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Background Brain metastases are a significant cause of mortality and morbidity for patients with melanoma. We hypothesize that the development of brain metastases may be explained by molecular heterogeneity between primary cutaneous melanoma (PCM) or extracranial (ECM) and brain (MBM) melanoma metastases. Materials and methods We compared next-generation sequencing, tumor mutational burden (TMB), and immunohistochemical staining for PD-L1 expression, among 132 MBM, 745 PCM, and 1190 ECM. Results The most common genetic alterations among MBM included: BRAF (52.4%), NRAS (26.6%), CDKN2A (23.3%), NF1 (18.9%), TP53 (18%), ARID2 (13.8%), SETD2 (11.9%), and PBRM1 (7.5%). Four genes were found with higher frequency among MBM compared to PCM or ECM: BRAF (52.4% v 40.4% v 40.9%), SETD2 (11.9% v 1.9% v 3.9%), PBRM1 (7.5% v 1.6% v 2.6%), and DICER1 (4.4% v 0.6% v 0.4%). MBM showed higher TMB (p = .04) and higher PD-L1 expression (p = .002), compared to PCM. PD-L1 expression was slightly higher among MBM compared to ECM (p = .042), but there was no difference between TMB (p = .21). Conclusions Our findings suggest a unique molecular profile for MBM, including higher rates of BRAF mutations, higher TMB and higher PD-L1 expression, and also implicate chromatin remodeling in the pathogenesis of MBM.

PURPOSE Phase III adjuvant trials have reported significant benefits in both relapse-free survival (RFS) and overall survival (OS) for high-dose interferon alfa (HDI) and ipilimumab at 10 mg/kg (ipi10). E1609 evaluated the safety and efficacy of ipilimumab at 3 mg/kg (ipi3) and ipi10 versus HDI. PATIENTS AND METHODS E1609 was a phase III trial in patients with resected cutaneous melanoma (American Joint Committee on Cancer 7th edition stage IIIB, IIIC, M1a, or M1b). It had 2 coprimary end points: OS and RFS. A 2-step hierarchic approach first evaluated ipi3 versus HDI followed by ipi10 versus HDI. RESULTS Between May 2011 and August 2014, 1,670 adult patients were centrally randomly assigned (1:1:1) to ipi3 (n = 523), HDI (n = 636), or ipi10 (n = 511). Treatment-related adverse events grade ≥ 3 occurred in 37% of patients receiving ipi3, 79% receiving HDI, and 58% receiving ipi10, with adverse events leading to treatment discontinuation in 35%, 20%, and 54%, respectively. Comparison of ipi3 versus HDI used an intent-to-treat analysis of concurrently randomly assigned patient cases (n = 1,051) and showed significant OS difference in favor of ipi3 (hazard ratio [HR], 0.78; 95.6% repeated CI, 0.61 to 0.99; P = .044; RFS: HR, 0.85; 99.4% CI, 0.66 to 1.09; P = .065). In the second step, for ipi10 versus HDI (n = 989), trends in favor of ipi10 did not achieve statistical significance. Salvage patterns after melanoma relapse showed significantly higher rates of ipilimumab and ipilimumab/anti–programmed death 1 use in the HDI arm versus ipi3 and ipi10 ( P ≤ .001). CONCLUSION Adjuvant therapy with ipi3 benefits survival versus HDI; for the first time to our knowledge in melanoma adjuvant therapy, E1609 has demonstrated a significant improvement in OS against an active control regimen. The currently approved adjuvant ipilimumab dose (ipi10) was more toxic and not superior in efficacy to HDI.

BackgroundMetastatic human epidermal growth receptor II (HER2) negative breast cancer remains incurable. Our phase I study showed that anti-CD3 × anti-HER2 bispecific antibody armed activated T cells (HER2 BATs) may be effective against HER2-tumors. This phase II trial evaluates the efficacy and immune responses of HER2 BATs given to patients with metastatic HER2-estrogen and/or progesterone receptor positive (HR+) and triple negative breast cancer (TNBC) as immune consolidation after chemotherapy. The primary objective of this study was to increase the traditional median time to progression after failure of first-line therapy of 2–4 months with the secondary endpoints of increasing overall survival (OS) and immune responses.MethodsHER2- metastatic breast cancer (MBC) patients received 3 weekly infusions of HER2 BATs and a boost after 12 weeks.ResultsThis phase II study included 24 HER2-HR+ and 8 TNBC patients who received a mean of 3.75 and 2.4 lines of prior chemotherapy, respectively. Eight of 32 evaluable patients were stable at 4 months after the first infusion. There were no dose limiting toxicities. Tumor markers decreased in 13 of 23 (56.5%) patients who had tumor markers. The median OS was 13.1 (95% CI 8.6 to 17.4), 15.2 (95% CI 8.6 to 19.8), and 12.3 (95% CI 2.1 to 17.8) months for the entire group, HER2-HR+, and TNBC patients, respectively. Median OS for patients with chemotherapy-sensitive and chemotherapy-resistant disease after chemotherapy was 14.6 (9.6–21.8) and 8.6 (3.3–17.3) months, respectively. There were statistically significant increases in interferon-γ immunospots, Th1 cytokines, Th2 cytokines, and chemokines after HER2 BATs infusions.ConclusionsIn heavily pretreated HER2-patients, immune consolidation with HER2 BATs after chemotherapy appears to increase the proportion of patients who were stable at 4 months and the median OS for both groups as well as increased adaptive and innate antitumor responses. Future studies combining HER2 BATs with checkpoint inhibitors or other immunomodulators may improve clinical outcomes.

BackgroundThe impact of immune-related adverse events (irAEs) occurring from adjuvant use of immunotherapy and of their management on relapse-free survival (RFS) and overall survival (OS) outcomes is currently not well understood.Patients and methodsE1609 enrolled 1673 patients with resected high-risk melanoma and evaluated adjuvant ipilimumab 3 mg/kg (ipi3) and 10 mg/kg (ipi10) versus interferon-α. We investigated the association of irAEs and of use of immunosuppressants with RFS and OS for patients treated with ipilimumab (n=1034).ResultsOccurrence of grades 1–2 irAEs was associated with RFS (5 years: 52% (95% CI 47% to 56%) vs 41% (95% CI 31% to 50%) with no AE; p=0.006) and a trend toward improved OS (5 years: 75% (95% CI 71% to 79%) compared with 67% (95% CI 56% to 75%) with no AE; p=0.064). Among specific irAEs, grades 1–2 rash was most significantly associated with RFS (p=0.002) and OS (p=0.003). In multivariate models adjusting for prognostic factors, the most significant associations were seen for grades 1–2 rash with RFS (pConclusionsRash and endocrine irAEs were independent prognostic factors of RFS and OS in patients treated with adjuvant ipilimumab. Patients experiencing lower grade irAEs derived the most benefit, but we found no significant evidence supporting a negative impact of high dose corticosteroids and immunosuppressants more commonly used to manage grades 3–4 irAEs.

Combination immunotherapy with sequential administration may enhance metastatic melanoma (MM) patients with long-term disease control. High Dose Aldesleukin/Recombinant Interleukin-2 (HD rIL-2) and ipilimumab (IPI) offer complementary mechanisms against MM. This phase IV study assessed the sequenced use of HD rIL-2 and IPI in MM patients. Eligible Stage IV MM patients were randomized to treatment with either two courses of HD rIL-2(600,000 IU/kg) followed by four doses of IPI 3 mg/kg or vice-versa. The primary objective was to compare one-year overall survival (OS) with historical control (46%, Hodi et al., NEJM 2010). Secondary objectives were 1-year progression-free survival (PFS), objective response rate (ORR), and adverse events (AEs) profile. Evaluable Population (EP) included patients who received at least 50% of planned treatment with each drug. Thirteen and 16 patients were randomized to receive HD rIL-2 first, and IPI first, respectively. One-year OS rate was 75% for intention to treat population. Eighteen patients were included in EP, 8 in HD rIL-2, 10 in IPI first arm. In EP, 1-year OS, PFS and ORR rates were 87%, 68%, and 50%, respectively. The frequency of AEs was similar in both arms with 13 patients experiencing Grade 3 or higher AEs, 3 resulting in the end of study participation. There was one HD rIL-2-related death, from cerebral hemorrhage due to thrombocytopenia. In this study with small sample size, HD rIL-2 and IPI were safe to administer sequentially in MM patients and showed more than additive effects. 1-year OS was superior to that of IPI alone from historical studies.

Background Sex differences in tumor immunity and response to immunotherapy were shown in murine models and descriptive analyses from recent clinical trials. Female sex hormones have been implicated in melanoma development and response to systemic therapy. We hypothesized a gender difference in response to adjuvant immunotherapy with ipilimumab (3 or 10 mg/kg; ipi3 or ipi10) versus high dose IFNα (HDI) as tested in the E1609 trial. Methods E1609 demonstrated significant overall survival (OS) benefit with ipi3 versus HDI.1 We investigated treatment efficacy between ipi and HDI in the subgroups by sex (female, male), age ( Results The subgroups of female, stage IIIC, PS=1, ulcerated, in-transit without lymph node involvement demonstrated significant improvement in overall survival (OS) and/or relapse free survival (RFS) with ipi3 versus HDI as summarized in table 1. Female sex was significant for both OS and RFS and was further explored. In investigating RFS with ipi3 versus HDI, a multivariate Cox regression model including sex, treatment and interaction term of sex*treatment, indicated a significant interaction between sex and treatment (P = 0.026). Including sex, PS (0 vs. 1), age ( Conclusions Female sex was independently associated with RFS adjuvant immunotherapeutic benefit from ipi3, supporting a potentially important role for female related factors in the immune response against melanoma, and these warrant further investigation. Trial Registration NCT01274338 Ethics Approval The study protocol was approved by the institutional review board (IRB) of each participating institution and conducted in accordance with Good Clinical Practice guidelines as defined by the International Conference on Harmonisation. This study was monitored by the ECOG-ACRIN DataSafety Monitoring Committee and the NCI. Consent All patients provided IRB-approved written informed consent. Reference Tarhini AA, Lee SJ, Hodi FS, Rao UNM, Cohen GI, Hamid O, Hutchins LF, Sosman JA, Kluger HM, Eroglu Z, Koon HB, Lawrence DP, Kendra KL, Minor DR, Lee CB, Albertini MR, Flaherty LE, Petrella TM, Streicher H, Sondak VK, Kirkwood JM. Phase III Study of Adjuvant Ipilimumab (3 or 10 mg/kg) Versus High-Dose Interferon Alfa-2b for Resected High-Risk Melanoma: North American Intergroup E1609. J Clin Oncol. 2020 Feb 20;38(6):567–575. PMID: 31880964.

The incidence of CNS progression in patients with high-risk regional melanoma (stages IIIAN2a-IIIC) is not well characterized. Data from the S0008 trial provided an opportunity to examine the role of CNS progression in treatment failure and survival. All patients were surgically staged. Following wide excision and full regional lymphadenectomy, patients were randomized to receive adjuvant biochemotherapy (BCT) or high-dose interferon alfa-2B (HDI). CNS progression was retrospectively identified from data forms. Survival was measured from date of CNS progression. A total of 402 eligible patients were included in the analysis (BCT: 199, HDI: 203). Median follow-up (if alive) was over 7years (range: 1month to 11years). The site of initial progression was identifiable in 80% of relapsing patients. CNS progression was a component of systemic melanoma relapse in 59/402 patients (15% overall). In 34/402 patients (9%) CNS progression represented the initial site of treatment failure. CNS progression was a component of initial progression in 27% of all patients whose melanoma relapsed (59/221). The risk of CNS progression was highest within 3years of randomization. The difference in CNS progression rates between treatment arms was not significant (BCT=25, HDI=34, P=0.24). Lymph node macrometastases strongly associated with CNS progression (P=0.001), while ulceration and head and neck primaries were not significant predictors. This retrospective analysis of the S0008 trial identified a high brain metastasis rate (15%) in regionally advanced melanoma patients. Further studies are needed to establish whether screening plus earlier treatment would improve survival following CNS progression.

Purpose To test the efficacy of 4 weeks of intravenous (IV) induction with high-dose interferon (IFN) as part of the Eastern Cooperative Oncology Group regimen compared with observation (OBS) in patients with surgically resected intermediate-risk melanoma. Patients and Methods In this intergroup international trial, eligible patients had surgically resected cutaneous melanoma in the following categories: (1) T2bN0, (2) T3a-bN0, (3) T4a-bN0, and (4) T1-4N1a-2a (microscopic). Patients were randomly assigned to receive IFN α-2b at 20 MU/m2/d IV for 5 days (Monday to Friday) every week for 4 weeks (IFN) or OBS. Stratification factors were pathologic lymph node status, lymph node staging procedure, Breslow depth, ulceration of the primary lesion, and disease stage. The primary end point was relapse-free survival. Secondary end points included overall survival, toxicity, and quality of life. Results A total of 1,150 patients were randomly assigned. At a median follow-up of 7 years, the 5-year relapse-free survival rate was 0.70 (95% CI, 0.66 to 0.74) for OBS and 0.70, (95% CI, 0.66 to 0.74) for IFN ( P = .964). The 5-year overall survival rate was 0.83 (95% CI, 0.79 to 0.86) for OBS and 0.83 (95% CI, 0.80 to 0.86) for IFN ( P = .558). Treatment-related grade 3 and higher toxicity was 4.6% versus 57.9% for OBS and IFN, respectively ( P < .001). Quality of life was worse for the treated group. Conclusion Four weeks of IV induction as part of the Eastern Cooperative Oncology Group high-dose IFN regimen is not better than OBS alone for patients with intermediate-risk melanoma as defined in this trial.

60 Background: E1609 evaluated adjuvant ipilimumab at 3 mg/kg (ipi3) and 10 mg/kg (ipi10) versus high-dose interferon-α (HDI). In-depth analysis of irAEs and the use of immunosuppressants and hormone replacement may provide important lessons for management and future research. Methods: E1609 enrolled 1670 adult pts with resected cutaneous melanoma (AJCC7 IIIB, IIIC, M1a, M1b); Table. We investigated the characteristics of irAEs, corticosteroid, immunosuppressant and hormone use on the ipi arms and association with outcome. Stratified log-rank test was used and since most irAEs were observed within 3 months of initiating ipi, a 3-month landmark adjustment analysis was conducted. Results: The rates of corticosteroid, immunosuppressant and hormone use by treatment are summarized in Table and none had a significant association with RFS or OS. Significant association between occurrence of grade 1-4 irAEs (vs. no AE) and RFS was observed [5-year RFS: 0.49, 95% CI: (0.45, 0.52) compared to 0.41, 95% CI: (0.31, 0.50); landmark p=0.010]. Occurrence of grade 1-2 irAEs appeared to have a stronger association with RFS [5-years RFS: 0.52, 95% CI: (0.47, 0.56) compared to 0.41, 95% CI: (0.31,0.50) with no AE; p=0.006] and a trend towards improved OS [5-year OS: 0.75, 95%CI:( 0.71, 0.79) compared to 0.67, 95% CI: (0.56, 0.75) with no AE; p=0.064]. Among specific irAEs, rash was most significantly associated with RFS (p = 0.004 and 0.002) and OS (p = 0.007 and 0.003) for grade 1-4 and grade 1-2, respectively, followed by endocrinopathies, and weaker associations seen with other AEs. Conclusions: Adjuvant therapy with ipi is associated with significant irAEs that appear to be related to the immune mechanism of action. Corticosteroids and immunosuppressants were not shown to negatively affect the clinical outcomes. Predictors of irAE risk and understanding the underlying mechanisms are a major gap and are currently actively being investigated. Clinical trial information: NCT01274338. [Table: see text]

Background Data on the characteristics of patients who are likely to experience adverse events, both immune-related and non-immune-related, from programmed cell death-1 (PD1) inhibitors are limited. Patients and methods Data from patients who received ≥1 dose of single-agent PD1 inhibitor between August 3, 2011 and August 31, 2016 were obtained from our Institution's pharmacy database. AEs were graded using Common Terminology Criteria for Adverse Events version 4. Results One hundred and eighty-two patients received at least one dose of single-agent PD1 inhibitor prior to data cut-off. After excluding 14 patients with uncommon malignancies, the total number of patients were 168. The median age was 63 (range=24-92) years. There were 87 (52%) cases of non-small cell lung cancer (NSCLC), 35 (21%) of renal cell carcinoma (RCC), 12 (7%) of melanoma, 18 (11%) of Hodgkin's lymphomas, eight (5%) of head and neck squamous cell carcinoma (HNSCC) and eight (5%) of small cell lung cancer. Considering grade 2 or more AEs, 30 (18%) patients had kidney injury, 34 (20%) hypothyroidism, 36 (21%) transaminitis, 20 (12%) pneumonitis, and 18 (11%) colitis. Patients with RCC had higher odds of experiencing grade 2 or more kidney injury than patients with other primary tumor types (adjusted p=0.025), whereas patients with Hodgkin's lymphoma and HNSCC had higher odds of grade 2 hypothyroidism (adjusted p=0.005). Patients with NSCLC had higher risk of death with pneumonitis than those whose primary cancer was not NSCLC (adjusted p=0.005). Discussion The increased odds of patients with Hodgkin's lymphoma and HNSCC experiencing grade 2 or more hypothyroidism may be related to previous radiation exposure. Most patients with RCC had undergone nephrectomy, making them more susceptible to acute kidney injury. When pneumonitis occurred in patients with primary NSCLC, the overall survival was significantly worse. The duration of PD1 therapy was significantly associated with onset of pneumonitis (p=0.007). Conclusion The site of primary tumor or metastasis may help predict the most common AEs in patients treated with PD1 inhibitors.

Background Preclinical studies suggest that BRAF inhibitors enhance anti-tumor immunity and antigen presentation. Combination BRAF inhibition with immunotherapy is an appealing therapeutic approach. We sequenced vemurafenib with HD IL-2 in patients with BRAF-mutated metastatic melanoma to improve long term outcomes. Methods Eligible patients were HD IL-2 eligible with metastatic BRAF V600 mutated melanoma. Cohort 1 was treatment na��ve and received vemurafenib 960 mg BID for 6 weeks before HD IL-2. Cohort 2 received vemurafenib for 7���18 weeks before enrollment. Both cohorts received HD IL-2 at 600,000 IU/kg every 8 h days 1���5 and days 15���19. The primary objective was to assess complete responses (CR) at 10 weeks ��3 (assessment 1) and 26 weeks ��3 (assessment 2) from the start of HD IL-2. Results Fifty-three patients were enrolled, (cohort 1, n���=���38; cohort 2, n���=���15). Of these, 39 underwent assessment 1 and 15 assessment 2. The CR rate at assessment 1 was 10% (95% CI 3���24) for both cohorts combined, and 27% (95% CI 8���55) at assessment 2. Three-year survival was 30 and 27% for cohort 1 and cohort 2, respectively. No unexpected toxicities occurred. A shift in the melanoma treatment landscape during this trial adversely affected accrual, leading to early trial closure. Conclusions Vemurafenib in sequence with HD IL-2 did not change the known toxicity profile for either agent. Lower than expected response rates to vemurafenib were observed. Overall response rates and durability of responses appear similar to that observed with HD IL-2 alone. Trial registration NCTN, NCT01683188. Registered 11 September 2012, http://www.clinicaltrials.gov/NCT01683188

Purpose To determine the optimal dose and schedule of anthracycline and taxane administration as adjuvant therapy for early-stage breast cancer. Patients and Methods A 2 × 2 factorial design was used to test two hypotheses: (1) that a novel continuous schedule of doxorubicin-cyclophosphamide was superior to six cycles of doxorubicin-cyclophosphamide once every 2 weeks and (2) that paclitaxel once per week was superior to six cycles of paclitaxel once every 2 weeks in patients with node-positive or high-risk node-negative early-stage breast cancer. With 3,250 patients, a disease-free survival (DFS) hazard ratio of 0.82 for each randomization could be detected with 90% power with two-sided α = .05. Overall survival (OS) was a secondary outcome. Results Interim analyses crossed the futility boundaries for demonstrating superiority of both once-per-week regimens and once-every-2-weeks regimens. After a median follow-up of 6 years, a significant interaction developed between the two randomization factors (DFS P = .024; OS P = .010) in the 2,716 patients randomly assigned in the original design, which precluded interpretation of the two factors separately. Comparing all four arms showed a significant difference in OS (P = .040) but not in DFS (P = .11), with all treatments given once every 2 weeks associated with the highest OS. This difference in OS seemed confined to patients with hormone receptor–negative/human epidermal growth factor receptor 2 (HER2) –negative tumors (P = .067), with no differences seen with hormone receptor–positive/HER2-negative (P = .90) or HER2-positive tumors (P = .40). Conclusion Patients achieved a similar DFS with any of these regimens. Subset analysis suggests the hypothesis that once-every-2-weeks dosing may be best for patients with hormone receptor–negative/HER2-negative tumors.

BACKGROUND: ExteNET showed that 1 year of neratinib, an irreversible pan-HER tyrosine kinase inhibitor, significantly improves 2-year invasive disease-free survival after trastuzumab-based adjuvant therapy in women with HER2-positive breast cancer. We report updated efficacy outcomes from a protocol-defined 5-year follow-up sensitivity analysis and long-term toxicity findings. METHODS: In this ongoing randomised, double-blind, placebo-controlled, phase 3 trial, eligible women aged 18 years or older (≥20 years in Japan) with stage 1-3c (modified to stage 2-3c in February, 2010) operable breast cancer, who had completed neoadjuvant and adjuvant chemotherapy plus trastuzumab with no evidence of disease recurrence or metastatic disease at study entry. Patients who were eligible patients were randomly assigned (1:1) via permuted blocks stratified according to hormone receptor status (hormone receptor-positive vs hormone receptor-negative), nodal status (0 vs 1-3 vs or ≥4 positive nodes), and trastuzumab adjuvant regimen (given sequentially vs concurrently with chemotherapy), then implemented centrally via an interactive voice and web-response system, to receive 1 year of oral neratinib 240 mg/day or matching placebo. Treatment was given continuously for 1 year, unless disease recurrence or new breast cancer, intolerable adverse events, or consent withdrawal occurred. Patients, investigators, and trial funder were masked to treatment allocation. The predefined endpoint of the 5-year analysis was invasive disease-free survival, analysed by intention to treat. ExteNET is registered with ClinicalTrials.gov, number NCT00878709, and is closed to new participants. FINDINGS: Between July 9, 2009, and Oct 24, 2011, 2840 eligible women with early HER2-positive breast cancer were recruited from community-based and academic institutions in 40 countries and randomly assigned to receive neratinib (n=1420) or placebo (n=1420). After a median follow-up of 5·2 years (IQR 2·1-5·3), patients in the neratinib group had significantly fewer invasive disease-free survival events than those in the placebo group (116 vs 163 events; stratified hazard ratio 0·73, 95% CI 0·57-0·92, p=0·0083). The 5-year invasive disease-free survival was 90·2% (95% CI 88·3-91·8) in the neratinib group and 87·7% (85·7-89·4) in the placebo group. Without diarrhoea prophylaxis, the most common grade 3-4 adverse events in the neratinib group, compared with the placebo group, were diarrhoea (561 [40%] grade 3 and one [BACKGROUND: ExteNET showed that 1 year of neratinib, an irreversible pan-HER tyrosine kinase inhibitor, significantly improves 2-year invasive disease-free survival after trastuzumab-based adjuvant therapy in women with HER2-positive breast cancer. We report updated efficacy outcomes from a protocol-defined 5-year follow-up sensitivity analysis and long-term toxicity findings.METHODS: In this ongoing randomised, double-blind, placebo-controlled, phase 3 trial, eligible women aged 18 years or older (≥20 years in Japan) with stage 1-3c (modified to stage 2-3c in February, 2010) operable breast cancer, who had completed neoadjuvant and adjuvant chemotherapy plus trastuzumab with no evidence of disease recurrence or metastatic disease at study entry. Patients who were eligible patients were randomly assigned (1:1) via permuted blocks stratified according to hormone receptor status (hormone receptor-positive vs hormone receptor-negative), nodal status (0 vs 1-3 vs or ≥4 positive nodes), and trastuzumab adjuvant regimen (given sequentially vs concurrently with chemotherapy), then implemented centrally via an interactive voice and web-response system, to receive 1 year of oral neratinib 240 mg/day or matching placebo. Treatment was given continuously for 1 year, unless disease recurrence or new breast cancer, intolerable adverse events, or consent withdrawal occurred. Patients, investigators, and trial funder were masked to treatment allocation. The predefined endpoint of the 5-year analysis was invasive disease-free survival, analysed by intention to treat. ExteNET is registered with ClinicalTrials.gov, number NCT00878709, and is closed to new participants.FINDINGS: Between July 9, 2009, and Oct 24, 2011, 2840 eligible women with early HER2-positive breast cancer were recruited from community-based and academic institutions in 40 countries and randomly assigned to receive neratinib (n=1420) or placebo (n=1420). After a median follow-up of 5·2 years (IQR 2·1-5·3), patients in the neratinib group had significantly fewer invasive disease-free survival events than those in the placebo group (116 vs 163 events; stratified hazard ratio 0·73, 95% CI 0·57-0·92, p=0·0083). The 5-year invasive disease-free survival was 90·2% (95% CI 88·3-91·8) in the neratinib group and 87·7% (85·7-89·4) in the placebo group. Without diarrhoea prophylaxis, the most common grade 3-4 adverse events in the neratinib group, compared with the placebo group, were diarrhoea (561 [40%] grade 3 and one [INTERPRETATION: At the 5-year follow-up, 1 year of extended adjuvant therapy with neratinib, administered after chemotherapy and trastuzumab, significantly reduced the proportion of clinically relevant breast cancer relapses-ie, those that might lead to death, such as distant and locoregional relapses outside the preserved breast-without increasing the risk of long-term toxicity. An analysis of overall survival is planned after 248 events.FUNDING: Wyeth, Pfizer, and Puma Biotechnology.

Purpose High-dose interferon (IFN) for 1 year (HDI) is the US Food and Drug Administration–approved adjuvant therapy for patients with high-risk melanoma. Efforts to modify IFN dose and schedule have not improved efficacy. We sought to determine whether a shorter course of biochemotherapy would be more effective. Patients and Methods S0008 (S0008: Chemotherapy Plus Biological Therapy in Treating Patients With Melanoma) was an Intergroup phase III trial that enrolled high-risk patients (stage IIIA-N2a through IIIC-N3), randomly assigning them to receive either HDI or biochemotherapy consisting of dacarbazine, cisplatin, vinblastine, interleukin-2, IFN alfa-2b (IFN-α-2b) and granulocyte colony-stimulating factor given every 21 days for three cycles. Coprimary end points were relapse-free survival (RFS) and overall survival (OS). Results In all, 432 patients were enrolled. Grade 3 and 4 adverse events occurred in 57% and 7% of HDI patients and 36% and 40% of biochemotherapy patients, respectively. At a median follow-up of 7.2 years, biochemotherapy improved RFS (hazard ratio [HR], 0.75; 95% CI, 0.58 to 0.97; P = .015), with a median RFS of 4.0 years (95% CI, 1.9 years to not reached [NR]) versus 1.9 years for HDI (95% CI, 1.2 to 2.8 years) and a 5-year RFS of 48% versus 39%. Median OS was not different (HR, 0.98; 95% CI, 0.74 to 1.31; P = .55), with a median OS of 9.9 years (95% CI, 4.62 years to NR) for biochemotherapy versus 6.7 years (95% CI, 4.5 years to NR) for HDI and a 5-year OS of 56% for both arms. Conclusion Biochemotherapy is a shorter, alternative adjuvant treatment for patients with high-risk melanoma that provides statistically significant improvement in RFS but no difference in OS and more toxicity compared with HDI.

Associations between HLA class I antigen expression and the efficacy of a melanoma vaccine (Melacine; Corixa Corp.) were initially described in stage IV melanoma. Similar associations were observed in S9035, a phase III adjuvant trial evaluating Melacine for 2 years compared with observation in patients with stage II melanoma. This report provides long-term results. The effects of treatment on relapse-free survival (RFS) and overall survival (OS) were evaluated, and prespecified analyses investigated associations between treatment and HLA expression. Multivariable analyses were adjusted for tumor thickness, ulceration and site, method of nodal staging, and sex. P = 0.01 was considered statistically significant in subset analyses to account for multiple comparisons. For the entire study population of 689 patients, there were no significant differences in RFS or OS by treatment arm. HLA serotyping was performed on 553 (80%) patients (vaccine, 294; observation, 259). Among the subpopulation with HLA-A2 and/or HLA-Cw3 serotype, vaccine arm patients (n = 178) had marginally improved RFS (adjusted P = 0.02) and significantly improved OS compared with observation arm patients (n = 145), with 10-year OS of 75% and 63%, respectively [hazard ratio (HR), 0.62; 99% confidence interval (CI), 0.37–1.02; P = 0.01]. There was no impact of HLA-A2 and/or HLA-Cw3 expression on observation arm patients. An analysis of mature data from S9035 indicates a significant OS benefit from adjuvant vaccine therapy for patients with HLA-A2– and/or HLA-Cw3–expressing melanoma. The possibility of interactions between HLA type and outcome should be considered in future immunotherapy trials. Further investigations of melanoma-associated antigens present in Melacine and presented by HLA-A2 and HLA-Cw3 may be warranted. Cancer Immunol Res; 2(10); 981–7. ©2014 AACR.

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.

Summary Background Addition of a MEK inhibitor to a BRAF inhibitor enhances tumour growth inhibition, delays acquired resistance, and abrogates paradoxical activation of the MAPK pathway in preclinical models of BRAF -mutated melanoma. We assessed the safety and efficacy of combined BRAF inhibition with vemurafenib and MEK inhibition with cobimetinib in patients with advanced BRAF -mutated melanoma. Methods We undertook a phase 1b study in patients with advanced BRAF V600 -mutated melanoma. We included individuals who had either recently progressed on vemurafenib or never received a BRAF inhibitor. In the dose-escalation phase of our study, patients received vemurafenib 720 mg or 960 mg twice a day continuously and cobimetinib 60 mg, 80 mg, or 100 mg once a day for either 14 days on and 14 days off (14/14), 21 days on and 7 days off (21/7), or continuously (28/0). The primary endpoint was safety of the drug combination and to identify dose-limiting toxic effects and the maximum tolerated dose. Efficacy was a key secondary endpoint. All patients treated with vemurafenib and cobimetinib were included in safety and efficacy analyses (intention-to-treat). The study completed accrual and all analyses are final. This study is registered with ClinicalTrials.gov, number NCT01271803. Findings 129 patients were treated at ten dosing regimens combining vemurafenib and cobimetinib: 66 had recently progressed on vemurafenib and 63 had never received a BRAF inhibitor. Dose-limiting toxic effects arose in four patients. One patient on a schedule of vemurafenib 960 mg twice a day and cobimetinib 80 mg once a day 14/14 had grade 3 fatigue for more than 7 days; one patient on a schedule of vemurafenib 960 mg twice a day and cobimetinib 60 mg once a day 21/7 had a grade 3 prolongation of QTc; and two patients on a schedule of vemurafenib 960 mg twice a day and cobimetinib 60 mg 28/0 had dose-limiting toxic effects—one developed grade 3 stomatitis and fatigue and one developed arthralgia and myalgia. The maximum tolerated dose was established as vemurafenib 960 mg twice a day in combination with cobimetinib 60 mg 21/7. Across all dosing regimens, the most common adverse events were diarrhoea (83 patients, 64%), non-acneiform rash (77 patients, 60%), liver enzyme abnormalities (64 patients, 50%), fatigue (62 patients, 48%), nausea (58 patients, 45%), and photosensitivity (52 patients, 40%). Most adverse events were mild-to-moderate in severity. The most common grade 3 or 4 adverse events were cutaneous squamous-cell carcinoma (12 patients, 9%; all grade 3), raised amounts of alkaline phosphatase (11 patients, 9%]), and anaemia (nine patients, 7%). Confirmed objective responses were recorded in ten (15%) of 66 patients who had recently progressed on vemurafenib, with a median progression-free survival of 2·8 months (95% CI 2·6–3·4). Confirmed objective responses were noted in 55 (87%) of 63 patients who had never received a BRAF inhibitor, including six (10%) who had a complete response; median progression-free survival was 13·7 months (95% CI 10·1–17·5). Interpretation The combination of vemurafenib and cobimetinib was safe and tolerable when administered at the respective maximum tolerated doses. The combination has promising antitumour activity and further clinical development is warranted in patients with advanced BRAF V600 -mutated melanoma, particularly in those who have never received a BRAF inhibitor; confirmatory clinical testing is ongoing. Funding F Hoffmann-La Roche/Genentech.

1080 Background: This study presents a phase II cell therapy trial in 32 women with metastatic or locally advanced HER2- breast cancer (BrCa) who received infusions of anti-CD3 x anti-HER2 bispecific antibody armed activated T cells (BATs). This phase II study (NCT 01022138) was conducted to determine if BATs infusions could improve time to progression (TTP) and overall survival (OS), as well as to confirm the toxicity profile of BATs. Methods: The phase II included 32 patients with a median of 4 lines of therapy (7 TNBC and 25 HR/PR+ HER2- patients) with an average age of 52.5 years (range 28-75 years). Twenty-one patients had ≥3 lines of prior therapy and 11 patients had 1-2 lines. Peripheral blood mononuclear cells (PBMC) were stimulated with anti-CD3 antibody and expanded in IL-2, armed with HER2Bi, and aliquoted for the clinical trial. Patients received oncologist’s choice of chemotherapy (4 cycles/4 months) followed by 3 infusions of BATs given once per week for 3 weeks and a boost given 12 weeks after the 3rd infusion. Results: Fifteen of 32 (ORR of 46.8%) who had received any cells had stable disease (SD) at 1 month after the last infusion, and 8 of 15 (25%) had SD > 4 months. For patients who completed 3 or 4 infusions (17-83 x 109 BATs), 8 of 31 patients had TTP > 4 months. One patient completed 2 infusions (17 x 109 BATs). There were no dose limiting toxicities (DLTs). Tumor markers decreased in 13 of 23 (56.5%) patients with evaluable markers. The median OS was 13.8, 16.5, and 12.4 months for all, ER/PR+, and TNBC, respectively. OS for all patients with chemosensitive (chemoS) and chemoresistant (chemoR) disease was 14.6 and 8.6 months (NS), respectively. OS for chemoS and chemoR disease in HER2- ER/PR+ patients was 16.5 and 8.6 months (NS), respectively. OS for chemoS and chemoR disease in TNBC patients was 12.4 and 22.6 months, respectively (NS). The median TTP for all, HER2- ER/PR+, and TNBC patients was 2.7, 2.9, and 1.4 months, respectively. Increases in serum IL-2 and IL-12 were associated with BATs infusions. Conclusions: Targeting HER2- tumors was safe. There were trends toward improved survival in patients who were HER2-/ER/PR+ TNBC, patients who were chemoS, was associated with increased TTP and OS in all groups, and was associated with decreased tumor markers in those who received 4 infusions. Immune studies showed evidence for induction of adaptive immunity directed at breast cancer antigens. Targeting metastatic HER2- BrCa with BATs shows promise. Clinical trial information: NCT 01022138.

9504 Background: Phase III adjuvant trials reported significant benefits in relapse-free survival (RFS) for 6 FDA-approved regimens and overall survival (OS) for HDI and ipi10 versus observation or placebo. E1609 evaluated the relative safety and efficacy of ipi at 3 and 10 mg/kg compared to HDI, which was the adjuvant standard until recently. Methods: E1609 had 2 co-primary endpoints: OS and RFS; considered positive if either co-primary endpoint comparison was positive. Activated on 5/25/2011 and completed accrual 8/15/2014. A 2-step hierarchical approach evaluated ipi3 vs HDI followed by ipi10 vs HDI. Patients were stratified by AJCC7 stage (IIIB, IIIC, M1a, M1b). Based on protocol criteria, the primary evaluation was conducted using a data cutoff of 2/15/2019. Results: Final adult patient accrual was 1670; 523 randomized to ipi3, 636 to HDI and 511 to ipi10. Treatment related adverse events (AEs) Grade 3 or higher were experienced by 37% pts with ipi3, 79% with HDI and 58% with ipi10, and those of any grade leading to treatment discontinuation were 35% with ipi3, 20% HDI and 54% ipi10. AEs were mostly immune related and consistent with the known toxicity profiles of these agents. Gr5 AEs considered at least possibly related were 3 with ipi3, 2 with HDI and 8 with ipi10. First step comparison of OS and RFS of ipi3 vs. HDI utilized an ITT analysis of concurrently randomized cases (N = 1051) and showed significant OS difference in favor of ipi3; HR 0.78, 95.6% RCI (.61, 1.00); p = 0.044. The prespecified efficacy boundary was crossed. For RFS, HR 0.85, 99.4% CI (.66, 1.09), p = 0.065. In the 2nd step comparison of ipi10 vs. HDI (N = 989), there were trends towards improvement in OS [HR 0.88, 95.6% CI (.69, 1.12)] and RFS [HR 0.84, 99.4% CI (.65, 1.09)] in favor of ipi10 that were not statistically significant. Conclusions: Adjuvant therapy with ipi3 benefits survival of resected high-risk melanoma pts; for the first time in the history of melanoma adjuvant therapy, E1609 has demonstrated a significant improvement in the primary endpoint of OS against an active control regimen previously shown to have OS and RFS benefits, supporting early systemic adjuvant therapy for high-risk melanoma. Clinical trial information: NCT01274338.

9565 Background: Nearly 50% of metastatic melanoma patients develop brain metastases, warranting further investigation into the biology of this event. Methods: We analyzed 132 MBM and 745 CM submitted to Caris Life Sciences from 2015-2018, using next generation sequencing of a 44 or 592 cancer-related gene panel, tumor mutational burden (TMB), and PD-L1 expression by IHC. Genomic alterations (GA), including somatic mutations or CNA, were reported. High TMB (TMB-H) was defined as ≥17 mut/Mb. Comparison of molecular profiles, including cancer-related genes and recurrently altered pathways, between tumor sites and by genomic subgroup (BRAF, NRAS, KIT, NF1), was performed using Fisher’s exact test. Results: Among 132 MBM, 72.7% were male, with median age 62 yo (range 25-83). The most common GAs among MBM were: BRAF (52.4%), NRAS (26.6%), CDKN2A (23.3%), NF1 (18.9%), TP53 (18%), ARID2 (13.8%), SETD2 (11.9%), and PBRM1 (7.5%). Compared to CM, MBM were more often TMB-H (53.7% v 38%, p = .025), with higher PD-L1 expression, using both a ≥1% (54.4% v 35.6%, p = .002) and ≥5% cut-off (32.9% v 15.9%, p = .0006). MBM showed higher rates of GAs among: SETD2 (11.9% v 1.9%, p = .0008), BRAF (52.4% v 35.6%, p = .017), PBRM1 (7.5% v 1.6%, p = .018), KRAS (4% v 1%, p = .026), CCND1 (2.9% v 0%, p = .03), and DICER1 (4.4% v 0.6%, p = .04), compared to CM. Alterations of the MAPK (87.9% v 77.8%, p = .015) and SWI/SNF (22.1% v 11.6%, p = .036) pathway were more frequent in MBM, than CM. When analyzed by genomic subgroup, BRAF+ MBM had more GAs involving the PI3K pathway (20% v 5.1%, p = .027), compared to BRAF WT MBM. NRAS+ MBM had higher PD-L1 expression at the ≥1% cutoff (66.7% v 38.6%, p = .05), but not ≥5%, compared to NRAS WT MBM. NF1+ MBM had more GAs involving the SWI/SNF (60% v 11.6%, p = .003) pathway, as opposed to NF1 WT MBM. No significant associations were seen between KIT status, TMB, PD-L1 or other pathways among MBM. Conclusions: In this cross-sectional study, MBM demonstrated higher PD-L1 expression and were more often TMB-H, compared to CM. MBM also featured more GAs involving BRAF and the MAPK pathway. We identified two novel genes, PBRM1 and SETD2, as well as recurrent alterations of the SWI/SNF pathway, supporting future studies of chromatin remodeling pathways in MBM.

Purpose: Signaling pathway stimulation by activating mutations of oncogenes occurs in most melanomas and can provide excellent targets for therapy, but the short-term therapeutic success is limited by intrinsic and acquired resistance. The mitogen-activated protein kinase and phosphoinositide 3-kinase/AKT/mTOR pathways are activated in most cutaneous melanomas. The purpose of this trial was to prospectively evaluate 2 molecularly targeted drug combinations in patients with untreated metastatic melanoma. Experimental Design: This randomized phase II study enrolled patients between May 2008 and November 2009 with nonocular melanoma, no prior systemic chemotherapy, and no history of brain metastasis. Arm A received oral sorafenib 200 mg twice daily plus i.v. temsirolimus 25 mg weekly; and arm B received oral sorafenib 400 mg every morning, 200 mg every night daily plus oral tipifarnib 100 mg twice daily, 3 weeks of every 4. The primary objectives were to evaluate progression-free survival (PFS), objective response rate, and toxicity for the 2 regimens. Results: On arm A (63 evaluable patients), the median PFS was 2.1 months and median overall survival (OS) was 7 months. Three patients achieved partial response (PR). Thirty-nine evaluable patients were accrued to arm B, which closed after first-stage accrual; the median PFS was 1.8 months and OS was 7 months, with 1 patient achieving PR. Conclusions: The combinations of molecularly targeted agents tested did not show sufficient activity to justify further use. Newer agents and improved patient selection by characterization of the molecular targets in individual tumors show great promise and should be incorporated into future studies, along with appropriate laboratory correlates. Clin Cancer Res; 18(4); 1129–37. ©2012 AACR.

On the basis of retrospective experience at individual centers, it appears that patients with stage IV melanoma who undergo complete resection have a favorable outcome compared with patients with disseminated stage IV disease. The Southwest Oncology Group (SWOG) performed a prospective trial in patients with metastatic melanoma who were enrolled before complete resection of their metastatic disease and provided prospective outcomes in the cooperative group setting.Based on their physical examination and radiologic imaging studies, patients with a stage IV melanoma judged amenable to complete resection underwent surgery within 28 days of enrollment. All eligible patients were followed with scans (computed tomography or positron emission tomography) every 6 months until relapse and death.Seventy-seven patients were enrolled from 18 different centers. Of those, 5 patients were ineligible; 2 had stage III disease alone; and 3 had no melanoma in their surgical specimen. In addition, 8 eligible patients had incompletely resected tumor. Therefore, the primary analysis included 64 completely resected patients. Twenty patients (31%) had visceral disease. With a median follow-up of 5 years, the median relapse-free survival was 5 months (95% CI, 3-7 months) whereas median overall survival was 21 months (95% CI, 16-34 months). Overall survivals at 3 and 4 years were 36% and 31%, respectively.In a prospective multicenter setting, appropriately selected patients with stage IV melanoma achieved prolonged overall survival after complete surgical resection. Although median relapse-free survival was only 5 months, patients could still frequently undergo subsequent surgery for isolated recurrences. This patient population is appropriate for aggressive surgical therapy and for trials evaluating adjuvant therapy.

BACKGROUND: Chemotherapy has not been reported to have a significant impact on survival for patients with metastatic melanoma. Bortezomib was shown to have additive/synergistic effects with several chemotherapeutic agents, including paclitaxel and platinum. A phase 1 trial of this 3-drug combination reported that 6 of 28 patients treated with bortezomib followed by paclitaxel and carboplatin achieved a partial response (including 2 of 5 patients with metastatic melanoma). METHODS: A 2-stage phase 2 clinical trial was conducted to assess the antitumor activity of this 3-agent combination in patients with metastatic melanoma who had received at most 1 prior chemotherapy for metastatic disease. Treatment included bortezomib at a dose of 1.3 mg/m2 intravenously on Days 1, 4, and 8; paclitaxel at a dose of 175 mg/m2; and carboplatin at an area under the concentration (AUC) of 6 on Day 2 of a 21-day cycle. The primary endpoint of this trial was tumor response rate (TRR). RESULTS: Seventeen eligible patients were enrolled. A median of 4 cycles were administered (range, 1-7 cycles). Three patients discontinued treatment due to persistent grade 4 (based on National Cancer Institute Common Terminology Criteria for Adverse Events [version 3.0]) neutropenia with grade 3 leukopenia (2 patients) or grade 4 pulmonary embolism (1 patient). Grade ≥3 toxicities included neutropenia (71%), leukopenia (41%), thrombocytopenia (29%), and arthralgia (12%). Two partial responses were observed (TRR, 11.8%). Four patients had stable disease at >12 weeks. The median progression-free survival was 3.2 months, and the median overall survival was 7.0 months. CONCLUSIONS: Due to insufficient clinical efficacy, this trial did not proceed to second-stage accrual. The combination of paclitaxel, carboplatin, and bortezomib demonstrated limited clinical benefit and was associated with significant toxicity. Cancer 2010. © 2010 American Cancer Society.

PurposeHigh-dose interleukin-2 (IL-2) induces responses in 15% to 20% of patients with advanced melanoma; 5% to 8% are durable complete responses (CRs). The HLA-A2–restricted, modified gp100 peptide (210M) induces T-cell immunity in vivo and has little antitumor activity but, combined with high-dose IL-2, reportedly has a 42% (13 of 31 patients) response rate (RR). We evaluated 210M with one of three different IL-2 schedules to determine whether a basis exists for a phase III trial.Patients and MethodsIn three separate phase II trials, patients with melanoma received 210M subcutaneously during weeks 1, 4, 7, and 10 and standard high-dose IL-2 during weeks 1 and 3 (trial 1), weeks 7 and 9 (trial 2), or weeks 1, 4, 7, and 10 (trial 3). Immune assays were performed on peripheral-blood mononuclear cells collected before and after treatment.ResultsFrom 1998 to 2003, 131 patients with HLA-A2–positive were enrolled. With 60-month median follow-up time, the overall RR for 121 assessable patients was 16.5% (95% CI, 10% to 26%); the RRs were 23.8% in trial 1 (42 patients), 12.5% in trial 2 (40 patients), and 12.8% in trial 3 (39 patients). There were 11 CRs (9%) and nine partial responses (7%), with 11 patients (9%) progression free at ≥ 30 months. Immune studies including assays of CD3-ζ expression and numbers of CD4+/CD25+/FoxP3+regulatory T cells, CD15+/CD11b+/CD14–immature myeloid-derived cells, and CD8+gp100 tetramer-positive cells in the blood did not correlate with clinical benefit.ConclusionThe results again demonstrate efficacy of high-dose IL-2 in advanced melanoma but did not demonstrate the promising clinical activity reported with vaccine and high-dose IL-2 in any of three phase II trials.

BACKGROUND. Southwest Oncology Group protocol 0026 evaluated interferon alpha-2b plus thalidomide in patients with disseminated melanoma. Endpoints were 6-month progression-free survival rate, response rate, and toxicity. METHODS. Twenty-six patients with Stage IV melanoma, measurable or nonmeasurable disease, performance status of 0–2, and adequate renal and hepatic functions were registered. One prior systemic therapy for Stage IV disease was required. Interferon was administered subcutaneously (1 million U) twice daily; thalidomide was orally administered (200–400 mg) each evening in a dose-escalating manner. Response evaluations using Response Evaluation Criteria in Solid Tumors were performed every 8 weeks. RESULTS. After 2 sudden deaths and 1 grade 4 treatment-related pulmonary embolism, this study was temporarily closed. One patient with deep-vein thrombosis and 2 with grade 3 cardiac arrhythmias were reported. The relationship of these events to the treatment was worrisome but not definitive. Grade 3 treatment-related adverse events occurred in 14 of 26 patients. Because of concern for patient safety the study was permanently closed. No treatment responses were seen in the 22 evaluable patients. Estimated 6-month progression-free survival rate was 15% (95% confidence interval [CI], 2%–29%), estimated 6-month overall survival was 58% (95% CI, 39%–77%), and estimated response probability was 0 of 22 (95% CI, 0%–15%). CONCLUSIONS. This regimen demonstrated a lack of response and was associated with multiple severe toxicities. Further investigation of interferon alpha-2b and thalidomide in this dose and schedule is not warranted. Cancer 2007. © 2007 American Cancer Society.

Objective The primary aim of this study was to estimate the rate of clinical and pathologic response to preoperative docetaxel, doxorubicin, and infusional 5-fluorouracil in patients with locally advanced breast cancer. Secondary objective included the determination of toxicity profile. Patients and methods Thirty-nine patients (median age 49 years) with histologically confirmed locally advanced breast cancer (stage IIIA or IIIB) were studied. Patients received 4 courses of chemotherapy with docetaxel (75 mg/m2 iv over 1 hour), doxorubicin (50 mg/m2 iv bolus), and 5-fluorouracil (300 mg/m2/d as continuous iv infusion on days 1-5). Treatment cycles were repeated every 21 days. Prophylactic filgastrim 5 microg/kg s/c QD was administered to all patients. Definitive surgery was performed after the completion of 4 cycles of therapy. Pathologic complete response was defined as the absence of invasive cancer in both the breast and ipsilateral axillary lymph nodes. Results The clinical objective response rate (partial plus complete) was 87% (95% confidence interval [CI]: 76-98%). Three patients (8%) had complete pathologic response. Two patients progressed preoperatively. Thirteen patients (33%) developed neutropenic fever. Fifty-three percent of the patients were hospitalized for treatment related complications. No cardiotoxicity or treatment related deaths were observed. Conclusions Triple cytotoxic therapy based on concurrent doxorubicin and docetaxel with infusional 5-flourouracil (5-FU) does not appear to significantly improve the pathologic response in patients with locally advanced breast cancer.

To evaluate the toxicity and efficacy of interferon and thalidomide combination in a phase II clinical trial.Eligibility included metastatic renal cancer with a maximum of two prior regimens, performance status of 0-2 and adequate renal, hepatic and bone marrow function.Twenty patients were enrolled on this phase II trial. Median age was 60.5 years (Range: 39-75 years). 17 patients had visceral metastases (lung/liver/both) and 3 patients had lymph node only metastases. A total of 26 cycles of 4 weeks each were administered; median of 1 cycle and range from 0-9 cycles. The therapy was poorly tolerated with grade 3 adverse events noted in 12 (60%) of the 20 patients. No objective responses were noted. Of the 14 response evaluable patients, one had an unconfirmed response (38% decrease in size) and one had prolonged disease stabilization for 10 months. The median time to progression was 1.0 month and median survival was 2.8 months. Pre and post therapy PET scans were performed nine weeks apart on one patient. The mean standardized uptake values (SUV) declined from 1.45 (SUV min-max 0.89-1.76) to 1.12 (SUV min-max 0.55-1.47), denoting anti vascular effect. The patient did not have an objective response but had a disease stabilization sustained for 10 months.The combination of interferon and thalidomide has minimal efficacy and considerable toxicity which makes this combination unworthy of future investigation in metastatic renal cancer.

Purpose. Medical Oncology is a rapidly growing specialty, not only in its membership, but in its knowledge base as well. In order to keep pace with the changing profile of health care delivery and still ensure uniform quality subspecialty training, a template for education is needed. Design and Results. An Ad Hoc Committee was created from the American Society of Clinical Oncology (ASCO) membership in 1997. Goals of training were discussed, and curriculum guidelines were created. The great expansion in knowledge related to cancer care has led to this current revision of the initial curriculum. The goals of this second edition of ASCO curriculum remain the same and emphasize formal instruction in the following: (1) the treatment of individual malignancies, with an emphasis on a coordinated multidisciplinary approach; (2) a clinical experience that emphasizes patient management in both the inpatient and outpatient settings; (3) the ability to perform specified procedures; and (4) the key tools in basic science that apply to patient management. This document should be considered the educational framework around which a training program is developed. The American Society of Clinical Oncology was founded in 1965, and by 1979, the membership had grown to 2,950. Today, more than 20,000 physicians are members of ASCO. Since the first subspecialty examination in medical oncology was offered in 1973, the number of certified medical oncologists has risen to over 8,000. Medical Oncology is not only one of the youngest subspecialties in internal medicine, but also one of the fastest growing. The recent years have witnessed an explosion in medical technology. The pharmacopoeia of chemotherapeutic agents has grown from the three available agents in 1950 to over 50 antineoplastic agents. Molecular diagnostic testing is now commonplace, and more widespread use of genetic screening is on the horizon. Moreover, an entirely new area of clinical research trials has been initiated in pharmacologic cancer prevention. At the same time, health care has become an “industry” that has resulted in the shift of the majority of cancer care to the outpatient setting, with a focus on costcontainment. It is a challenge to develop a curriculum for training physicians in so dynamic an environment. While the American Board of Internal Medicine (ABIM) and Accreditation Council on Graduate Medical Education (ACGME) create a basic structure for subspecialty training, the specific items that are to be included in the training curriculum are not within their purview. ASCO leadership has thus taken on the task of creating a “Competence Comprising Curriculum” for From the University of Vermont, Burlington, VT; Northwestern University, Chicago, IL; University of California-San Francisco, San Francisco; Scripps Clinic; Moores UCSD Cancer Center, San Diego, CA; Memorial Sloan-Kettering Cancer Center; New York University Medical Center, New York; Albert Einstein Cancer Center, Bronx, NY; Wayne State University, Detroit, MI; University of Wisconsin, Madison, WI; University of Colorado Health Science Center, Denver, CO; Texas Oncology PA, Dallas; University of Texas M.D. Anderson Cancer Center, Houston, TX; Lineberger Comprehensive Cancer Center, Chapel Hill, NC; Mayo Clinic, Jacksonville, FL; Massachusetts General Hospital, Boston, MA.

Purpose The practice patterns of medical oncologists at a large National Cancer Institute Comprehensive Cancer Center in Detroit, MI were evaluated to better understand factors associated with accrual to breast cancer clinical trials. Patients and Methods From 1996 to 1997, physicians completed surveys on 319 of 344 newly evaluated female breast cancer patients. The 19-item survey included clinical data, whether patients were offered clinical trial (CT) participation and enrollment, and when applicable, reasons why they were not. Multivariate analyses using logistic regression were performed to evaluate predictors of an offer and enrollment. Results The patients were 57% white, 32% black, and 11% other/unknown race. One hundred six (33%) were offered participation and 36 (34%) were enrolled. In multivariate analysis, CTs were less likely offered to older women (mean age, 52 years for those offered v 57 years for those not offered; P = .0005) and black women (21% of blacks offered v 42% of whites; P = .0009). Women with stage 1 disease, poor performance status, and those who were previously diagnosed were also less likely to be offered trials. None of these factors were significant predictors of enrollment. Women were not offered trials because of ineligibility (57%), lack of available trials (41%), and noncompliance (2%). Reasons for failed enrollment included patient refusal (88%) and failed eligibility (12%). Conclusion It is important for cooperative groups to design studies that will accommodate a broader spectrum of patients. Further work is needed to assess ways to improve communication about breast cancer CT participation to all eligible women.

Despite the evaluation of many different chemotherapy and immunotherapy drugs, the median survival in metastatic melanoma remains in the range of 6 to 9 months. Combination chemotherapy or combination immunotherapy has not produced a significant advantage over single-agent therapy but is associated with greater toxicity. Based on the potential for additive or synergistic activity with the combination of chemotherapy and biotherapy, many investigators have evaluated biochemotherapy in patients with advanced melanoma. Aggregate results suggest that biochemotherapy is tolerable and produces a response rate in the range of 50% with a complete response rate of 10%. Although these phase II results appear superior to previous results with chemotherapy or immunotherapy alone, the true benefits of biochemotherapy can only be determined with the results of randomized phase III trials; therefore, biochemotherapy should be considered an as yet experimental therapy. Many other issues regarding biochemotherapy, such as sequence, outpatient administration, and use in the adjuvant setting, for stage III melanoma are being actively evaluated.

5-Fluoro-Pyrimidinone (5FP) is an oral pro-drug of 5-Fluorouracil (5FU), and is converted to 5FU by hepatic aldehyde oxidase. Preclinically, 5FP demonstrated anti-tumor activity against colon 38 and P 388 leukemia models in mice. Using an accelerated titration trial design with one patient cohorts and initial 100% escalations, a Phase I trial was conducted to determine the maximum tolerated dose (MTD) of 5FP and describe its toxicity and pharmacokinetic profile.5FP was administered orally once daily for 5 days every 4 weeks. The initial dose level was 23 mg/m2/d. Using single patient cohorts, escalation proceeded according to accelerated titration 4B design, initially by 100% and subsequently 30-35% escalations (exact escalation determined by pill size) until dose limiting toxicity was observed. A total of 19 patients were enrolled with a median age of 56 years and median performance status of 1. Most patients were heavily pre-treated with chemotherapy, radiation therapy, or both, and patient population included a wide variety of tumor types.Dose escalation proceeded rapidly to 1715 mg/m2/d with the only toxicities observed being nausea and vomiting. The large number of pills necessary at that point required a formulation change, which resulted in appreciable hematologic toxicity. This led to rapid de-escalation of dose in subsequent patients, with the MTD finally being determined to be 625 mg/m2/d. The DLTs observed were grade 4 neutropenia for greater than 5 days and grade 3 anemia. Other toxicities included nausea, vomiting, fatigue, constipation and mucositis. Pharmacology studies confirmed that SFP was converted to 5FU in humans at all dose levels. However, the extent of conversion decreased over the five daily treatments, but returned for the subsequent cycle. The hematologic toxicity was not related to 5FU exposure per course.5FP is a tolerable oral outpatient therapy. Accelerated titration was an efficient way of conducting this phase I trial. The recommended phase 2 dose is 625 mg/m2/d orally for 5 days every 28 days.

9500 Background: In the U.S., 3 regimens have regulatory approval as adjuvant therapy for high-risk melanoma, including high-dose interferon-alfa (HDI) and ipilimumab 10 mg/kg (ipi10). Ipilimumab 3 mg/kg (ipi3) has regulatory approval for metastatic inoperable melanoma. The toxicity of ipi is dose- dependent, and following the recent approval of adjuvant ipi10, it has become urgent to evaluate the relative safety and efficacy of adjuvant ipi at the 2 dose levels that have been tested in E1609. Methods: E1609 randomized patients (pts) with resected high-risk melanoma (stratified by stages IIIB, IIIC, M1a, M1b) to ipi10 or ipi3 versus HDI. Co-primary endpoints were RFS and OS. The current analysis investigates the relative safety and preliminary, non-comparative RFS of the ipi arms as of 3/2/17. Results: E1609 was activated on 5/25/11 and completed adult pt accrual on 8/15/14. Accrual to ipi10 was suspended due to toxicity between 9/23-11/16/2013. Final adult pt accrual was 1670 including 511 ipi10, 636 HDI and 523 ipi3 pts. Treatment related adverse events (AEs) were reported among 503 ipi10 and 516 ipi3 pts. Worst degree (Gr 3+) AEs were experienced by 57% ipi10 and 36.4% ipi3 pts and were mostly immune related (Table 1). AEs led to discontinuation of treatment in 271 (53.8 %) of 503 ipi10 and in 180 (35.2 %) of 512 ipi3 pts during the initial 4 dose induction phase. Gr5 AEs considered at least possibly related were 8 with ipi10 and 2 with ipi3. At a median follow-up of 3.1 years, an unplanned RFS analysis of ipi3 and ipi10 on concurrently randomized pts showed no difference between the 2 arms. Three-year RFS rate was 54% (95% CI: 49, 60) with ipi10 and 56% (50, 61) with ipi3. Conclusions: Adjuvant therapy of pts with high-risk melanoma is associated with significantly more toxicity at ipi10 compared to ipi3. An unplanned RFS analysis of concurrently randomized pts on the 2 ipi arms showed no difference in RFS. Clinical trial information: NCT01274338. [Table: see text]

521 Background: S0221 investigated weekly vs q 2 week dosing of doxorubicin/cyclophosphamide (AC) and paclitaxel (P) in patients (pts) with high risk early breast cancer as previously reported (JCO 33:58-64, 2015). After enrollment of 2716 pts randomization to the two AC arms was stopped for futility and an additional 578 pts received 4 cycles of q 2 week AC and were randomized to P weekly (Pw) or P q 2 weeks (P2). We report updated results of the original trial design and the first report of the 578 pts treated with AC x 4 and Pw x 12 or P2 x 6. Methods: Between December 2003 and November 2010, 2716 pts were randomized in a 2x2 factorial design to 1) 15 weeks of weekly AC (A 24 mg/m2/week and C 60 mg/m2/day po) vs 6 cycles of q 2 week AC (A 60 mg/m2 and C 600 mg/m2) and 2) Pw (paclitaxel 80 mg/m2/week x 12) vs P2 (paclitaxel 175 mg/m2 q 2 weeks x 6), with growth factor support as previously described. After study amendment 578 patients received 4 cycles of q 2 week AC followed by Pw or P2. Updated survival was assessed using log-rank tests and Cox regression models. Results: At a median follow-up of 8.5 years, among the pts treated in the original protocol, there were no significant differences among the four treatments for DFS (p=0.21) or OS (p=0.08). The triple-negative subset had worse DFS (P

37 Background: Immunotherapy, such as PD-1 and PD L1, has been recently approved in melanoma and genitourinary cancers (GU) such as renal cell carcinoma and urothelial carcinoma. There is an unmet need to determine factors predictive of response, to guide therapeutic selection in these cancers. We evaluated NLR (ratio of absolute values of neutrophils to lymphocytes) as predictors of response, progression free survival (PFS) and overall survival (OS) in patients treated with PD1 or PD L1 inhibitors. We extrapolated from renal cell data with NLR and used a value of 4 as cutoff. Other known prognostic clinical factors assessed were age, race, and smoking status. Methods: Regulatory approval was obtained. A retrospective chart review of melanoma and genitourinary cancer patients at Karmanos Cancer Institute, treated with ICI was conducted. Data were collected on demographics, smoking status, pretherapy NLR, and post 4 doses of ICI. Association with clinical outcomes (response rate, PFS and OS) was conducted by univariable and multivariable analyses. A log-rank test was used to compare PFS and OS. Results: 143 pts, (59 GU and 84 Melanoma) were evaluated with median age of 61yrs (range, 24-87). 11 pts (19%) and 5 (6%) were African American (AA) in GU and melanoma respectively. 61 pts (43%) were smokers in total. Pretherapy NLR

Recently published phase III trials involving interleukin-2, ipilimumab and vemurafenib redefine 'standard-of-care' for metastatic melanoma and demonstrate improved survival compared with dacarbazine. All three therapies are potential first-line options for patients with metastatic melanoma, with optimal treatment strategies evolving based on tumor mutation status, disease burden, performance status and comorbidities.

High-dose interferon is the current standard of care for the adjuvant treatment of high-risk cutaneous melanoma. Despite numerous clinical trials using interferon in a variety of doses and schedules, none have demonstrated a meaningful clinical improvement relative to standard high-dose interferon. Recently however, a phase III trial using biochemotherapy demonstrated a superior relapse-free survival benefit over standard interferon. In addition, several agents approved for use in metastatic melanoma are being investigated in the adjuvant setting.

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.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.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.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.

Purpose This open-label, multicenter study was designed to allow access to vemurafenib for patients with metastatic melanoma, bridging the time between end of enrollment in the phase III registration trial (December 2010) and commercial availability following US Food and Drug Administration approval of vemurafenib for the treatment of unresectable or metastatic BRAF-mutated melanoma (August 2011). Patients and methods Eligible patients had metastatic melanoma with a BRAF mutation (detected by the cobas 4800 BRAF V600 Mutation Test). Unlike previous vemurafenib trials, patients with poor performance status (PS) and treated brain metastases were permitted. Enrolled patients received oral vemurafenib 960 mg twice daily. Results Of 374 patients enrolled at 29 US sites (December 2010 to October 2011), 371 patients received vemurafenib and were followed up for a median of 2.8 months (the study had a prespecified end upon vemurafenib approval and commercial availability). At baseline, most patients (75%) had stage M1c disease, and 19% had an Eastern Cooperative Oncology Group PS of 2 or 3; 72% of patients had received prior systemic therapy for metastatic melanoma, 27% received prior ipilimumab, and 29% radiotherapy for prior brain metastases. Because reassessment data to confirm response were not available for most patients, point estimates of objective response rate (ORR) are reported. Among 241 efficacy-evaluable patients, the ORR was 54% (median time to response, 1.9 months). The ORR in non-central nervous system sites in patients with previously treated brain metastases (n = 68) was 53%. The ORR in prior ipilimumab-treated patients (n = 68) was 52%. For patients with PS of 0 or 1 (n = 210) and 2 or 3 (n = 31), the ORRs were 55%, and 42%, respectively. The safety profile observed was consistent with that reported in previous studies. The number of patients with grade 3 or 4 treatment-related adverse events was higher in patients with PS 2 or 3 than in those with PS 0 or 1 (10% vs. 5%, respectively). Adverse events requiring a dose reduction (at least 1 level) occurred in 11% of patients, and 9 patients (2%) experienced events leading to vemurafenib withdrawal, including 2 with repeated QT interval prolongation. Discussion This study confirmed the established rapid and high tumor response rate achievable with vemurafenib in BRAF mutation-positive metastatic melanoma. Several groups not included in previous studies, including patients with previously treated brain metastases, Eastern Cooperative Oncology Group PS 2 to 3, or previous ipilimumab treatment had benefitted from vemurafenib similar to the overall population. No new safety signals were detected.

Malignant melanoma is increasing in frequency at a rapid rate in the United States. Metastatic disease is chemoresistant with DTIC considered the most active single agent. CI-980 is a synthetic mitotic inhibitor that blocks the assembly of tubulin and microtubules. It has shown cytotoxic activity against a broad spectrum of murine and human tumor cell tines. CI-980 can cross the blood brain barrier, is effective when given orally or parenterally, and is active against multidrug resistant cell lines overexpressing P-glycoprotein. In this trial, patients with disseminated melanoma with measurable disease, SWOG performance status of 0-1, no prior chemotherapy or immunotherapy for metastatic disease, and adequate hepatic and renal function, were enrolled. Treatment with CI-980 was given by 72 h continuous i.v. infusion at a dose of 4.5 mg/m2/day, days 1-3 every 21 days. Twenty-four patients were registered on this study with no patients ineligible. They ranged in age from 33-78 with performance status of 0 in 15 patients and 1 in 9 patients. Nineteen patients had visceral disease with 12 having liver involvement. There were no confirmed responses. The overall response rate was 0% (95% CI 0%-14%). The median overall survival is eleven months (95% CI 4-14 months). The most common toxicities were hematologic and consisted of leukopenia/granulocytopenia and anemia, with nausea/vomiting and malaise/fatigue/weakness also frequent. CI-980 administered at this dose and schedule has insufficient activity in the treatment of disseminated malignant melanoma to warrant further investigation.

BACKGROUND Some studies have suggested that women with metastatic malignant melanoma have a better survival rate than men. However, little is known about the effect of gender on survival in combination with other clinical variables and treatment variables. Thus, an analysis of 813 eligible patients from 15 consecutive Southwest Oncology Group (SWOG) Phase II or III trials evaluating chemotherapy or chemoimmunotherapy for metastatic melanoma was performed. METHODS A multivariate Cox regression model was used. RESULTS Poor performance status (P < 0.001), more organ sites with metastases (OSM) (P < 0.001), liver involvement (P < 0.001), and nonliver visceral involvement (P = 0.01) were highly significant predictors of worse survival, whereas the disease free interval (P = 0.08) had borderline significance. After adjustment for all factors, there was no difference in overall survival between men and women (P = 0.19). Women had a longer disease free interval (P = 0.003) and fewer OSM (P = 0.004) at study registration than men. CONCLUSIONS The current study found that performance status, OSM, and type of visceral involvement were independent predictors of survival in patients with metastic malignant melanoma and should be used as stratification factors in future Phase III trials. However, the current study also found that gender did not appear to be a significant independent predictor of survival for this stage of disease. A longer disease free interval from initial diagnosis and fewer OSMs may partly explain the improved outcome reported for women in selected trials. The study concluded that further investigation of the biologic differences at early stage diagnosis should be undertaken to determine whether women truly have a different pace of disease progression and a different metastatic pattern. Cancer 2001;91:1148–55. © 2001 American Cancer Society.

Objectives: CI-994 (N-acetyl dinaline, PD123654) is a novel oral agent active in a broad variety ofmurine and human tumor xenografts. While cytotoxic in theBrown Norway (BN) rat leukemia model, growth inhibition inother murine and human tumor xenografts is predominantlycytostatic. Its specific mechanism of action remains unknown.Following CI-994 administration, inhibition of both histonedeacetylation and cellular proliferation at the G1 to Stransition phase of the cell cycle are observed. This Phase 1study in patients with solid tumors was carried out todetermine a maximum tolerated daily oral dose (MTD) for CI-994administered on a chronic basis. Methods: Fifty-threepatients received CI-994 daily for treatment durations rangingfrom 2 to 10 weeks. Dosage escalation proceeded in 2 phases;an Acute Dosing Phase (n = 11) to define the MTD for CI-994administered over 2 weeks and a Chronic Dosing Phase (n = 29)to define the MTD for daily administration for 8 weeks. Uponcompletion of the Chronic Dosing Phase, a third cohort ofpatients (n = 13) received CI-994 at the recommended Phase 2dose and schedule with 2 additional single doses of drugadministered separated by a 1-week washout to assess theeffect of food on CI-994 pharmacokinetics. Results:Thrombocytopenia was dose limiting at the MTD of 8mg/m2/day for 8 weeks. Other toxicities includedfatigue and gastrointestinal effects such as nausea, vomiting,diarrhea, constipation and mucositis. Pharmacokinetic studiesrevealed that peak plasma levels and AUC's generally increasedwith dose and that food intake did not affect the rate orextent of drug absorption. One patient with heavilypre-treated adenocarcinoma of the lung achieved a PartialResponse (PR) lasting over 2 years and 3 additional patientsachieved Stable Disease (SD), 1 each with non-small cell lung,colorectal, and renal cancer. Conclusions: Therecommended Phase 2 starting dose is 8 mg/m2/dayfor 8 weeks repeated after a 2-week drug-freeinterval.

PURPOSE: Pivotal trial E1684 of adjuvant high-dose interferon alfa-2b (IFNα2b) therapy in high-risk melanoma patients demonstrated a significant relapse-free and overall survival (RFS and OS) benefit compared with observation (Obs). PATIENTS AND METHODS: A prospective, randomized, three-arm, intergroup trial evaluated the efficacy of high-dose IFNα2b (HDI) for 1 year and low-dose IFNα2b (LDI) for 2 years versus Obs in high-risk (stage IIB and III) melanoma with RFS and OS end points. RESULTS: A total of 642 patients were enrolled (608 patients eligible), of whom a majority (75%) had nodal metastasis (50% had nodal recurrence). Unlike E1684, E1690 allowed entry of patients with T4 (> 4 mm) deep primary tumors, regardless of nodal dissection, and 25% of the patients entered onto this trial had deep primary tumors (compared with 11% in E1684). At 52 months’ median follow-up, HDI demonstrated an RFS benefit exceeding that of LDI compared with Obs. The 5-year estimated RFS rates for the HDI, LDI, and Obs arms were 44%, 40%, and 35%, respectively. The hazards ratio for the intent-to-treat analysis of HDI versus Obs was 1.28 (P2 = .05); for LDI versus Obs, it was 1.19 (P2 = .17). By Cox analysis, the impact of HDI on RFS achieved significance (P2 = .03). The RFS benefit was equivalent for node-negative and node-positive patients. Neither HDI nor LDI has demonstrated an OS benefit compared with Obs at this time. A major improvement in the median OS of patients in the E1690 Obs arm was noted in comparison with E1684 (6 years v 2.8 years). An analysis of salvage therapy for patients who relapsed on E1690 demonstrated that a significantly larger proportion of patients in the Obs arm received IFNα-containing salvage therapy compared with the HDI arm; this therapy was unavailable to patients during E1684, and patients with undissected regional nodes were not included in E1684. This study did not specify therapy at recurrence. Analysis of treatments received at recurrence demonstrated significantly more frequent use of IFNα2b at relapse from Obs than from HDI, which may have confounded interpretation of the survival benefit of assigned treatments in E1690. CONCLUSION: The results of the intergroup E1690 trial demonstrate an RFS benefit of IFNα2b that is dose-dependent and significant for HDI by Cox multivariable analysis.

Ocular melanoma is an uncommon malignancy that, in the presence of metastatic disease, has a poor prognosis for response to treatment and survival. Patients with ocular melanoma are often excluded from clinical trials because of the impression that these patients have a poorer response rate to treatment with anticancer agents and poorer survival, possibly related to the predominance of the liver as a site of metastasis. Sixty-four eligible patients with advanced melanoma arising from ocular primary tumors were entered into seven phase II clinical trials of anticancer therapy activated by the Southwest Oncology Group (SWOG) during the 1980s. Eligible patients with nonocular primaries entered into these trials (420 patients) served as a comparison group for survival, pretreatment characteristics, and response rates. Multivariate Cox model analysis of survival data (with survival from the time of study registration as the primary end-point) was conducted. Among the 484 patients observed, patients with ocular melanoma were older than those with nonocular primary tumors and were more likely to have visceral metastasis, metastasis to the liver, and only one metastatic site at registration, primarily to viscera and liver. The median overall survival after registration to study for both groups was 5 months. There was no significant difference in overall survival between patients with ocular melanoma and those with nonocular melanoma after adjusting for a number of prognostic factor (p = 0.43). Furthermore, the overall objective response rate of patients with ocular melanoma in these studies was not significantly different from that achieved in the nonocular group (9% vs. 11%; p = 1.00). Patients with advanced ocular or nonocular melanoma have similar response rates and survival in this series of cooperative group phase II trials. Patients with ocular primaries should not be excluded from investigational studies in advanced melanoma.

Objectives. To test the use of 1 mg/day of oral diethylstilbesterol (DES) as a treatment for patients with advanced prostate cancer who had failed primary hormonal therapy. Approximately 40,000 men this year will experience first-line hormonal therapy failure for their metastatic prostate cancer. At this time there is no standard therapy for men whose first-line hormonal manipulation has failed. This clinical problem has been exacerbated by the use of prostate-specific antigen (PSA) as a proved biomarker to follow disease progression. Patients who are experiencing hormonal therapy failure now present with a rising PSA, and virtually all are asymptomatic. The dilemma of how to treat these patients represents a new clinical problem for the medical oncologist and urologist that needs to be answered. Methods. We conducted a Phase II trial of oral DES in 21 patients. Patients were followed for response by PSA criteria and toxicity. A decrease in two serial measurements of PSA of greater than 50% from baseline was judged to be a partial response. Results. Nine of 21 patients achieved a PSA response (43% response rate with 95% confidence intervals of 22% to 64%) leading to early cessation of this Phase II trial. Eight of 13 patients (62%) who had only one prior hormone manipulation that failed demonstrated a PSA response, whereas only 1 of 8 patients (13%) who had received two or more hormone treatments responded ( P = 0.07). The median follow-up is 82 weeks (range 8 to 122) among 16 surviving patients. The survival rate at 2 years is 63% (95% confidence interval 41% to 99%). Conclusions. DES appears to be an active agent for second-line hormone therapy for metastatic prostate cancer. Because it has been taken off the market for economic reasons, DES should be considered for development under the orphan drug strategy.

Background: A phase III, randomized, double-blind, multicenter trial of active specific immunotherapy (ASI) using vaccinia melanoma oncolysate (VMO) was performed in patients with stage III (American Joint Commission on Cancer) melanoma to determine the efficacy of VMO to increase the disease-free interval (DFI) or overall survival (OS) in these patients. Two interim analyses of data from this trial were performed in May 1994 and June 1995. Although the results from these analyses showed no statistically significant improvement in DFI or OS in all patients using VMO, two subsets—men aged 44–57 years with one to five positive nodes and all patients with clinical stage I and pathologic stage II disease—showed an overall survival advantage with VMO therapy. A final analysis of data from this trial was performed in May 199 6 and is reported here. The design of future melanoma vaccine trials is discussed based on information learned from this first randomized, multicenter trial of ASI therapy. Study Design: A polyvalent VMO was prepared using melanoma cells derived from four melanoma cell lines and vaccinia vaccine virus (V). Patients were accrued from 11 United States institutions and were randomized by the Statistical Center at the University of Alabama, Birmingham. Two hundred fifty patients were randomized to treatment with either VMO (1 U containing 2 mg of total protein derived from 5 × 10 6 melanoma cells and 10 5.6 50% tissue culture infectious dose of vaccinia virus) or control V (1 U containing 10 5.4 50% tissue culture infectious dose of vaccinia virus) once a week for 13 weeks and then once every 2 weeks for a total of 12 months, or until recurrence. Patient data were collected by the Statistical Center and analyzed as of May 1996 for DFI and OS using Wilcoxon test and log-rank analysis. Results: Two hundred seventeen patients were found to be eligible according to the inclusion criteria. Data from these patients were analyzed for DFI and OS after a median followup of 46.3 months (50.2 months for VMO and 41.3 months for V). This final analysis showed no statistically significant increase in either DFI (p = 0.61) or OS (p = 0.79) of patients treated with VMO (n = 104) compared with V (n = 113). At 2-, 3-, and 5-year intervals, 47.8%, 43.8%, and 41.7% of patients treated with VMO were disease-free, respectively, compared with 51.2%, 44.8%, and 40.4% of patients treated with V. At the same intervals, 70.0%, 60.0%, and 48.6% of patients treated with VMO survived, compared with 65.4%, 55.6%, and 48.2% of patients treated with V. In a retrospective subset analysis, male patients aged 44–57 years (n = 20) with one to five positive nodes showed 18.9%, 26.82%, and 21.3% improvement in survival at 2-, 3-, and 5-year intervals, respectively, after treatment with VMO when compared with V (n = 18) (p = 0.046). Conclusions: This study was a randomized, multicenter, placebo-controlled evaluation of an active specific immunotherapeutic agent to increase the DFI or OS of patients with stage III melanoma in a surgical adjuvant setting. In this trial, ASI with VMO when compared with V showed no difference in either DFI or OS. In a retrospective subset analysis, however, a subset of men with one to five positive nodes, between the ages of 44 and 57 years, showed a survival advantage with VMO. This result suggests that one must include a detailed subset analysis in the design of future trials of ASI for patients with American Joint Commission on Cancer stage III melanoma. An appropriate control arm also must be included in ASI trials.

PURPOSE Both paclitaxel and carboplatin have single-agent activity against carcinoma of the urothelium. We evaluated the combination of paclitaxel and carboplatin in the treatment of advanced cancers of the urothelium. PATIENTS AND METHODS Patients with cancers of the urothelium who had no prior chemotherapy (prior adjuvant chemotherapy > 6 months allowed) were eligible for treatment. Eligibility requirements were performance status of 2 or less, creatinine level less than 2.0 mg/dL, granulocyte count (AGC) 1,500/microL or greater, platelet count 100,000/microL or greater, and total bilirubin level less than 1.5 mg/dL. Paclitaxel 200 mg/m2 followed by carboplatin (area under the curve [AUC] 5, Calvert formula) were administered every 21 days. Patients were evaluated for toxicity weekly and assessed for response every 6 weeks. RESULTS Thirty-six patients were entered onto the study and 35 patients were assessable for response. A total of 184 cycles were administered (median, six cycles per patient). Nine patients required one dose reduction, and seven patients required two dose reductions for a nadir AGC less than 500/microL, with only one episode of febrile neutropenia and sepsis. Myalgias and arthralgias of grades 1 to 2 occurred in 16 patients and usually lasted 2 to 3 days after treatment. There were no treatment delays because of toxicity. There were 18 responses; seven complete responses (CRs) and 11 partial responses (PRs) (response rate 51.5%; 95% confidence interval, 35 to 68). Median response durations for CR and PR were 6 and 4 months, respectively. Overall median survival was 9.5 months. CONCLUSION The combination of paclitaxel and carboplatin is an active and well-tolerated regimen for the treatment of advanced urothelial carcinoma. Because of the modest toxicity of this combination, paclitaxel and carboplatin should be considered for addition to other agents with activity in urothelial carcinomas.

PURPOSE The combination of carmustine (BCNU), dacarbazine (DTIC), cisplatin (DDP), and tamoxifen (Tam) has been reported in small series to provide a response rate of 50%, but with significant myelosuppression and risk of thromboembolic complications. We performed this phase II study to assess the antitumor activity and important toxicities of this combination in the cooperative group setting. PATIENTS AND METHODS Seventy-nine eligible patients were treated with BCNU 150 mg/m2/d, every 6 weeks, DTIC 220 mg/m2/d on days 1 to 3 every 3 weeks, DDP 25 mg/m2/d on days 1 to 3 every 3 weeks, and Tam 20 mg orally daily throughout treatment. Treatment cycles were repeated every 6 weeks in responding or stable patients for a maximum duration of 1 year. RESULTS Twelve objective responses were achieved (response rate 15%, 95% confidence interval 8%-25%). Five responses were complete (CR) and seven were partial (PR). The median response duration was 8+ (range, 4-19+) months, (16+ [4-19+] for CR and 8+ [4-11] for PR), and the median survival of the entire group was 9 months. The toxicities were predominantly neutropenia and thrombocytopenia. Four patients developed thromboembolic events. Two patients died while on protocol therapy, one with complications of neutropenia, and the other with disease progression. CONCLUSION The activity of this regimen is in the range reported for single agents or DTIC plus DDP, and the addition of BCNU and Tam appears to increase toxicity. We do not recommend this combination for routine treatment of advanced melanoma or as the control arm in randomized studies of combination therapy.

Differences in overall survival and response rates are often noted when promising single-institution phase II treatment regimens are evaluated in a cooperative group setting. One reason for this discrepancy may be the differences in patient characteristics at the time of registration. In the metastatic melanoma literature, the prognostic factors for survival that are most frequently identified are the number of metastatic sites, visceral involvement, performance status, liver involvement, and possibly the disease-free interval and gender. A prognostic factor for response appears to be sites of involvement. A comparison of patient characteristics and outcome was conducted for patients entered in similar phase II melanoma trials at a single institution versus those in a cooperative group. Sixty-four patients at Wayne State University (WSU) were compared with 96 patients who had nearly identical eligibility criteria and were registered in the Southwest Oncology Group (SWOG). All patients were receiving comparable phase II treatments for metastatic melanoma. Southwest Oncology Group patients were significantly older ( p < 0.001), had worse performance status (p = 0.03), had more visceral involvement (p = 0.001), and were more likely to have two or more metastatic sites (p = 0.02). No significant differences in gender ( p = 0.55). absence or presence of liver involvement (p = 0.12), or disease-free interval were noted. These disparities, despite similar eligibility, may partly explain the observed differences in survival (WSU median = 10 months, SWOG median = 7 months; p = 0.13) and response rates (WSU = 31%, SWOG = 15%; p = 0.02) between the two groups of patients. Investigators should report these important patient characteristics in treatment reports. These differences highlight the difficulty in comparing single-institution and cooperative-group phase II trials, even with comparable patient eligibility. This serves to emphasize the need for well-designed phase III trials when comparing treatment approaches and stratification for the prognostic factors identified.

Based on the reports of substantial improvement in the response rate w ith the addition of tamoxifen to a multiagent chemotherapy regimen for metastatic melanoma, Southwest Oncology Group (SWOG)-8921 was initiated. A prior regimen (SWOG-8804) of dacarbazine (DTIC) 750 mg/m(2) i.v. day 1 and cisplatin 100 mg/m(2) day 1 repeated every 3 weeks produced a 13% response rate in patients with metastatic melanoma without brain metastasis. SWOG-8921 using identical chemotherapy and schedule added tamoxifen 10 mg twice daily. There were 55 eligible patients registered, median age 52, with 37 men and 18 women. Fifty (91%) patients had evidence of visceral metastasis at registration. There were 10 responders (2 complete and 8 partial responses) for an 18% response rate (95% CI, 9-31%). The response rate in women was 28% (95% CI, 10-53%; in men, 14% (95% CI, 5-29%). Tamoxifen has produced a small increase in the response rate when added to the present combination and schedule of chemotherapy. Further Phase III trials will be necessary to assess whether there is a statistical advantage to the use of tamoxifen when combined with chemotherapy and whether there are statistical differences between men and women.

Previous reports of autologous bone marrow transplant (auto-BMT) have demonstrated that myeloablative therapy followed by cyclosporin A (CsA), with and without interferon (IFN), can generate autoreactive cytotoxic T lymphocytes (auto-CTL) with potential therapeutic benefit. This is the first report of an attempt to generate auto-CTL using CsA and IFN after a non-myeloablative regimen. Cyclophosphamide (CTX) 1,200 mg/m2 i.v. day 1 was followed by CsA and IFN-alpha days 2-28, administered in a sequential three-step Phase I dose-escalation scheme. Patients were evaluated twice weekly for clinical evidence of graft-versus-host (GVH) reaction. Peripheral blood mononuclear cells (PBMCs) were obtained before treatment, at time of clinical GVH reaction, and days 21 and 28, and analyzed for auto-CTL, natural killer (NK) cell, and lymphokine-activated killer (LAK) cell activity. Patients also underwent punch skin biopsy at the time of clinical GVH reaction or day 21 to identify histologic evidence of GVH. Fourteen patients completed therapy and were evaluable for immunologic studies and anti-tumor response. No increase in auto-CTL, NK cell, or LAK cell activity was seen. Clinical or histologic evidence of GVH reaction did not occur. We conclude that this myelosuppressive dose of CTX combined with CsA and IFN is unable to generate clinical or immunologic evidence of an auto-GVH reaction. Further efforts are warranted to evaluate other therapeutic attempts to generate auto-CTL with anti-tumor activity based on preliminary results of clinical benefit in auto-BMT.