Final Results for Adjuvant Dabrafenib plus Trametinib in Stage III Melanoma.

BACKGROUND: The 5-year results of this trial showed that adjuvant therapy with dabrafenib plus trametinib resulted in longer relapse-free survival and distant metastasis-free survival than placebo among patients with BRAF V600-mutated stage III melanoma. Longer-term data were needed, including data regarding overall survival. METHODS: We randomly assigned 870 patients with resected stage III melanoma with BRAF V600 mutations to receive 12 months of dabrafenib (150 mg twice daily) plus trametinib (2 mg once daily) or two matched placebos. Here, we report the final results of this trial, including results for overall survival, melanoma-specific survival, relapse-free survival, and distant metastasis-free survival. RESULTS: The median duration of follow-up was 8.33 years for dabrafenib plus trametinib and 6.87 years for placebo. Kaplan-Meier estimates for overall survival favored dabrafenib plus trametinib over placebo, although the benefit was not significant (hazard ratio for death, 0.80; 95% confidence interval [CI], 0.62 to 1.01; P = 0.06 by stratified log-rank test). A consistent survival benefit was seen across several prespecified subgroups, including the 792 patients with melanoma with a BRAF V600E mutation (hazard ratio for death, 0.75; 95% CI, 0.58 to 0.96). Relapse-free survival favored dabrafenib plus trametinib over placebo (hazard ratio for relapse or death, 0.52; 95% CI, 0.43 to 0.63), as did distant metastasis-free survival (hazard ratio for distant metastasis or death, 0.56; 95% CI, 0.44 to 0.71). No new safety signals were reported, a finding consistent with previous trial reports. CONCLUSIONS: After nearly 10 years of follow-up, adjuvant therapy with dabrafenib plus trametinib was associated with better relapse-free survival and distant metastasis-free survival than placebo among patients with resected stage III melanoma. The analysis of overall survival showed that the risk of death was 20% lower with combination therapy than with placebo, but the benefit was not significant. Among patients with melanoma with a BRAF V600E mutation, the results suggest that the risk of death was 25% lower with combination therapy. (Funded by GlaxoSmithKline and Novartis; COMBI-AD ClinicalTrials.gov number, NCT01682083; EudraCT number, 2012-001266-15.).

Five-Year Analysis of Adjuvant Dabrafenib plus Trametinib in Stage III Melanoma.

BACKGROUND: In the previously reported primary analysis of this phase 3 trial, 12 months of adjuvant dabrafenib plus trametinib resulted in significantly longer relapse-free survival than placebo in patients with resected stage III melanoma with BRAF V600E or V600K mutations. To confirm the stability of the relapse-free survival benefit, longer-term data were needed. METHODS: We randomly assigned 870 patients who had resected stage III melanoma with BRAF V600E or V600K mutations to receive 12 months of oral dabrafenib (at a dose of 150 mg twice daily) plus trametinib (2 mg once daily) or two matched placebos. The primary end point was relapse-free survival. Here, we report 5-year results for relapse-free survival and survival without distant metastasis as the site of the first relapse. Overall survival was not analyzed, since the required number of events to trigger the final overall survival analysis had not been reached. RESULTS: The minimum duration of follow-up was 59 months (median patient follow-up, 60 months for dabrafenib plus trametinib and 58 months for placebo). At 5 years, the percentage of patients who were alive without relapse was 52% (95% confidence interval [CI], 48 to 58) with dabrafenib plus trametinib and 36% (95% CI, 32 to 41) with placebo (hazard ratio for relapse or death, 0.51; 95% CI, 0.42 to 0.61). The percentage of patients who were alive without distant metastasis was 65% (95% CI, 61 to 71) with dabrafenib plus trametinib and 54% (95% CI, 49 to 60) with placebo (hazard ratio for distant metastasis or death, 0.55; 95% CI, 0.44 to 0.70). No clinically meaningful between-group difference in the incidence or severity of serious adverse events was reported during the follow-up period. CONCLUSIONS: In the 5-year follow-up of a phase 3 trial involving patients who had resected stage III melanoma with BRAF V600E or V600K mutations, 12 months of adjuvant therapy with dabrafenib plus trametinib resulted in a longer duration of survival without relapse or distant metastasis than placebo with no apparent long-term toxic effects. (Funded by GlaxoSmithKline and Novartis; COMBI-AD ClinicalTrials.gov number, NCT01682083; EudraCT number, 2012-001266-15.).

The concomitant use of proton pump inhibitors and BRAF/MEK inhibitors in metastatic melanoma.

BACKGROUND: Proton-pump inhibitors (PPIs) are commonly used by patients with cancer, although they could reduce the absorption of oral anticancer targeted therapies. The US Food and Drug Administration states that the effect of PPIs on the efficacy of dabrafenib use by patients with metastatic melanoma is unknown. As a precautionary measure, the European Society for Medical Oncology recommends avoiding PPIs for patients receiving dabrafenib. OBJECTIVES: To determine the effect of the concomitant use of PPIs and BRAF/MEK inhibitors in patients with metastatic melanoma. METHODS: Patients with advanced melanoma receiving BRAF/MEK inhibitors as first-line treatments between 2015 and 2017 in France were selected using the French National Health Insurance database. We compared time-to-treatment discontinuation (TTD) and overall survival (OS) according to concomitant PPI exposure. We balanced the baseline characteristics of patients exposed and nonexposed to PPIs using an overlap weighting method based on a propensity score. RESULTS: The metastatic melanoma cohort comprised 1028 patients receiving BRAF/MEK inhibitors, including 361 (35.1%) patients using PPIs. PPI users had more comorbidities and a more severe metastatic disease. After having equally distributed metastatic sites and comorbidities across patients exposed and nonexposed to PPIs, concomitant PPI use was not associated with shorter TTD [weighted hazard ratio (wHR) 1.03, 95% confidence interval (CI) 0.86-1.24] or OS (wHR 1.11, 95% CI 0.88-1.39). Consistent results were observed when restricting the population to patients receiving dabrafenib, or when narrowing exposure to PPIs with stronger inhibition of cytochromes. CONCLUSIONS: In a population-based cohort of patients with advanced melanoma, the concomitant use of PPIs and BRAF/MEK inhibitors was not associated with worse outcome.

Risk of irAEs in patients with autoimmune diseases treated by immune checkpoint inhibitors for stage III or IV melanoma: results from a matched case-control study.

OBJECTIVE: To quantify the risk of immune-related adverse events (irAEs) in patients with pre-existing autoimmune disease (pAID) treated by immune checkpoint inhibitors (ICIs) for stage III or IV melanoma. METHODS: Case-control study performed on a French multicentric prospective cohort of patients with melanoma, matched for irAE risk factors and oncological staging. Risk of irAE was assessed by logistic regression. RESULTS: 110 patients with pAID were included and matched with 330 controls, from March 2013 to October 2020. Over a median follow-up period of 7.2 months for cases and 6.9 months for controls, the ORs of developing all-grade and grade ≥3 irAEs among cases compared with controls were 1.91 (95% CI (1.56 to 2.27)) and 1.44 (95% CI (1.08 to 1.82)), respectively. Patients with pAID had an increased risk of multiple irAEs (OR 1.46, 95% CI (1.15 to 2.67)) and a shorter time to irAE onset. In contrast, there were no difference in irAE-related mortality nor in the rate of treatment discontinuation, and a landmark analysis revealed a better survival at 24 months among cases (p=0.02). Thirty per cent of cases experienced a pAID flare during follow-up, and baseline immunosuppression did not prevent irAE occurrence. Last, we report associations between the pAID clinical subsets and organ-specific irAEs. CONCLUSION: In our study, patients with pAID were at greater risk of all-grade, severe and multiple irAEs, yet had a better 24-month survival than controls. Thus, patients with pAID should be eligible for ICI therapy but benefit from a close monitoring for irAE occurrence, especially during the first months of therapy.

Immune checkpoint inhibitors in patients aged 80 or older with advanced non-small cell lung cancer or melanoma: a real-life multicentre study.

BACKGROUND: Data regarding characteristics, safety and survival outcomes of patients aged 80 or older treated with immune checkpoint inhibitors (ICI) in routine oncology practice are limited. MATERIALS AND METHODS: We retrospectively collected data of patients aged 80 and older with advanced non-small cell lung cancer (NSCLC) or melanoma treated with anti-PD1, anti-PD-L1 or anti-CTLA-4 regardless of the treatment line, in 14 institutions, between January 2014 and June 2017. Progression-free survival (PFS) and overall survival (OS) were estimated with the Kaplan Meier method. Toxicity was assessed according to CTCAE 5.0. Multivariate analyses were performed with the Cox model. RESULTS: Eighty-two patients were included (36 with NSCLC, 45 with melanoma). Their median age was 82 years (range 80-93). Nivolumab and pembrolizumab were mainly used. In the NSCLC group, median PFS and OS were 2.3 months (95%CI 1.8-6.1) and 8.8 months (95%CI 5.5-18.1), respectively. In the melanoma group, median PFS and OS were 10.2 months (95%CI 4.5-20.0) and 24.5 months (95%CI 14.1-NR), respectively. The albumin level was found to be independently associated with a better OS in both groups. Grade 3-4 toxicities occurred in 15 patients (18.5%). One patient died from ICI-induced pulmonary toxicity. CONCLUSION: Our study findings suggest that treatment with ICI in elderly patients with NSCLC and melanoma has a risk-benefit ratio that supports its use. However, we report in this cohort that one in five patients has a grade 3-4 IRAEs leading to treatment discontinuation. Geriatric assessment prior to initiation of therapy and during therapy should be routine in patients aged 80 years and older.

Adjuvant and concurrent temozolomide for 1p/19q non-co-deleted anaplastic glioma (CATNON; EORTC study 26053-22054): second interim analysis of a randomised, open-label, phase 3 study.

BACKGROUND: The CATNON trial investigated the addition of concurrent, adjuvant, and both current and adjuvant temozolomide to radiotherapy in adults with newly diagnosed 1p/19q non-co-deleted anaplastic gliomas. The benefit of concurrent temozolomide chemotherapy and relevance of mutations in the IDH1 and IDH2 genes remain unclear. METHODS: This randomised, open-label, phase 3 study done in 137 institutions across Australia, Europe, and North America included patients aged 18 years or older with newly diagnosed 1p/19q non-co-deleted anaplastic gliomas and a WHO performance status of 0-2. Patients were randomly assigned (1:1:1:1) centrally using a minimisation technique to radiotherapy alone (59·4 Gy in 33 fractions; three-dimensional conformal radiotherapy or intensity-modulated radiotherapy), radiotherapy with concurrent oral temozolomide (75 mg/m2 per day), radiotherapy with adjuvant oral temozolomide (12 4-week cycles of 150-200 mg/m2 temozolomide given on days 1-5), or radiotherapy with both concurrent and adjuvant temozolomide. Patients were stratified by institution, WHO performance status score, age, 1p loss of heterozygosity, the presence of oligodendroglial elements on microscopy, and MGMT promoter methylation status. The primary endpoint was overall survival adjusted by stratification factors at randomisation in the intention-to-treat population. A second interim analysis requested by the independent data monitoring committee was planned when two-thirds of total required events were observed to test superiority or futility of concurrent temozolomide. This study is registered with ClinicalTrials.gov, NCT00626990. FINDINGS: Between Dec 4, 2007, and Sept 11, 2015, 751 patients were randomly assigned (189 to radiotherapy alone, 188 to radiotherapy with concurrent temozolomide, 186 to radiotherapy and adjuvant temozolomide, and 188 to radiotherapy with concurrent and adjuvant temozolomide). Median follow-up was 55·7 months (IQR 41·0-77·3). The second interim analysis declared futility of concurrent temozolomide (median overall survival was 66·9 months [95% CI 45·7-82·3] with concurrent temozolomide vs 60·4 months [45·7-71·5] without concurrent temozolomide; hazard ratio [HR] 0·97 [99·1% CI 0·73-1·28], p=0·76). By contrast, adjuvant temozolomide improved overall survival compared with no adjuvant temozolomide (median overall survival 82·3 months [95% CI 67·2-116·6] vs 46·9 months [37·9-56·9]; HR 0·64 [95% CI 0·52-0·79], p<0·0001). The most frequent grade 3 and 4 toxicities were haematological, occurring in no patients in the radiotherapy only group, 16 (9%) of 185 patients in the concurrent temozolomide group, and 55 (15%) of 368 patients in both groups with adjuvant temozolomide. No treatment-related deaths were reported. INTERPRETATION: Adjuvant temozolomide chemotherapy, but not concurrent temozolomide chemotherapy, was associated with a survival benefit in patients with 1p/19q non-co-deleted anaplastic glioma. Clinical benefit was dependent on IDH1 and IDH2 mutational status. FUNDING: Merck Sharpe & Dohme.

Melanoma recurrence patterns and management after adjuvant targeted therapy: a multicentre analysis.

BACKGROUND: Adjuvant targeted therapy (TT) improves relapse free survival in patients with resected BRAF mutant stage III melanoma. The outcomes and optimal management of patients who relapse after adjuvant TT is unknown. METHODS: Patients from twenty-one centres with recurrent melanoma after adjuvant TT were included. Disease characteristics, adjuvant therapy, recurrence, treatment at relapse and outcomes were examined. RESULTS: Eighty-five patients developed recurrent melanoma; nineteen (22%) during adjuvant TT. Median time to first recurrence was 18 months and median follow-up from first recurrence was 31 months. Fifty-eight (68%) patients received immunotherapy (IT) or TT as 1st line systemic therapy at either first or subsequent recurrence and had disease that was assessable for response. Response to anti-PD-1 (±trial agent), combination ipilimumab-nivolumab, TT rechallenge and ipilimumab monotherapy was 63%, 62% 25% and 10% respectively. Twenty-eight (33%) patients had died at census, all from melanoma. Two-year OS was 84% for anti-PD-1 therapy (±trial agent), 92% for combination ipilimumab and nivolumab, 49% for TT and 45% for ipilimumab monotherapy (p = 0.028). CONCLUSIONS: Patients who relapse after adjuvant TT respond well to subsequent anti-PD-1 based therapy and have outcomes similar to those seen when first line anti-PD-1 therapy is used in stage IV melanoma.

Increased thyroid uptake on 18F-FDG PET/CT is associated with the development of permanent hypothyroidism in stage IV melanoma patients treated with anti-PD-1 antibodies.

PURPOSE: To determine performances of 2-deoxy-2-(18F)fluoro-D-glucose (18F-FDG) positron emission tomography (PET) to detect the development of permanent thyroid dysfunction (PTD), and to evaluate the prognostic value of early increased thyroid uptake in stage IV melanoma patients treated with anti-programmed death 1 (anti-PD-1) antibodies. METHODS: Twenty-nine patients were retrospectively enrolled. PTD was defined as symptomatic thyroid disorder requiring long-term specific treatment. On the first PET performed during follow-up, maximal standardized uptake value of the thyroid (SUVmax-Th) and SUVmax-Th/SUVmax-blood-pool ratio (Th/B) were measured. Areas under ROC curves (AUC) of these parameters for the diagnostic of PTD were compared. Cutoff values were defined to maximize the Youden's index. Survival analyses were performed according to the Kaplan-Meier method and compared using the log-rank method between patients with and without enhanced thyroid uptake according to cutoff values defined with the Hothorn and Lausen method. RESULTS: Four patients presented PTD. Median SUVmax-Th and Th/B were, respectively, 2.11 and 1.00. The median follow-up period was 21.7 months. AUC were 1.0 (CI95% 0.88-1.0) for both parameters. Optimal cutoff values were, respectively, SUVmax-Th > 4.1 and Th/B > 2.0, both conferring sensitivities of 100% (CI95% 40-100%) and specificities of 100% (CI95% 86-100%). The median progression-free survival and overall survival were 11.3 months and 33.5 months, respectively. Using optimized cutoffs, there was no statistically significant difference of survival. CONCLUSION: SUVmax-Th > 4.1 and Th/B > 2.0 provided perfect diagnostic performances to detect patients that developed PTD. No significant survival difference was found between patients with and without increased thyroid uptake.

Non-IDH1-R132H IDH1/2 mutations are associated with increased DNA methylation and improved survival in astrocytomas, compared to IDH1-R132H mutations.

Somatic mutations in the isocitrate dehydrogenase genes IDH1 and IDH2 occur at high frequency in several tumour types. Even though these mutations are confined to distinct hotspots, we show that gliomas are the only tumour type with an exceptionally high percentage of IDH1R132H mutations. Patients harbouring IDH1R132H mutated tumours have lower levels of genome-wide DNA-methylation, and an associated increased gene expression, compared to tumours with other IDH1/2 mutations ("non-R132H IDH1/2 mutations"). This reduced methylation is seen in multiple tumour types and thus appears independent of the site of origin. For 1p/19q non-codeleted glioma (astrocytoma) patients, we show that this difference is clinically relevant: in samples of the randomised phase III CATNON trial, patients harbouring tumours with IDH mutations other than IDH1R132H have a better outcome (hazard ratio 0.41, 95% CI [0.24, 0.71], p = 0.0013). Such non-R132H IDH1/2-mutated tumours also had a significantly lower proportion of tumours assigned to prognostically poor DNA-methylation classes (p < 0.001). IDH mutation-type was independent in a multivariable model containing known clinical and molecular prognostic factors. To confirm these observations, we validated the prognostic effect of IDH mutation type on a large independent dataset. The observation that non-R132H IDH1/2-mutated astrocytomas have a more favourable prognosis than their IDH1R132H mutated counterpart indicates that not all IDH-mutations are identical. This difference is clinically relevant and should be taken into account for patient prognostication.

Quality-of-life assessment in French patients with metastatic melanoma in real life.

BACKGROUND: Significant progress was recently observed in the treatment of metastatic melanoma (MM). With >50% of patients now reaching a second line of treatment and a significant improvement in the survival rate, an assessment of quality of life (QoL) during the whole course of the disease becomes necessary. The objective of this study was to describe the QoL of patients with MM in France, from their diagnosis of advanced disease to their death, in real life. METHODS: QoL data were collected through MelBase, a prospective, French, multicentric cohort dedicated to the follow-up of adults with MM. QoL was assessed using the EuroQoL-5D questionnaire and the Functional Assessment of Cancer Treatment (FACT)-Melanoma questionnaire at the time of study inclusion, every 3 months, and at the time of each treatment change until death. To assess longitudinal changes from baseline to death, mixed-effect models for repeated-measures analyses were used to control for baseline covariates. RESULTS: QoL was assessed in 1435 patients who were included in the study between 2013 and 2018. The median follow-up was 9.4 months, and 47% of patients died during follow-up. During first-line treatment, the model-based, mean utility score was 0.830 (95% CI, 0.818-0.843), the mean FACT-General score was 77.22 (95% CI, 76.23-78.22), and the mean FACT-Melanoma score was 129.46 (95% CI, 128.02-130.90). At the time of a change in treatment line, there was a decrease of -0.027 (95% CI, -0.03, -0.02) in the utility score, -1.82 (95% CI, -1.88, -1.76) in the FACT-General score, and -2.98 (95% CI, -3.05, -2.91) in the FACT-Melanoma score compared with first-line treatment. CONCLUSIONS: In the MelBase cohort, the QoL among patients with MM seems to be fairly stable over the whole disease course, although a small but significant decrease at time therapy is changed is observed.

Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma.

BACKGROUND: Combination therapy with the BRAF inhibitor dabrafenib plus the MEK inhibitor trametinib improved survival in patients with advanced melanoma with BRAF V600 mutations. We sought to determine whether adjuvant dabrafenib plus trametinib would improve outcomes in patients with resected, stage III melanoma with BRAF V600 mutations. METHODS: In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned 870 patients with completely resected, stage III melanoma with BRAF V600E or V600K mutations to receive oral dabrafenib at a dose of 150 mg twice daily plus trametinib at a dose of 2 mg once daily (combination therapy, 438 patients) or two matched placebo tablets (432 patients) for 12 months. The primary end point was relapse-free survival. Secondary end points included overall survival, distant metastasis-free survival, freedom from relapse, and safety. RESULTS: At a median follow-up of 2.8 years, the estimated 3-year rate of relapse-free survival was 58% in the combination-therapy group and 39% in the placebo group (hazard ratio for relapse or death, 0.47; 95% confidence interval [CI], 0.39 to 0.58; P<0.001). The 3-year overall survival rate was 86% in the combination-therapy group and 77% in the placebo group (hazard ratio for death, 0.57; 95% CI, 0.42 to 0.79; P=0.0006), but this level of improvement did not cross the prespecified interim analysis boundary of P=0.000019. Rates of distant metastasis-free survival and freedom from relapse were also higher in the combination-therapy group than in the placebo group. The safety profile of dabrafenib plus trametinib was consistent with that observed with the combination in patients with metastatic melanoma. CONCLUSIONS: Adjuvant use of combination therapy with dabrafenib plus trametinib resulted in a significantly lower risk of recurrence in patients with stage III melanoma with BRAF V600E or V600K mutations than the adjuvant use of placebo and was not associated with new toxic effects. (Funded by GlaxoSmithKline and Novartis; COMBI-AD ClinicalTrials.gov, NCT01682083 ; EudraCT number, 2012-001266-15 .).

Implementation of a molecular tumor board at a regional level to improve access to targeted therapy.

BACKGROUND: With the development of precision oncology, Molecular Tumor Boards (MTB) are developing in many institutions. However, the implementation of MTB in routine clinical practice has still not been thoroughly studied. MATERIAL AND METHODS: Since the first drugs approved for targeted therapies, patient tumor samples were centralized to genomic testing platforms. In our institution, all tumor samples have been analyzed since 2014 by Next Generation Sequencing (NGS). In 2015, we established a regional MTB to discuss patient cases with 1 or more alterations identified by NGS, in genes different from those related to drug approval. We conducted a retrospective comparative analysis to study whether our MTB increased the prescriptions of Molecular Targeted Therapies (MTT) and the inclusions of patients in clinical trials with MTT, in comparison with patients with available NGS data but no MTB discussion. RESULTS: In 2014, 86 patients had UGA, but the results were not available to clinicians and not discussed in MTB. During the years 2015 and 2016, 113 patients with an UGA (unreferenced genomic alteration) were discussed in MTB. No patients with an UGA were included in 2014 in a clinical trial, versus 2 (2%) in 2015-2016. 13 patients with an UGA (12%) were treated in 2015-2016 with a MTT whereas in 2014, no patient (p = 0.001). CONCLUSIONS: In this retrospective analysis, we showed that the association of large-scale genomic testing and MTB was feasible, and could increase the prescription of MTT. However, in routine clinical practice, the majority of patients with UGA still do not have access to MTT.

Patient-reported outcomes in patients with resected, high-risk melanoma with BRAFV600E or BRAFV600K mutations treated with adjuvant dabrafenib plus trametinib (COMBI-AD): a randomised, placebo-controlled, phase 3 trial.

BACKGROUND: In the phase 3 COMBI-AD study, patients with resected, stage III melanoma with BRAFV600E or BRAFV600K mutations received adjuvant dabrafenib plus trametinib or placebo. The primary analysis showed that dabrafenib plus trametinib significantly improved relapse-free survival at 3 years. These results led to US Food and Drug Administration approval of dabrafenib plus trametinib as adjuvant treatment for patients with resected stage III melanoma with BRAFV600E or BRAFV600K mutations. Here, we report the patient-reported outcomes from COMBI-AD. METHODS: COMBI-AD was a randomised, double-blind, placebo-controlled, phase 3 study done at 169 sites in 25 countries. Study participants were aged 18 years or older and had complete resection of stage IIIA (lymph node metastases >1 mm), IIIB, or IIIC cutaneous melanoma as per American Joint Committee on Cancer 7th edition criteria, with BRAFV600E or BRAFV600K mutations, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned (1:1) via an interactive voice response system, stratified by mutation type and disease stage, to receive oral dabrafenib (150 mg twice daily) plus oral trametinib (2 mg once daily) or matching placebos for 12 months. Patients, physicians, and the investigators who analysed the data were masked to treatment allocation. The primary endpoint was relapse-free survival, reported elsewhere. Health-related quality of life, reported here, was a prespecified exploratory endpoint, and was assessed with the European Quality of Life 5-Dimensions 3-Levels (EQ-5D-3L) questionnaire in the intention-to-treat population. We used a mixed-model repeated-measures analysis to assess differences in health-related quality of life between groups. This study is registered with ClinicalTrials.gov, number NCT01682083. The trial is ongoing, but is no longer recruiting participants. FINDINGS: Between Jan 31, 2013, and Dec 11, 2014, 870 patients were enrolled and randomly assigned to receive dabrafenib plus trametinib (n=438) or matching placebos (n=432). Data were collected until the data cutoff for analyses of the primary endpoint (June 30, 2017). The median follow-up was 34 months (IQR 28-39) in the dabrafenib plus trametinib group and 33 months (20·5-39) in the placebo group. During the 12-month treatment phase, there were no significant or clinically meaningful changes from baseline between groups in EQ-5D-3L visual analogue scale (EQ-VAS) or utility scores. During treatment, there were no clinically meaningful differences in VAS scores or utility scores in the dabrafenib plus trametinib group between patients who did and did not experience the most common adverse events. During long-term follow-up (range 15-48 months), VAS and utility scores were similar between groups and did not differ from baseline scores. At recurrence, there were significant decreases in VAS scores in both the dabrafenib plus trametinib group (mean change -6·02, SD 20·57; p=0·0032) and the placebo group (-6·84, 20·86; p<0·0001); the mean change in utility score also differed significantly at recurrence for both groups (dabrafenib plus trametinib -0·0626, 0·1911, p<0·0001; placebo -0·0748, 0·2182, p<0·0001). INTERPRETATION: These findings show that dabrafenib plus trametinib did not affect patient-reported outcome scores during or after adjuvant treatment, and suggest that preventing or delaying relapse with adjuvant therapy could be beneficial in this setting. FUNDING: Novartis.

Interim results from the CATNON trial (EORTC study 26053-22054) of treatment with concurrent and adjuvant temozolomide for 1p/19q non-co-deleted anaplastic glioma: a phase 3, randomised, open-label intergroup study.

BACKGROUND: The role of temozolomide chemotherapy in newly diagnosed 1p/19q non-co-deleted anaplastic gliomas, which are associated with lower sensitivity to chemotherapy and worse prognosis than 1p/19q co-deleted tumours, is unclear. We assessed the use of radiotherapy with concurrent and adjuvant temozolomide in adults with non-co-deleted anaplastic gliomas. METHODS: This was a phase 3, randomised, open-label study with a 2 × 2 factorial design. Eligible patients were aged 18 years or older and had newly diagnosed non-co-deleted anaplastic glioma with WHO performance status scores of 0-2. The randomisation schedule was generated with the electronic EORTC web-based ORTA system. Patients were assigned in equal numbers (1:1:1:1), using the minimisation technique, to receive radiotherapy (59·4 Gy in 33 fractions of 1·8 Gy) alone or with adjuvant temozolomide (12 4-week cycles of 150-200 mg/m2 temozolomide given on days 1-5); or to receive radiotherapy with concurrent temozolomide 75 mg/m2 per day, with or without adjuvant temozolomide. The primary endpoint was overall survival adjusted for performance status score, age, 1p loss of heterozygosity, presence of oligodendroglial elements, and MGMT promoter methylation status, analysed by intention to treat. We did a planned interim analysis after 219 (41%) deaths had occurred to test the null hypothesis of no efficacy (threshold for rejection p<0·0084). This trial is registered with ClinicalTrials.gov, number NCT00626990. FINDINGS: At the time of the interim analysis, 745 (99%) of the planned 748 patients had been enrolled. The hazard ratio for overall survival with use of adjuvant temozolomide was 0·65 (99·145% CI 0·45-0·93). Overall survival at 5 years was 55·9% (95% CI 47·2-63·8) with and 44·1% (36·3-51·6) without adjuvant temozolomide. Grade 3-4 adverse events were seen in 8-12% of 549 patients assigned temozolomide, and were mainly haematological and reversible. INTERPRETATION: Adjuvant temozolomide chemotherapy was associated with a significant survival benefit in patients with newly diagnosed non-co-deleted anaplastic glioma. Further analysis of the role of concurrent temozolomide treatment and molecular factors is needed. FUNDING: Schering Plough and MSD.

Dabrafenib plus trametinib in patients with BRAFV600-mutant melanoma brain metastases (COMBI-MB): a multicentre, multicohort, open-label, phase 2 trial.

BACKGROUND: Dabrafenib plus trametinib improves clinical outcomes in BRAFV600-mutant metastatic melanoma without brain metastases; however, the activity of dabrafenib plus trametinib has not been studied in active melanoma brain metastases. Here, we report results from the phase 2 COMBI-MB trial. Our aim was to build on the current body of evidence of targeted therapy in melanoma brain metastases through an evaluation of dabrafenib plus trametinib in patients with BRAFV600-mutant melanoma brain metastases. METHODS: This ongoing, multicentre, multicohort, open-label, phase 2 study evaluated oral dabrafenib (150 mg twice per day) plus oral trametinib (2 mg once per day) in four patient cohorts with melanoma brain metastases enrolled from 32 hospitals and institutions in Europe, North America, and Australia: (A) BRAFV600E-positive, asymptomatic melanoma brain metastases, with no previous local brain therapy, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; (B) BRAFV600E-positive, asymptomatic melanoma brain metastases, with previous local brain therapy, and an ECOG performance status of 0 or 1; (C) BRAFV600D/K/R-positive, asymptomatic melanoma brain metastases, with or without previous local brain therapy, and an ECOG performance status of 0 or 1; and (D) BRAFV600D/E/K/R-positive, symptomatic melanoma brain metastases, with or without previous local brain therapy, and an ECOG performance status of 0, 1, or 2. The primary endpoint was investigator-assessed intracranial response in cohort A in the all-treated-patients population. Secondary endpoints included intracranial response in cohorts B, C, and D. This study is registered with ClinicalTrials.gov, number NCT02039947. FINDINGS: Between Feb 28, 2014, and Aug 5, 2016, 125 patients were enrolled in the study: 76 patients in cohort A; 16 patients in cohort B; 16 patients in cohort C; and 17 patients in cohort D. At the data cutoff (Nov 28, 2016) after a median follow-up of 8·5 months (IQR 5·5-14·0), 44 (58%; 95% CI 46-69) of 76 patients in cohort A achieved an intracranial response. Intracranial response by investigator assessment was also achieved in nine (56%; 95% CI 30-80) of 16 patients in cohort B, seven (44%; 20-70) of 16 patients in cohort C, and ten (59%; 33-82) of 17 patients in cohort D. The most common serious adverse events related to study treatment were pyrexia for dabrafenib (eight [6%] of 125 patients) and decreased ejection fraction (five [4%]) for trametinib. The most common grade 3 or worse adverse events, regardless of study drug relationship, were pyrexia (four [3%] of 125) and headache (three [2%]). INTERPRETATION: Dabrafenib plus trametinib was active with a manageable safety profile in this melanoma population that was consistent with previous dabrafenib plus trametinib studies in patients with BRAFV600-mutant melanoma without brain metastases, but the median duration of response was relatively short. These results provide evidence of clinical benefit with dabrafenib plus trametinib and support the need for additional research to further improve outcomes in patients with melanoma brain metastases. FUNDING: Novartis.

Paclitaxel/carboplatin with or without belinostat as empiric first-line treatment for patients with carcinoma of unknown primary site: A randomized, phase 2 trial.

BACKGROUND: The objective of this study was to evaluate the efficacy of belinostat, a histone deacetylase inhibitor, when added to paclitaxel/carboplatin in the empiric first-line treatment of patients with carcinoma of unknown primary site (CUP). METHODS: In this randomized phase 2 trial, previously untreated patients with CUP were randomized to receive belinostat plus paclitaxel/carboplatin (group A) or paclitaxel/carboplatin alone (group B) repeated every 21 days. Patients were re-evaluated every 2 cycles, and those without disease progression continued treatment for 6 cycles. Patients in group A then continued receiving single-agent belinostat, whereas patients in group B stopped treatment. The primary endpoint was progression-free survival (PFS): The authors postulated that the addition of belinostat would improve PFS from 5 months (expected with paclitaxel/carboplatin) to 8 months. RESULTS: In total, 89 patients were randomized (group A, n = 44; group B, n = 45), and the demographics and disease characteristics were balanced between the 2 groups. The addition of belinostat to paclitaxel/carboplatin did not improve PFS (group A, 5.4 months [95% confidence interval, 3.0-6.0 months]; group B, 5.3 months [95% confidence interval, 2.8-6.6 months]; P = .85). Overall survival was 12.4 months for group A versus 9.1 months for group B (P = .20). The response rate favored the belinostat group (45% vs 21%; P = .02). Belinostat resulted in a modest increase in treatment toxicity. CONCLUSIONS: The addition of belinostat to paclitaxel/carboplatin did not improve the PFS of patients with CUP who were receiving first-line therapy, although the patients who received belinostat had a higher investigator-assessed response rate. Future trials in CUP should focus on specific subsets, defined either by the predicted tissue of origin or by the identification of targetable molecular abnormalities.

A phase I dose escalation study to determine the optimal biological dose of irosustat, an oral steroid sulfatase inhibitor, in postmenopausal women with estrogen receptor-positive breast cancer.

Steroid sulfatase (STS) inhibition may have a therapeutic role in suppression of endocrine-responsive breast cancer. This study aimed to determine the optimal biological dose and recommended dose (RD) of the STS inhibitor irosustat. A three-part, open-label, multicenter, dose escalation study of irosustat in estrogen receptor-positive breast cancer patients involved administration of a single dose of irosustat with a 7-day observation period; followed by a daily oral dose of irosustat for 28 days; and an extension phase, in which the daily oral dose of irosustat was continued at the discretion of the investigator and as long as the patient was benefitting from the treatment. Five doses of irosustat were tested (1, 5, 20, 40, and 80 mg) in 50 patients. After 28 days of daily administration of irosustat, all the evaluated patients in the 5, 20, 40, and 80 mg cohorts achieved ≥95 % STS inhibition in peripheral blood mononuclear cells and corresponding endocrine suppression. The maximum tolerated dose was not reached, and the 40 mg dose was established as the RD. The median time to disease progression in the 40 mg cohort was 11.2 weeks. Disease stabilization was achieved in 10 % of patients potentially indicative of drug activity. Dry skin was the most frequent adverse event. The RD of irosustat is 40 mg. Disease stabilization occurred in 10 % of this heavily pretreated patient population. A larger study is required to define an accurate response rate to irosustat as a single agent and whether co-administration with an aromatase inhibitor is needed.

A phase I, open-label, single-arm study for QT assessment of eribulin mesylate in patients with advanced solid tumors.

BACKGROUND: Several cancer therapies can prolong cardiac repolarization. This study assessed the potential of eribulin to affect cardiac repolarization in patients with advanced solid tumors. METHODS: In this Phase I, open-label, single-arm study, patients received eribulin mesylate (1.4 mg/m(2); Days 1 and 8 of a 21-day cycle). The primary objective was to assess the effect of eribulin on the QTcF pre- and post-infusion; QTcF and QTcNi were compared for ability to remove heart-rate dependence of the QT interval. Relationship between concentration of eribulin and ΔQTc was explored using linear mixed-effects analysis. Secondary objectives explored pharmacokinetics, safety, and tolerability. RESULTS: Twenty-six patients were enrolled. QTcNi was more effective than QTcF in correcting for heart-rate dependency of the QT interval. On Day 1, mean ΔQTcNi were ~0 at all timepoints. An apparent time-dependent increase in ΔQTc was observed: on Day 8, changes from baseline were larger and more variable, without clear relation to plasma levels of eribulin. Day 8 predose ΔQTcNi was 5 ms, post-infusion mean values ranged from 2 to 9 ms (largest mean ΔQTcNi at 6 h). No new or unexpected toxicities were reported. CONCLUSION: Eribulin demonstrated an acceptable safety profile and a minor prolongation of QTc not expected to be of clinical concern in oncology patients.

Phase I Study of Androgen Deprivation Therapy in Combination with Anti-PD-1 in Melanoma Patients Pretreated with Anti-PD-1.

PURPOSE: Androgen deprivation regenerates the thymus in adults, expanding of T-cell receptor V ß repertoire in blood and lymphoid organs and tumor-infiltrating lymphocytes in human prostate tumors. In melanoma murine models, androgen receptor promotes metastases and androgen blockade potentiates antitumor vaccine efficacy. This phase I study evaluated the safety, efficacy, and pharmocodynamics of androgen deprivation with the gonadotropin releasing hormone (GnRH) agonist triptorelin combined with nivolumab in male patients with melanoma resistant to anti-PD-1. PATIENTS AND METHODS: Adult male patients with advanced melanoma who progressed under anti-PD-1 containing regimens received triptorelin 3.75 mg every 4 weeks, nivolumab 3 mg/kg every 2 weeks, and bicalutamide 50 mg once daily during the first 28 days. Tumor response was first assessed after 3 months; adverse events (AE) were monitored throughout the study. T-cell receptor excision circles (TREC), a biomarker of thymus activity, were explored throughout the study. RESULTS: Of 14 patients, 4 were locally advanced and 10 had distant metastases. There were no grade 4 or 5 AEs. Five grade three AEs were reported in 4 patients. According to RECIST v1.1, best overall response was partial response (PR) in one patient with a pancreas metastasis, stable disease (SD) in 5 patients, and progressive disease in 8 patients. According to iRECIST, a second PR occurred after an initial pseudoprogression, TRECs increased in 2 patients, one with PR who also had an increase in TILs, and the second with SD. CONCLUSIONS: This combination was well tolerated. Disease control was obtained in 42.8% (RECIST) and 50% (iRECIST). The evidence for thymus rejuvenation was limited.

Safety and tolerability of long-term treatment with darolutamide in patients with metastatic castration-resistant prostate cancer.

BACKGROUND: In patients with metastatic castration-resistant prostate cancer, darolutamide was well tolerated for 25 months, but minimal long-term safety data are available. METHODS: Treatment-emergent adverse events (TEAEs) for patients receiving darolutamide for a median of 38 months (n = 13) are described in this pooled analysis of individual patient data from phase 1/2 studies. RESULTS: All patients reported TEAEs (mostly grade 1/2). The most common TEAEs were diarrhea, abdominal pain, and nausea. Serious TEAEs were reported in six patients (none related to darolutamide). All treatment-related TEAEs (n = 5) were grade 1. CONCLUSIONS: Long-term darolutamide treatment was well tolerated; no new safety signals observed. In patients with mCRPC, long-term darolutamide treatment was well tolerated and no new safety signals were observed. These findings are consistent with previous reports, demonstrating a favorable safety and tolerability profile of darolutamide.