localized melanoma; however, those with regional involvement (stage III disease) are at a higher risk for disease progression even with complete surgical resection.1,2 • In phase 3 trials involving patients with previously untreated advanced or metastatic BRAF V600-mutant melanoma, dabrafenib plus trametinib combination therapy improved clinical outcomes and was well tolerated.3,4 • The COMBI‑AD study (NCT01682083) is a randomized, double-blind, placebo-controlled, phase 3 trial that evaluated the efficacy and safety of dabrafenib plus trametinib combination therapy in patients with completely resected, high-risk, stage III, BRAF V600E/K-mutant melanoma without prior anticancer therapy.5 Figure 1. Study Rationale3, 5–8 Time From Randomisation, months O S , p ro p o rt io n a liv e 0 6 12 18 24 30 36 42 1.0 0.0 0.8 0.6 0.4 0.2 48 54 60 66 Dabrafenib Dacarbazine Dabrafenib plus trametinib Dabrafenib plus placebo pERK Proliferation, survival, invasion, metastasis RAS MEK mut BRAF Dabrafenib MAPK pathway Trametinib Overall Survival Benefit in BRAF V600–Mutant Stage IV Melanoma Can we prevent stage IV? MAPK, mitogen-activated protein kinase; mut, mutated; pERK, phosphorylated extracellular signal- regulated kinase. Figure 2. Study Design 1:1 Dabrafenib 150 mg BID + trametinib 2 mg QD (n = 438) 2 matched placebos (n = 432) N = 870 Follow-upb until end of studyc Median follow-up for primary analysis: 2.8 years • Primary endpoint: RFSd • Secondary endpoints: OS,e DMFS, FFR, safety Treatment duration: 12 monthsa R A N D O M I S A T I O N Key eligibility criteria • Completely resected stage IIIA (lymph node metastasis > 1 mm), IIIB, or IIIC cutaneous melanoma • BRAF V600E/K mutation • Surgically free of disease ≤ 12 weeks before randomisation • ECOG performance status 0 or 1 • No prior radiotherapy or systemic therapy Stratification • BRAF mutation status (V600E, V600K) • Disease stage (IIIA, IIIB, IIIC) BID, twice daily; DMFS, distant metastasis–free survival; ECOG, Eastern Cooperative Oncology Group; FFR, freedom from relapse; OS, overall survival; QD, once daily; RFS, relapse-free survival. a Or until disease recurrence, death, unacceptable toxicity, or withdrawal of consent. b Patients were followed for disease recurrence until the first recurrence and thereafter for survival. c The study will be considered complete and final OS analysis will occur when ≈ 70% of randomized patients have died or are lost to follow-up. d Study was designed to provide > 90% power (assuming ≈ 410 RFS events observed) to detect an HR of 0.71 with an overall 2-sided type I error rate of 5%. New primary melanoma considered as an event. e OS was to be tested only if the primary endpoint (RFS) significantly favoured the combination arm. Figure 3. Primary Analysis: RFS and OS Median follow-up: 2.8 years 438 413 405 392 382 373 355 336 325 299 282 276 263 257 233 202 194 147 116 110 66 52 42 19 7 2 0 432 387 322 280 263 243 219 203 198 185 178 175 168 166 158 141 138 106 87 86 50 33 30 9 3 0 0 No. at Risk 0 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 P ro p o rt io n A liv e a n d R e la p se F re e 1 y, 88% 2 y, 67% 3 y, 58%1 y, 56% 2 y, 44% 3 y, 39% Relapse-Free Survival (primary endpoint) Overall Survival Months From Randomisation Group Events, n (%) Median (95% CI), months HR (95% CI) Dabrafenib plus trametinib 166 (38) Placebo 248 (57) NR (44.5-NR) 16.6 (12.7-22.1) 0.47 (0.39-0.58); P <.001 1 y, 97% 2 y, 91% 3 y, 86% 1 y, 94% 2 y, 83% 3 y, 77% 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 P ro p o rt io n A liv e Group Events, n (%) Median (95% CI), months HR (95% CI) Dabrafenib plus trametinib 60 (14) Placebo 93 (22) NR (NR-NR) NR (NR-NR) 0.57 (0.42-0.79); P = .0006a 438 426 432 425 0 2 416 415 4 414 410 6 408 401 8 401 386 10 395 378 12 387 362 14 381 346 16 376 337 18 370 328 20 366 323 22 362 308 24 352 303 26 328 284 28 301 269 30 291 252 32 233 202 34 180 164 36 164 152 38 105 94 40 82 64 42 67 51 44 28 17 46 12 7 48 5 1 50 0 0 52 0 0 54 No. at Risk Months From Randomisation Data cutoff: 30 June 2017. NR, not reached. a Prespecified significance boundary (P = .000019); next interim analysis planned when 50% of events have occurred. Figure 4. Primary Analysis: RFS by Subgroup 0.01 1.000.10 0.51 0.37 0.51 0.33 0.43 0.43 10.00Hazard Ratio Favours Dabrafenib Plus Trametinib 0.45 0.50 0.38 0.51 0.55 0.43 0.48 0.54V600K (n = 78) V600E (n = 792) Male (n = 482) Female (n = 388) < 65 years (n = 712) ≥ 65 years (n = 158) Disease stage IIIA (n = 154) Disease stage IIIB (n = 356) Disease stage IIIC (n = 347) Micrometastasis(n = 309) Macrometastasis(n = 319) Micrometastasis and ulceration (n = 143) Micrometastasis and no ulceration (n = 165) Macrometastasis and ulceration (n = 116) Macrometastasis and no ulceration (n = 201) 1 nodal metastatic mass (n = 360) 2–3 nodal metastatic masses (n = 308) ≥ 4 nodal metastatic masses (n = 145) 0.52 0.49 0.44 0.44 Favours Placebo Data cutoff: 30 June 2017. Figure 5. RFS: Stage IIIA 83 81 81 80 79 77 76 74 73 70 68 66 62 62 58 52 51 40 34 33 12 6 5 3 0 0 71 67 59 56 55 53 50 46 45 44 43 42 41 41 39 34 32 22 20 20 6 4 4 0 0 0 Months From Randomisation Dabrafenib plus trametinib Placebo No. at Risk 0 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 P ro p o rt io n A liv e a n d R e la p se F re e 2 y, 84.3% 3 y, 79.3%1 y, 79.3% 1 y, 97.5% 2 y, 69.5% 3 y, 62.9% Group Events, n (%) HR (95% CI) Dabrafenib plus trametinib 15 (18) NR (NR-NR) NR (NR-NR) 0.44 (0.23-0.84)Placebo 23 (32) Median (95% CI), months NR, not reached. Figure 6. RFS: Stage IIIB 169 161 158 151 147 142 134 126 121 110 103 101 99 96 84 72 70 50 40 38 32 25 21 10 4 2 187 177 154 135 126 116 102 95 92 84 79 79 74 73 67 57 57 49 38 38 27 19 18 7 2 0 Dabrafenib plus trametinib Placebo No. at Risk 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 1 y, 87.2% 2 y, 65.6% 3 y, 57.3%1 y, 58.8% 2 y, 43.7% 3 y, 38.5% 0 0 52 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 P ro p o rt io n A liv e a n d R e la p se F re e Group Events, n (%) HR (95% CI) Dabrafenib plus trametinib 64 (38) NR (33.2-NR) 17.2 (13.8-27.5) 0.50 (0.37-0.67)Placebo 110 (59) Median (95% CI), months Months From Randomisation NR, not reached. Figure 7. RFS: Stage IIIC 181 167 162 157 152 150 142 133 128 116 109 107 100 97 89 76 71 56 41 38 21 20 16 6 3 0 166 137 103 84 77 69 64 59 58 54 53 51 50 49 49 47 46 33 27 26 15 9 7 2 1 0 Dabrafenib plus trametinib Placebo No. at Risk 0 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 P ro p o rt io n A liv e a n d R e la p se F re e Months From Randomisation 1 y, 85.6% 2 y, 60.9% 3 y, 50.2% 1 y, 42.2% 2 y, 34.2% 3 y, 30.0% 0 0 52 Group Events, n (%) HR (95% CI) Dabrafenib plus trametinib 84 (46) 39.5 (27.4-NR) 7.4 (5.6-11.5) 0.45 (0.33-0.60)Placebo 111 (67) Median (95% CI), months NR, not reached. Figure 8. RFS: Stage IIIB and IIIC 350 328 320 308 299 292 276 259 249 226 212 208 199 193 173 148 141 106 81 76 53 45 37 16 7 2 353 314 257 219 203 185 166 154 150 138 132 130 124 122 116 104 103 82 65 64 42 28 25 9 3 0 Dabrafenib plus trametinib Placebo No. at Risk 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 0 0 52 1 y, 86% 2 y, 63% 3 y, 54% 1 y, 51% 2 y, 39% 3 y, 35% 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 P ro p o rt io n A liv e a n d R e la p se F re e Months From Randomisation Group Events, n (%) HR (95% CI) Dabrafenib plus trametinib 148 (42) 44.5 (33.1-NR) 12.8 (9.5-16.9) 0.48 (0.39-0.59)Placebo 221 (63) Median (95% CI), months NR, not reached. Figure 9. RFS: Micrometastases 152 144 143 138 136 133 129 123 122 114 110 107 102 102 96 85 82 60 51 50 24 14 12 5 1 1 157 149 134 121 116 109 99 92 89 84 80 79 75 75 69 60 58 45 36 36 17 12 12 3 2 0 Dabrafenib plus trametinib Placebo No. at Risk 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 0 0 52 1 y, 93.6% 2 y, 77.4% 3 y, 70.3%1 y, 70.0% 2 y, 55.6% 3 y, 49.5% 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 P ro p o rt io n A liv e a n d R e la p se F re e Months From Randomisation Group Events, n (%) HR (95% CI) Dabrafenib plus trametinib 39 (26) NR (NR-NR) 33.1 (19.8-NR) 0.44 (0.30-0.64)Placebo 72 (46) Median (95% CI), months NR, not reached. Figure 10. RFS: Macrometastases 158 150 147 142 138 135 128 120 115 107 99 97 96 92 79 67 63 48 35 32 26 23 18 8 2 0 161 148 122 102 93 85 75 68 67 61 59 57 55 54 52 46 45 37 32 31 23 14 12 5 0 0 Dabrafenib plus trametinib Placebo No. at Risk 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 0 0 52 1 y, 87.2% 2 y, 66.7% 3 y, 58.1% 1 y, 51.4% 2 y, 38.2% 3 y, 35.4% 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 P ro p o rt io n A liv e a n d R e la p se F re e Months From Randomisation Group Events, n (%) HR (95% CI) Dabrafenib plus trametinib 61 (39) NR (33.1-NR) 13.6 (8.3-19.2) 0.43 (0.31-0.58)Placebo 101 (63) Median (95% CI), months NR, not reached. Figure 11. RFS: Without Primary Tumour Ulceration 253 243 240 234 228 222 215 207 201 184 175 172 162 157 141 120 119 95 76 72 40 30 24 12 2 0 249 230 192 172 161 152 137 128 126 120 116 115 111 109 104 90 88 64 53 53 30 21 20 5 0 0 Dabrafenib plus trametinib Placebo No. at Risk 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 0 0 52 1 y, 90.8% 2 y, 70.3% 3 y, 63.3% 1 y, 59.8% 2 y, 50.4% 3 y, 44.2% 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 P ro p o rt io n A liv e a n d R e la p se F re e Months From Randomisation Group Events, n (%) HR (95% CI) Dabrafenib plus trametinib 87 (34) NR (45.6-NR) 24.4 (15.9-41.2) 0.49 (0.37-0.64)Placebo 130 (52) Median (95% CI), months NR, not reached. Figure12. RFS: With Primary Tumour Ulceration 179 165 160 153 150 148 138 127 122 113 106 103 100 99 91 81 74 52 40 38 26 22 18 7 5 2 177 153 127 105 99 88 80 73 70 63 60 58 55 55 52 49 48 40 32 31 18 12 10 4 3 0 Dabrafenib plus trametinib Placebo No. at Risk 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 0 0 52 1 y, 85.4% 2 y, 63.0% 3 y, 52.2% 1 y, 50.2% 2 y, 35.7% 3 y, 32.3% 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 P ro p o rt io n A liv e a n d R e la p se F re e Group Events, n (%) HR (95% CI) Dabrafenib plus trametinib 76 (42) 44.5 (29.3-NR) 12.0 (8.3-16.6) 0.46 (0.34-0.61)Placebo 114 (64) Months From Randomisation Median (95% CI), months NR, not reached. Table 1. Type of Recurrence at First Recurrence Type of recurrence, n (%) Dabrafenib Plus Trametinib (n = 166) Placebo (n = 248) Distant recurrence 103 (62) 133 (54) Local/regional recurrence 61 (37) 114 (46) Secondary primary melanoma 7 (4) 8 (3) Death 3 (2) 1 (< 1) Table 2. Primary Analysis: Safety Summary AE Category, n (%) Dabrafenib Plus Trametinib (n = 435) Placebo (n = 432) Any AE 422 (97) 380 (88) AEs related to study treatment 398 (91) 272 (63) Grade 3/4 AEs related to study treatment 136 (31) 21 (5) Any SAE 155 (36) 44 (10) SAEs related to study treatment 117 (27) 17 (4) AEs leading to dose interruption 289 (66) 65 (15) AEs leading to dose reduction 167 (38) 11 (3) AEs leading to treatment discontinuationa 114 (26) 12 (3) Fatal AEs related to study drug 0 0 AE, adverse event; SAE, serious adverse event. a Most common AEs leading to treatment discontinuation in the dabrafenib plus trametinib arm were pyrexia (9%) and chills (4%). • Most common AEs in the dabrafenib plus trametinib arm were pyrexia (63%) and fatigue (47%) Table 3. Characterisation of Pyrexia Events Dabrafenib Plus Trametinib (n = 435) Placebo (n = 432) Patients with pyrexia events, n (%) 292 (67) 66 (15) Median time to onset of first pyrexia occurrence (range), days 23 (1-28) 53 (1-373) Median duration of pyrexia (range), days 3 (1-92) 3 (1-340) Pyrexia event characteristics, n (%)a Serious adverse event Grade 3 Grade 4 71 (24) 24 (8) 1 (< 1) 4 (6) 2 (3) 0 Number of pyrexia occurrences, n (%)a 1 2 ≥ 3 83 (28) 57 (20) 152 (52) 45 (68) 11 (17) 10 (15) a Percentage based on number of patients with pyrexia. Table 4. Pyrexia Management and Outcome Dabrafenib Plus Trametinib (n = 435) Placebo (n = 432) Action taken with dabrafenib/trametinib, n (%)a Drug withdrawn Dose reduced Drug interrupted 40 (14)/27 (9) 86 (29)/18 (6) 202 (69)/121 (41) — — — Recovered/resolved, n (%)a 289 (99) 64 (97) a Percentage based on number of patients with pyrexia. Table 5. Secondary Malignanciesa Dabrafenib Plus Trametinib (n = 435) Placebo (n = 432) New primary melanoma 11 (3) 10 (2) New cuSCC or keratoacanthoma 8 (2) 7 (2) New basal cell carcinoma 19 (4) 14 (3) New nonskin malignancies 10 (2) • Endometrial, n = 2 • Lung, breast, renal cell, adenocarcinoma NOS, chronic myeloid leukaemia, B-cell lymphoma, lymphoma, prostate, n = 1 each 4 (1) • Colon, pancreatic, renal cell, bladder transitional cell, n = 1 each cuSCC, cutaneous squamous cell carcinoma; NOS, not otherwise specified. a Includes events occurring after randomisation. Data presented as: n (%). Conclusions • Dabrafenib plus trametinib reduced the risk of disease recurrence vs placebo in patients with resected stage III, BRAF V600E/K–mutant melanoma; this result was statistically significant and clinically meaningful – RFS HR, 0.47 (95% CI, 0.39-0.58; P < .001) – OS HR, 0.57 (95% CI, 0.42-0.79, P = .0006 [prespecified significance boundary, P = .000019]) • RFS benefit was observed in all patient subgroups – Stage IIIA HR, 0.44; stage IIIB HR, 0.50; stage IIIC HR, 0.45 – Micrometastases HR, 0.44; macrometastases HR, 0.43 – Nonulcerated HR, 0.49; ulcerated HR, 0.46 • Although pyrexia was the most common AE, it was well characterised and manageable • Dabrafenib plus trametinib represents a significant advance for the adjuvant treatment of stage III BRAF V600–mutant melanoma Acknowledgements • We thank the patients and their families for their participation • We also thank study site staff, additional investigators, and others for their contributions • This study was sponsored by GlaxoSmithKline; dabrafenib and trametinib are assets of Novartis AG as of 2 March 2015 • Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals Corporation References 1. Gershenwald JE, et al. CA Cancer J Clin. 2017;67(6):472-492. 2. Siegel RL, et al. CA Cancer J Clin. 2017;67(1):7-30. 3. Long GV, et al. Ann Oncol. 2017;28(7):1631-1639. 4. Robert C, et al. N Engl J Med. 2015;372(1):30-39. 5. Long GV, et al. N Engl J Med. 2017;377(19):1813-1823. 6. Long GV, et al. J Clin Oncol. 2011;29:1239-1246. 7. Jakob JA, et al. Cancer. 2012;118:4014-4023. 8. Chapman PB, et al. J Clin Oncol. 2017;35:[abstract 9526]. Poster Presentation at the Winter Clinical Dermatology Conference; January 12–17, 2018; Kaanapali, HI. This was previously presented at the 9th World Congress of Melanoma/14th International Congress of the Society for Melanoma Research