BRAF Wild-type Metastatic Melanoma Research Articles

Basal and one-month differed neutrophil, lymphocyte and platelet values and their ratios strongly predict the efficacy of checkpoint inhibitors immunotherapy in patients with advanced BRAF wild-type melanoma

BackgroundTo evaluate the capability of basal and one-month differed white blood cells (WBC), neutrophil, lymphocyte and platelet values and their ratios (neutrophils-to-lymphocytes ratio, NLR, and platelets-to-lymphocytes ratio, PLR) in predicting the response to immune checkpoint inhibitors (ICI) in metastatic melanoma (MM).MethodsWe performed a retrospective study of 272 BRAF wild-type MM patients treated with first line ICI. Bivariable analysis was used to correlate patient/tumor characteristics with clinical outcomes. Variations between time 1 and time 0 (Δ) of blood parameters were also calculated and dichotomized using cut-off values assessed by ROC curve.ResultsAt baseline, higher neutrophils and NLR negatively correlated with PFS, OS and disease control rate (DCR). Higher PLR was also associated with worse OS. In multivariable analysis, neutrophils (p = 0.003), WBC (p = 0.069) and LDH (p = 0.07) maintained their impact on PFS, while OS was affected by LDH (p < 0.001), neutrophils (p < 0.001) and PLR (p = 0.022), while DCR by LDH (p = 0.03) and neutrophils (p = 0.004). In the longitudinal analysis, PFS negatively correlated with higher Δplatelets (p = 0.039), ΔWBC (p < 0.001), and Δneutrophils (p = 0.020), and with lower Δlymphocytes (p < 0.001). Moreover, higher ΔNLR and ΔPLR identified patients with worse PFS, OS and DCR. In the multivariable model, only ΔNLR influenced PFS (p = 0.004), while OS resulted affected by higher ΔWBC (p < 0.001) and lower Δlymphocytes (p = 0.038). Higher ΔWBC also affected the DCR (p = 0.003). When clustering patients in 4 categories using basal LDH and ΔNLR, normal LDH/lower ΔNLR showed a higher PFS than high LDH/higher ΔNLR (20 vs 5 months). Moreover, normal LDH/higher Δlymphocytes had a higher OS than high LDH/lower Δlymphocytes (50 vs. 10 months).ConclusionsBaseline and early variations of blood cells, together with basal LDH, strongly predict the efficacy of ICI in MM. Our findings propose simple, inexpensive biomarkers for a better selection of patient treatments. Prospective multicenter studies are warranted to confirm these data.

122 Poster - Targeting BRAF WT metastatic melanomas: Identifying ERBB4 mutant alleles as biomarkers for novel combinatorial treatment strategies

Background: The treatment of metastatic melanoma (MM) has been dramatically improved through the use of BRAF and MEK inhibitors in patients whose tumors harbor activating mutations in BRAF. However, these mutations occur in only ∼50% of MMs and a targeted therapy(ies) has yet to be identified for those MMs that contain wild-type (WT) BRAF. Using The Cancer Genome Atlas melanoma (TCGA-SKCM) dataset, we discovered that 20% of BRAF WT melanomas harbor a missense mutation in ERBB4, which encodes a member of the epidermal growth factor receptor (EGFR/ ErbB1) family of receptor tyrosine kinases. Hence, our goal is to evaluate whether ERBB4 mutant alleles function as biomarkers and targets for therapeutic intervention in BRAF WT MMs.

Abstract 5932: Targeting BRAF WT metastatic melanomas: Identifying ERBB4 mutations as biomarkers for novel combinatorial treatment strategies

Abstract Introduction: The treatment of metastatic melanoma (MM) has been dramatically improved through the use of BRAF and MEK inhibitors in patients whose tumors harbor activating mutations in BRAF. However, these mutations occur in only ~50% of MMs and a targeted therapy(ies) has yet to be identified for those MMs that contain wild-type (WT) BRAF. Using The Cancer Genome Atlas metastatic melanoma (TCGA-SKCM) dataset, we have discovered that 50% of BRAF WT melanomas harbor a missense mutation in ERBB4, which encodes a member of the epidermal growth factor receptor (EGFR/ErbB1) family of receptor tyrosine kinases. Hence, our goal is to evaluate whether ERBB4 mutant alleles function as biomarkers and targets for therapeutic intervention in BRAF WT MMs. Experimental Procedures/Data Summary: Of the 469 genomes in the TCGA-SKCM dataset, 70 harbor at least one missense mutation in ERBB4, resulting in a total of 76 unique ERBB4 missense mutations. These mutations do not appear to be random occurrences, but instead appear to be the result of selection. For example, the incidence of ERBB4 mutant alleles is greatly reduced in melanomas that possess BRAF driver mutations and/or driver events in PI3K pathway genes. In contrast, the incidence of ERBB4 mutant alleles is markedly elevated in melanomas that possess genetic alterations that result in elevated RAS signaling. Indeed, melanomas that possess an ERBB4 mutant allele AND a genetic alteration that results in elevated RAS signaling are associated with a marked decrease in survival. Taken together, these data indicate that ERBB4 mutant alleles cause elevated PI3K signaling, which cooperates with elevated RAS signaling to drive the genesis and/or progression of BRAF WT MMs. The existence of 76 unique ERBB4 mutations in the TCGA-SKCM dataset highlights one of the challenges in identifying the ERBB4 mutant alleles that function as bona fide BRAF WT MM drivers. The other challenge is that ERBB4 functions as a context-dependent oncogene and tumor suppressor gene. Hence, we will describe the ongoing development and validation of innovative, positive-selection screens for gain-of-function ERBB4 mutant alleles and for loss-of-function ERBB4 mutant alleles from the library of ERBB4 mutant alleles found in the TCGA-SKCM dataset. The gain-of-function ERBB4 mutant alleles would enhance ERBB4 signaling in contexts in which ERBB4 functions as an MM oncogene, whereas the loss-of-function ERBB4 mutant alleles would disrupt ERBB4 signaling in contexts in which ERBB4 functions as an MM tumor suppressor gene. Conclusions: In silico analyses of the TCGA-SKCM dataset indicate that ERBB4 mutant alleles function as drivers of BRAF WT MM. We will present our progress in developing and validating positive selection strategies to identify which of the 76 ERBB4 mutant alleles found in the TCGA-SKCM dataset function as bona fide drivers of BRAF WT MMs. Citation Format: Lauren Lucas, Richard Cullum, Damien Waits, Taraswi Ghosh, Laura Cook, David Kaufmann, Jessica Markham, Cristina Rael, Kenneth Halanych, Allan David, David Riese. Targeting BRAF WT metastatic melanomas: Identifying ERBB4 mutations as biomarkers for novel combinatorial treatment strategies [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5932.

SAT-116 An Affair of the Heart - First Case Report of Immune Checkpoint Inhibitor Associated Cardiac Sarcoidosis Presenting with Non-PTH Medicated Hypercalcemia

Background:Immune checkpoint inhibitors (ICI) are an effective new tool in the treatment of malignancy by rescuing exhausted T-cells and enhancing anti-tumor immunity. The offset of immune self-tolerance can result in autoimmune adverse effects involving gastrointestinal, pulmonary and endocrine systems. Lung and skin sarcoidosis have been described in association with ICI use. We present the first case of non-PTH medicated hypercalcemia due to cardiac sarcoidosis in the setting of immunotherapy.Case Presentation:A 71-year-old man was referred to endocrinology for hypercalcemia. He had a fourteen-year history of scalp melanoma in remission until February 2019, when routine surveillance scans suggested metastatic disease. Computer tomography of the chest showed mediastinal and hilar lymphadenopathy (largest node 5.2 cm) and numerous pulmonary nodules (largest 1.7 cm). Biopsy of the largest pulmonary nodule and mediastinal lymph node (LN) confirmed BRAF wild-type metastatic melanoma. Ipilimumab/nivolumab (antiCTLA4/antiPD-1) combination therapy was started. After two cycles, hypercalcemia was noted on routine laboratory surveillance. He was asymptomatic and physical exam was unremarkable. Initial workup revealed: calcium 10.6 mg/dL (8.6-10.2), albumin 4 g/dL (3.5 - 5.2), phosphorus 3.8 mg/dL (2.7 - 4.5), PTH <0.6 pg/mL (15.0 - 65.0), PTHrP <2.0 pmol/L (0.0 - 2.3), 25 hydroxyvitamin D 22. 9 ng/mL (30 - 60), vitamin A 0.59 mg/L (0.30 - 1.20). He denied taking calcium-containing supplements. He was treated with hydration and immunotherapy was continued for two cycles, followed by single agent nivolumab. After three months on ICI, the metastatic lesions were reduced in size by 30%. His calcium peaked at 12.5 mg/dL and was treated with 4mg of intravenous Zoledronic acid without resolution. He developed worsening functional status, symptomatic hypotension, and elevated troponins. Cardiac MRI demonstrated myocarditis and nivolumab-induced myocarditis was suspected. Surprisingly, endomyocardial biopsy revealed multiple granulomas suggestive of sarcoidosis. AFB, PAS and Congo red stains were negative. He was treated with supportive care and glucocorticoids with resolution of hypercalcemia and improved cardiac function. Unfortunately, serum 1,25 dihydroxy vitamin D was not successfully measured until after the first dose of prednisone and was found at the upper limit of our reference range 62.0 pg/mL (19.9-79.3).Conclusion:Immune checkpoint inhibitors are effective agents in treating various cancers. Adverse effects due to autoimmunity are common and early recognition of life-threatening complications is critical. Although cutaneous and pulmonary sarcoidosis have been described with ICI, to our knowledge, this is the first case report of ICI-related cardiac sarcoidosis presenting with PTH-independent hypercalcemia.

PCN96 COST-EFFECTIVENESS OF TREATMENT SEQUENCES FOR BRAF WILD-TYPE METASTATIC MELANOMA IN REAL LIFE IN FRANCE

Since 2011 seven innovative drugs were commercialized for the treatment of metastatic melanoma (MM), significantly improving patient survival and management cost in 1st line of treatment. With 52% of patients now reaching a second line of treatment, the optimal sequence in patients with BRAF wild-type metastatic melanoma (MM) remains unclear. To inform policy makers about the value of these sequences, we performed a cost-effectiveness analysis comparing treatment sequences for BRAF wild-type MM in real life in France. Four sequences were compared: Anti-PD1-Ipilimumab, Ipilimumab-Anti-PD1, Ipilimumab+Nivolumab-Chemotherapies, Chemotherapies-Immunotherapies. Clinical (efficacy and utility) and economic data were extracted from the prospective MelBase cohort, collecting individual data in 1,435 MM patients from 26 French hospitals, from MM diagnosis until death. To adjust for confounding effects and differences in patient characteristics among groups, the inverse probability of treatment weighted with a propensity score (PS) for multiple treatments was used. The PS was estimated using generalized boosted modeling. Survival was estimated by the Kaplan-Meier method. Costs were calculated from the health insurance perspective using French tariffs. Survival and costs were extrapolated using a multistate model, describing the 10-year course of the disease. Among the 1435 patients, effectiveness was assessed on 843 wild-type patients included between 2013 and 2019. In the base case, the 4 sequences remains on the efficiency frontier. The incremental cost-effectiveness ratio (ICER) of Anti-PD1-Ipilimumab is 136,255€ / QALY gained compared with Chemotherapies-Immunotherapies. The ICER of Ipilimumab-Anti-PD1 is 115,960€ per QALY gained compared with Anti-PD1-Ipilimumab. The ICER of Ipilimumab+Nivolumab-Chemotherapies is 806,340€ per QALY gained compared with Ipilimumab-Anti-PD1. For patients with BRAF wild-type MM, for thresholds between 0 and 800,000€, only Chemotherapies-Immunotherapies sequences has more than 55% chance of being efficient in France based on observational data.

Single Center Experience Study with Pembrolizumab in Patients with BRAF Mutant Negative Metastatic Melanoma

Abstract The aim of the paper was to determine the efficacy, toxicity and progression free survival with anti-PD-1 immunotherapy pembrolizumab in BRAF wild type metastatic melanoma patients with good performance status (ECOG PS 0-1). From February 2017 to April 2018, 17 patients with BRAF mutant wild type metastatic melanoma were enrolled in the study. Only 3/17 patient had received chemotherapy previously. The aim of the study was to confirm the efficacy of pembrolizumab immunotherapy in patients with good performance status (ECOG 0-1). Treatment consisted of pembrolizumab 2 mg/kg Q3 weeks continued until disease progression or intolerable toxicity. Secondary end points included toxicity and progression-free survival (defined as the time from randomization to documented disease progression according to RECIST). The overall response rate (ORR) was 11/17 (53.0 %), with complete response (CR) 0, partial response (PR) 3 (18 %), stable disease (SD) 8 (47%), and progressive disease (PD) 6 (35%). A total number of 97 consecutive cycles were administered. Adverse effects were mild. The most common toxicity was pneumonitis grade 1. None of the patients in the study demonstrated grade 2, 3 and 4 toxicity. No treatment-related deaths occurred. The median time to disease progression was 5.8 months. Anti-PD-1 pembrolizumab immunotherapy appeared to be a beneficial therapeutic approach with less toxicity for metastatic BRAF wild type melanoma patients with good PS.

Sequential, Multiple Assignment, Randomized Trial Designs in Immuno-oncology Research.

Clinical trials investigating immune checkpoint inhibitors have led to the approval of anti-CTLA-4 (cytotoxic T-lymphocyte antigen-4), anti-PD-1 (programmed death-1), and anti-PD-L1 (PD-ligand 1) drugs by the FDA for numerous tumor types. In the treatment of metastatic melanoma, combinations of checkpoint inhibitors are more effective than single-agent inhibitors, but combination immunotherapy is associated with increased frequency and severity of toxicity. There are questions about the use of combination immunotherapy or single-agent anti-PD-1 as initial therapy and the number of doses of either approach required to sustain a response. In this article, we describe a novel use of sequential, multiple assignment, randomized trial (SMART) design to evaluate immune checkpoint inhibitors to find treatment regimens that adapt within an individual based on intermediate response and lead to the longest overall survival. We provide a hypothetical example SMART design for BRAF wild-type metastatic melanoma as a framework for investigating immunotherapy treatment regimens. We compare implementing a SMART design to implementing multiple traditional randomized clinical trials. We illustrate the benefits of a SMART over traditional trial designs and acknowledge the complexity of a SMART. SMART designs may be an optimal way to find treatment strategies that yield durable response, longer survival, and lower toxicity. Clin Cancer Res; 24(4); 730-6. ©2017 AACR.

Digoxin Plus Trametinib Therapy Achieves Disease Control in BRAF Wild-Type Metastatic Melanoma Patients

This is the first prospective study of a combination therapy involving a cardenolide and a MEK inhibitor for metastatic melanoma. Whereas BRAF mutant melanomas can exhibit profound responses to treatment with BRAF and MEK inhibitors, there are fewer options for BRAF wild-type melanomas. In preclinical studies, we discovered that cardenolides synergize with MEK inhibitor to promote the regression of patient-derived xenografts irrespective of BRAF mutation status. We therefore conducted a phase 1B study of digoxin 0.25 mg and trametinib 2 mg given orally once daily in 20 patients with advanced, refractory, BRAF wild-type melanomas. The most common adverse events were rash, diarrhea, nausea, and fatigue. The response rate was 4/20 or 20% with response durations of 2, 4, 6, and 8 months. The disease control rate (including partial responses and stable disease) was 13/20 or 65% of patients, including 5/6 or 83% of patients with NRAS mutant melanomas and 8/14 or 57% of NRAS wild-type melanomas. Patients with stable disease had disease control for 2, 2, 2, 4, 5, 6, 7, 10, and 10 months. Xenografts from four patients recapitulated the treatment responses observed in patients. Based on these pilot results, an expansion arm of digoxin plus MEK inhibitor is warranted for NRAS mutant metastatic melanoma patients who are refractory or intolerant of immunotherapy. Key pointsDigoxin plus trametinib is well tolerated and achieves a high rate of disease control in BRAF wild-type metastatic melanoma patients.

Cost-Effectiveness of Immune Checkpoint Inhibition in BRAF Wild-Type Advanced Melanoma

Purpose Patients who are diagnosed with stage IV metastatic melanoma have an estimated 5-year relative survival rate of only 17%. Randomized controlled trials of recent US Food and Drug Administration-approved immune checkpoint inhibitors-pembrolizumab (PEM), nivolumab (NIVO), and ipilumumab (IPI)-demonstrate improved patient outcomes, but the optimal treatment sequence in patients with BRAF wild-type metastatic melanoma remains unclear. To inform policy makers about the value of these treatments, we developed a Markov model to compare the cost-effectiveness of different strategies for sequencing novel agents for the treatment of advanced melanoma. Materials and Methods We developed Markov models by using a US-payer perspective and lifetime horizon to estimate costs (2016 US$) and quality-adjusted life years (QALYs) for treatment sequences with first-line NIVO, IPI, NIVO + IPI, PEM every 2 weeks, and PEM every 3 weeks. Health states were defined for initial treatment, first and second progression, and death. Rates for drug discontinuation, frequency of adverse events, disease progression, and death obtained from randomized phase III trials were used to determine the likelihood of transition between states. Deterministic and probabilistic sensitivity analyses were conducted to evaluate model uncertainty. Results PEM every 3 weeks followed by second-line IPI was both more effective and less costly than dacarbazine followed by IPI then NIVO, or IPI followed by NIVO. Compared with the first-line dacarbazine treatment strategy, NIVO followed by IPI produced an incremental cost effectiveness ratio of $90,871/QALY, and first-line NIVO + IPI followed by carboplatin plus paclitaxel chemotherapy produced an incremental cost effectiveness ratio of $198,867/QALY. Conclusion For patients with treatment-naive BRAF wild-type advanced melanoma, first-line PEM every 3 weeks followed by second-line IPI or first-line NIVO followed by second-line IPI are the most cost-effective, immune-based treatment strategies for metastatic melanoma.

Nivolumab improved survival vs dacarbazine in patients with untreated advanced melanoma

The hazard ratio (HR) for death was 0.42 (99.79% CI 0.25–0.73; P < 0.0001) in favor of nivolumab, with 1year OS rate 73% (95% CI, 66%–79%) for nivolumab vs 42% (95% CI, 33%–51%) for dacarbazine. Median OS was not reached for nivolumab and was 10.8 months for dacarbazine. Median progression-free survival (PFS) was 5.1 months for nivolumab and 2.2 months for dacarbazine (HR for death or progression 0.43, 95% CI 0.34–0.56; P < 0.0001). Objective response rate was 40% (84/210) vs 14% (29/208) for nivolumab and dacarbazine, respectively (P < 0.0001). Median duration of response was not reached for nivolumab and 6 months for dacarbazine. At the time of data cutoff, responses were ongoing in 86% (72/84) of nivolumab and 52% (15/29) of dacarbazine responders. PD-L1 positivity (using a 5% tumor cell surface staining cutoff) appeared to be associated with improved OS in the nivolumab arm (85% of PD-L1+ and 71% of PD-L1-/ indeterminate patients alive at the time of last followup). Both PD-L1+ and PD-L1-/indeterminate patients receiving nivolumab had improved OS vs dacarbazine (un-stratified HR 0.30, 95% CI, 0.15–0.60 in PD-L1+ patients; 0.48, 95% CI, 0.32–0.71 in PD-L1-/indeterminate patient, both in favor of the nivolumab arm). The most common nivolumab-related adverse events (AEs) were fatigue, pruritus, and nausea. Drug-related grade 3–4 AEs were reported in 12% vs 18% of patients receiving nivolumab vs dacarbazine, respectively. AEs led to discontinuation in 7% and 12% of dacarbazinevs nivolumab-treatment patients, respectively. Conclusions Compared to dacarbazine, nivolumab significantly improved OS and PFS in previously untreated patients with BRAF wild-type metastatic melanoma with an acceptable safety profile.

Ipilimumab Induced Encephalitis: A Case Report

Background: Cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) is a helper T cell protein receptor that down regulates the immune system when bound to antigen presenting cells. Ipilimumab selectively binds to CTLA-4 inhibiting the immune tolerance to tumour cells and has recently been approved for the treatment of metastatic melanoma. Autoimmune sequelae are side-effects of such immunomodulatory therapies. We describe the first case of ipilimumab induced delayed onset encephalitis. Case: A 71 year-old man with BRAF wild-type metastatic melanoma received ipilimumab as first-line therapy. He presented with generalised weakness and headache following cycle 2 of ipilimumab. Blood analyses confirmed panhypopituitarism and MRI showed lymphocytic infiltration of pituitary gland, confirming autoimmune hypophysitis. Hormone replacement and a course of dexamethasone resolved the initial symptoms. Two months later he developed myoclonic jerks, drowsiness and mood elevation. CSF protein was raised with normal white and no malignant cells. Ipilimumab was stopped and high dose methylprednisolone was intiated resulting in improvement within 24hours. Post methylprednisolone electroencephalogram showed normal background activity with no seizures. Discussion: Gastrointestinal (colitis, nausea), skin (pruritis, rash) and fatigue are the most common (30-40%) ipilimumab induced side effects. Endocrinopathies are reported in 1-2% of patients. CTLA-4 is expressed by pituitary gland thereby being susceptible for lymphocytic hypophysitis following ipilimumab. Neurological side effects are even rarer yet (<1%). Autoimmune encephalitis can be a delayed response and in our case was around 2 months after second dose of ipilimumab therapy. No cases of delayed onset ipilimumab induced encephalitis have been described as yet, but with increasing use of immune therapies which up-regulate T cells, rarer immune sequelae are likely to be on the rise. Conclusion: Ipilimumab caused delayed onset autoimmune encephalitis and hypophysitis that was steroid responsive. Multi-specialty approach with early intervention of a neurologist and endocrinologist is a must for improved identification, treatment and outcomes.

NRAS mutation: A potential biomarker of clinical response to immune-based therapies in metastatic melanoma (MM).

9019 Background: NRAS mutant (mut) MM comprises a distinct, molecularly defined cohort of this disease that appears to have a poor prognosis compared to other genetic subsets. In contrast to BRAF mut MM, there are no effective small molecule inhibitors specifically targeting NRAS. Immune based therapy (IT) has become a mainstay in MM treatment, especially in BRAF wild type (WT) patients (pts). Biomarkers to predict which pts will benefit from IT have not been validated. The goal of this study was to evaluate whether genetic subtype (specifically NRAS) has a role in predicting benefit from IT in BRAF WT MM. Methods: We identified 173 pts from 3 institutions who underwent clinical genotyping (exome or PCR based) for NRAS and BRAF mutation from 1/09 – 8/12 and were treated with IT (defined as IL-2, ipilimumab (ipi), or anti-PD-1 (nivolumab, MK3475)/ PD-L1 (MPDL3280A)). Only BRAF WT pts were included. Primary endpoints were response rate (RR) and clinical benefit rate (CBR), defined as RR + stable disease lasting &gt;24 wks to IT (best response as assessed by treating clinicians in any line of IT). Secondary endpoints were overall survival (OS) and progression-free survival (PFS) from first line IT. Results: Of the 173 pts, 59 had NRAS mut MM compared to 114 WT/WT (no mutation in NRAS or BRAF). Improved clinical outcomes were seen in the NRAS mut compared to WT/WT cohort in terms of RR (32% vs. 18%, p=0.042), and CBR (49% vs. 30%, p=0.012). Improvements in PFS and OS did not reach statistical significance. By specific IT, NRAS mutation predicted benefit compared to WT/WT for anti-PD-1/PD-L1 (RR 78% vs. 19%, p=0.002; CBR 78% vs. 29%, p=0.013, n=30) and ipi (RR 18% vs. 12%, p=0.315; CBR 41% vs. 22%, p=0.018, n=137). No significant differences were observed with IL-2 (RR 33% vs. 28%, p=0.730; CBR 33% vs. 39%, p=0.741, n=33). Conclusions: This study demonstrates that pts with NRAS mut MM achieve increased clinical benefit from IT compared to pts with BRAF/NRAS WT MM. A larger, prospective analysis is necessary to validate and expand on these results, including those with BRAF mut and KIT mut MM. However, our data suggest that NRAS mutation status may be a biomarker of response to IT in MM and that molecularly targeted immunotherapy may be feasible.

A clinical and translational phase II trial of sequential axitinib and carboplatin/paclitaxel in advanced melanoma.

8580 Background: Several clinical trials adding VEGF signaling inhibitors to chemotherapy have not demonstrated any benefit over chemotherapy alone in advanced melanoma potentially due to decreased tumor cell proliferation induced by VEGF blockade. We tested the hypothesis that sequential administration of axitinib followed by carboplatin and paclitaxel may be more effective than chemotherapy alone in metastatic melanoma. Methods: We conducted a prospective phase II trial of this combination in previously treated metastatic melanoma patients. Patients had an ECOG PS 0-1, and normal organ function. Axitinib 5 mg PO bid was taken on days 1 through 14 of each 21-day treatment cycle, and carboplatin (AUC=5) with paclitaxel (175 mg/m2) was administered on day 1 starting with cycle 2. FLT-PET scans were performed on 6 patients to assess tumor cell proliferation on days 1, 14, 17, and 20 of cycle 1. Results: Treatment has been well tolerated. The most common grade 3 AEs have been neutropenia, hypertension, and gastrointestinal events. Grade 4 non-hematologic AEs have not been observed. 4 of 5 patients completing FLT-PET scans to date showed increases (23% to 92%) in SUV values during the axitinib holiday. The fifth patient had a single, minimally FLT avid lesion at baseline (SUV=1.9). In 30 evaluable patients, there have been 4 confirmed PRs, 2 unconfirmed PRs, and 3 patients with 28.6, 29.3, and 29.5% decreases in tumor size by RECIST. Overall, 19 patients have had SD and 5 have had PD as the best response. With a median follow-up of 8.3 months and 17 patients still active, the median PFS is 6.9 months, and 23 patients (77%) are still alive. 26 of 30 evaluable patients have been wild type for BRAF-V600E/K mutations. Conclusions: Axitinib followed by carboplatin and paclitaxel has been well tolerated and effective in a largely BRAF wild-type metastatic melanoma population. Given the urgent need for effective therapies in this population, this regimen warrants phase III testing.