Characteristics of Patients With a Complete Response Treated With Dabrafenib + Trametinib Combination Therapy: Findings From Pooled COMBI-d and COMBI-v 5-Year Analysis Caroline Robert,1 Jean Jacques Grob,2 Daniil Stroyakovskiy,3 Boguslawa Karaszewska,4 Axel Hauschild,5 Evgeny Levchenko,6 Vanna Chiarion Sileni,7 Jacob Schachter,8 Claus Garbe,9 Igor Bondarenko,10 Paul Nathan,11 Antoni Ribas,12 Michael A. Davies,13 Keith Flaherty,14 Paul Burgess,15 Monique Tan,16 Eduard Gasal,16 Dirk Schadendorf,17 Georgina V. Long18 1Gustave Roussy and Paris-Sud-Paris-Saclay University, Villejuif, France; 2Aix-Marseille University, Marseille, France; 3Moscow City Oncology Hospital, Moscow, Russia; 4Przychodnia Lekarska KOMED, Konin, Poland; 5University Hospital Schleswig-Holstein, Kiel, Germany; 6Petrov Research Institute of Oncology, St Petersburg, Russia; 7Melanoma Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, Padova, Italy; 8Ella Lemelbaum Institute for Immuno-Oncology and Melanoma, Sheba Medical Center, Tel Hashomer, and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; 9Department of Dermatology, University of Tübingen, Tübingen, Germany; 10Dnipropetrovsk State Medical Academy, Dnipropetrovsk, Ukraine; 11Mount Vernon Cancer Centre, Northwood, UK; 12University of California, Los Angeles, CA; 13The University of Texas MD Anderson Cancer Center, Houston, TX; 14Dana-Farber Cancer Institute/Harvard Medical School and Massachusetts General Hospital, Boston, MA; 15Novartis Pharma AG, Basel, Switzerland; 16Novartis Pharmaceuticals Corporation, East Hanover, NJ; 17University Hospital Essen, Essen, and German Cancer Consortium, Heidelberg, Germany; 18Melanoma Institute Australia, The University of Sydney, and Royal North Shore and Mater Hospitals, Sydney, NSW, Australia Background • Dabrafenib (D) + trametinib (T) has been approved in multiple regions for the treatment of patients with BRAF V600–mutant unresectable or metastatic melanoma and as adjuvant therapy in patients with resected BRAF V600–mutant stage III melanoma1-4 • First-line D+T led to approximately one-third of patients with BRAF V600E/K–mutant unresectable or metastatic melanoma surviving to ≥ 5 years in pooled COMBI-d/v analysis5,6 – Five-year survival rates were higher in patients with normal lactate dehydrogenase (LDH) levels at baseline (43%) and in patients with normal LDH levels and < 3 organ sites with metastases at baseline (55%) • In pooled analyses, best overall response appeared to be associated with progression-free survival (PFS; Figure 1) and overall survival (OS; Figure 2), with patients achieving complete response (CR) having the best long-term outcomes5,7 – Median duration of CR was 36.7 months (95% CI, 24.1 months-not reached [NR])5 – Five-year PFS rates were 49% and 19% in patients with CR and the overall population, respectively5 – Five-year OS rates were 71% and 34% in patients with CR and the overall population, respectively5 • Increasing evidence, including recent analyses published by the US Food and Drug Administration at ASCO 2019, suggests that deeper antitumor responses are associated with longer survival8,9 • We present additional analyses to characterize outcomes and clinical features of patients who achieved CR in Phase III randomized COMBI-d/v trials to identify those most likely to derive the greatest clinical benefit from first-line D+T therapy Figure 1. PFS, According to Best Response5 Best response Complete response Partial response Stable disease P F S P ro b a b ili ty 0.0 0.2 0.4 0.6 0.8 1.0 0 6 12 18 24 Months Since Randomization 54 60 66 72 78 42 37 20 1 0 30 36 42 48 109 107 96 88 75 65 57 50 47 No. at risk 2 years, 72% 4 years, 52% 5 years, 49% 3 years, 60% 2 years, 28% 4 years, 17% 5 years, 16% 3 years, 19% 2 years, 6% 4 years, 5% 5 years, 1% 3 years, 6% 27 21 11 1 0274 224 129 87 68 56 43 36 30 2 1 0 0 0130 38 18 13 5 5 5 5 4 Complete response Partial response Stable disease PFS, progression-free survival. Figure 2. OS, According to Best Response5 Best response Complete response Partial response Stable disease O S P ro b a b ili ty 0 6 12 18 24 Months Since Randomization 54 60 66 72 78 73 72 48 4 0 30 36 42 48 109 108 103 101 97 91 88 82 77 No. at risk 78 73 46 11 0274 266 220 165 134 116 106 95 85 17 15 8 0 0130 99 54 38 32 26 23 22 18 Complete response Partial response Stable disease 2 years, 91% 4 years, 76% 5 years, 71% 3 years, 85% 2 years, 52% 4 years, 35% 5 years, 32% 3 years, 42% 2 years, 29% 4 years, 18% 5 years, 16% 3 years, 22% 0.0 0.2 0.4 0.6 0.8 1.0 OS, overall survival. Methods • This analysis included treatment-naive patients randomized to D+T in COMBI-d and COMBI-v who achieved a confirmed CR and who may or may not have subsequently remained in CR at the data cutoff for the 5-year pooled analysis (COMBI-d, December 10, 2018; COMBI-v, October 8, 2018) • An overview of patients included in the pooled analysis is presented in Table 1 Table 1. Overview of Overall Population and Patients With CR Included in COMBI-d/v 5-Year Analysis Study – D+T Arm ITT Population, n Patients With CR, na Median Follow-Up for Patients With CR (range), mo COMBI-d (NCT01584648) 211 39 68.0 (5.0-73.0) COMBI-v (NCT01597908) 352 70 64.0 (7.0-74.0) Pooled 563 109 64.0 (5.0-74.0) CR, complete response; D, dabrafenib; ITT, intention to treat; T, trametinib. a Includes patients who achieved a confirmed CR and who may or may not have subsequently remained in CR at the data cutoff date. Results Duration of Response • Median duration of response (DOR) was longer in patients with CR than in patients with partial response (PR; Table 2) – In patients with CR, median DOR was estimated to be > 60 months in COMBI-d and was 49.7 months in COMBI-v (Table 2) Table 2. DOR in Patients Treated With D+T With CR or PR Patients With CR Patients With PR COMBI-d Patients, n Median DOR (95% CI), mo 39 NR (34.5-NR) 107 9.2 (7.2-10.5) COMBI-v Patients, n Median DOR (95% CI), mo 70 49.7 (27.6-NR) 167 10.8 (8.5-11.3) CR, complete response; D, dabrafenib; DOR, duration of response; NR, not reached; PR, partial response; T, trametinib. Baseline Characteristics in Patients With and Without CR • A higher proportion of patients who achieved CR had Eastern Cooperative Oncology Group performance status (ECOG PS) 0, normal LDH levels, and < 3 organ sites with metastases at baseline compared with patients who did not have a CR (Table 3) Table 3. Baseline Characteristics in Patients With and Without CR Patients With CRa (n = 109) Patients Without CR (n = 454) Age, median (range), years 57 (26-80) 55 (18-91) Male, n (%) 50 (46) 269 (59) Stage IV M1c, n (%) 42 (39) 318 (70) ECOG PS, n (%) 0 ≥ 1 Missing 94 (86) 14 (13) 1 (< 1) 309 (68) 141 (31) 4 (< 1) LDH level, n (%) Normal > ULN Missing 98 (90) 11 (10) 0 267 (59) 183 (40) 4 (< 1) ≥ 3 disease sites, n (%) 17 (16) 258 (57) Sum of lesion diameters, median, mm 34.0 69.0 CR, complete response; ECOG PS, Eastern Cooperative Oncology Group performance status; LDH, lactate dehydrogenase; ULN, upper limit of normal. a Includes patients who achieved CR and who may or may not have subsequently remained in CR at the data cutoff date, including those who were subsequently withdrawn from study or lost to follow-up prior to documented progression. Patient Disposition • At the time of this analysis, 41% of patients with CR were still receiving D+T or had entered follow-up (Table 4) • Of 109 patients with CR, 55 (50%) had ongoing CR at the data cutoff date Table 4. Disposition of Patients With CR n (%) Patients With CR (n = 109) Died 31 (28) Ongoing On treatment In follow-up 45 (41) 21 (19) 24 (22) Withdrawn from study Study closed Consent withdrawn Loss to follow-up Investigator discretion 33 (30) 23 (21) 5 (5) 3 (3) 2 (2) CR, complete response. Treatment Status in Patients Who Achieved CR • Median time to CR was 5.6 months (95% CI, 4.0-7.3 months) • Of 109 patients who achieved a CR, 88 (81%) discontinued D and/or T • The most common reason for discontinuation of D or T was disease progression (Table 5) – A higher proportion of patients who had a PR discontinued D or T due to disease progression (≈ 72%) compared with patients who achieved a CR (≈ 42%) Table 5. Overview of Reasons for Discontinuation of D or T in Patients Who Achieved CR n (%) D (n = 88) T (n = 88) Disease progression 38 (43) 36 (41) Adverse events 20 (23) 23 (26) Patient/proxy decision 13 (15) 12 (14) Study closed 11 (13) 12 (14) Investigator discretion 5 (6) 4 (5) Loss to follow-up 1 (1) 1 (1) CR, complete response; D, dabrafenib; T, trametinib. • Of 109 patients who achieved a CR, 46 (42%) discontinued D and/or T while in response – Adverse events were the most common reason for discontinuation of D (35%) or T (39%) in patients still in CR (Figure 3) Figure 3. Reasons for Stopping (A) Dabrafenib or (B) Trametinib in Patients Who Remained in CR at Time of Discontinuation (n = 46) Adverse events 35% Patient/proxy decision 24% Study closed 24% Investigator discretion 11% Disease progressiona 4% Loss to follow-up 2% Adverse events 39% Patient/proxy decision 24% Study closed 24% Investigator discretion 9% Disease progressiona 2% Loss to follow-up 2% A B CR, complete response. a Treatment discontinued before the date of disease progression, but disease progression occurred prior to the data cutoff date. Baseline Characteristics in Patients Whose Disease Did or Did Not Progress After CR • Baseline characteristics were similar overall in patients whose disease did or did not progress after they achieved a CR (Table 6) Patterns of Progression • Of 109 patients with CR, 54 (50%) had disease progression and 48 had new lesions – Common sites of new lesions included the central nervous system (CNS; 54%), lung (17%), lymph nodes (17%), and skin/subcutaneous tissue (13%) • In patients with CR whose disease progressed, the patterns of progression were similar to those observed in the overall population (n = 359) – In the overall population, common sites of progression included the CNS (40%), lung (21%), lymph nodes (21%), and liver (14%) – The CNS was the only site of new lesions in 19 of 26 patients (73%) with CR and 104 of 144 patients (72%) in the overall population Table 6. Baseline Characteristics in Patients With CR Whose Disease Did or Did Not Progress Patients With CR Whose Disease Progressed (n = 54) Patients With CR Whose Disease Did Not Progress (n = 55) Age, median (range), years 56 (26-80) 57 (31-77) Male, n (%) 26 (48) 24 (44) Stage IV M1c, n (%) 20 (37) 22 (40) ECOG PS, n (%) 0 ≥ 1 Missing 47 (87) 7 (13) 0 47 (85) 7 (13) 1 (2) LDH, n (%) Normal > ULN 47 (87) 7 (13) 51 (93) 4 (7) ≥ 3 disease sites, n (%) 10 (19) 7 (13) Sum of lesion diameters, median, mm 35.0 33.0 CR, complete response; ECOG PS, Eastern Cooperative Oncology Group performance status; LDH, lactate dehydrogenase; ULN, upper limit of normal. Subsequent Therapy • Common posttreatment anticancer therapy for patients who achieved a CR included targeted therapy (23%), and anti–programmed death receptor 1 (PD-1; 19%), and anti–cytotoxic T-lymphocyte–associated antigen 4 immunotherapies (16%) (Table 7) Table 7. Summary of Posttreatment Anticancer Therapy n (%) Patients With CR (n = 109) Any subsequent therapy 43 (39) Radiotherapy 21 (19) Surgery 5 (5) Targeted therapy Dabrafenib Trametinib Vemurafenib Cobimetinib Binimetinib Encorafenib 25 (23) 20 (18) 14 (13) 6 (6) 4 (4) 2 (2) 2 (2) Immunotherapy Ipilimumab Pembrolizumab Nivolumab 28 (26) 17 (16) 13 (12) 8 (7) Chemotherapy 10 (9) CR, complete response. Conclusions • Pooled analysis of the COMBI-d/v studies showed that patients who were treated with D+T and achieved CR (19%) demonstrated improved survival outcomes compared with the overall population – CRs showed durability, with a median duration of 36.7 months and 55 patients (50%) still in CR as of the last disease assessment – Median DOR was longer in patients with CR than in patients with PR • A higher proportion of patients who achieved CR had ECOG PS 0, normal LDH levels, and < 3 organ sites with metastases at baseline compared with patients without CR • Select baseline factors may be useful for identifying patients with advanced BRAF V600E/K–mutant melanoma who may derive the greatest clinical benefit from first-line D+T combination therapy, although additional analyses are needed for validation • Increasing evidence suggests that CR is associated with long-term benefit.8,9 To further improve outcomes, a trial combining D+T with the anti–PD-1 inhibitor spartalizumab in patients with metastatic BRAF V600–mutant melanoma (NCT02967692) is ongoing Acknowledgments The authors thank the patients and their families for their participation. We also thank all investigators and site staff for their contributions. Statistical support needed to conduct this post hoc analysis was provided by Novartis Pharmaceuticals Corporation. We also thank Maurizio Voi, MD (Novartis Pharmaceuticals Corporation), for guidance and critical review and Jorge J. Moreno-Cantu, MSc, PhD (Novartis Pharmaceuticals Corporation), for editorial assistance. We thank Zareen Khan, PhD, from ArticulateScience LLC, for medical editorial assistance with this presentation, which was funded by Novartis Pharmaceuticals Corporation, East Hanover, NJ, in accordance with Good Publication Practice (GPP3) (https://www.ismpp.org/gpp3) guidelines and International Committee of Medical Journal Editors recommendations. This study was sponsored by GlaxoSmithKline; dabrafenib and trametinib are assets of Novartis AG as of March 2, 2015. References 1. Tafinlar (dabrafenib) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2020. 2. Mekinist (trametinib) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2020. 3. Tafinlar (dabrafenib) [summary of product characteristics]. Camberley, UK: Novartis Pharmaceuticals UK Ltd; 2020. https://www.ema.europa.eu/en/documents/product- information/tafinlar-epar-product-information_en.pdf. Accessed July 31, 2020. 4. Mekinist (trametinib) [summary of product characteristics]. Camberley, UK: Novartis Pharmaceuticals UK Ltd; 2020. https://www.ema.europa.eu/en/documents/product- information/mekinist-epar-product-information_en.pdf. Accessed July 31, 2020. 5. Robert C, et al. N Engl J Med. 2019;381:626-636. 6. Nathan P, et al. J Clin Oncol. 2019;37:abstract 9507. 7. Long GV, et al. Lancet Oncol. 2016;17:1743-1754. 8. Osgood C, et al. J Clin Oncol. 2019;37:abstract 9508. 9. McCoach CE, et al. Ann Oncol. 2017;28:2707-2714. Poster presentation at the Fall Clinical Dermatology Conference; October 29-November 1, 2020; Las Vegas, NV. 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