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Background D+T has been approved for several indications, including BRAF V600–mutant unresectable or metastatic melanoma and as adjuvant therapy following resected BRAF V600–mutant stage III melanoma. Pyrexia is a common adverse event but is generally low-grade and manageable; further characterization may optimize management and reduce permanent treatment (tx) discontinuation due to pyrexia. Methods Trial databases were queried for reports of pyrexia in pts treated with D and/or T, including adjuvant therapy. Indications included unresectable, metastatic, or resected stage III melanoma; non-small cell lung cancer (NSCLC); colorectal cancer, and other BRAF–mutation positive solid tumors. Data for D+T was compiled from the following trials: COMBI-AD (NCT01682083), COMBI-d (NCT01584648), COMBI-v (NCT01597908), and BRF113928 (NCT01336634). Pyrexia was graded according to the Common Terminology Criteria for Adverse Events version 4.0. Results A total of 1991 pts were included from clinical trials (D+T, n=1076; D, n=586; T, n=329). Pyrexia was observed in 904 pts: D+T, 61% (660/1076); D, 33% (196/586); T, 15% (48/329). Of pts treated with D+T, 6% (62/1076) experienced grade 3 events and 1 of 1076 pts experienced a grade 4 event. The median time to onset was 27 d (range, 1-716 d). Recurrent any-grade pyrexia occurred in 41% (442/1076) of pts; 29% had ≥ 3 episodes. Of the 442 pts with recurrent pyrexia, 377 (85%) experienced a subsequent event within 3mo of the first pyrexia episode. No pyrexia-related deaths were reported. Outcomes were reported for 2252 of 2253 events in pts treated with D+T across trials. Pyrexia management strategies included: tx interruption (939/2253 events [42%]), dose reduction (225/2253 [10%]), and tx discontinuation (62/2253 [3%]); ≥ 98% of events were reported to be resolved following each of the aforementioned interventions. Conclusions Pyrexia in pts treated with D+T is typically low-grade, occurs early during tx exposure, and most pts experience ≤ 1 episode. Tx interruption was the most frequent intervention strategy used in clinical trials. Pyrexia can be effectively managed with nearly all events reported to have been resolved at the time of the analysis. Clinical trial identification Pooled analysis of data from the following trials: NCT01227889, NCT01153763, NCT01266967, NCT01072175, NCT00880321, NCT01336634, NCT01584648, NCT01597908, NCT01682083, NCT01245062, NCT01037127, NCT00687622. Editorial acknowledgement Allison Lytle, PhD, from ArticulateScience LLC, funded by Novartis Pharmaceuticals Corporation. Legal entity responsible for the study Novartis Pharmaceuticals Corporation. Funding Novartis Pharmaceuticals Corporation. Disclosure C. Robert: Non-remunerated activity/ies, Medical writing assistance: ArticulateScience LLC; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Roche; Advisory / Consultancy: MSD; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy: Array; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Merck. D. Schadendorf: Non-remunerated activity/ies, Medical writing assistance: ArticulateScience LLC; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche/Genentech; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck Sharp & Dohme; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Merck Serono; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Amgen; Honoraria (self), Advisory / Consultancy: Immunocore; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Incyte; Honoraria (self), Advisory / Consultancy: 4SC; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Pierre Fabre; Honoraria (self), Advisory / Consultancy: Mologen; Advisory / Consultancy: Sanofi/Regeneron; Speaker Bureau / Expert testimony: Roche; Travel / Accommodation / Expenses: Merck; Honoraria (self): Sysmex; Honoraria (self): Grunenthal Group; Honoraria (self): Agenus; Honoraria (self): Array BioPharma; Honoraria (self): AstraZeneca; Honoraria (self): LEO Pharma; Honoraria (self): Pfizer; Honoraria (self): Philogen; Honoraria (self): Regeneron. R. Dummer: Non-remunerated activity/ies, Medical writing assistance: ArticulateScience LLC; Advisory / Consultancy, Intermittent, project focused consulting and/or advisory relationship: Novartis; Advisory / Consultancy, Intermittent, project focused consulting and/or advisory relationship: Merck Sharp & Dhome; Advisory / Consultancy, Intermittent, project focused consulting and/or advisory relationship: Bristol-Myers Squibb; Advisory / Consultancy, Intermittent, project focused consulting and/or advisory relationship: Roche; Advisory / Consultancy, Intermittent, project focused consulting and/or advisory relationship: Amgen; Advisory / Consultancy, Intermittent, project focused consulting and/or advisory relationship: Takeda; Advisory / Consultancy, Intermittent, project focused consulting and/or advisory relationship: Pierre Fabre; Advisory / Consultancy, Intermittent, project focused consulting and/or advisory relationship: Sun Pharma; Advisory / Consultancy, Intermittent, project focused consulting and/or advisory relationship: Sanofi; Advisory / Consultancy, Intermittent, project focused consulting and/or advisory relationship: Catalym. K.T. Flaherty: Non-remunerated activity/ies, Medical writing assistance: ArticulateScience LLC; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Genentech; Advisory / Consultancy: Merck; Advisory / Consultancy: Lilly; Advisory / Consultancy: Amgen; Advisory / Consultancy, Research grant / Funding (institution): Sanofi; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Oncoceutics; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Adaptimmune; Advisory / Consultancy: Aeglea Biotherapeutics; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Loxo; Advisory / Consultancy: Roche; Advisory / Consultancy: Asana Biosciences; Advisory / Consultancy: Incyte; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Shattuck Labs; Advisory / Consultancy: Tolero Pharmaceuticals; Advisory / Consultancy: Array BioPharma; Advisory / Consultancy, Shareholder / Stockholder / Stock options: FOGPharma; Advisory / Consultancy: Neon Therapeutics; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Tvardi; Advisory / Consultancy: Takeda; Advisory / Consultancy: Varestem; Advisory / Consultancy: Boston Biomedical; Advisory / Consultancy, Travel / Accommodation / Expenses: Pierre Fabre; Advisory / Consultancy: Cell Medica; Advisory / Consultancy, Travel / Accommodation / Expenses: Debiopharm Group; Shareholder / Stockholder / Stock options: Clovis Oncology; Shareholder / Stockholder / Stock options: X4 Pharma; Shareholder / Stockholder / Stock options: PIC Therapeutics; Shareholder / Stockholder / Stock options: Fount Therapeutics; Shareholder / Stockholder / Stock options: Apricity Health; Shareholder / Stockholder / Stock options: Vivid Biosciences; Shareholder / Stockholder / Stock options: Checkmate Pharmaceuticals; Shareholder / Stockholder / Stock options: Strata Oncology. H.A. Tawbi: Non-remunerated activity/ies, Medical writing assistance: ArticulateScience LLC; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): Merck; Research grant / Funding (institution): GlaxoSmithKline; Advisory / Consultancy: Roche; Advisory / Consultancy: Array; Research grant / Funding (institution): Celgene. A.M. Menzies: Non-remunerated activity/ies, Medical writing assistance: ArticulateScience LLC; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: MSD; Advisory / Consultancy: Novartis; Advisory / Consultancy: Roche; Advisory / Consultancy: Pierre Fabre. A. D'Amelio: Non-remunerated activity/ies, Medical writing assistance: ArticulateScience LLC; Shareholder / Stockholder / Stock options, Full / Part-time employment: Novartis; Shareholder / Stockholder / Stock options: GlaxoSmithKline. E. de Jong: Non-remunerated activity/ies, Medical writing assistance: ArticulateScience LLC; Shareholder / Stockholder / Stock options, Full / Part-time employment: Novartis. E. Gasal: Non-remunerated activity/ies, Medical writing assistance: ArticulateScience LLC; Shareholder / Stockholder / Stock options, Full / Part-time employment: Novartis. G.V. Long: Non-remunerated activity/ies, Medical writing assistance: ArticulateScience LLC; Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Roche/Genentech; Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: Merck; Honoraria (self), Advisory / Consultancy: Novartis; Advisory / Consultancy: Array BioPharma; Advisory / Consultancy: Pierre Fabre.

Purpose To report 5-year landmark analysis efficacy and safety outcomes in patients with BRAF V600–mutant metastatic melanoma (MM) who received BRAF inhibitor dabrafenib (D) and MEK inhibitor trametinib (T) combination therapy versus D monotherapy in the randomized phase II BRF113220 study part C. Patients and Methods BRAF inhibitor–naive patients with BRAF V600–mutant MM were randomly assigned 1:1:1 to receive D 150 mg twice a day, D 150 mg twice a day plus T 1 mg once daily, or D 150 mg twice a day plus T 2 mg once daily (D + T 150/2). Patients who received D monotherapy could cross over to D + T 150/2 postprogression. Efficacy and safety were analyzed 4 and 5 years after initiation in patients with ≥ 5 years of follow-up. Results As of October 13, 2016, 18 patients who received D + T 150/2 remained in the study (13 [24%] of 54 enrolled at this dose plus five [11%] of 45 initially administered D who crossed over to D + T). With D + T 150/2, overall survival (OS; 4 years, 30%; 5 years, 28%) and progression-free survival (4 and 5 years, both 13%) appeared to stabilize with extended follow-up. Increased OS was observed in patients who received D + T with baseline normal lactate dehydrogenase (5 years, 45%) and normal lactate dehydrogenase with fewer than three organ sites with metastasis (5 years, 51%). With extended follow-up, one additional patient who received D + T 150/2 improved from a partial to a complete response. No new safety signals were observed. Conclusion This 5-year analysis represents the longest follow-up to date with BRAF + MEK inhibitor combination therapy in BRAF V600–mutant MM. Consistent with trends observed in landmark analyses with shorter follow-up, this therapy elicits durable plateaus of long-term OS and progression-free survival that last ≥ 5 years in some patients with MM.

The use of darbepoetin alfa to treat anemia in patients with lower-risk myelodysplastic syndromes (MDS) was evaluated in a phase 3 trial. Eligible patients had low/intermediate-1 risk MDS, hemoglobin ⩽10 g/dl, low transfusion burden and serum erythropoietin (EPO) ⩽500 mU/ml. Patients were randomized 2:1 to receive 24 weeks of subcutaneous darbepoetin alfa 500 μg or placebo every 3 weeks (Q3W), followed by 48 weeks of open-label darbepoetin alfa. A total of 147 patients were randomized, with median hemoglobin of 9.3 (Q1:8.8, Q3:9.7) g/dl and median baseline serum EPO of 69 (Q1:36, Q3:158) mU/ml. Transfusion incidence from weeks 5–24 was significantly lower with darbepoetin alfa versus placebo (36.1% (35/97) versus 59.2% (29/49), P=0.008) and erythroid response rates increased significantly with darbepoetin alfa (14.7% (11/75 evaluable) versus 0% (0/35 evaluable), P=0.016). In the 48-week open-label period, dose frequency increased from Q3W to Q2W in 81% (102/126) of patients; this was associated with a higher hematologic improvement–erythroid response rate (34.7% (34/98)). Safety results were consistent with a previous darbepoetin alfa phase 2 MDS trial. In conclusion, 24 weeks of darbepoetin alfa Q3W significantly reduced transfusions and increased rates of erythroid response with no new safety signals in lower-risk MDS (registered as EudraCT#2009-016522-14 and NCT#01362140).

A comprehensive literature search was performed to examine the influence of changes in erythropoietin-stimulating agent (ESA) label and reimbursement policies on utilization of red blood cell transfusions and patient hemoglobin levels in US cancer patients receiving chemotherapy or anemia management. Studies conducted in ESA-treated patients showed an increase in transfusion rates when comparing the post-intervention period with pre-intervention period (range of relative change: 15-125%). Results from studies conducted in patients receiving chemotherapy irrespective of anemia treatment were variable; single-institution-based studies tended to show a decrease in transfusion rates (range of relative change: -3.2 to -24.1%), while multiple-institution-based studies suggested an increase in transfusion rates (range of relative change: 12-182%). Studies showed decreases in hemoglobin levels during chemotherapy or at ESA initiation, and decreased ESA utilization.

Pharmacovigilance (PV) is the science and activities relating to the detection, assessment, understanding, and prevention of adverse effects or other problems related to medical products after they have been licensed for marketing. The purpose of PV is to advance the safe use of marketed medical products. Regulatory agencies and license holders collaborate to collect data reported by health care providers, patients, and the public as well as data from systematic reviews, meta-analyses, and individual clinical and nonclinical studies. They validate and analyze the data to determine whether safety signals exist, and if warranted, develop an action plan to mitigate the identified risk. Erythropoiesis-stimulating agents (ESAs) provide an example of how PV is applied in reality. Among other approved indications, ESAs may be used to treat anemia in patients with chemotherapy-induced anemia. ESAs increase hemoglobin levels and reduce the need for transfusions; they are also associated with a known increased risk of thromboembolic events. Starting in 2003, emerging data suggested that ESAs might reduce survival. As a result of PV activities by regulatory agencies and license holders, labeling for ESAs addresses these risks. Meta-analyses and individual clinical studies have confirmed that ESAs increase the risk of thromboembolic events, but when used as indicated, ESAs have not been shown to have a significant effect on survival or disease progression. Ongoing safety studies will provide additional data in the coming years to further clarify the risks and benefits of ESAs.

Background: Significant advancements, including development of immune checkpoint inhibitors and targeted therapies, have transformed outcomes in patients (pts) with unresectable or metastatic melanoma. However, pts who do not respond or who progress while receiving these regimens have limited options. Spartalizumab (PDR001) is a high-affinity, humanized monoclonal antibody blocking the programmed cell death 1 (PD-1) receptor. This study is evaluating combinations of spartalizumab with novel compounds to restore antitumor T-cell activity in pts with melanoma progressing after prior PD-1 blockade therapy. Methods: This randomized, open-label, 2-part, multicenter, open-platform, Phase II study (NCT03484923; PLATforM) will evaluate the safety and efficacy of spartalizumab combination treatment in pts with unresectable or metastatic melanoma progressing after prior anti-PD-1/L1 therapy and, if the tumor harbors a BRAF V600 mutation, a BRAF inhibitor. The primary endpoint is objective response rate per RECIST v1.1, with duration of response and assessment of paired tumor biopsies for biomarkers of antitumor T-cell activity as part of the secondary endpoints. Part 1, “selection”, will begin with 3 combination arms: (1) spartalizumab + LAG525 (LAG-3 antibody), (2) spartalizumab + capmatinib (c-MET inhibitor), and (3) spartalizumab + canakinumab (IL-1β antagonist). The PLATforM study will use an adaptive design during the selection part that allows for dropping arms for futility, adding new arms, and selecting 1 or multiple arms for further expansion. Bayesian methodology will be used with specific probability criteria for futility and efficacy assessments at each interim analysis. Pts (≈ 60-85) will be stratified by baseline lactate dehydrogenase level and randomized equally to all open arms during the selection part. Part 2, “expansion”, will further investigate the efficacy and safety of treatment combination(s) selected during part 1. The sample size for part 2 will be adaptive and based on predictive power calculations considering the results from part 1. Previously presented at ESMO 2018, FPN 1304TiP, Weber et al. Reused with permission. Citation Format: Caroline Robert, Reinhard Dummer, Ana Arance, Antoni Ribas, Jeffrey Weber, Georgina V. Long, John Haanen, Paul Nathan, Paolo A. Ascierto, Eduard Gasal, Anthony D'Amelio, Severine Bettinger, Aislyn D. Boran, Dirk Schadendorf. A randomized, open-label, open-platform, Phase II study evaluating the efficacy and safety of novel spartalizumab (PDR001) combinations in previously treated unresectable or metastatic melanoma (PLATforM) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT120.

9531 Background: Checkpoint inhibitors and targeted therapies have improved outcomes in pts with BRAF V600–mutant advanced melanoma; however, many pts progress and new treatment (tx) strategies are needed. BRAF inhibition increases T-cell infiltration, melanoma antigen expression, and PD-1/PD-L1 expression, which may lead to synergistic activity with anti–PD-1 therapy. Methods: COMBI-i is investigating first-line S 400 mg Q4W + D 150 mg BID + T 2 mg QD in pts with unresectable or metastatic BRAF V600–mutant melanoma (NCT02967692). Here we report pooled efficacy and safety data from parts 1 (run-in cohort) and 2 (biomarker cohort). Response was assessed per RECIST v1.1. Results: 36 pts were enrolled (part 1: n = 9; part 2: n = 27); 18 (50%) had stage IV M1c and 15 (42%) had elevated LDH levels. At the data cutoff (median follow-up, 15.2 mo), tx was ongoing in 17 pts (47%). The confirmed objective response rate (ORR) by investigator assessment was 75% (n = 27), with 33% complete responses (CRs; n = 12). Medians for duration of response (DOR; 7/27 pts with events), progression-free survival (PFS; 13/36 pts with events), and overall survival (OS; 7/36 pts with events) were not reached. 12-mo DOR rate was 71.4% (95% CI, 49%-85%). 12-mo PFS and OS rates were 65.3% (95% CI, 47%-79%) and 85.9% (95% CI, 69%-94%), respectively. In pts with high baseline LDH: ORR was 67%, with 3 CRs (20%), median PFS was 10.7 mo (events in 10/15 pts [67%]), and median OS was not reached, with events in 6/15 pts (40%). All pts had ≥ 1 AE; 27 (75%) had grade ≥ 3 AEs. 6 pts (17%) had AEs leading to discontinuation of all 3 study drugs. Any-grade AEs in ≥ 40% of pts included pyrexia, chills, fatigue, cough, and arthralgia. Grade ≥ 3 AEs in > 3 pts were neutropenia, pyrexia, and increased lipase. One pt died of cardiac arrest that was not considered related to study tx. Conclusions: S+D+T showed promising and durable ORR (75%) with CR in 33% of pts. With > 15 mo of follow-up, median PFS was not reached. The safety profile was manageable reflecting individual toxicities of D, T, and S. The global, placebo-controlled, randomized phase 3 (part 3) of COMBI-i is ongoing. Clinical trial information: NCT02967692.

187 Background: BTCs are rare, aggressive malignancies with poor prognoses. Treatment options and outcomes after first-line therapy are not well defined. Median progression-free survival (PFS) in second-line BTC is < 5 mo. Combined BRAF + MEK inhibition is efficacious in BRAF V600–mutated anaplastic thyroid cancer, melanoma, and lung cancer, but less so in BRAF V600E-mutated colorectal cancer. Activating BRAF V600E mutations have been reported in 0% to 20% of BTCs; thus, D (BRAF inhibitor) + T (MEK inhibitor) was evaluated as a treatment for pts with BRAF V600E–mutated BTC in the ROAR basket trial. Methods: In this phase II, open-label trial, pts with BRAF V600E mutations in 9 rare tumor types, including BTC, received D (150 mg BID) + T (2 mg QD) until unacceptable toxicity, disease progression, or death. Eligible pts had advanced or metastatic cancer and had been treated with ≥ 1 prior systemic therapy. The primary endpoint was investigator-assessed overall response rate (ORR). Secondary endpoints included duration of response (DOR), PFS, overall survival (OS), biomarker correlates, and safety. Results: Thirty-three pts with BTC had enrolled at data cutoff (January 3, 2018). BRAF V600E mutations were centrally confirmed in 30 of 33 pts with BTC (91%). Median age was 58 y, and 78% had received ≥ 2 prior lines of systemic therapy. 32 of 33 pts with BTC were evaluable. Investigator-assessed ORR was 41% (13/32; 95% CI, 24%-59%), with 6 of 13 responses ongoing at data cutoff, 7 of 13 pts (54%) had a DOR ≥ 6 mo. Median PFS was 7.2 mo (95% CI, 4.6-10.1 mo), and median OS was 11.3 mo (95% CI, 7.3-17.6 mo). Grade 3/4 adverse events in ≥ 3 pts were increased γ-glutamyltransferase (n = 3 [9%]) and decreased white blood cell count (n = 3 pts [9%]). Biomarker analyses demonstrate a heterogeneous genetic landscape, and suggest a higher baseline expression of MAPK pathway genes in the pts who did not respond to D + T. Conclusions: D + T demonstrated promising efficacy in pts with BTC, with a favorable safety profile. These pts should be considered for BRAF mutation analysis, and D + T should be considered for pts with BRAF V600E-mutated BTC. Clinical trial information: NCT02034110.

Introduction: The phase 3 COMBI-i study (NCT02967692) is evaluating spartalizumab (S; PDR001) in combination with dabrafenib + trametinib (D+T) in treatment-naive patients (pts) with BRAF V600–mutant metastatic melanoma. COMBI-i comprises 3 parts: (1) safety run-in; (2) biomarker part; and (3) double-blind, randomized, placebo-controlled part. In part 1, 9/9 pts had confirmed responses (Dummer et al. ASCO-SITC 2018). The primary objective for part 2 is to evaluate changes in PD-L1 levels and CD8+ cells after treatment with S+D+T. Here, we report first efficacy, safety, and biomarker data for part 2. Methods: In the biomarker cohort, tissue samples were collected at baseline (BL) and, if visible lesions were present, after 2-3 wk, after 8-12 wk, and at disease progression. CD8 and PD-L1 (using DAKO 28-8 assay) were examined by IHC. Any remaining tumor material was analyzed for additional biomarkers (eg, LAG3, TIM3, FOXP3, CD163). Peripheral blood mononuclear cells and plasma samples were collected at several time points for flow cytometry, ctDNA analysis, and cytokine profiling. Results: At the data cutoff (27 Oct 2017) 23 pts received S 400 mg Q4W + D 150 mg BID + T 2 mg QD. 13 pts had completed 8 wk of treatment and median follow-up was 2.0 mo (range, 0.1-3.5). At study entry, median age was 62 y. 20 pts (87%) had stage IV disease and 3 had unresectable stage III disease; 8/9 pts with stage IV M1c had elevated LDH. Adverse events (AEs) of any grade occurred in 91% of pts; 22% (n=5) were grade 3/4. No AEs led to discontinuation. Any-grade AEs occurring in ≥ 15% of pts included pyrexia (n=14, 61%), arthralgia, fatigue, rash, and vomiting (n=4 each, 17%). The only grade 3/4 event occurring in > 1 pt was pyrexia (n=2, 8.7%), which was managed with dose interruption. All 7 pts evaluable for response at first post-BL assessment at wk 12 had an unconfirmed partial response; no pts had progressive disease. In preliminary analyses of matched paired BL and on-treatment tumor samples (n=9), 4/9 tumors had no intratumoral CD8+ cells and 5/9 had very few intratumoral CD8+ cells at BL. After 2-3 wk of S+D+T treatment, 8/9 pts had an increase in intratumoral CD8+ cells; most increases were substantial. CD8+/PD-L1 and other tissue-specific and circulating biomarkers will be presented in a larger set of samples. Conclusions: Although follow-up was limited and pt numbers were small, initial data support use of the anti–PD-1 antibody S with D+T in pts with BRAF V600–mutant unresectable or metastatic melanoma. The manageable safety profile and promising efficacy are consistent with part 1 findings from COMBI-i. Initial biomarker data suggest that S+D+T has a beneficial effect on the tumor immune microenvironment, particularly on enhancing intratumoral CD8+ T-cell infiltration. Citation Format: Reinhard Dummer, Dirk Schadendorf, Paul Nathan, Hussein Tawbi, Caroline Robert, Paolo A. Ascierto, Antoni Ribas, Celeste Lebbé, Mario Mandala, Naoya Yamazaki, Erika Richtig, Wilson H. Miller, Eduard Gasal, Mathilde Kaper, Jan C. Brase, Bijoyesh Mookerjee, Georgina V. Long. The anti-PD-1 antibody spartalizumab (PDR001) in combination with dabrafenib and trametinib in previously untreated patients with advanced BRAF V600-mutant melanoma: First efficacy, safety, and biomarker findings from the part 2 biomarker cohort of COMBi-i [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT182.

189 Background: Checkpoint inhibitors and targeted therapies have improved outcomes in pts with advanced BRAF V600–mutant melanoma; however, many still progress and die from this disease. Thus, new treatment strategies are needed. BRAF and MEK inhibitor combinations (eg, D+T) may reverse immunosuppressive phenotypes induced by oncogenic BRAF and improve sensitivity to checkpoint inhibitors by enhancing HLA and melanocytic antigen expression and tumor antigen–specific T-lymphocyte recognition. Methods: The phase 3 COMBI-i study (NCT02967692) is evaluating the anti–PD-1 antibody PDR001 in combination with D+T in treatment-naive pts with BRAF V600–mutant unresectable or metastatic melanoma in 3 parts: 1, safety run-in; 2, biomarker cohort; and 3, randomized, double-blind, placebo-controlled part. Here we report preliminary findings for 9 pts in part 1 dosed with PDR001 400 mg Q4W + D 150 mg BID + T 2 mg QD. Response was assessed at wk 12 and Q8W thereafter. Results: At data cutoff (16 Jul 2017; median follow-up, 2.7 mo), all 9 pts completed the 8-wk dose-limiting toxicity (DLT) period, during which 1 DLT (transaminitis [AST and ALT > 8 × ULN]; n = 1) occurred. Adverse events (AEs) of any grade occurring in > 3 pts included pyrexia (n = 9), headache (n = 6), chills (n = 4), and vomiting (n = 4). Grade 3/4 AEs reported in > 1 pt included hepatitis (n = 3), increased lipase (n = 2), and increased transaminases (n = 2). AEs leading to discontinuation occurred in 2 pts (22%; transaminitis, n = 1; grade 3 hepatitis, n = 1) who permanently discontinued PDR001 but were still receiving D+T at the data cutoff. All 9 pts responded: 3 (33%) achieved a complete response (confirmed, n = 1), and 6 (67%) had partial responses (confirmed, n = 1). Additional safety and efficacy results for these 9 pts, all ongoing at the data cutoff, will be presented. Conclusions: These preliminary results indicate that PDR001 can be combined with D+T with a manageable safety profile and demonstrate promising activity in pts with BRAF V600–mutant melanoma. Clinical trial information: NCT02967692.

9505 Background: D (BRAF inhibitor) + T (MEK inhibitor) combination therapy is associated with rapid clinical responses and has improved clinical outcomes in pts with BRAFV600–mutant MM, but long-term (˃ 3 y) clinical efficacy and safety data are limited. The longest follow-up to date of a randomized trial evaluating D+T at the approved dose (150 mg BID/2 mg QD [150/2]) was of the phase II study BRF113220 (part C; median, 45.6 mo) in which durable outcomes were achieved in some pts with BRAFV600–mutant MM (3-y OS, 38%). Here, we report updated 5-y landmark analyses to further characterize the impact of D+T in MM. Methods: Pts with BRAFV600–mutant mm enrolled in BRF113220 part C (NCT01072175) were randomized 1:1:1 to receive monotherapy D (150 mg BID), D+T (150 mg BID/1 mg QD), or D+T (150/2). Pts who progressed on D alone could cross over to the D+T 150/2 arm. Pt disposition, pt demographics, and 4- and 5-y efficacy and safety were analyzed for both the D-alone and D+T (approved 150/2 dose) arms. Results: This updated analysis represents an additional ≈ 2 y of follow-up (D and D+T arms; n = 54 each). As of 13 Oct 2016, 45 pts (83%) on D alone had crossed over to D+T. 20 pts were ongoing (D, n = 7 [13%]; D+T, n = 13 [24%]); 80% of D pts and 70% of D+T pts had died. D+T OS remained superior to D alone. The 4- and 5-y OS rates with D+T were 30% and 28%, respectively, demonstrating a stabilization of the OS curve. The PFS curve for D+T also remained stable (4- and 5-y: both 13%). Consistent with earlier results, the best OS for pts who received D+T was seen in pts with normal LDH (5-y, 45%) and normal LDH with disease in < 3 organ sites (5-y, 51%). At the 5-y landmark, 1 additional pt who received D+T improved from a partial to a complete response. Additional follow-up revealed no new safety signals with D+T. Detailed analyses of D crossover pts, responders, and post-progression therapy will be presented. Conclusions: This longest follow-up to date of BRAF + MEK inhibitor combination therapy in pts with BRAFV600–mutant mm revealed stable OS and PFS lasting ≥ 5 y with consistent tolerability. These results demonstrate that some pts with mm can achieve durable benefit with D+T therapy. Clinical trial information: NCT01072175.

Background: Although erythropoiesis-stimulating agents (ESAs) are recommended in clinical guidelines to treat anemia in patients with lower-risk MDS, ESAs are not widely approved for this indication due to a lack of PBO-controlled trials. Aim: To evaluate the use of darbepoetin alfa (DAR) to treat anemia in patients with IPSS low / int-1 risk MDS in a phase 3 randomized controlled trial (EudraCT2009-016522-14, NCT01362140). Methods: Patients, enrolled from 12/2011 to 8/2014 in 9 European countries, had MDS per WHO 2008 criteria with IPSS low/int-1 risk, anemia [hemoglobin (Hb) ≤10 g/dL], low transfusion burden [12 g/dL and decreased if Hb increased by >1.5 g/dL in 3 wk without transfusions. Key endpoints were transfusion incidence from wk 5-24 and erythroid response (HI-E) per IWG 2006 criteria (≥1.5 g/dL Hb increase from baseline sustained for 8 wk without transfusions). Results: Randomized patients [N = 147, 55% male, all Caucasian, median age 74 (min-max: 28-88) years] had median Hb of 9.3 (min-max: 5.5-10.6) g/dL and median baseline EPO level of 69 (min-max: 4.3-497) mU/mL; 50.7% were IPSS low risk and 49.3% int-1 risk, IPSS-R rates were very low: 10%, low: 61%, intermediate: 23%, and high: 3%, IPSS karyotype rates were good: 91% and intermediate: 9%, and WHO classification was RA: 15%, RARS: 14%, RCMD: 44%, del5q: 9%, RAEB-1: 16%, and MDS-U/unknown: 2%. Completion rates for the 24-wk double-blind portion were DAR: 89% (87/98) and PBO: 80% (39/49). Transfusion incidence from wk 5-24 was significantly reduced with DAR [DAR: 36.1% (35/97) vs. PBO: 59.2% (29/49), p = 0.008]. In the 48-wk OL DAR period, 50.8% (64/126) of patients had transfusions. More DAR patients achieved HI-E in the double-blind period [DAR: 14.7% (11/75 evaluable) vs. PBO: 0% (0/35 evaluable), p = 0.016]. All 11 patients with HI-E had baseline EPO ≤100 mU/mL, 4/11 had a dose withheld for Hb >12 g/dL, and 10/11 had no transfusions in the 16 wk prior to randomization (none had transfusions in the 8 wk prior). In the 48-wk OL DAR period, 34.7% (34/98) of patients achieved HI-E; 11/38 (29%) prior PBO arm, 23/87 (26%) prior DAR arm (10 of the prior DAR had HI-E in the 24-wk portion); 6/34 had transfusions in the 16 wk prior to randomization, 30/34 received Q2W dosing at some point, 30/34 had baseline EPO ≤100 mU/mL, and 26/34 had doses withheld. Improved HI-E and transfusion responses were seen with more favorable status for IPSS-R but not IPSS (Figure). In the 48-wk OL DAR period, dose frequency increased from Q3W to Q2W in 81% (102/126) of patients; doses were held or reduced frequently (Table). Safety results from this trial (Table) were consistent with the previous DAR phase 2 MDS trial (Gabrilove BJH 2008, 142:379-393), with similar AML rates observed in PBO and DAR arms. Conclusion/Summary: In this phase 3, randomized, double-blind, PBO-controlled trial in anemic IPSS low/int-1 risk MDS patients, 24 wk of darbepoetin alfa Q3W significantly reduced transfusions and increased HI-E rates with no new safety signals. Most patients met criteria to change to Q2W dosing during the 48-wk OL period, suggesting that Q2W dosing may offer more benefit. The true clinical benefit of darbepoetin alfa may have been underestimated in this trial due to the nature of IWG 2006 HI-E criteria and the trial design (Hb measured Q3W, dose held if Hb >12 g/dL and decreased if Hb increased by >1.5 g/dL); additional ad hoc analyses are underway. Disclosures Platzbecker: Novartis: Honoraria, Research Funding; Janssen-Cilag: Honoraria, Research Funding; TEVA Pharmaceutical Industries: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding. Symeonidis:Amgen Inc.: Research Funding. Oliva:Amgen Inc.: Honoraria; Celgene: Honoraria, Speakers Bureau; La Jolla: Honoraria; Novartis: Speakers Bureau. Goede:Amgen Inc.: Honoraria. Delforge:Amgen Inc.: Honoraria. Mayer:Amgen Inc.: Research Funding. Badre:Amgen Inc.: Employment, Equity Ownership. Gasal:Amgen Inc.: Employment, Equity Ownership. Mehta:Amgen Inc.: Employment, Equity Ownership. Franklin:Amgen Inc.: Employment, Equity Ownership.

e20109 Background: Unresectability is a frequent inclusion criterion for clinical trials in metastatic melanoma. However, no consensus definition of unresectability exists. In OPTiM, a phase 3 tria...