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BACKGROUND Interleukin 2 (IL-2) is a growth factor for T and natural killer cells, promotes proinflammatory cytokines, and can lead to durable responses in patients with melanoma. Vascular endothelial growth factor (VEGF) promotes angiogenesis and modulates host innate and adaptive immunity. High VEGF levels were found to be associated with nonresponse to IL-2. Ziv-aflibercept may deplete VEGF and thereby enhance antitumor T-cell responses, thus supporting a combination immunotherapeutic strategy with IL-2. METHODS NCI 8628 was a phase 2 trial of ziv-aflibercept and IL-2 (arm A) versus IL-2 alone (arm B) randomized at 2:1, respectively. Eligible patients had inoperable American Joint Committee on Cancer stage III or stage IV melanoma. The primary endpoint was progression-free survival (PFS). RESULTS A total of 89 patients were enrolled and 84 patients were treated. The median follow-up was 41.4 months. Among treated patients (55 patients in arm A and 29 patients in arm B), PFS was significantly improved in favor of arm A, with a median of 6.9 months (95% confidence interval [95% CI], 4.1-8.7 months) versus 2.3 months (95% CI, 1.6-3.5 months) (P

Recent progress in the treatment of advanced melanoma has led to unprecedented improvements in overall survival and, as these new melanoma treatments have been developed and deployed in the clinic, much has been learned about the natural history of the disease. Now is the time to apply that knowledge toward the design and clinical evaluation of new chemoprevention agents. Melanoma chemoprevention has the potential to reduce dramatically both the morbidity and the high costs associated with treating patients who have metastatic disease. In this work, scientific and clinical melanoma experts from the national Melanoma Prevention Working Group, composed of National Cancer Trials Network investigators, discuss research aimed at discovering and developing (or repurposing) drugs and natural products for the prevention of melanoma and propose an updated pipeline for translating the most promising agents into the clinic. The mechanism of action, preclinical data, epidemiological evidence, and results from available clinical trials are discussed for each class of compounds. Selected keratinocyte carcinoma chemoprevention studies also are considered, and a rationale for their inclusion is presented. These data are summarized in a table that lists the type and level of evidence available for each class of agents. Also included in the discussion is an assessment of additional research necessary and the likelihood that a given compound may be a suitable candidate for a phase 3 clinical trial within the next 5 years.

BACKGROUND KIT-directed tyrosine kinase inhibitors such as imatinib have demonstrated benefits in KIT-mutant (KIT+) mucosal, acral, vulvovaginal, and chronically sun-damaged (CSD) melanoma. Dasatinib has superior preclinical activity in comparison with other tyrosine kinase inhibitors against cells with the most common KIT mutation, exon 11L576P. The ECOG-ACRIN E2607 trial assessed dasatinib in patients with these melanoma subtypes. METHODS Patients received 70 mg of oral dasatinib twice daily. The primary objective for this 2-stage phase 2 trial was response rate. Stage I was open to KIT+ and wild-type KIT (KIT–) mucosal, acral, and CSD melanoma (n = 57). Stage II accrued only KIT+ tumors (n = 30). To enrich the trial for KIT+ tumors, vulvovaginal melanoma was added, and CSD melanoma was removed from eligibility. Secondary objectives included progression-free survival (PFS), overall survival (OS), and safety. RESULTS From May 2009 to December 2010, the first stage enrolled 57 patients. Among the evaluable patients, 3 of 51 (5.9%) achieved a partial response: all were KIT–. Stage II closed early because of slow accrual (November 2011 to December 2015). In stage II, 4 of 22 evaluable patients (18.2%) had a partial response; the median duration was 4.2 months. The median PFS was 2.1 months (n = 73; 95% confidence interval [CI], 1.5-2.9 months). The median OS was 7.5 months (95% CI, 6.0-11.9 months). In exploratory analyses, no differences were seen in PFS or OS with the KIT status or subtype. Dasatinib was discontinued because of adverse events in 9 of 75 patients (12%). CONCLUSIONS The dasatinib response rate among KIT+ melanoma patients was low. In view of its clinical activity, it is recommended that imatinib remain the KIT tyrosine kinase inhibitor of choice for unresectable KIT+ melanoma. Cancer 2017;123:2688-97. © 2017 American Cancer Society.

Author(s): Jeter, Joanne M; Bowles, Tawnya L; Curiel-Lewandrowski, Clara; Swetter, Susan M; Filipp, Fabian V; Abdel-Malek, Zalfa A; Geskin, Larisa J; Brewer, Jerry D; Arbiser, Jack L; Gershenwald, Jeffrey E; Chu, Emily Y; Kirkwood, John M; Box, Neil F; Funchain, Pauline; Fisher, David E; Kendra, Kari L; Marghoob, Ashfaq A; Chen, Suephy C; Ming, Michael E; Albertini, Mark R; Vetto, John T; Margolin, Kim A; Pagoto, Sherry L; Hay, Jennifer L; Grossman, Douglas; Ellis, Darrel L; Kashani-Sabet, Mohammed; Mangold, Aaron R; Markovic, Svetomir N; Jr, Meyskens Frank L; Nelson, Kelly C; Powers, Jennifer G; Robinson, June K; Sahni, Debjani; Sekulic, Aleksandar; Sondak, Vernon K; Wei, Maria L; Zager, Jonathan S; Dellavalle, Robert P; Thompson, John A; Weinstock, Martin A; Leachman, Sancy A; Cassidy, Pamela B

BACKGROUND Aberrant Notch activation confers a proliferative advantage to many human tumors, including melanoma. This phase 2 trial assessed the antitumor activity of RO4929097, a gamma-secretase inhibitor of Notch signaling, with respect to the progression-free and overall survival of patients with advanced melanoma. METHODS Chemotherapy-naive patients with metastatic melanoma of cutaneous or unknown origin were treated orally with RO4929097 at a dose of 20 mg daily 3 consecutive days per week. A 2-step accrual design was used with an interim analysis of the first 32 patients and with continuation of enrollment if 4 or more of the 32 patients responded. RESULTS Thirty-six patients from 23 institutions were enrolled; 32 patients were evaluable. RO4929097 was well tolerated, and most toxicities were grade 1 or 2. The most common toxicities were nausea (53%), fatigue (41%), and anemia (22%). There was 1 confirmed partial response lasting 7 months, and there were 8 patients with stable disease lasting at least through week 12, with 1 of these continuing for 31 months. The 6-month progression-free survival rate was 9% (95% confidence interval [CI], 2%-22%), and the 1-year overall survival rate was 50% (95% CI, 32%-66%). Peripheral blood T-cell assays showed no significant inhibition of the production of interleukin-2, a surrogate pharmacodynamic marker of Notch inhibition, and this suggested that the drug levels were insufficient to achieve Notch target inhibition. CONCLUSIONS RO4929097 showed minimal clinical activity against metastatic melanoma in this phase 2 trial, possibly because of inadequate exposure to therapeutic drug levels. Although Notch inhibition remains a compelling target in melanoma, the results do not support further investigation of RO4929097 with this dose and schedule. Cancer 2015;121:432–440. © 2014 American Cancer Society.

BACKGROUND: Serum and plasma levels of vascular endothelial growth factor (VEGF) correlate with prognosis in patients with metastatic breast cancer (MBC). VEGF binds to 2 receptors on endothelial cells, VEGFR-1 and VEGFR-2. RPI.4610 (Angiozyme0) is an antiangiogenic ribozyme targeting the VEGFR-1 mRNA. Preclinical and phase 1 studies suggested that RPI.4610 is a well-tolerated agent with clinical activity in solid tumors. The authors' trial evaluated the efficacy of RPI.4610 in the treatment of patients with progressive MBC. METHODS: This phase 2, multicenter, single-arm study was designed to assess the objective response rate of RPI.4610 in patients with MBC who had experienced disease progression with at least 1 course of chemotherapy for MBC. Patients received daily subcutaneous injections of RPI.4610 100 mg/m2 for 12 weeks. RESULTS: Most patients (93%) had received at least 2 lines of chemotherapy previously; 69% of patients had received at least 3 lines of chemotherapy. Median follow-up was 2.76 months (range, 0.89-36.6 months). No partial responses nor complete responses were found. Median progression-free survival was 1.41 months (95% confidence interval [CI], 1.35-1.45). The median overall survival from start of treatment was 11.89 months (95% CI, 4.11-23.66). Treatment-related adverse events (AEs) were primarily grade 1 to 2 in intensity. Most common AEs were: injection site reactions, abdominal pain, anorexia, chromaturia, constipation, dyspnea, fatigue, headache, pain at the injection site, nausea, vomiting, and fever. CONCLUSIONS: Although RPI.4610 demonstrated a well-tolerated safety profile, its lack of clinical efficacy precludes this drug from further development. Cancer 2012.© 2012 American Cancer Society.

The advent of ipilimumab and the BRAF inhibitors (BRAFi) vemurafenib and dabrafenib has revolutionized the treatment of melanoma. Until a few years ago, the 1-year survival rate in the advanced melanoma population was only 25.5%. However, treatment with these new agents has resulted in approximately half of patients still being alive at 1 year (46% with ipilimumab and more than 50% with vemurafenib). Moreover, the use of these drugs in novel combinations, such as combination tyrosine kinase inhibitors (TKIs) that block sequential or parallel steps in important oncogenic pathways or immune checkpoint blockers with complementary mechanisms of action appear likely to improve the clinical benefit even more than single-agent therapy. The positive results observed in the pivotal clinical trials of ipilimumab and vemurafenib suggested the next logical step was combined ipilumumab and BRAFi treatment, but the phase 1 trial demonstrated increased toxicity (mainly liver and skin). Because the alternative BRAF inhibitor dabrafenib causes a substantial incidence of fever and inflammatory symptoms, it is also not likely to be safely combinable with ipilimumab. Thus, sequential treatment may provide a better opportunity to potentiate these agents’ efficacy. Emerging evidence from retrospective analyses of patient outcomes from clinical trials and Expanded Access Programs (EAPs) have shown that the sequence of first ipilimumab, then BRAFi is associated with superior outcomes than the reverse sequence, and at our own institute, sequential treatment with ipilimumab and BRAFi showed a longer median overall survival (OS) than single-agent treatment. The experience reported in this issue by Ackerman et al is consistent with the reported data that show longer survival among patients treated with immunotherapy first. Given that in Europe, the Committee for Medicinal Products for Human Use (CHMP) recently extended ipilimumab’s indication to first-line treatment, the main question now is which is the best sequence, ipilimumab followed by BRAFi or BRAFi followed by ipilimumab? In attempting to address this question, we need to take into account a number of important considerations. First, although the ipilimumab treatment course consists of just 4 injections, there are data favoring higher over lower doses that were further explored in a recently completed phase 3 trial (data not yet analyzed). We also observed in a large review of the outcomes from the Italian EAP (855 patients from 55 centers treated with ipilimumab) that the 23% of patients who received 1 or 2 ipilimumab injections had significantly worse median OS compared with the 77% of patients who received 3 to 4 injections (1.7 versus 10.8 months). Although the reasons for failure to complete the prescribed 4 treatments most likely included both severe immune-related adverse events as well as rapidly progressive tumor requiring alternative therapy, it is also likely that the mechanism of action of ipilimumab requires a particular minimum number of doses as well as time following therapy to exert its antitumor immune effects. Regarding the mechanism and kinetics of response to BRAFi, it is well known that a fraction of patients, generally identified as those who had the most unfavorable prognostic features prior to therapy, experience aggressive tumor growth and short survival following the development of BRAFi resistance and are too ill to benefit from immunotherapy. The data reported by Ackerman et al suggest that the response rates to BRAFi treatment are similar regardless of whether given before or after ipilimumab (66% and 57%, respectively, P5 .31), indicating that the action of BRAFi is the same in both scenarios. Another important consideration is the potential effect of BRAFi treatment on the immune

Melanoma patients who develop brain metastasis have a very poor prognosis, in part because of relative resistance to external beam radiotherapy and in part because of the low activity and poor central nervous system (CNS) penetration of the available systemic agents. Three articles in this issue of Cancer summarize retrospective analyses of melanoma patients with brain metastases. Although the articles investigate similar questions, each considers different patient characteristics, and the results of the articles provide different and diverging conclusions. Herein, we summarize the results and the authors’ conclusions from each of the 3 articles, examine potential limitations of each article’s conclusions, attempt to synthesize the results, and conclude with ideas for future research.

BACKGROUND To the authors' knowledge, no satisfactory therapy is available for patients with refractory germ cell neoplasms. The activity and safety of arsenic trioxide in refractory germ cell tumors was assessed. METHODS Twenty patients were treated with arsenic trioxide at a dose of 0.25 mg/kg/day and administered intravenously over 1 to 2 hours on Days 1-5 and repeated every 28 days. RESULTS There were no complete or partial responses. The median progression-free survival was 1 month and the median overall survival was 2 months. Three patients died as a result of adverse events believed to be possibly related to treatment: ventricular arrhythmia, adult respiratory distress syndrome, and pneumonitis. CONCLUSIONS In the current study, arsenic trioxide in the dose regimen and schedule employed was found to have no activity in men with refractory germ cell malignancies. Treatment was associated with severe toxicity. Dismal overall survival reflects the poor outcome in this patient group and highlights the acute need for new agents with activity in refractory germ cell neoplasms. Cancer 2006. © 2006 American Cancer Society.

Background. Chemotherapy with a doxorubicin-containing regimen results in high overall response rates in the treatment of metastatic adenocarcinoma of the breast; the combination of doxorubicin, etoposide, and cyclophosphamide has produced a response rate of 84% in untreated patients with stage IV disease. Recent data suggest that selected groups of patients with metastatic disease treated with high-dose chemotherapy and stem cell support may enjoy unmaintained, long-term remission. This study was designed to establish the feasibility of administering the combination of high-dose infusional doxorubicin, etoposide, and cyclophosphamide followed by autologous stem cell rescue in patients with responsive metastatic, or high-risk primary breast cancer. Methods. Criteria for patient enrollment included the presence of high-risk primary breast cancer (stage II with ≥ 10 involved axillary nodes or stages III A or B) or stage IV disease in complete or partial response; Karnofsky performance status of 80% or more; no prior radiation therapy to the left side of the chest; exposure to a 150-mg/m2 or smaller cumulative dose of doxorubicin, and a ventricular ejection fraction of 55% or more. Chemotherapy consisted of escalating doses of doxorubicin given by a 96-hour continuous intravenous infusion, followed by 60 mg/kg of etoposide and 100 mg/kg cyclophosphamide, both given intravenously. On Day 0, autologous bone marrow with or without peripheral stem cells, or granulocyte colony-stimulating factor primed peripheral stem cells alone were reinfused. Results. Thirty-five patients were treated in this study. There were no treatment-related deaths. No patient had a decrease in cardiac ejection fraction below 50% as a consequence of high-dose chemotherapy. Two patients suffered grade 3 mucositis at the highest level of doxorubicin (200 mg/m2). Of 21 patients treated for primary high-risk breast cancer, 19 are recurrence free, with a median follow-up of more than 8 months (≥ 4–36 months). Five of fourteen patients with stage IV disease remain progression free at greater than or equal to 5, 7, 9, 15, and 42 months. For patients with stage IV breast cancer, the median progression-free survival after high-dose chemotherapy was 9 months; the median overall survival had been reached at 22 months. Conclusions. The phase II dose of doxorubicin in this combination therapy has been established at 165 mg/m2, with dose-limiting toxicity defined as mucositis. Further trials to define the role of this safe and effective high-intensity regimen in the treatment of breast cancer are indicated.

BACKGROUND. The combination of temozolomide (TMZ) and thalidomide was reported to produce a high response rate, including shrinkage of brain metastases, in patients with metastatic melanoma. The authors tested the efficacy of a regimen including TMZ, thalidomide, and whole brain radiation therapy (WBRT) in patients with brain (CNS) metastases from melanoma. METHODS. Patients with melanoma, CNS metastases documented by magnetic resonance imaging, and no prior systemic chemotherapy received WBRT, 30 Gray in 10 fractions, Days 1 to 5 and 8 to 12; TMZ, 75 mg/m2/day, Weeks 1 to 6; and thalidomide, 100 mg/day, Weeks 1 to 4, then escalated by 100 mg/day at Weeks 5, 7, and 9 as tolerated to a maximum of 400 mg/day. CNS and systemic tumor response was assessed at Week 10. Patients without CNS or clinically significant systemic disease progression received additional cycles of TMZ at 10-week intervals. RESULTS. Thirty-nine patients received treatment, and 3 exhibited CNS response (1 complete response, 2 partial responses) (response rate, 7.6%; 95% confidence interval, 0.7%-16.1%), all unconfirmed by repeat imaging. Seven patients had stable CNS disease at 10 weeks. No patient exhibited a systemic response. Only 4 patients received 2 cycles of therapy, and just 1 received 3. Median time to progression was 7 weeks, and median overall survival was 4 months. Grade 3-4 side effects included deep venous thrombosis (3), pulmonary embolism (1), and CNS events (12). Eighteen (45%) patients required admission for side effects (7) and/or symptomatic disease progression (11). CONCLUSIONS. The efficacy of TMZ, thalidomide, and WBRT in the treatment of CNS metastatic melanoma is low. Other treatment approaches should be considered for this patient population. Cancer 2008. © 2008 American Cancer Society.