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

Background: In the primary analysis of the ERIVANCE BCC trial, vismodegib, the first US Food and Drug Administration-approved Hedgehog pathway inhibitor, showed objective response rates (ORRs) by independent review facility (IRF) of 30% and 43% in metastatic basal cell carcinoma (mBCC) and locally advanced BCC (laBCC), respectively. ORRs by investigator review were 45% (mBCC) and 60% (laBCC). Herein, we present long-term safety and final investigator-assessed efficacy results in patients with mBCC or laBCC.Methods: One hundred four patients with measurable advanced BCC received oral vismodegib 150 mg once daily until disease progression or intolerable toxicity. The primary end point was IRF-assessed ORR. Secondary end points included ORR, duration of response (DOR), progression-free survival, overall survival (OS), and safety.Results: At data cutoff (39 months after completion of accrual), 8 patients were receiving the study drug (69 patients in survival follow-up). Investigator-assessed ORR was 48.5% in the mBCC group (all partial responses) and 60.3% in the laBCC group (20 patients had complete response and 18 patients had partial response). ORRs were comparable across patient subgroups, including aggressive histologic subtypes (eg, infiltrative BCC). Median DOR was 14.8 months (mBCC) and 26.2 months (laBCC). Median OS was 33.4 months in the mBCC cohort and not estimable in the laBCC cohort. Adverse events remained consistent with clinical experience. Thirty-three deaths (31.7%) were reported; none were related to vismodegib.Conclusions: This long-term update of the ERIVANCE BCC trial demonstrated durability of response, efficacy across patient subgroups, and manageable long-term safety of vismodegib in patients with advanced BCC.Trial Registration: This study was registered prospectively with Clinicaltrials.gov , number NCT00833417 on January 30, 2009. [ABSTRACT FROM AUTHOR]

Background: Survival of patients with brain metastasis particularly from historically more radio-resistant malignancies remains dismal. A phase I study of concurrent bortezomib and whole brain radiotherapy was conducted to determine the tolerance and safety of this approach in patients with previously untreated brain metastasis.Methods: A phase I dose escalation study evaluated the safety of bortezomib (0.9, 1.1, 1.3, 1.5, and 1.7 mg/m2) given on days 1, 4, 8 and 11 of whole brain radiotherapy. Patients with confirmed brain metastasis were recruited for participation. The primary endpoint was the dose-limiting toxicity, defined as any ≥ grade 3 non-hematologic toxicity or grade ≥ 4 hematologic toxicity from the start of treatment to one month post irradiation. Time-to-Event Continual Reassessment Method (TITE-CRM) was used to determine dose escalation. A companion study of brain diffusion tensor imaging MRI was conducted on a subset of patients to assess changes in the brain that might predict delayed cognitive effects.Results: Twenty-four patients were recruited and completed the planned therapy. Patients with melanoma accounted for 83% of all participants. The bortezomib dose was escalated as planned to the highest dose of 1.7 mg/m2/dose. No grade 4/5 toxicities related to treatment were observed. Two patients had grade 3 dose-limiting toxicities (hyponatremia and encephalopathy). A partial or minor response was observed in 38% of patients. Bortezomib showed greater demyelination in hippocampus-associated white matter structures on MRI one month after radiotherapy compared to patients not treated with bortezomib (increase in radial diffusivity +16.8% versus 4.8%; p = 0.0023).Conclusions: Concurrent bortezomib and whole brain irradiation for brain metastasis is well tolerated at one month follow-up, but MRI changes that have been shown to predict delayed cognitive function can be detected within one month of treatment. [ABSTRACT FROM AUTHOR]

In the phase II/III RELATIVITY-047 trial, a novel fixed-dose combination (FDC) of nivolumab plus relatlimab (NIVO + RELA; a programmed death-1 and a lymphocyte-activation gene 3 inhibitor, respectively) significantly improved progression-free survival (PFS) versus NIVO in patients with previously untreated unresectable or metastatic melanoma (median follow-up, 13.2 months) with stable health-related quality of life (HRQoL), although grade three or four treatment-related adverse events (TRAEs) were more frequent with the combination. Updated HRQoL results (median follow-up, 19.3 months) are presented. Patients were randomised to receive intravenous NIVO + RELA (480 mg and 160 mg, respectively) or NIVO (480 mg) every 4 weeks. HRQoL was assessed using the Functional Assessment of Cancer Treatment-Melanoma (FACT-M) and EQ-5D-3L questionnaires at baseline, before dosing at each treatment cycle, and at follow-up (posttreatment) visits. Consistent with the initial analysis, HRQoL remained stable with NIVO + RELA on treatment and was similar to that with NIVO. Mean changes from baseline did not exceed clinically meaningful thresholds. HRQoL results were consistent across instruments and scales/subscales. Despite an increased rate of grade three or four TRAEs with NIVO + RELA versus NIVO, the proportion of patients reporting that they were bothered 'quite a bit' or 'very much' by TRAEs was low and comparable between treatments. Results from the RELATIVITY-047 trial show that the PFS benefit with NIVO + RELA FDC over NIVO was obtained with stable patient-reported HRQoL, supporting NIVO + RELA as a first-line treatment option for patients with advanced melanoma. • Nivolumab plus relatlimab (NIVO + RELA) improves PFS versus nivolumab in melanoma, with added toxicity. • In RELATIVITY-047, quality of life (QoL) was stable/similar with both treatments. • Results were consistent across all QoL instruments and subscales. • QoL results suggest that the two treatments had similar overall tolerability. • These results support NIVO + RELA as a first-line option for melanoma. [ABSTRACT FROM AUTHOR]

Background: Combination nivolumab plus ipilimumab was efficacious in patients with asymptomatic melanoma brain metastases (MBM) in CheckMate 204, but showed low efficacy in patients with symptomatic MBM. Here, we provide final 3-year follow-up data from the trial.Methods: This open-label, multicentre, phase 2 study (CheckMate 204) included adults (aged ≥18 years) with measurable MBM (0·5-3·0 cm in diameter). Asymptomatic patients (cohort A) had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and no neurological symptoms or baseline corticosteroid use; symptomatic patients (cohort B) had an ECOG performance status of 0-2 with stable neurological symptoms and could be receiving low-dose dexamethasone. Nivolumab 1 mg/kg plus ipilimumab 3 mg/kg was given intravenously every 3 weeks for four doses, followed by nivolumab 3 mg/kg every 2 weeks for up to 2 years, until disease progression or unacceptable toxicity. The primary endpoint was intracranial clinical benefit rate (complete responses, partial responses, or stable disease lasting ≥6 months) assessed in all treated patients. Intracranial progression-free survival and overall survival were key secondary endpoints. This study is registered with ClinicalTrials.gov, NCT02320058.Findings: Between Feb 19, 2015, and Nov 1, 2017, 119 (72%) of 165 screened patients were enrolled and treated: 101 patients were asymptomatic (cohort A; median follow-up 34·3 months [IQR 14·7-36·4]) and 18 were symptomatic (cohort B; median follow-up 7·5 months [1·2-35·2]). Investigator-assessed intracranial clinical benefit was observed in 58 (57·4% [95% CI 47·2-67·2]) of 101 patients in cohort A and three (16·7% [3·6-41·4]) of 18 patients in cohort B; investigator-assessed objective response was observed in 54 (53·5% [43·3-63·5]) patients in cohort A and three (16·7% [3·6-41·4]) patients in cohort B. 33 (33%) patients in cohort A and three (17%) patients in cohort B had an investigator-assessed intracranial complete response. For patients in cohort A, 36-month intracranial progression-free survival was 54·1% (95% CI 42·7-64·1) and overall survival was 71·9% (61·8-79·8). For patients in cohort B, 36-month intracranial progression-free survival was 18·9% (95% CI 4·6-40·5) and overall survival was 36·6% (14·0-59·8). The most common grade 3-4 treatment-related adverse events (TRAEs) were increased alanine aminotransferase and aspartate aminotransferase (15 [15%] of 101 patients each) in cohort A; no grade 3 TRAEs occurred in more than one patient each in cohort B, and no grade 4 events occurred. The most common serious TRAEs were colitis, diarrhoea, hypophysitis, and increased alanine aminotransferase (five [5%] of each among the 101 patients in cohort A); no serious TRAE occurred in more than one patient each in cohort B. There was one treatment-related death (myocarditis in cohort A).Interpretation: The durable 3-year response, overall survival, and progression-free survival rates for asymptomatic patients support first-line use of nivolumab plus ipilimumab. Symptomatic disease in patients with MBM remains difficult to treat, but some patients achieve a long-term response with the combination.Funding: Bristol Myers Squibb. [ABSTRACT FROM AUTHOR]

Purpose: To determine the recommended phase 2 dose of RRx-001, a radiosensitizer with vascular normalizing properties, when used with whole-brain radiation therapy (WBRT) for brain metastases and to assess whether quantitative changes in perfusion magnetic resonance imaging (MRI) after RRx-001 correlate with response.Methods and Materials: Five centers participated in this phase 1/2 trial of RRx-001 given once pre-WBRT and then twice weekly during WBRT. Four dose levels were planned (5 mg/m2, 8.4 mg/m2, 16.5 mg/m2, 27.5 mg/m2). Dose escalation was managed by the time-to-event continual reassessment method algorithm. Linear mixed models were used to correlate change in 24-hour T1, Ktrans (capillary permeability), and fractional plasma volume with change in tumor volume.Results: Between 2015 and 2017, 31 patients were enrolled. Two patients dropped out before any therapy. Median age was 60 years (range, 30-76), and 12 were male. The most common tumor types were melanoma (59%) and non-small cell lung cancer (18%). No dose limiting toxicities were observed. The most common severe adverse event was grade 3 asthenia (6.9%, 2 of 29). The median intracranial response rate was 46% (95% confidence interval, 24-68) and median overall survival was 5.2 months (95% confidence interval, 4.5-9.4). No neurologic deaths occurred. Among 10 patients undergoing dynamic contrast-enhanced MRI, a reduction in Vp 24 hours after RRx-001 was associated with reduced tumor volume at 1 and 4 months (P ≤ .01).Conclusions: The addition of RRx-001 to WBRT is well tolerated with favorable intracranial response rates. Because activity was observed across all dose levels, the recommended phase 2 dose is 10 mg twice weekly. A reduction in fractional plasma volume on dynamic contrast-enhanced MRI 24 hours after RRx-001 suggests antiangiogenic activity associated with longer-term tumor response. [ABSTRACT FROM AUTHOR]

Background: Nivolumab plus ipilimumab or nivolumab alone resulted in longer progression-free and overall survival than ipilimumab alone in a trial involving patients with advanced melanoma. We now report 5-year outcomes in the trial.Methods: We randomly assigned patients with previously untreated advanced melanoma to receive one of the following regimens: nivolumab (at a dose of 1 mg per kilogram of body weight) plus ipilimumab (3 mg per kilogram) every 3 weeks for four doses, followed by nivolumab (3 mg per kilogram every 2 weeks); nivolumab (3 mg per kilogram every 2 weeks) plus ipilimumab-matched placebo; or ipilimumab (3 mg per kilogram every 3 weeks for four doses) plus nivolumab-matched placebo. The two primary end points were progression-free survival and overall survival in the nivolumab-plus-ipilimumab group and in the nivolumab group, as compared with the ipilimumab group.Results: At a minimum follow-up of 60 months, the median overall survival was more than 60.0 months (median not reached) in the nivolumab-plus-ipilimumab group and 36.9 months in the nivolumab group, as compared with 19.9 months in the ipilimumab group (hazard ratio for death with nivolumab plus ipilimumab vs. ipilimumab, 0.52; hazard ratio for death with nivolumab vs. ipilimumab, 0.63). Overall survival at 5 years was 52% in the nivolumab-plus-ipilimumab group and 44% in the nivolumab group, as compared with 26% in the ipilimumab group. No sustained deterioration of health-related quality of life was observed during or after treatment with nivolumab plus ipilimumab or with nivolumab alone. No new late toxic effects were noted.Conclusions: Among patients with advanced melanoma, sustained long-term overall survival at 5 years was observed in a greater percentage of patients who received nivolumab plus ipilimumab or nivolumab alone than in those who received ipilimumab alone, with no apparent loss of quality of life in the patients who received regimens containing nivolumab. (Funded by Bristol-Myers Squibb and others; CheckMate 067 ClinicalTrials.gov number, NCT01844505.). [ABSTRACT FROM AUTHOR]

Background: Previously reported results from the phase 3 CheckMate 067 trial showed a significant improvement in objective responses, progression-free survival, and overall survival with nivolumab plus ipilimumab or nivolumab alone compared with ipilimumab alone in patients with advanced melanoma. The aim of this report is to provide 4-year updated efficacy and safety data from this study.Methods: In this phase 3 trial, eligible patients were aged 18 years or older with previously untreated, unresectable, stage III or stage IV melanoma, known BRAFV600 mutation status, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned 1:1:1 to receive intravenous nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four doses, followed by nivolumab 3 mg/kg every 2 weeks, or nivolumab 3 mg/kg every 2 weeks plus placebo, or ipilimumab 3 mg/kg every 3 weeks for four doses plus placebo. Randomisation was done via an interactive voice response system with a permuted block schedule (block size of six) and stratification by PD-L1 status, BRAF mutation status, and metastasis stage. The patients, investigators, study site staff, and study funder were masked to the study drug administered. The co-primary endpoints were progression-free survival and overall survival. Efficacy analyses were done on the intention-to-treat population, whereas safety was assessed in all patients who received at least one dose of study drug. The results presented in this report reflect the 4-year update of the ongoing study with a database lock date of May 10, 2018. This study is registered with ClinicalTrials.gov, number NCT01844505.Findings: Between July 3, 2013, and March 31, 2014, 945 patients were enrolled and randomly assigned to nivolumab plus ipilimumab (n=314), nivolumab (n=316), or ipilimumab (n=315). Median follow-up was 46·9 months (IQR 10·9-51·8) in the nivolumab plus ipilimumab group, 36·0 months (10·5-51·4) in the nivolumab group, and 18·6 months (7·6-49·5) in the ipilimumab group. At a minimum follow-up of 48 months from the date that the final patient was enrolled and randomised, median overall survival was not reached (95% CI 38·2-not reached) in the nivolumab plus ipilimumab group, 36·9 months (28·3-not reached) in the nivolumab group, and 19·9 months (16·9-24·6) in the ipilimumab group. The hazard ratio for death for the combination versus ipilimumab was 0·54 (95% CI 0·44-0·67; p<0·0001) and for nivolumab versus ipilimumab was 0·65 (0·53-0·79; p<0·0001). Median progression-free survival was 11·5 months (95% CI 8·7-19·3) in the nivolumab plus ipilimumab group, 6·9 months (5·1-10·2) in the nivolumab group, and 2·9 months (2·8-3·2) in the ipilimumab group. The hazard ratio for progression-free survival for the combination versus ipilimumab was 0·42 (95% CI 0·35-0·51; p<0·0001) and for nivolumab versus ipilimumab was 0·53 (0·44-0·64; p<0·0001). Treatment-related grade 3-4 adverse events were reported in 185 (59%) of 313 patients who received nivolumab plus ipilimumab, 70 (22%) of 313 who received nivolumab, and 86 (28%) of 311 who received ipilimumab. The most common treatment-related grade 3 adverse events were diarrhoea in the nivolumab plus ipilimumab group (29 [9%] of 313) and in the nivolumab group (nine [3%] of 313) and colitis in the ipilimumab group (23 [7%] of 311); the most common grade 4 adverse event in all three groups was increased lipase (15 [5%] of 313 in the combination group, ten [3%] of 313 in the nivolumab group, and four [1%] of 311 in the ipilimumab group). Serious adverse events were not analysed for the 4-year follow-up. In total for the study, there were four treatment-related deaths: two in the nivolumab plus ipilimumab group (one cardiomyopathy and one liver necrosis), one in the nivolumab group (neutropenia), and one in the ipilimumab group (colon perforation). No additional treatment-related deaths have occurred since the previous (3-year) analysis.Interpretation: The results of this analysis at 4 years of follow-up show that a durable, sustained survival benefit can be achieved with first-line nivolumab plus ipilimumab or nivolumab alone in patients with advanced melanoma.Funding: Bristol-Myers Squibb. [ABSTRACT FROM AUTHOR]

Background: Epigenetic alterations have been strongly associated with tumour formation and resistance to chemotherapeutic drugs, and epigenetic modifications are an attractive target in cancer research. RRx-001 is activated by hypoxia and induces the generation of reactive oxygen and nitrogen species that can epigenetically modulate DNA methylation, histone deacetylation, and lysine demethylation. The aim of this phase 1 study was to assess the safety, tolerability, and pharmacokinetics of RRx-001.Methods: In this open-label, dose-escalation, phase 1 study, we recruited adult patients (aged >18 years) with histologically or cytologically confirmed diagnosis of advanced, malignant, incurable solid tumours from University of California at San Diego, CA, USA, and Sarah Cannon Research Institute, Nashville, TN, USA. Key eligibility criteria included evaluable disease, Eastern Cooperative Group performance status of 2 or less, an estimated life expectancy of at least 12 weeks, adequate laboratory parameters, discontinuation of all previous antineoplastic therapies at least 6 weeks before intervention, and no residual side-effects from previous therapies. Patients were assigned to receive intravenous infusions of RRx-001 at increasing doses (10 mg/m(2), 16·7 mg/m(2), 24·6 mg/m(2), 33 mg/m(2), 55 mg/m(2), and 83 mg/m(2)) either once or twice-weekly for at least 4 weeks, with at least three patients per dose cohort and allowing a 2-week observation period before dose escalation. Samples for safety and pharmacokinetics analysis, including standard chemistry and haematological panels, were taken on each treatment day. The primary objective was to assess safety, tolerability, and dose-limiting toxic effects of RRx-001, to determine single-dose pharmacokinetics, and to identify a recommended dose for phase 2 trials. All analyses were done per protocol. Accrual is complete and follow-up is still on-going. This trial is registered with ClinicalTrials.gov, number NCT01359982.Findings: Between Oct 10, 2011, and March 18, 2013, we enrolled 25 patients and treated six patients in the 10 mg/m(2) cohort, three patients in the 16·7 mg/m(2) cohort, three patients in the 24·6 mg/m(2) cohort, four patients in the 33 mg/m(2) cohort, three patients in the 55 mg/m(2), and six patients in the 83 mg/m(2) cohort. Pain at the injection site, mostly grade 1 and grade 2, was the most common adverse event related to treatment, experienced by 21 (84%) patients. Other common drug-related adverse events included arm swelling or oedema (eight [32%] patients), and vein hardening (seven [28%] patients). No dose-limiting toxicities were observed. Time constraints related to management of infusion pain from RRx-001 resulted in a maximally feasible dose of 83 mg/m(2). Of the 21 evaluable patients, one (5%) patient had a partial response, 14 (67%) patients had stable disease, and six (29%) patients had progressive disease; all responses were across a variety of tumour types. Four patients who had received RRx-001 were subsequently rechallenged with a treatment that they had become refractory to; all four responded to the rechallenge.Interpretation: RRx-001 is a well-tolerated novel compound without clinically significant toxic effects at the tested doses. Preliminary evidence of activity is promising and, on the basis of all findings, a dose of 16·7 mg/m(2) was recommended as the targeted dose for phase 2 trials.Funding: EpicentRx (formerly RadioRx). [ABSTRACT FROM AUTHOR]