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This study aimed to assess the prognostic value of thyroid dysfunctions in metastatic melanoma patients on anti-programmed death-1 (anti-PD-1). A total of 110 stage IV or inoperable stage III melanoma patients treated with anti-PD-1 alone or in association with anti-CTLA-4 (T-lymphocyte antigen-4) antibody from January 2015 to December 2017 at our institution were enrolled in this retrospective study. Median follow-up was 32.8 months. Transitory thyroid dysfunctions and permanent thyroid dysfunctions were distinguished. The main criterion was progression-free survival. Secondary criteria were best response and overall survival. Survival curves were compared with log-rank tests and a cox proportional hazard ratio model was used to adjust patients and melanoma characteristics. Thirty-eight (35%) thyroid dysfunctions were observed during the follow-up, including 25 transitory thyroid dysfunctions (23%) and 13 permanent thyroid dysfunctions (12%). Progression-free survival was longer in patients with thyroid dysfunction (18.1 months) than in patients without thyroid dysfunction (3.9 months, P = 0.0085). In multivariate analysis, thyroid dysfunctions were not an independent predictive factor for progression-free survival. Patients with thyroid dysfunction had a longer overall survival (P = 0.0021), and thyroid dysfunctions were associated with a lower mortality risk (hazard ratio = 0.40; P = 0.005). Best response was positively associated with thyroid dysfunctions (P = 0.048). Thyroid dysfunctions induced by anti-PD-1 were not an independent predictive factor for progression-free survival in metastatic melanoma patients but seemed associated with a better response and increased overall survival.

Purpose: In BRAFV600MUT metastatic melanoma, cyclin D–CDK4/6–INK4–Rb pathway alterations are involved in resistance to MAPK inhibitors, suggesting a clinical benefit of cyclin-dependent kinase 4 (CDK4) inhibitors. In this phase I–II study, we aimed to establish the MTD of palbociclib when added to vemurafenib. Patients and Methods: Patients with BRAFV600E/KMUT metastatic melanoma harboring CDKN2A loss and RB1 expression were included and stratified into two groups according to previous BRAF inhibitor treatment (no:strata 1; yes:strata 2). Treatment comprised palbociclib once daily for 14 days followed by a 7-day break + continuous dosing of vemurafenib. The primary endpoint was the occurrence of dose-limiting toxicity (DLT), and the secondary endpoints included the best response, survival, pharmacokinetics, and tumor molecular profiling. Results: Eighteen patients were enrolled, with 15 in strata 2. Characteristics at inclusion were American Joint Committee on Cancer stage IVM1c (N = 16; 88.9%), high lactate dehydrogenase (N = 9; 50.0%), and median number of previous treatments of 2. One and 5 patients experienced DLT in strata 1 and 2, respectively, defining the MTD at palbociclib 25 mg and vemurafenib 960 mg in strata 2. No significant evidence for drug–drug interactions was highlighted. The median progression-free survival was 2.8 months, and 5 (27.8%) patients showed a clinical response. The baseline differential mRNA expression analysis and in vitro data revealed the role of CHEK2 in the response to palbociclib. Conclusions: Although the combination of palbociclib + fixed-dose vemurafenib did not allow an increased palbociclib dosage above 25 mg, a significant clinical benefit was achieved in pretreated patients with melanoma. An association between the transcriptomic data and clinical response was highlighted.

International audience; 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.

Pimasertib is a selective, potent mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor. The aim of this study was to describe the efficacy, safety, and pharmacodynamics of pimasertib at pharmacologically active doses in a cohort of patients with locally advanced/metastatic melanoma from a first-in-human study of pimasertib. This was a phase I, open-label, two-part, dose-escalation study. Part 1 was conducted in patients with solid tumors and identified the maximum tolerated dose, while Part 2 was restricted to patients with advanced/metastatic melanoma. Endpoints included safety, pharmacodynamics, and antitumor activity. We present data for patients with melanoma only from both parts of the study. In total, 93 patients with melanoma received pimasertib, 89 of whom received pharmacologically active doses (28–255 mg/day) across four dose regimens in the two parts of the study. The objective response rate was 12.4% (11/89): complete response (n = 1) and partial response (PR; n = 10). Six patients responded for > 24 weeks. Nine of the 11 responders had tumors with B-Raf Proto-Oncogene, Serine/Threonine Kinase (BRAF; n = 6) and/or NRAS Proto-Oncogene, GTPase (NRAS; n = 3) mutations. Forty-six patients had stable disease (SD). In patients with ocular melanoma (n = 13), best overall response was PR (n = 1), SD (n = 11), and disease progression (n = 1). Phosphorylated extracellular signal-regulated kinase (pERK) levels were substantially reduced within 2 h of treatment and inhibition was sustained with continuous twice-daily dosing. Treatment-related, recurrent, grade 3 or higher adverse events were reported in eight patients, including diarrhea, and skin and ocular events. Results from this phase I study indicate that pimasertib has clinical activity in patients with locally advanced/metastatic melanoma, particularly BRAF- and NRAS-mutated tumors, at clinically relevant doses associated with pERK inhibition in peripheral blood mononuclear cells. ClinicalTrials.gov, NCT00982865

The Ras/Raf/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (Ras/Raf/MEK/ERK) signaling cascade is frequently constitutively activated in human cancers. Pimasertib is a selective and potent adenosine triphosphate non-competitive MEK1/2 inhibitor. Our objectives were to describe the results of a phase I, first-in-human, dose-escalation trial of pimasertib that investigated the maximum tolerated dose, recommended phase II dose, and safety, as well as other endpoints. Four dosing schedules of pimasertib (once daily [qd], 5 days on, 2 days off; qd, 15 days on, 6 days off; continuous qd; continuous twice daily [bid]) were evaluated in patients with advanced solid tumors. Each treatment cycle lasted 21 days. The primary objective was to determine the maximum tolerated dose based on dose-limiting toxicities (DLTs) evaluated during cycle 1, and the recommended phase II dose (RP2D). Secondary objectives included safety, pharmacokinetics, pharmacodynamics, and antitumor activity. Overall, 180 patients received pimasertib (dose range 1–255 mg/day). DLTs were mainly observed at doses ≥ 120 mg/day and included skin rash/acneiform dermatitis and ocular events, such as serous retinal detachment. The most common drug-related adverse events were consistent with class effects, including diarrhea, skin disorders, ocular disorders, asthenia/fatigue, and peripheral edema. The median time to maximum pimasertib concentration was 1.5 h across dosing schedules, and the apparent terminal half-life was 5 h across qd dosing schedules. Pimasertib decreased ERK phosphorylation within 2 h of administration, which was maintained for up to 8 h at higher doses and prolonged with bid dosing. Based on the safety profile and efficacy signals, a continuous bid regimen was the preferred dosing schedule and the RP2D was defined as 60 mg bid. ClinicalTrials.gov, NCT00982865.

International audience; 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.

Summary Background In the phase 3 COMBI-AD study, patients with resected, stage III melanoma with BRAF V600E or BRAF V600K 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 BRAF V600E or BRAF V600K 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 BRAF V600E or BRAF V600K 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 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.

Background: The European Organisation for Research and Treatment of Cancer (EORTC) 1325/KEYNOTE-054 trial assessed pembrolizumab versus placebo in patients with resected high-risk stage III melanoma. At 15-month median follow-up, pembrolizumab improved recurrence-free survival (hazard ratio [HR] 0·57 [98·4% CI 0·43–0·74], p1 mm), IIIB, or IIIC (without in-transit metastasis), and with an Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible. Patients were randomly assigned (1:1) via a central interactive voice response system to receive intravenous pembrolizumab 200 mg or placebo every 3 weeks for up to 18 doses or until disease recurrence or unacceptable toxicity. Randomisation was stratified according to disease stage and region, using a minimisation technique, and clinical investigators, patients, and those collecting or analysing the data were masked to treatment assignment. The two coprimary endpoints were recurrence-free survival in the intention-to-treat (ITT) population and in patients with PD-L1-positive tumours. The secondary endpoint reported here was distant metastasis-free survival in the ITT and PD-L1-positive populations. This study is registered with ClinicalTrials.gov, NCT02362594, and EudraCT, 2014-004944-37. Findings: Between Aug 26, 2015, and Nov 14, 2016, 1019 patients were assigned to receive either pembrolizumab (n=514) or placebo (n=505). At an overall median follow-up of 42·3 months (IQR 40·5–45·9), 3·5-year distant metastasis-free survival was higher in the pembrolizumab group than in the placebo group in the ITT population (65·3% [95% CI 60·9–69·5] in the pembrolizumab group vs 49·4% [44·8–53·8] in the placebo group; HR 0·60 [95% CI 0·49–0·73]; p

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 R132H mutated counterpart indicates that not all IDH-mutations are identical. This difference is clinically relevant and should be taken into account for patient prognostication.

International audience; Background: BRAF and MEK inhibitors combination, including dabrafenib (D) and trametinib (T) have transformed the treatment of BRAF V600-mutant advanced melanoma patients, including patients with brain metastasis (BM). In a large phase IIIb, single-arm, open-label, multicenter French study, we assessed safety, response to treatment, progression-free survival (PFS) and factors associated with progression, and stratified the population into risk groups. Methods: Patients with unresectable, advanced, BRAF V600-mutant melanoma were included, including those with the presence of BM, Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≤2, elevated lactate dehydrogenase (LDH) or previous melanoma treatments. Responses were determined locally, without central review. PFS was estimated using the Kaplan–Meier analysis and modelled with multivariate Cox model. Risk subgroups were identified using a regression tree analysis. Results: Between March 2015 and November 2016, 856 patients received at least one D + T dose. Overall, 92% had stage IV melanoma, 38% ECOG PS ≥1, 32% BM and 37.5% elevated LDH. Median PFS was 8.02 months (95% confidence interval [CI] 7.33–8.77). Significant factors associated with lower PFS were ECOG PS ≥1, elevated LDH, ≥3 metastatic sites and presence of BM. Patients with

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], pInterpretation: 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.

International audience; Background: The 'obesity paradox' suggests that higher body mass index (BMI) is associated with better survival values in metastatic melanoma patients, especially those receiving targeted and immune checkpoint inhibitor therapy. Higher BMI is also associated with higher incidences of treatment-related adverse events (TRAEs). This study assesses whether BMI is associated with survival outcomes and adverse events in metastatic melanoma patients with systemic therapy.Patients and methods: This multicentric retrospective study, conducted from 1 March 2013 to 29 April 2019, enrolled adults with unresectable stage III or IV melanoma from the French multicentric prospective cohort-MelBase (NCT02828202). Patients with first-line chemotherapy and targeted and immune therapy were included. Underweight people and those with metastatic mucosal or ocular melanoma were excluded. BMI was categorized using the World Health Organization criteria. Co-primary outcomes included the association between BMI and progression-free survival and overall survival, stratified by treatment type, sex, and age. Secondary endpoints were the association of BMI with overall response and TRAEs. Multivariate analyses were carried out.Results: A total of 1214 patients were analyzed. Their median age was 66.0 years (range, 53-75). Male predominance was observed [n = 738 (61%)]. Most patients received immune checkpoint inhibitor therapy (63%), followed by targeted therapy (32%), and had stage M1c disease (60.5%). Obese patients represented 22% of the cohort. The median follow-up duration was 13.5 months (range, 6.0-27.5). In the pooled analysis, no positive or negative association between BMI and progression-free survival (P = 0.88)/overall survival (P = 0.25) was observed, regardless of treatment type, sex, and age. These results were nonsignificant in the univariate and multivariate analyses. The objective response rate, according to BMI category, did not differ significantly regardless of age. TRAEs were not associated with BMI.Conclusion: The observed lack of an association between BMI and survival demonstrates that BMI is not a valuable marker of systemic treatment-related outcomes in metastatic melanoma. Future approaches might focus on the whole-body distribution.

Introduction Mucosal melanomas (MM) of the female genital tract are rare a. We aimed to study the prognostic factors of vulvar and vaginal locations of MM. Material and method A multicenter, retrospective cohort study conducted between 01/01/2000 and 01/06/2019. Result Of the 33 patients included 25 (75.8 %) had vulvar (VuM) and eight (24.2 %) vaginal melanomas (VaM). VaMs were deeper: median Breslow index: 17.5 mm [3.5−22] versus 4.3 mm [0.35−18] (p = 0.013). Average follow-up was 24.0 ± 59.8 months. Twenty-six patients (78.8 %) experienced recurrence. Disease-free survival was 52.9 % at 1 year (64.7 % for VuM and 14.3 % for VaM) and 8.4 % at 3 years (11 % for VuM and 0% for VaM) (p = 0.002). Median time to the first recurrence was 9.01 months [CI95 %: 2.07–56.71]. VaM recurred earlier than VuM (3.12 months [CI95 %: 2.07–12.49] versus 17.72 [CI95 %: 3.58–56.71], p = 0.011). VaM had a higher risk of recurrence (HR = 5.64 [CI95 %: 2.01–15.82], p = 0.001) in multivariate analysis. Overall survival was 88.5 % at 1 year (100 % for VuM and 50 % for VaM), and 59.4 % at 3 years (69.3 % for VuM and 25 % for VaM). Women with VaM died earlier: median specific death occurrence of 8.76 months [CI95 %: 6.54–24.72] versus 39.61 [CI95 %: 21.89–209.21], p = 0.013 (HR = 5.08 [CI95 %: 1.39–18.60], p = 0.014). A lesion size ≥3 cm was associated with an increased risk of mortality (HR = 8.45 [CI95 %: 1.60–44.52], p = 0.012). In multivariate analysis, vaginal location remained an independent and predictive variable of a higher risk of specific death (HR = 8.56 [CI95 %: 1.95–37.64], p = 0.005). Conclusion A vaginal location of MM is associated with a poorer prognosis than a vulvar location.

Importance Since 2011, many patients with metastatic melanoma have been treated with ipilimumab therapy and have developed severe immune-related adverse events (AEs). Because several immune therapies are now available to treat metastatic melanoma, a better knowledge of mechanisms and recurrence risks of immune-related AEs is needed before reintroduction of immunotherapies. Objectives To evaluate the risk of a recurrence of immune toxic effects associated with anti–programmed cell death 1 antibody (anti–PD-1) therapy after discontinuation of ipilimumab monotherapy because of severe AEs. Design, Settings, and Participants This cohort study conducted at 19 French melanoma referral centers included patients with metastatic melanoma who experienced severe immune-related AEs after ipilimumab therapy and then were treated with anti–PD-1 therapy between February 1, 2013, and December 31, 2016. The study cutoff was June 1, 2017. Statistical analysis was performed from June 1, 2016, to August 31, 2017. Exposures Monotherapy with at least 1 cycle of ipilimumab that was associated with a grade 3 or 4 immune-related AE and subsequent treatment with at least 1 cycle of an anti–PD-1 (nivolumab or pembrolizumab) therapy. Main Outcomes and Measures The primary outcome was the rate of immune-related AEs associated with anti–PD-1 therapy. Secondary outcomes were characteristics of ipilimumab-related and anti–PD-1 immune–related AEs and overall response rate and overall survival associated with anti–PD-1 therapy. Results Of 56 patients with metastatic melanoma included in the study, all of whom experienced severe immune-related AEs after ipilimumab therapy (31 [55%] male; mean [SD] age, 64 [14.9] years), 20 (36%) experienced at least 1 immune-related AE associated with pembrolizumab (6 of 20 [30%]) or nivolumab (14 of 20 [70%]) therapy. A total of 12 patients (21%) experienced grade 3 or 4 immune-related AEs, and among these patients, 4 (33%) presented with the same immune-related AE as with ipilimumab therapy. Severe immune-related AEs were resolved with use of systemic corticosteroids (7 [58%]) and/or anti–tumor necrosis factor (1 [8%]), and no grade 5 toxic effects were reported. Five patients discontinued anti–PD-1 therapy because of immune-related AEs. The overall response rate was 43%, with a median overall survival of 21 months (interquartile range, 18 to ongoing). Conclusions and Relevance The findings suggest that anti–PD-1 therapy may be associated with reduced risk of toxic effects and improved survival among patients who have experienced severe toxic effects after ipilimumab therapy.

Background: Combining anti-VEGF/Ang2 and anti-PD-1 therapy promotes an immunopermissive state, supportive of T-cell-mediated tumour cell destruction. This phase Ib study is assessing BI 836880 plus ezabenlimab in patients (pts) with advanced solid tumours. In Part 1 (dose escalation in pts with advanced NSCLC), the recommended phase 2 dose (RP2D) was determined as BI 836880 720 mg + ezabenlimab 240 mg IV q3w. Here, we report updated results, including data from Part 2 (expansion cohorts). Methods: Part 2 has 7 cohorts: metastatic (m) NSCLC after checkpoint inhibitor (CPI) monotherapy (Cohort A);mNSCLC after chemotherapy (CT) + CPI (Cohort B);mSCLC after CT ± CPI (Cohort C);recurrent GBM (1st and 2nd recurrence;Cohort D);immunotherapy-resistant m-melanoma (Cohort E);HCC after prior sorafenib or lenvatinib (Cohort F);and previously untreated unresectable HCC (Cohort G). Primary endpoint is objective response rate (complete response [CR] + partial response [PR]). Results: As of March 2021, 215 pts have been treated (Part 1: 14, Part 2: 201 [Cohort A, 35;B, 32;C, 19;D, 31;E, 32;F, 29;G, 23];70% male, median age 62 yrs). Any and ≥G3 AEs (any-cause) were reported in 183 (85%) and 72 (33%) pts. 118 (55%) pts had drug-related AEs, most commonly asthenia (13%) and hypertension (12%). 7 pts had G4 AEs (non-related hyperkalaemia + cardiac arrest, laryngospasm, gastrointestinal perforation;drug-related anaphylactic reaction, cholestatic hepatitis, acute pancreatitis, increased transaminases);9 pts had G5 AEs (non-related COVID-19 pneumonia, epilepsy, intracranial haemorrhage, cardio-respiratory arrest, haemoptysis, hepatic failure, general physical health deterioration, Glasgow coma scale abnormal + shortness of breath;drug-related tracheal haemorrhage). 35 (16%) pts had immune-related AEs and 15 (7%) had AEs leading to discontinuation. 179 pts were evaluable for response: 1 had confirmed CR (Cohort F), 22 had PR (Part 1: 2;Part 2: 20 [Cohort A, 4;C, 5;D, 4;E, 3;F, 3;G, 1]) and 110 had stable disease. 106 pts remain on treatment. Conclusions: BI 836880 plus ezabenlimab had a manageable safety profile, with preliminary activity in a range of tumour types. Clinical trial identification: NCT03468426. Editorial acknowledgement: Medical writing support for the development of this manuscript, under the direction of the authors, was provided by Hannah Simmons MSc, of Ashfield MedComms, an Ashfield Health company, and funded by Boehringer Ingelheim. Legal entity responsible for the study: Boehringer Ingelheim. Funding: Boehringer Ingelheim. Disclosure: N. Girard: Financial Interests, Personal, Advisory Role: Roche, Eli Lilly, Boehringer Ingelheim, AstraZeneca, Novartis, Pfizer, BMS, MSD, Takeda, GSK, AbbVie, Pharmamar, Janssen, Sanofi;Financial Interests, Personal, Funding, Travel/accommodation/expenses: Roche, AstraZeneca, BMS MSD Oncology;Financial Interests, Institutional, Research Grant: Roche, AstraZeneca, Boehringer Ingelheim. M. Wermke: Financial Interests, Personal, Advisory Role: MSD, Novartis, Kite, Heidelberg Pharma, Roche, Boehringer Ingelheim;Financial Interests, Personal, Other, Honoraria: BMS, Merck, Roche, Novartis, Kite, Boehringer Ingelheim, AstraZeneca;Financial Interests, Personal, Funding, Travel/Accommodation/Expenses: Glenmark, BMS, AstraZeneca. E. Ledin: Financial Interests, Personal and Institutional, Research Grant: Boehringer Ingelheim. D. Kim: Financial Interests, Personal, Advisory Role: Health Insurance Review & Assessment Service, Korea;Financial Interests, Personal, Invited Speaker: Korean Association for Lung Cancer, Korean Cancer Association, Korean Society of Medical Oncology, Taiwan Lung Cancer Society;Financial Interests, Institutional, Principal Investigator, Clinical Trial Funding: Alpha Biopharma, Amgen, AstraZeneca/Medimmune, Boehringer-Ingelheim, Bridge BioTherapeutics, Chong Keun Dang, Daiich-Sankyo, GSK, Hanmi, Janssen, Merus, MIrati Therapeutics, MSD, Novartis, ONO Pharmaceutical, Pfizer, Roche/Genentech, Takeda, TP Therapeuti;Non-Financial Interests, Person l, Advisory Role: Amgen, AstraZeneca, BMS / ONO Pharmaceuticals, Daiich-Sankyo, GSK, Janssen, Pfizer, SK Biopharm, Takeda, Yuhan;Non-Financial Interests, Personal, Member of the Board of Directors: Asian Thoracic Oncology Research Group, Korean Association for Lung Cancer, Korean Cancer Association, Korean Society of Medical Oncology;Other, Personal, Funding, Travel support for advisory board meeting attendance: Amgen, Daiichi-Sankyo. J. Bennouna: Financial Interests, Personal, Other, Honoraria: Bristol Myers Squibb, MSD, AstraZeneca, Roche, Servier, Bayer, AMGEN;Financial Interests, Personal, Advisory Role: Bristol Myers Squibb, MSD, AstraZeneca, Roche;Financial Interests, Institutional, Research Grant: AstraZeneca. T. Lesimple: Financial Interests, Personal, Advisory Role: MSD, Novartis, BMS, Pierre Fabre;Financial Interests, Personal, Speaker’s Bureau: MSD, Novartis;Financial Interests, Institutional, Research Grant: Roche. E. Felip: Financial Interests, Personal, Advisory Board: Amgen;Financial Interests, Personal, Advisory Board: AstraZeneca;Financial Interests, Personal, Advisory Board: BAYER;Financial Interests, Personal, Advisory Board: Beigene;Financial Interests, Personal, Advisory Board: Boehringer-Ingelheim;Financial Interests, Personal, Advisory Board: Bristol-Myers Squibb;Financial Interests, Personal, Advisory Board: Eli Lilly;Financial Interests, Personal, Advisory Board: F. Hoffman-La Roche;Financial Interests, Personal, Advisory Board: Glaxo Smith Kline;Financial Interests, Personal, Advisory Board: Janssen;Financial Interests, Personal, Advisory Board: Medical Trends;Financial Interests, Personal, Advisory Board: Merck Sharp & Dohme;Financial Interests, Personal, Advisory Board: Merck Serono;Financial Interests, Personal, Advisory Board: Peptomyc;Financial Interests, Personal, Advisory Board: Pfizer;Financial Interests, Personal, Advisory Board: Puma;Financial Interests, Personal, Advisory Board: Regeneron;Financial Interests, Personal, Advisory Board: Sanofi;Financial Interests, Personal, Advisory Board: Syneos Health;Financial Interests, Personal, Advisory Board: Takeda;Financial Interests, Personal, Speaker’s Bureau: Amgen;Financial Interests, Personal, Speaker’s Bureau: AstraZeneca;Financial Interests, Personal, Speaker’s Bureau: Bristol-Myers Squibb;Financial Interests, Personal, Speaker’s Bureau: Eli Lilly;Financial Interests, Personal, Speaker’s Bureau: F. Hoffmann-La Roche;Financial Interests, Personal, Speaker’s Bureau: Janssen;Financial Interests, Personal, Speaker’s Bureau: Medscape;Financial Interests, Personal, Speaker’s Bureau: Merck Sharp & Dohme;Financial Interests, Personal, Speaker’s Bureau: Merck Serono;Financial Interests, Personal, Speaker’s Bureau: Peervoice;Financial Interests, Personal, Speaker’s Bureau: Pfizer;Financial Interests, Personal, Speaker’s Bureau: Springer;Financial Interests, Personal, Speaker’s Bureau: Touch Medical;Financial Interests, Personal, Member, Independent Member of the Board: Grifols. D. Berz: Financial Interests, Personal, Other, Honoraria: Oncocyte;Other, Personal, Other, Honoraria: Sun Pharma;Other, Personal, Other, Honoraria: Caris;Other, Personal, Other, Honoraria: Takeda;Other, Personal, Other, Honoraria: Natera;Other, Personal, Other, Honoraria: Jazz Pharma;Other, Personal, Other, Honoraria: Genentech;Financial Interests, Personal, Advisory Role: Oncocyte;Other, Personal, Advisory Role: Sun Pharma;Other, Personal, Advisory Role: Biocept;Other, Personal, Advisory Role: Prelude;Financial Interests, Personal, Speaker’s Bureau: Oncocyte;Other, Personal, Speaker’s Bureau: Caris;Other, Personal, Speaker’s Bureau: Sun Pharma;Other, Personal, Speaker’s Bureau: AstraZeneca;Other, Personal, Speaker’s Bureau: Takeda;Other, Personal, Speaker’s Bureau: Merck;Other, Personal, Speaker’s Bureau: Natera;Other, Personal, Speaker’s Bureau: Jazz Pharma. C. Mascaux: Financial Interests, Personal, Advisory Role: Roche;Financial Interests, Personal, Advisory Role: Astr Zeneca;Financial Interests, Personal, Advisory Role: Kephren;Financial Interests, Personal, Advisory Role: Bristol-Myers Squibb;Financial Interests, Personal, Advisory Role: MSD;Financial Interests, Personal, Advisory Role: Pfizer;Financial Interests, Personal, Other, Honoraria: Roche;Financial Interests, Personal, Other, Honoraria: AstraZeneca;Financial Interests, Personal, Other, Honoraria: Kephren;Financial Interests, Personal, Other, Honoraria: Bristol-Myers Squibb;Financial Interests, Personal, Other, Honoraria: MSD;Financial Interests, Personal, Other, Honoraria: Pfizer;Financial Interests, Personal, Other, travel, accommodations, expenses: Roche;Financial Interests, Personal, Other, travel, accommodations, expenses: AstraZeneca;Financial Interests, Personal, Other, travel, accommodations, expenses: Boehringer Ingelheim;Financial Interests, Personal, Other, travel, accommodations, expenses: Takeda. M. Voskoboynik: Financial Interests, Personal, Advisory Role: AstraZeneca. H.T. Landsteiner: Financial Interests, Personal, Full or part-time Employment: Boehringer Ingelheim. V. Chen: Financial Interests, Personal, Full or part-time Employment: Boehringer Ingelheim. G. Jayadeva: Financial Interests, Personal, Full or part-time Employment: Boehringer Ingelheim. J. Alt: Financial Interests, Personal, Other, Honoraria: AstraZeneca, Boehringer Ingelheim, BMS, Pfizer, Roche, Takeda;Financial Interests, Personal, Advisory Role: AstraZeneca, Boehringer Ingelheim, BMS, Roche;Financial Interests, Personal, Funding, Travel/accommodation/expenses: AstraZeneca, Boehringer Ingelheim, BMS. B. Hackanson: Financial Interests, Personal, Advisory Role: Boehringer Ingelheim, MSD, AstraZeneca, BMS. All other authors have declared no conflicts of interest.

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.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.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; P0.001). 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.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 .).

Item does not contain fulltext 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 x 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/m(2) temozolomide given on days 1-5); or to receive radiotherapy with concurrent temozolomide 75 mg/m(2) 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

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.).

This study investigated the efficacy and safety of pimasertib (MEK1/MEK2 inhibitor) versus dacarbazine (DTIC) in patients with untreated NRAS-mutated melanoma. Phase II, multicenter, open-label trial. Patients with unresectable, stage IIIc/IVM1 NRAS-mutated cutaneous melanoma were randomized 2:1 to pimasertib (60 mg, oral twice-daily) or DTIC (1000 mg/m2, intravenously) on Day 1 of each 21-day cycle. Patients progressing on DTIC could crossover to pimasertib. Primary endpoint: investigator-assessed progression-free survival (PFS), secondary endpoints: overall survival (OS), objective response rate (ORR), quality of life (QoL), and safety. Overall, 194 patients were randomized (pimasertib n = 130, DTIC n = 64), and 191 received treatment (pimasertib n = 130, DTIC n = 61). PFS was significantly improved with pimasertib versus DTIC (median 13 versus 7 weeks, respectively, hazard ratio (HR) 0.59, 95% confidence interval (CI) 0.42&ndash, 0.83, p = 0.0022). ORR was improved with pimasertib (odds ratio 2.24, 95% CI 1.00&ndash, 4.98, p = 0.0453). OS was similar between treatments (median 9 versus 11 months, respectively, HR 0.89, 95% CI 0.61&ndash, 1.30), 64% of patients receiving DTIC crossed over to pimasertib. Serious adverse events (AEs) were more frequent for pimasertib (57%) than DTIC (20%). The most common treatment-emergent AEs were diarrhea (82%) and blood creatine phosphokinase (CPK) increase (68%) for pimasertib, and nausea (41%) and fatigue (38%) for DTIC. Most frequent grade &ge, 3 AEs were CPK increase (34%) for pimasertib and neutropenia (15%) for DTIC. Mean QoL scores (baseline and last assessment) were similar between treatments. Pimasertib has activity in NRAS-mutated cutaneous melanoma and a safety profile consistent with known toxicities of MEK inhibitors. Trial registration: ClinicalTrials.gov, NCT01693068

International audience; 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 followup period was 21.7 months. AUC were 1.0 (CI 95% 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% (CI 95% 40-100%) and specificities of 100% (CI 95% 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.

Objective Immune checkpoint inhibitors (ICIs) for cancer therapy frequently induce immune-related adverse effects (IRAEs). Therefore, most patients with preexisting autoimmune diseases have been excluded from clinical trials of ICIs. This study was undertaken to evaluate the safety and efficacy of ICIs in patients with preexisting autoimmune disease and cancer. Methods A retrospective cohort study was conducted from January 2017 to January 2018 via 3 French national networks of experts in oncology and autoimmunity. Adults with preexisting autoimmune disease who were receiving ICIs were assessed for the occurrence of flare of preexisting autoimmune disease, other IRAEs, and cancer response. Results The study included 112 patients who were followed up for a median of 8 months. The most frequent preexisting autoimmune diseases were psoriasis (n = 31), rheumatoid arthritis (n = 20), and inflammatory bowel disease (n = 14). Twenty-four patients (22%) were receiving immunosuppressive therapy at ICI initiation. Autoimmune disease flare and/or other IRAE(s) occurred in 79 patients (71%), including flare of preexisting autoimmune disease in 53 patients (47%) and/or other IRAE(s) in 47 patients (42%), with a need for immunosuppressive therapy in 48 patients (43%) and permanent discontinuation of ICI in 24 patients (21%). The median progression-free survival was shorter in patients receiving immunosuppressive therapy at ICI initiation (3.8 months versus 12 months; P = 0.006), confirmed by multivariable analysis. The median progression-free survival was shorter in patients who experienced a flare of preexisting autoimmune disease or other IRAE, with a trend toward better survival in the subgroup without immunosuppressant use or ICI discontinuation. Conclusion Our findings indicate that flares or IRAEs occur frequently but are mostly manageable without ICI discontinuation in patients with a preexisting autoimmune disease. Immunosuppressive therapy at baseline is associated with poorer outcomes.

Korrespondenz zu 10.1200/JCO.18.01768 (Hess) und 10.1200/JCO.18.02075 (Hindié)

International audience; The prognosis of advanced melanoma has been greatly improved by new therapeutic agents and clinicians rely on dynamic signals to drive their therapeutic choices. Although the kinetics of metastatic disease seem to be correlated with survival, progression of the localized disease is not predictable.Objective: To assess whether progression of metastatic disease is associated with the time to the first distant recurrence of melanoma.Design, Setting, and Participants: This study was conducted from March 1, 2013, to September 1, 2017, among 638 adults with unresectable stage III or IV melanoma within the French multicentric prospective cohort MelBase. Patients treated with first-line immunotherapies, targeted therapies, or chemotherapy were included. Patients with unknown primary or de novo metastatic melanoma were not included. Data were analyzed from March 1, 2013, to December 1, 2017.Main Outcomes and Measures: The date of primary excision and time to first distant recurrence, progression-free survival, and overall survival were collected. Cox proportional hazards regression models were planned to assess the association between time to first distant recurrence and progression-free survival or overall survival, which was evaluated in terms of hazard ratio (HR). Time to recurrence was analyzed both as a continuous and categorical variable (24 months).Results: A total of 638 patients (272 women and 366 men; median age, 64 years [interquartile range, 52-73 years]) were included in the study. The median time from primary excision to first distant recurrence was 25 months (interquartile range, 12-55 months). There was no evidence of association of the time to recurrence with progression-free survival, both when analyzed as a continuous variable (HR, 0.99; 95% CI, 0.99-1.01) or after categorization (12-24 months: HR, 0.75; 95% CI, 0.56-1.02; >24 months: HR, 0.62; 95% CI; 0.47-1.01). There was no evidence of association of the time to recurrence with overall survival, both when analyzed as a continuous variable (HR, 0.99; 95% CI, 0.98-1.02) or after categorization (12-24 months: HR, 0.76; 95% CI, 0.54-1.07; >24 months: HR, 0.61; 95% CI, 0.54-1.03). Those results remained nonsignificant after stratification by treatment.Conclusions and Relevance: In the MelBase cohort, time to recurrence of metastatic melanoma appears not to be associated with progression-free survival or overall survival.

International audience; Background: Melanoma brain metastases (MBMs) are historically associated with poor prognosis. Radiation therapy is conventionally associated with a high local control rate. Development of targeted therapy and immunotherapy has improved overall survival (OS) and intracranial response rate, but about 50% of patients failed to respond to these novel therapies. The objective of this study was to assess the impact of combined radiotherapy (cRT) on overall survival in a large multicenter real-life prospective cohort of patients with MBM treated with immunotherapy or targeted therapy.Patients and methods: Clinical data from 262 patients with MBM were collected via MelBase, a French multicentric biobank prospectively enrolling unresectable stage III or IV melanoma. Two groups were defined: patients receiving cRT (cRT group) or not receiving cRT (no-cRT group). Primary end-point was OS. Propensity score weighting was used to correct for indication bias.Results: Among the 262 patients, 93 (35%) received cRT (cRT group). The patients were treated with immunotherapy in 69% and 60% and with targeted therapy in 31% and 40% of the cRT and no-cRT groups, respectively. With a median follow-up of 6.9 months, median OS was 16.8 months and 6.9 months in the cRT and no-cRT groups, respectively. After propensity score weighting, cRT was associated with longer OS (hazard ratio = 0.6, 95% confidence interval: 0.4-0.8; p=0.007). Median OS after ponderation was 15.3 months and 6.2 months in the cRT and no-cRT groups, respectively.Conclusion: This study shows that cRT may be associated with a significant decrease of 40% in the risk of death in patients with MBM treated with systemic therapy.

2579 Background: In preclinical studies, the combination of anti-VEGF/Ang2 and anti-PD-1 therapy has been shown to promote an immunopermissive state, which is supportive of T-cell-mediated tumor cell destruction. BI 836880 is a humanized bispecific nanobody that targets VEGF and Ang2, and ezabenlimab (BI 754091) is an anti-PD-1 antibody. Phase I studies investigating each as monotherapies have reported safety and preliminary antitumor activity. This ongoing Phase Ib study is evaluating the combination of BI 836880 and ezabenlimab in pts with advanced solid tumors. In Part 1 (dose escalation), the combination was feasible in pts with advanced NSCLC, with a recommended Phase II dose (RP2D) of BI 836880 720 mg + ezabenlimab 240 mg IV q3w. Here, we report updated results from Part 2 (expansion phase), which is assessing the antitumor activity and safety of the RP2D. Methods: Seven cohorts are currently recruiting pts in Part 2: metastatic (m) NSCLC after checkpoint inhibitor (CPI) monotherapy (Cohort A); mNSCLC after chemotherapy (CT) + CPI (Cohort B); mSCLC after CT ± CPI (Cohort C); 1st and 2nd recurrences of glioblastoma (GBM; Cohort D); immunotherapy-resistant m-melanoma (Cohort E); hepatocellular carcinoma (HCC) after prior sorafenib or lenvatinib ± CPI (Cohort F); and previously untreated/unresectable HCC (Cohort G). Primary endpoint is objective response rate (complete response + partial response [PR]). Results: As of January 2021, 196 pts have received BI 836880 plus ezabenlimab (14 in Part 1, 182 in Part 2 [Cohort A, 26; B, 30; C, 19; D, 31; E, 32; F, 28; G, 16]). 134 (68%) pts were male, median age was 63 years and 102 (52%) had prior CPI use. Any grade and ≥G3 adverse events (AEs; any cause) were reported by 160 (82%) and 62 (32%) pts, most commonly (all%/≥G3%) hypertension (20/8), asthenia (20/3), diarrhea, decreased appetite, and nausea (all 11/1). 95 (48%) pts had a drug-related AE, most commonly hypertension and asthenia (both 11%). 6 pts had a G4 AE (non-related: hyperkalemia + cardiac arrest, laryngospasm, gastrointestinal perforation; drug-related: anaphylactic reaction, acute pancreatitis, transaminases increased); 8 pts had a G5 AE (non-related: general physical health deterioration, epilepsy, hemoptysis, cardio-respiratory arrest, hepatic failure, intracranial hemorrhage, COVID-19 pneumonia; drug-related tracheal hemorrhage). 30 (15%) pts had immune-related AEs (3% ≥G3), including hypothyroidism (3%). 11 (6%) pts had an AE leading to discontinuation. Overall, 145 pts were evaluable for response: 9 pts achieved confirmed PR (2 pts in Part 1 and 7 in Part 2 [NSCLC, n = 3; SCLC, n = 1; GBM, n = 1; melanoma, n = 1; and 2nd-line HCC, n = 1]), 87 pts had stable disease and 49 pts had progressive disease. 111 pts remain on treatment. Conclusions: BI 836880 plus ezabenlimab had a manageable safety profile. The combination showed preliminary antitumor activity in a range of tumor types. Clinical trial information: NCT03468426.

Immune checkpoint inhibitors and targeted therapies have profoundly altered the management of several cancers over the past decade. Metastatic melanoma has been at the forefront of these changes. We provide here a nationwide overview and an assessment of changes in survival in France. We included 10,936 patients receiving a systemic treatment for metastatic cutaneous melanoma between 2010 and 2017 using the French National Health Insurance database (Système National des Données de Santé). Over the study period, there was a doubling of the number of new patients receiving a systemic treatment. Cytotoxic chemotherapy was progressively replaced by targeted therapy and immune checkpoint inhibitors. Patients having initiated a first-line treatment since June 2015 gained 46% overall survival compared with those initiating treatment before 2012. Overall survival at 24 months rose from 21% to 44%. We provide real-world evidence for the improvement of overall survival in the past decade among patients with metastatic melanoma. Although the characteristics of the patients treated can vary across periods, this type of exhaustive real-world data provides evidence from broader populations than those included in clinical trials.

Background Sentinel lymph-node (LN) biopsy (SLNB) is a valuable tool to assess the regional LN status in Merkel cell carcinoma (MCC). However, its prognostic value is still debated. This study was undertaken to assess SLNB usefulness for MCC management and to determine the impact of SLNB status on disease-free survival (DFS) and overall survival (OS) by comparing SLNB-positive versus -negative patients according to demographic, clinical and treatment characteristics. Patients and methods In this retrospective, multicenter observational study, SLNB was proposed to all patients referred for clinically N0 MCC. Treatment schedule consisted of wide-margin surgical resection of primary MCC followed by adjuvant radiation therapy (aRT) to the primary site and, for SLNB-positive patients, radical LN dissection followed by regional aRT. Univariate and multivariate analyses determined factors associated with DFS and OS. Results Among 87 patients with successful SLNB, 21 (24.1%) were SLNB-positive. Median follow-up for the entire series was 39 months; respective 3-year DFS and OS rates were 73% and 81.4%, respectively. Univariate analysis (all patients) identified SLNB-negativity as being associated with prolonged OS (P = 0.013) and aRT (all sites considered) was associated with longer DFS (P = 0.004) and OS (P = 0.018). Multivariate analysis (all patients) retained SLNB status and aRT (all sites considered) as being associated with improved DFS (P = 0.014 and 0.0008) and OS (P = 0.0020 and 0.0019). Moreover, for SLNB-negative patients, tumor-bed irradiation was also significantly associated with prolonged DFS (P = 0.006) and OS (P = 0.014). Conclusion(s) The present study demonstrates that SLNB-negativity is a strong predictor of longer DFS and OS in stage I and II MCC patients. The similar benefit for aRT on tumor bed observed in this study has to be confirmed by a prospective study. The results advocate for SLNB being considered to all MCC patients.

10031 Background: Obesity is an established risk factor for several cancers and higher body mass index (BMI) is associated with poor prognosis. These data are still debated in melanoma. Furthermore, recently the concept of “obesity paradox” has emerged. In a large cohort published by McQuade JL et al, higher BMI was associated with better survival in patients with metastatic melanoma (MM) especially for those treated with targeted therapy (TT) and immune checkpoint inhibitors (ICI). We studied the association between BMI and progression-free survival (PFS) and overall survival (OS) in patients with MM treated with systemic therapies. Methods: This study was conducted from the prospective MelBase cohort (NCT02828202). Patients with MM treated with first-line ICI, TT, or CT were included. BMI was categorized by WHO criteria. Underweight patients were excluded. The co-primary outcomes were the associations between BMI and PFS or OS, stratified by treatment, sex and age. Multivariate analyses were performed. Results: A total of 1214 patients were analyzed. The majority of them were treated with ICI, followed by TT. Obese patients represented 22% of cohort (Table). Median follow-up was 13.5 months. The patients who were overweight or obese did not have different PFS (p = 0.88) or OS (p = 0.25) than patients with normal BMI. Stratifying this cohort by treatment received, age, sex and others parameters (such as LDH, number of metastatic site) did not revealed any difference. Multivariate analysis did not change the results. Conclusions: BMI was not associated with clinical outcomes in our cohort, especially in ICI and TT groups. Thus, we did not confirm the results presented by McQuade Jl et al. with a cohort quite similar in term of size. Because BMI is too simplistic and then an imperfect measure of body composition, the published data are not reproducible. We caution the oncologists, about BMI as valuable predictive marker of survival for melanoma patients. [Table: see text]

Purpose Dabrafenib plus trametinib improved relapse-free survival (RFS) versus placebo (hazard ratio [HR], 0.47; P < .001) in patients with resected BRAF V600–mutant stage III melanoma (BRF115532; COMBI-AD; ClinicalTrials.gov identifier: NCT01682083). We present an updated RFS analysis on the basis of extended study follow-up and a cure-rate model analysis to estimate the fraction of patients expected to remain relapse free long term. Methods In this phase III trial, patients with resected BRAF V600–mutant stage III melanoma were randomly assigned to 12 months of adjuvant dabrafenib plus trametinib versus placebo. We report updated RFS (primary end point) and distant metastasis–free survival. RFS was also analyzed by subgroups defined by baseline disease stage (American Joint Committee on Cancer 7th and 8th editions), nodal metastatic burden, and ulceration status. The fraction of patients who remained relapse free long term was estimated using a Weibull mixture cure-rate model. Results At median follow-up of 44 months (dabrafenib plus trametinib) and 42 months (placebo), 3- and 4-year RFS rates were 59% (95% CI, 55% to 64%) and 54% (95% CI, 49% to 59%) in the dabrafenib plus trametinib arm and 40% (95% CI, 35% to 45%) and 38% (95% CI, 34% to 44%) in the placebo arm, respectively (HR, 0.49; 95% CI, 0.40 to 0.59). Distant metastasis–free survival also favored dabrafenib plus trametinib (HR, 0.53; 95% CI, 0.42 to 0.67). The estimated cure rate was 54% (95% CI, 49% to 59%) in the dabrafenib plus trametinib arm compared with 37% (95% CI, 32% to 42%) in the placebo arm. Subgroup analysis of RFS demonstrated similar treatment benefit regardless of baseline factors, including disease stage, nodal metastatic burden, and ulceration. Conclusion Longer follow-up confirmed RFS benefit with dabrafenib plus trametinib. Subgroup analysis suggested that dabrafenib plus trametinib benefited patients regardless of baseline factors.

International audience; Purpose Since 2011, significant progress was observed in metastatic melanoma (MM), with the commercialisation of seven immunotherapies or targeted therapies, which showed significant improvement in survival. In France, in 2004, the cost of MM was estimated at €1634 per patient; this cost has not been re-estimated since. This study provided an update on survival and cost in real-life clinical practice. Methods Clinical and economic data (treatments, hospitalisations, radiotherapy sessions, visits, imaging and biological exams) were extracted from the prospective MelBase cohort, collecting individual data in 955 patients in 26 hospitals, from diagnosis of metastatic disease until death. Survival was estimated by the Kaplan-Meier method. Costs were calculated from the health insurance perspective using French tariffs. For live patients, survival and costs were extrapolated using a multistate model, describing the 5-year course of the disease according to patient prognostic factors and number of treatment lines. Results Since the availability of new drugs, the mean survival time of MM patients has increased to 23.6 months (95%confidence interval [CI] :21.2;26.6), with 58% of patients receiving a second line of treatment. Mean management costs increased to €269,682 (95%CI:244,196;304,916) per patient. Drugs accounted for 80% of the total cost. Conclusion This study is the first that evaluated the impact of immunotherapies and targeted therapies both on survival and cost in real-life conditions. Alongside the introduction of breakthrough therapies in the first and subsequent lines, MM has been associated with a significant increase in survival but also in costs, raising the question of financial sustainability.

Background Thirty to 60% of stage unresectable AJCC III and IV melanoma patients (pts) develop brain metastases (BM). This population has been excluded from most clinical trials. Using a large prospective trial including pts with advanced BRAFV600-mutant melanoma and allowing for BM, we assessed in the BM population factors associated with disease progression and stratified the population into risk groups using regression tree analysis (RTA). Methods This phase IIIb single arm, open label, multicenter, non randomized French study included pts with unresectable stage IIIc or IV BRAFV600-mutant melanoma. Selection criteria allowed for BM, ECOG ≤2, previous advanced melanoma treatments. Pts received dabrafenib (D) + trametinib (T) until progression. Progression-free survival (PFS) was estimated using the Kaplan Meier analysis and modeled with a multivariate Cox regression model. Risk subgroups were identified using an exponential RTA. Significance was set at p Results Between March 2015 and November 2016, 856 pts were included and 275 (32%) had BM. Median PFS was 5.68 months (95% CI, 5.29-6.87) in the BM population. Significant independent factors associated with lower PFS were ECOG ≥1, elevated serum LDH, ≥3 metastatic sites, and non naive status (Table). Pts with ECOG 0, Table: 1332P . Multivariate Cox proportional hazards analysis of PFS by prognostic factors N (%) HR 95% CI p value LDH at baseline * 115 (41.8) 1 (=reference) - - [1 - 2[ ULN 50 (18.2) 1.30 [0.83 - 2.04] 0.2473 ≥2 ULN 21 (7.6) 2.50 [1.37 - 4.58] 0.0030 Missing 89 (32.4) 1.44 [0.99 - 2.10] 0.0571 ECOG PS * O 144 (52.4) 1 (=reference) - - 1 91 (33.1) 1.36 [0.94 - 1.96] 0.0995 ≥2 40 (14.6) 2.17 [1.37 - 3.44] 0.0010 Metastatic sites * 84 (30.6) 1 (=reference) - - ≥3 191 (69.5) 1.58 [1.10 - 2.28] 0.0142 Status Naive 121 (44.0) 1 (=reference) - - Non naive 154 (56.0) 1.60 [1.14 - 2.25] 0.0061 * Factors included in the RTA. Conclusions To our knowledge, this is the first analysis from the largest prospective study in BRAF-mutated melanoma pts with BM. The study was carried out in difficult-to-treat pts and in conditions that were close to the real-world setting. ECOG >1, ≥3 metastatic sites and elevated LDH were associated with shorter PFS, a finding previously demonstrated only in pts without BM. Regression trees will be presented. Editorial acknowledgement Jone Iriondo-Alberdi (PhD) from ITEC Services. Legal entity responsible for the study Novartis Pharma S.A.S. (France). Funding Novartis Pharma S.A.S. (France). Disclosure C. Dutriaux: Honoraria (self), Advisory / Consultancy: Novartis. C. Robert: Advisory / Consultancy: Roche; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Merck Sharp & Dohme ; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Novartis; Advisory / Consultancy: Amgen; Advisory / Consultancy, Participation to Boards and Steering Committees: Pierre Fabre. J.J. Grob: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Merck Sharp & Dohme ; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: Merck; Honoraria (self), Advisory / Consultancy: Pierre Fabre; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Incyte. L. Mortier: Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: GSK/Novartis; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: Leo; Honoraria (self): Sanofi; Honoraria (self): Novartis; Honoraria (self): Pierre Fabre; Honoraria (self): Merck Serono. C. Lebbe: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Honoraria (self), Travel / Accommodation / Expenses: Merck Sharp & Dohme ; Honoraria (self): Roche; Honoraria (self): Novartis; Honoraria (self): Amgen; Honoraria (self): Merck; Honoraria (self): Pierre Fabre; Honoraria (self): Pfizer; Honoraria (self): Incyte. S. Mansard: Advisory / Consultancy: Novartis. F. Grange: Advisory / Consultancy: Novartis. E. Neidhardt: Honoraria (self): BMS. T. Lesimple: Advisory / Consultancy: Novartis; Advisory / Consultancy: MSD; Advisory / Consultancy: Incyte; Advisory / Consultancy: Pierre Fabre; Research grant / Funding (self): Roche. C. Bedane: Advisory / Consultancy: Novartis. S. Dalac-Rat: Advisory / Consultancy: Novartis; Advisory / Consultancy: Roche; Advisory / Consultancy: BMS; Advisory / Consultancy: Pierre Fabre. C. Nardin: Advisory / Consultancy: Novartis; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Merck Sharp & Dohme . A. Szenik: Full / Part-time employment: Novartis. A. Denden: Full / Part-time employment: Novartis. P. Saiag: Travel / Accommodation / Expenses: Amgen; Travel / Accommodation / Expenses, Non-remunerated activity/ies: Bristol-Myers Squibb; Travel / Accommodation / Expenses, Non-remunerated activity/ies: Merck Sharp & Dohme ; Travel / Accommodation / Expenses: Merck Serono; Travel / Accommodation / Expenses: Pfizer; Research grant / Funding (self), Travel / Accommodation / Expenses, Non-remunerated activity/ies: Roche-Genentech; Travel / Accommodation / Expenses: Pierre Fabre; Travel / Accommodation / Expenses: Novartis. All other authors have declared no conflicts of interest.

Preclinical and interim results from a clinical pharmacology study in patients with cancer indicated that enzastaurin might have the potential to prolong the QT. Rather than undertake a formal thorough QT study, the effect of enzastaurin on the QT was assessed by combining the QT corrected for heart rate (QTc) intervals from 3 clinical pharmacology studies totaling 85 patients with cancer receiving multiple therapeutic or supratherapeutic doses of enzastaurin. Neither a placebo nor an active control was used. Serial, replicate, time-matched electrocardiograms were collected during a no-drug baseline day and when enzastaurin and its major active metabolite, LSN326020, had achieved steady state. Plasma concentrations of enzastaurin and LSN326020 were determined at each electrocardiogram point to enable concentration-QT analyses. The cross-study analysis showed that enzastaurin resulted in a statistically significant prolongation of the QTc at therapeutic and supratherapeutic doses. At an enzastaurin maximum plasma concentration (Cmax ) of 3660 nmol/L, the predicted QTc using Fridericia's formula (QTcF) interval and its 90% confidence interval was 17.72 milliseconds (16.52-18.92 milliseconds). Likewise, at an LSN326020 Cmax value of 1718 nmol/L, the predicted QTcF interval was 20.23 milliseconds (18.72-21.74 milliseconds). The concentration-QTcF slopes for enzastaurin and LSN326020 were positive and statistically significantly different from zero (all P < .05).

OBJECTIVEThe goal of this study was to provide insight into the influence of gliomas on gestational outcomes, the impact of pregnancy on gliomas, and the identification of patients at risk.METHODSIn this multiinstitutional retrospective study, the authors identified 52 pregnancies in 50 women diagnosed with a glioma.RESULTSFor gliomas known prior to pregnancy (n = 24), we found the following: 1) An increase in the quantified imaging growth rates occurred during pregnancy in 87% of cases. 2) Clinical deterioration occurred in 38% of cases, with seizures alone resolving after delivery in 57.2% of cases. 3) Oncological treatments were immediately performed after delivery in 25% of cases. For gliomas diagnosed during pregnancy (n = 28), we demonstrated the following: 1) The tumor was discovered during the second and third trimesters in 29% and 54% of cases, respectively, with seizures being the presenting symptom in 68% of cases. 2) The quantified imaging growth rates did not significantly decrease after delivery and before oncological treatment. 3) Clinical deterioration resolved after delivery in 21.4% of cases. 4) Oncological treatments were immediately performed after delivery in 70% of cases. Gliomas with a high grade of malignancy, negative immunoexpression of alpha-internexin, or positive immunoexpression for p53 were more likely to be associated with tumor progression during pregnancy. Deliveries were all uneventful (cesarean section in 54.5% of cases and vaginal delivery in 45.5%), and the infants were developmentally normal.CONCLUSIONSWhen a woman harboring a glioma envisions a pregnancy, or when a glioma is discovered in a pregnant patient, the authors suggest informing her and her partner that pregnancy may impact the evolution of the glioma clinically and radiologically. They strongly advise a multidisciplinary approach to management.■ CLASSIFICATION OF EVIDENCE Type of question: association; study design: case series; evidence: Class IV.

Background: The objective was to assess the response rate and survival of patients with metastatic mucosal melanoma (MM) and uveal melanoma (UM) treated with anti-CTLA-4 or anti-PD-1 monoclonal antibodies (mAbs).Methods: A multicenter retrospective study was performed in 25 dermatology departments in France. All patients with stage III-C to IV MM or UM who were treated with anti-CTLA-4 or anti-PD-1 mAbs between 2008 and 2016 were included and compared after adjustment for main prognostic factors with a second cohort of patients treated with chemotherapy. Tumor response was evaluated according to RECIST v. 1.1 criteria at Week 12.Results: Four-hundred-and-thirty-nine patients were included, 229 MM (151 immunotherapy, 78 chemotherapy) and 210 UM (100 immunotherapy, 110 chemotherapy). Response rates of MM patients treated with immunotherapy were 18/151 (11.9%; 95% CI:7.2%-18.2%), versus 11/78 (14.1%, 95% CI:7.3%-23.8%) in patients treated with chemotherapy (p=0.87). No tumor response was observed in UM patients treated with immunotherapy, versus 4/110 responses (3.6%, 95% CI:1.0-9.0%) in patients treated with chemotherapy (p=0.15). The adjusted overall survival (OS) of MM patients treated with immunotherapy was longer than that of patients treated with chemotherapy HR=0.62 (95% CI: 0.43-0.91), p=0.014, with an unadjusted median OS of 15.97 months [interquartile range (IQR)=6.89-27.11] and 8.82 months [IQR=5.02-14.92], respectively. The adjusted OS of UM patients treated with immunotherapy was not significantly different from that of patients treated with chemotherapy (HR=0.98, 95% CI: 0.66-1.44) p=0.92, with an unadjusted median OS of 13.38 months [IQR=6.03-29.57] and 11.02 months [IQR=6.13-23.93], respectively.Conclusion: Immunotherapy significantly improves OS for MM. The prognosis of metastatic UM remains poor., Immunotherapy significantly improves OS for MM. The prognosis of metastatic UM remains poor.

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. Cancer 2015;121:1654–1661. © 2015 American Cancer Society.

Background It has been shown that androgens are immunosuppressive. Androgen deprivation with GnRH agonists regenerates the thymus and its functions in adults, leading to increase in blood and lymphoid organ lymphocytes, in naive lymphocytes with expansion of TCR Vbeta repertoire, and in Tumour Infiltrating Lymphocytes (TILs) in prostate tumours. This phase I study evaluated the safety of triptorelin in combination with nivolumab, as well as its potential to reverse resistance to PD-1 inhibitors in male melanoma patients. Methods Treatment consisted of triptorelin 3.75 mg i.m. every 4 weeks and nivolumab 3 mg/kg i.v. every 2 weeks. Bicalutamide 50 mg p.o. QD was added for the first 28 days. Evaluation of response was performed after 3 months. Triptorelin PK was assessed and various PDy markers were measured in blood and tumour samples. Planned treatment duration was 48 weeks. Results Fourteen male patients were included, of whom 11 were white and 3 were black, with mean age 65 years (range 45-82). At screening 4 were locally advanced while 10 had distant metastases (2 with M1a, 1 with M1b, 6 with M1c and 1 with M1d). Ten patients had cutaneous melanoma, 2 patients had mucosal melanoma, and 2 had an unknown primary. Safety: No grade 4 AEs were reported. Five grade 3 AEs were reported in 4 patients, of which one (abdominal pain) was attributed to triptorelin and resolved after 39 days (causing no treatment interruption as it started on the day treatment was discontinued due to progression), and one (neutropenia) was considered related to nivolumab and resolved following treatment interruption for 14 days. Efficacy: BOR (RECIST 1.1) was assessed as 2 PR, 5 SD, and 7 PD. The two patients with PR showed reductions from baseline in Target Lesions of 76% (one pancreas metastasis) and32% (two inguinal lymph nodes), following an initial pseudoprogression. Conclusion The association of triptorelin to nivolumab was well tolerated and yielded partial response in two patients. Legal entity responsible for the study Debiopharm International S.A. Funding Debiopharm International S.A. Disclosure C. Robert: Advisory / Consultancy: Novartis, Bristol-Myers Squibb, MSD, Roche, Sanofi, Amgen, Pierre Fabre. F.J. Lejeune: Honoraria (self): Debiopharm International SA. C. Lebbe: Honoraria (self): Roche, Bristol-Myers Squibb, Novartis, MSD, Amgen, Pierre Fabre, Pfizer, Incyte; Advisory / Consultancy: Roche, Bristol-Myers Squibb, Novartis, MSD, Amgen; Travel / Accommodation / Expenses: Bristol-Myers Squibb, MSD; Speaker Bureau / Expert testimony: Roche, Bristol-Myers Squibb, Novartis ,Amgen; Advisory / Consultancy: Aventis. T. Lesimple: Research grant / Funding (self): Roche; Advisory / Consultancy: MSD, Novartis, Pierre Fabre. E. Lundstrom: Full / Part-time employment: Debiopharm International SA. V. Nicolas: Full / Part-time employment: Debiopharm International SA. B. Gavillet: Full / Part-time employment: Debiopharm International SA. V. Gregoire: Full / Part-time employment: Debiopharm International SA. P. Crompton: Full / Part-time employment: Debiopharm International SA.

Background Uveal melanomas (UM) are BRAF-wild type tumors associated with dismal prognosis for which no systemic therapy is active. We report our experience with immune checkpoint inhibitors (ICI) in metastatic UM patients. Methods Ambispective cohort of metastatic UM patients treated with ICI in eight French centers. Response rate, progression-free survival (PFS) and overall survival were retrieved. Results 206 evaluable patients started their first ICI treatment between December 2012 and January 2019. The population consisted of 98 men and 108 women. Median age was 57.5 yo (19; 82). Seventy-four patients had been enucleated, 131 had received proton beam therapy, one had received brachytherapy. The median time to first metastasis was 29.4 months (0-380.4). ICI were first prescribed in first-line in 68 patients, in second-line in 79 patients, in third-line or more in 80 patients. One hundred forty-four patients received pembrolizumab (63%), 58 nivolumab (25%) and 21 ipilimumab (9%). Metastatic sites at initiation of ICI were liver, lung, skin, and bone for 201, three, one and one patients, respectively. Liver was the sole metastatic site in 201 patients. Patients received a median number of four ICI infusions (1-60+). Treatment was suspended because of immune side effects in 21 patients. Nine objective responses were observed (four complete and five partial responses; 4.4%) including one patient with a hypermutated, MBD4-deficient tumor. Fifty-seven patients showed stable disease as best response (27.7%). Median PFS in the whole cohort was 4.1 months (0; 30.4) in 1st line, 4.9 months (0; 42,6) in 2nd line and 3.1 (1; 17.,3) months in 3rd line. Median PFS was 4.1 months in the ICI-resistant population and 27.4 months in the ICI-sensitive population (log-rank p-test Conclusions ICI are associated with a low response rate in UM but with longer PFS and a trend for longer overall survival in ICI-sensitive tumors. Immunotherapies should be investigated in this disease. ICI-sensitive cases are currently being explored to identify biomarkers of response. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

Background BRAF and MEK inhibitors dabrafenib (D) and trametinib (T) have transformed BRAFV600-mutant melanoma patients’ (pts) treatment. In a large prospective trial of pts treated with combination D+T, which also included pts with brain metastasis (BM), we assessed factors associated with progression and stratified the population into risk groups using regression tree analysis (RTA). Methods This phase IIIb single arm, open label, multicenter, French study included in 40 centers pts with histologically confirmed unresectable stage IIIc or IV BRAFV600-mutant melanoma. Selection criteria allowed presence of BM, ECOG ≤2, previous advanced melanoma treatments (except BRAFi+MEKi combination). Progression-free survival (PFS) was estimated using the Kaplan Meier analysis and modeled with multivariate Cox regression model. Risk subgroups were identified using an exponential RTA. Significance was set at p Results Between March 2015 and November 2016, 914 pts were screened and 856 received at least 1 dose of D+T. Overall, 92% of pts had AJCC stage IV melanoma, 38% ECOG ≥1 and 32% BM. Among the 587 pts with known LDH at baseline, 38% had >ULN. Median PFS was 8.02 months (95%CI, 7.33-8.77). Significant independent factors associated with lower PFS were ECOG ≥1, elevated serum LDH, ≥3 metastatic sites, and presence of BM (Table). Pts with Table . 1338P Multivariate Cox proportional hazards analysis of PFS by prognostic factors - All Subjects Treated Population (N = 856) N (%) HR 95% CI p value LDH at baseline * 366 (42.8) 1 (=reference) - - [1 - 2[ ULN 160 (18.7) 1.64 [1.26 - 2.14] 0.0003 ≥2 ULN 61 (7.1) 2.45 [1.70 - 3.53] Missing 269 (31.4) 1.34 [1.05 - 1.71] 0.0167 ECOG * 0 531 (62.0) 1 (=reference) - - 1 242 (28.3) 1.49 [1.19 - 1.87] 0.0005 ≥2 83 (9.7) 2.32 [1.69 - 3.19] Metastatic sites * 344 (40.2) 1 (=reference) - - ≥3 445 (52.0) 1.61 [1.28 - 2.02] Missing 67 (7.8) 1.05 [0.63 - 1.74] 0.8494 Presence of brain metastasis * No 579 (67.6) 1 (=reference) - - Yes 275 (32.1) 1.38 [1.11 - 1.71] 0.0043 Missing 2 (0.23) - - - * Factors included in the RTA. Conclusions This is to date the largest prospective study in advanced BRAFV600-mutant melanoma pts treated with D+T. The study was carried out in conditions close to the real-world. We confirm findings of registration trials that LDH, ECOG and ≥3 metastatic sites are associated with shorter PFS, but the real-world setting introduces BM as a major prognostic factor. Editorial acknowledgement Jone Iriondo-Alberdi (PhD) from ITEC Services. Legal entity responsible for the study Novartis Pharma S.A.S. (France). Funding Novartis Pharma S.A.S. (France). Disclosure P. Saiag: Travel / Accommodation / Expenses: Amgen; Travel / Accommodation / Expenses, Non-remunerated activity/ies: Bristol-Myers Squibb; Travel / Accommodation / Expenses, Non-remunerated activity/ies: Merck Sharp & Dohme ; Travel / Accommodation / Expenses: Merck Serono; Travel / Accommodation / Expenses: Pfizer; Research grant / Funding (self), Travel / Accommodation / Expenses, Non-remunerated activity/ies: Roche-Genentech; Travel / Accommodation / Expenses: Pierre Fabre; Travel / Accommodation / Expenses, Non-remunerated activity/ies: Novartis. C. Robert: Advisory / Consultancy: Roche; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Merck Sharp & Dohme ; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Novartis; Advisory / Consultancy: Amgen; Advisory / Consultancy, Participation to Boards and Steering Committees: Pierre Fabre. J.J. Grob: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Merck Sharp & Dohme ; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: Merck; Honoraria (self), Advisory / Consultancy: Pierre Fabre; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Incyte. L. Mortier: Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: GSK/Novartis; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: Leo; Honoraria (self): Merck Serono; Honoraria (self): Sanofi; Honoraria (self): Pierre Fabre; Honoraria (self): Novartis. C. Lebbe: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Honoraria (self), Travel / Accommodation / Expenses: Merck Sharp & Dohme ; Honoraria (self): Roche; Honoraria (self): Novartis; Honoraria (self): Amgen; Honoraria (self): Merck; Honoraria (self): Pierre Fabre; Honoraria (self): Pfizer; Honoraria (self): Incyte. S. Mansard: Advisory / Consultancy: Novartis. F. Grange: Advisory / Consultancy: Novartis. E. Neidhardt: Travel / Accommodation / Expenses: BMS. T. Lesimple: Advisory / Consultancy: Novartis; Advisory / Consultancy: MSD; Advisory / Consultancy: Incyte; Advisory / Consultancy: Pierre Fabre; Research grant / Funding (self): Roche. C. Bedane: Advisory / Consultancy: Novartis. S. Dalac-Rat: Advisory / Consultancy: Novartis; Advisory / Consultancy: Roche; Advisory / Consultancy: BMS; Advisory / Consultancy: Pierre Fabre. C. Nardin: Advisory / Consultancy: Novartis; Advisory / Consultancy: BMS; Advisory / Consultancy: MSD. A. Szenik: Full / Part-time employment: Novartis. A. Denden: Full / Part-time employment: Novartis. C. Dutriaux: Honoraria (self), Advisory / Consultancy: Novartis. All other authors have declared no conflicts of interest.

9545 Background: Among mechanisms of resistance to BRAF inhibitors (BRAFi), cell cycle effectors including CDK4 have been involved in ERK reactivation. In this phase I-II open label study, we aimed to establish the Maximum Tolerated Dose (MTD) of PD0332991, an inhibitor of CDK4/6, when added to vemurafenib (VM) in metastatic melanoma patients. Methods: Patients with BRAFV600E/K mutated metastatic melanoma harbouring CDKN2A loss and RB1 expression were included. Patients were treated with a 14 days followed by 7 days rest daily dosing schedule of PD0332991 + continuous BID dosing of VM, and stratified into 2 groups according to previous BRAFi treatment (no group 1, yes group 2). Dose levels (PD0332991 (mg/QD)/VM (mg/BID) ranged from 25/720 to 200/960. The primary endpoint was the occurrence of a DLT within the first 2 cycles of therapy. Secondary endpoints included best response (RECIST), OS, PFS, pharmacokinetics parameters, tumour molecular profiling on baseline lesions using transcriptomic and NGS analysis. Results: Nineteen patients were enrolled, among them 16 (84%) in group 2, with 18.5 months median follow-up. Characteristics at baseline were: male 11 (58%), median age 54.4 years, unresectable stage IIIC 2 (11%), stage IV 17 (89%), M1C 12 (67%), high LDH 9 (47%), median time from advanced melanoma diagnosis to inclusion 26.8 months, ≥ 2 lines therapy 13 (68%). A DLT was observed for 1 and 5 patients in group 1 and 2 respectively, defining the MTD at PD0332991 25mg and VM 960mg in group 2. No significant evidence for drug-drug interaction between PD0332991 and VM was highlighted. In group 2, ORR was estimated to 4 (25%), SD to 8 (50%), median PFS to 9.3 months and median OS to 13.2 months. Baseline transcriptomic analysis revealed high alteration rate associated with clinical response and enrichment in genes related to MAPK, cell cycle and apoptosis pathways. Conclusions: While combination of fixed dose of PD0332991 + VM did not allow us to increase PD0332991 dosage above 25mg, significant clinical benefit was achieved in heavily pretreated patients; baseline molecular analysis revealed an association between transcriptomic data and clinical response. Clinical trial information: NCT02202200.

International audience; Background: The aim of the study was to analyse efficacy, safety, and health-related quality of life (HRQoL) for sorafenib treatment in patients with metastatic uveal melanoma. Methods: A multicentre, single-arm phase II trial was conducted. The primary objective was to determine the non-progression rate (RECIST) at 24 weeks for patients receiving sorafenib at a dose of 800 mg per day. Secondary endpoints included progression-free survival (PFS), overall survival (OS), toxicity, and HRQoL. Results: Thirty-two patients were included. Ten patients showed non-progression at 24 weeks (31.2%) without objective tumour responses. The estimated 24-week PFS was 31.2% (95% CI: 14.8%-47.6%) and the estimated 24-week OS was 62.5% (95% CI: 45.4%-79.6%). Ten patients (34.3%) had at least one grade 3 or 4 adverse reaction and 12 patients (41.4%) required dose modifications due to toxicity. At 24 weeks, no patient had an improvement in global HRQoL and 87.5% experienced a permanent increase in physical fatigue. Conclusions: Sorafenib demonstrated non-progression at 24 weeks in 31.2% of patients. However, 41.4% of patients required dose modifications due to toxicity and no improvement in HRQoL was demonstrated.

Purpose To compare the overall survival rates of good-prognosis carcinomas of an unknown primary site (CUPS) patients treated with cisplatin alone (C) or in combination with gemcitabine (CG). Patients and methods Good prognosis was defined according to the GEFCAPI (Groupe d’Etude Francais des Carcinomes de site Primitif Inconnu) classification by PS (Performance Status) ⩽1 and LDH (Lactate Deshydrogenase) within the normal range. Patients were randomly assigned to receive C or CG. Patients in the C arm received cisplatin 100 mg/m2 repeated every 3 weeks. In the CG arm, chemotherapy consisted of gemcitabine 1250 mg/m2 on days 1 and 8 and cisplatin 100 mg/m2 IV on day 1, repeated every 3 weeks. The original plan was to accrue 192 patients in order to detect a 20% difference in overall survival. Results Fifty-two patients were enrolled (arm A: 25; arm B: 27). The trial was stopped early due to insufficient accrual. The median overall survival (OS) rate was 11 months [95% confidence interval: 9–20] and 8 months [95% CI: 6–12], in the CG arm and in the C arm, respectively. The 1-year survival rate was 46% [95% CI: 28–64] in the combination arm and 35% [95% CI: 19–56] in the C arm (log rank test: p = 0.73). The median progression-free survival (PFS) rate was 5 [95% CI: 3–11] and 3 [95% CI: 1–8] months in the CG and in the C arm, respectively. The 1-year PFS rate was 29% [95% CI: 15–48] in the combination arm and 15% [95% CI: 5–35] in the C arm (log rank test: p = 0.27). No toxic deaths occurred. Grade 3–4 neutropenia (63% versus 12%) and grade 3–4 thrombocytopenia (37% versus 4%) were more frequent in the CG arm than in the C arm. Conclusion A non-significantly better outcome was observed with CG as compared to C in patients with CUP and a non-unfavourable prognosis. The toxicity profile of the combined arm was represented by haematologic toxicity with thrombocytopenia and leuconeutropenia. International collaboration is required to conduct phase III trials in patients with CUP.

Despite progress in the initial management of glioblastoma (GB), the vast majority of patients will experience recurrence within 2-3 years. The medical treatment of these recurrences is being modified by the use of antiangiogenic therapies. Twenty-four patients, who relapsed from GB after chemoradiation followed by adjuvant temozolomide in Rennes, were treated by conventional chemotherapy (nitrosourea) or by the combination of irinotecan and bevacizumab. In this retrospective analysis, overall survival from diagnosis of recurrence was significantly longer in patients treated with the combination of bevacizumab and irinotecan than with nitrosourea (5 months versus 11.5 months). The combination of irinotecan and bevacizumab appeared to provide clinical benefit to patients with recurrent GB.

MGMT status is now regarded as a strong predictive factor of response to standard treatment of newly diagnosed glioblastomas involving temozolomide (TMZ) and radiotherapy. MGMT promoter methylation is also a prognostic factor - independent of treatment - in anaplastic gliomas. The predictive function can be explained by the role of the DNA repair enzyme MGMT, which antagonizes the effects of alkylating agents such as TMZ. MGMT promoter methylation could also reflect a particular molecular phenotype with its own specific prognostic significance. Since MGMT status determination is becoming a crucial biological marker in new clinical glioma trials, and is beginning to be used in day-to-day clinical practice, there is currently a strong need to determine the best technique for MGMT analysis. A French multicenter study has been set up for this purpose.

Purpose: Gene expression studies provide molecular insights improving the classification of patients with high-grade gliomas. We have developed a risk estimation strategy based on a combined analysis of gene expression data to search for robust biomarkers associated with outcome in these tumors. Experimental Design: We performed a meta-analysis using 3 publicly available malignant gliomas microarray data sets (267 patients) to define the genes related to both glioma malignancy and patient outcome. These biomarkers were used to construct a risk-score equation based on a Cox proportional hazards model on a subset of 144 patients. External validations were performed on microarray data (59 patients) and on RT-qPCR data (194 patients). The risk-score model performances (discrimination and calibration) were evaluated and compared with that of clinical risk factors, MGMT promoter methylation status, and IDH1 mutational status. Results: This interstudy cross-validation approach allowed the identification of a 4-gene signature highly correlated to survival (CHAF1B, PDLIM4, EDNRB, and HJURP), from which an optimal survival model was built (P < 0.001 in training and validation sets). Multivariate analysis showed that the 4-gene risk score was strongly and independently associated with survival (hazard ratio = 0.46; 95% CI, 0.26–0.81; P = 0.007). Performance estimations indicated that this score added beyond standard clinical parameters and beyond both the MGMT methylation status and the IDH1 mutational status in terms of discrimination (C statistics, 0.827 versus 0.835; P < 0.001). Conclusion: The 4-gene signature provides an independent risk score strongly associated with outcome of patients with high-grade gliomas. Clin Cancer Res; 17(2); 317–27. ©2011 AACR.