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

Background Several observational studies have reported a decreased response to immune checkpoint inhibitors (ICI) following antibiotic use. ICI activity has been hypothesized to be impaired by antibiotic-induced gut dysbiosis. Methods Patients with advanced melanoma receiving an anti-PD-1 antibody as a first-line therapy between 2015 and 2017 in France were selected using the French Health Insurance database. We compared overall survival and time-to-treatment discontinuation according to antibiotic exposure in the 3 months prior to the initiation of anti-PD-1 antibody. To disentangle a causal effect of antibiotics from a confounding bias, we balanced characteristics of patients exposed and nonexposed to antibiotics using an overlap weighting method based on a propensity score. We also evaluated a control cohort of patients with advanced melanoma receiving first-line targeted therapy, as there is no rationale for decreased efficacy of targeted therapy following antibiotic treatment. Results The anti-PD-1 antibody cohort comprised 2605 individuals. Antibiotic exposure in the 3 months prior to anti-PD-1 antibody initiation was not associated with shorter overall survival (weighted hazard ratio = 1.01, 95% confidence interval = 0.88 to 1.17) or time-to-treatment discontinuation (weighted hazard ratio = 1.00, 95% confidence interval = 0.89 to 1.11). Consistent results were observed when the time frame of antibiotics was narrowed to 1 month prior to anti-PD-1 initiation or when exposure was restricted to antibiotics leading to more profound gut dysbiosis. Similar results were observed in the targeted therapy cohort. Conclusions In a large cohort of advanced melanoma patients, we showed that antibiotic use preceding anti-PD-1 antibody was not associated with worse outcome. Physicians should not delay immunotherapy for patients who have recently received antibiotics.

PURPOSE Mitogen-activating protein kinase inhibitors (MAPKis) are largely used in V600E/K BRAF–mutated metastatic melanomas, but data regarding effectiveness of targeted therapy in patients with rare BRAF mutations and molecular description of these infrequent mutations are scarce. PATIENTS AND METHODS A multicenter study was conducted on patients with metastatic melanoma harboring a well-identified mutation of BRAF and enrolled from March 2013 to June 2021 in the French nationwide prospective cohort MelBase. The molecular BRAF mutation pattern, response to MAPKis when applicable, and survival data were analyzed. RESULTS Of 856 selected patients, 51 (6%) harbored a non-V600E/K BRAF mutation involving codons V600 (24 of 51, 47%; V600G 27.4%, V600R 15.6%), K601 (6 of 51, 11.7%), and L597 (4 of 51, 7.8%). An objective response to MAPKis either BRAF inhibitor (BRAFi) alone or combined with MEK inhibitor was achieved in 56% (353 of 631) of V600E/K, 58% (11 of 19) of non-E/K V600, and 22% (2 of 9) of non-V600 BRAF-mutated patients, with a median progression-free survival of 7.7, 7.8, and 2.8 months, respectively. Overall, objective response rate was higher with BRAFi + MEK inhibitor combination than with BRAFi in monotherapy for each subset. CONCLUSION Rare BRAF mutations are not anecdotal in the metastatic melanoma population. Although data interpretation must remain careful owing to the limited size of some subsets of patients, non-E/K V600 BRAF mutations seem to confer a high sensitivity to targeted therapy, whereas MAPKis seem less effective in patients with non-V600 BRAF mutations. However, this strategy may be used as an alternative option in the case of immunotherapy failure in the latter population.

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.

Background: First-degree relatives (FDRs, defined as parents, children, and siblings) of melanoma patients are at a two-to-fivefold increased risk of developing melanoma themselves. FDRs are advised to perform self-skin examination (SSE) and annual medical total cutaneous examination (TCE) performed either by a dermatologist or a general practitioner, and to change their sun-related behavior. This advice is given orally to melanoma patients who are asked to relay the information to their FDRs. Objective: Our aim was to determine the impact of providing a tip sheet to melanoma patients intended to their first-degree relatives (FDRs) on early detection and sun-related behaviors in this group at increased risk of melanoma. Methods: A superiority, cluster-randomized trial was conducted at nine hospital centers. In the intervention group, dermatologists were asked to deliver to melanoma patients (index cases) the tip sheet and oral advice intended to their FDRs. The control group were asked to deliver the usual oral advice alone. The primary outcome was early detection of melanoma in FDRs with a medical TCE performed within one year after the first visit of the index case. Secondary outcomes were SSE and sun-related behaviors in FDRs. Results: A total of 48 index cases and 114 FDRS in the control group, 60 index cases and 166 FDRS in the intervention group were recruited. In the intervention group, 36.1% of FDRs performed a medical TCE as compared to 39.5% of FDRs in the control group (OR 0.9 [95% CI 0.5 to 1.5], p = 0.63). We did not find a between-group difference in SSE and sun-related behaviors. Conclusion: A tip sheet added to the usual oral advice did not increase medical TCE among FDRs of melanoma patients. Overall, the rate of TCE among FDRs was low. Research on other strategies is needed to increase melanoma detection in this population.

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.

BackgroundAcral melanoma is a rare melanoma subtype with poor prognosis. Importantly, these patients were not identified as a specific subgroup in the landmark melanoma trials involving ipilimumab and the anti-programmed cell death protein-1 (PD-1) agents nivolumab and pembrolizumab. There is therefore an absence of prospective clinical trial evidence regarding the efficacy of checkpoint inhibitors (CPIs) in this population. Acral melanoma has lower tumor mutation burden (TMB) than other cutaneous sites, and primary site is associated with differences in TMB. However the impact of this on the effectiveness of immune CPIs is unknown. We examined the efficacy of CPIs in acral melanoma, including by primary site.MethodsPatients with unresectable stage III/IV acral melanoma treated with CPI (anti-PD-1 and/or ipilimumab) were studied. Multivariable logistic and Cox regression analyses were conducted. Primary outcome was objective response rate (ORR); secondary outcomes were progression-free survival (PFS) and overall survival (OS).ResultsIn total, 325 patients were included: 234 (72%) plantar, 69 (21%) subungual and 22 (7%) palmar primary sites. First CPI included: 184 (57%) anti-PD-1, 59 (18%) anti-PD-1/ipilimumab combination and 82 (25%) ipilimumab. ORR was significantly higher with initial anti-PD-1/ipilimumab compared with anti-PD-1 (43% vs 26%, HR 2.14, p=0.0004) and significantly lower with ipilimumab (15% vs 26%, HR 0.49, p=0.0016). Landmark PFS at 1 year was highest for anti-PD-1/ipilimumab at 34% (95% CI 24% to 49%), compared with 26% (95% CI 20% to 33%) with anti-PD-1 and 10% (95% CI 5% to 19%) with ipilimumab. Despite a trend for increased PFS, anti-PD-1/ipilimumab combination did not significantly improve PFS (HR 0.85, p=0.35) or OS over anti-PD-1 (HR 1.30, p=0.16), potentially due to subsequent therapies and high rates of acquired resistance. No outcome differences were found between primary sites.ConclusionWhile the ORR to anti-PD-1/ipilimumab was significantly higher than anti-PD-1 and PFS numerically higher, in this retrospective cohort this benefit did not translate to improved OS. Future trials should specifically include patients with acral melanoma, to help determine the optimal management of this important melanoma subtype.

Despite the poor prognosis associated with melanoma brain metastases (BM), data concerning these patients and their inclusion in clinical trials remains scarce. We report here the efficacy results of a subgroup analysis in patients with BRAFV600-mutant melanoma and BM treated with BRAF and MEK inhibitors dabrafenib (D) and trametinib (T).This phase IIIb single-arm, open-label, multicenter, French study included patients with unresectable stage IIIc or IV BRAFV600-mutant melanoma with or without BM. The present analysis focuses on patients with BM. Response rates were determined clinically and/or radiologically as per standard clinical practice. Progression-free survival (PFS) was estimated using the Kaplan Meier analysis and modelled with multivariate Cox regression model. Risk subgroups were identified using an exponential regression tree analysis. Significance was set at plt; 0.05.Between March 2015 and November 2016, 856 patients were included and 275 (32%) patients had BM. Median PFS was 5.68 months (95% confidence interval [CI], 5.29-6.87). Significant independent factors associated with shorter PFS were ECOG ≥1, elevated serum lactate dehydrogenase (LDH), ≥3 metastatic sites, and non-naïve status. The binary-split classification and regression tree modelling identified baseline LDH and ECOG status as major prognostic factors.This is to date the largest, close to real-world, study in advanced BRAFV600-mutant melanoma patients with BM treated with D+T. ECOGgt;1, ≥3 metastatic sites and elevated LDH were associated with shorter PFS, a finding previously demonstrated only in patients without BM. Further studies are warranted to determine the optimal treatment sequence in this population.

MBD4 mutations have been reported in uveal melanomas, acute myeloid leukemias, colorectal adenocarcinomas, gliomas, and spiradenocarcinomas and cause a hypermutated phenotype. Although metastatic uveal melanomas (mUM) are usually resistant to immune checkpoint inhibitors (ICI), the first reported MBD4-mutated (MBD4m) patient responded to ICI, suggesting that MBD4 mutation may predict response to ICI.Retrospective cohort of mUM patients treated with ICI. MBD4 was sequenced in a subset of these patients.Three hundred mUM patients were included. Median follow-up was 17.3 months. Ten patients with an objective response and 20 cases with stable disease forgt;12 months were observed, corresponding to an objective response rate of 3.3% and a clinical benefit (i.e., responder patients and stable disease) rate of 10%. Of the 131 tumors sequenced for MBD4, five (3.8%) were mutated. MBD4 mutation was associated with a better objective response rate as three out of five MBD4m versus 4% of MBD4 wild-type patients responded (p lt; 0.001). Of these five responders, three presented progressive disease at 2.8, 13.9, and 22.3 months. Median PFS was 4.0 months in MBD4 wild-type and 22.3 months in MBD4m patients (HR = 0.22; p = 0.01). Median OS in MBD4def patients was unreached as compared to 16.6 months in MBD4pro (HR = 0.11; 95% CI: 0.02-0.86; log-rank p-test = 0.04; Fig. 2e).In mUM patients, MBD4 mutation is highly predictive for the response, PFS, and overall survival benefit to ICI. MBD4 could be a tissue-agnostic biomarker and should be sequenced in mUM, and other tumor types where MBD4 mutations are reported.

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.

e21601 Background: MBD4 encodes a glycosylase implicated in repair of lesions induced by DNA deamination and its inactivation in tumors is associated with a hypermutated phenotype. Uveal melanoma (UM) is a rare but aggressive form of melanoma carrying an extremely low mutation burden. Although metastatic UM (mUM) are usually resistant to immune checkpoint inhibitors (ICI), the first reported MBD4-mutated (MBD4m) patient responded to ICI, suggesting that MBD4 mutation may predict response to ICI. Since then, other MBD4-inactivated UMs, acute myeloid leukemias, colorectal adenocarcinomas, gliomas and spiradenocarcinoma cases have been reported. Methods: Retrospective cohort of mUM patients treated with ICI. MBD4 was sequenced in a subset of these patients. Results: Three hundred mUM patients were analyzed. Median follow-up was 17.3 months. Ten objective responses and 20 stable disease for > 12 months were observed, corresponding to an objective response rate of 3.3% and a clinical benefit (CB; i.e. responder patients and stable disease) rate of 10%. Median progression-free survivals (PFS) in patients without and with CB were 3.1 and 16.3 months, respectively (p < 0.0001). Of the 134 tumors sequenced for MBD4, five (3.7%) were mutated. MBD4 inactivation was associated with higher mutation burden (179 to 643 variants versus a median of 16 in MBD4 wild-type), better objective response rate as 60% of MBD4m versus 4% of MBD4-wild type patients responded (Fisher’s exact p-test = 0.0009). Median PFS was 4.0 months in MBD4-wild type and 22.3 months in MBD4m patients (HR = 0.22; p = 0.01). Median overall survival was 16.6 months in MBD4-wild type and unreached in MBD4m patients (HR = 0.11; p = 0.004). Conclusions: In mUM patients, MBD4 mutation is highly predictive for response to ICI, PFS and overall survival benefit. MBD4 could be a tissue-agnostic biomarker and should be sequenced in mUM and other tumor types where MBD4 mutations are reported.

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

90 Background: Darolutamide, a structurally distinct and highly potent androgen receptor inhibitor, had a consistently favorable safety and tolerability profile in patients with nonmetastatic castration-resistant prostate cancer in ARAMIS, and discontinuation rates due to adverse events (AEs) remained consistently low after longer follow-up. In previously reported phase 1/2 studies in patients with metastatic castration-resistant prostate cancer (mCRPC), darolutamide was well tolerated for up to 25 months. We report the safety and tolerability of extended treatment with darolutamide in these mCRPC studies. Methods: Data from three phase 1/2 studies (NCT02363855, NCT01317641/NCT01429064, and NCT01784757) in patients with mCRPC were pooled for analysis of long-term safety. Results are summarized descriptively. Results: Of 173 patients with mCRPC evaluable for safety in the 3 studies, 13 patients received > 2 years of darolutamide treatment; median duration of treatment was 38 months (range 24–90). Six patients received > 4 years of darolutamide treatment. Nine of 13 patients with > 2 years of darolutamide therapy initially received 600 mg BID; others received 200 mg (n = 1), 300 mg (n = 1), or 700 mg (n = 2) BID. Median age was 68 years in the > 2-years group, and most patients were white. Patients were enrolled from France (n = 4), Latvia (n = 3), United Kingdom (n = 3), Finland (n = 2), and Japan (n = 1). Most patients had normal renal function (n = 10) and hepatic function (n = 10), 12 patients had Eastern Cooperative Oncology Group performance status of 0, and 9 patients had a Gleason score ≥7. Prior systemic anticancer treatments taken by more than 1 patient were bicalutamide (n = 10); cyproterone (n = 3); and triptorelin and leuprorelin (n = 2 each). No patient received prior chemotherapy. All 13 patients reported AEs, most grade 1 or 2; 6 reported grade 3 AEs. Treatment-related AEs were reported in 5 patients, and all were grade 1 in severity. Serious AEs were reported in 6 patients, and all were judged not related to darolutamide. One patient treated with darolutamide for > 2 years had an AE (new neoplasm; not related to darolutamide) that led to treatment discontinuation. Conclusions: Extended darolutamide treatment > 2 years in this small group of patients with mCRPC was generally well tolerated, with safety and tolerability consistent with that previously reported. Clinical trial information: NCT02363855, NCT01317641/NCT01429064, and NCT01784757.

Background: BET proteins are epigenetic readers and activators of oncogenic pathways in cancer. CC-95775 is a novel oral small molecule bromodomain inhibitor. It is a non-specific inhibitor with potent activity against all 4 BET family members (BRD2, BRD3, BRD4, BRDT), and shows additional activity towards several non-BET bromodomain proteins. Methods: CC-95775-ST-001 is a phase 1 dose-escalation study of CC-95775 in patients with advanced STs. Primary objectives were to determine safety and recommended phase 2 dose (RP2D). Secondary and exploratory objectives were pharmacokinetics (PK), pharmacodynamics (PD) and antitumor activity. Four dose levels (DLs), from 400 to 1200 mg, administered on 4 consecutive days (Day 1 to Day 4) followed by 24 days off, every four weeks (Q4W), were evaluated. Results: As of 16 Apr 2021, 24 evaluable patients were enrolled and treated. The RP2D was 1200 mg (300 mg on days 1-4 and 24 days off, Q4W). One patient treated at 800 mg and two at 1200 mg had dose-limiting toxicities: QT prolongation, left ventricular ejection fraction (LVEF) decreased and abnormal T wave. The most common treatment-related adverse event (TRAE) was thrombocytopenia in 11 patients (45.8%), 2 of them grade 3 (8.3%) and 1 grade 4 (4.2%). Safety profile consisted mainly of gastrointestinal and general disorders. Five patients (20.8%) had transient serious TRAEs: nausea, QT prolongation, abnormal T wave, posterior reversible encephalopathy syndrome and acute kidney injury. Eleven patients 11 (45.8) had disease stabilization, 9 of them with a duration of ≥ 16 weeks and 4 of them ≥ 24 weeks: melanoma, chondrosarcoma, adenoid cystic carcinoma and chordoma. Plasma exposures increased in a dose-proportional manner across DLs. Across all dose groups, median Tmax was between ~ 2-4 h post-dose, indicating rapid absorption. The terminal half-life was approximately 30 h and repeated dosing leads to drug accumulation, as expected: ~2 - 3 fold for AUC and Cmax. CC-95775 induced ≥50% decrease of the PD biomarker CCR1 at the 4-hour timepoint in the 1200 mg cohort. Conclusions: CC-95775 was well tolerated and showed preliminary antitumor activity in heavily pretreated patients with advanced malignancies. The RP2D was 1200 mg Q4W. The favorable PD profile improved tolerability and enabled less frequent dosing. Further evaluation of CC-95775 alone or in combination in STs is warranted. Citation Format: Thierry Lesimple, María José de Miguel, Cristophe Le Tourneau, Mariano Ponz-Sarvise, Marie Paule Sablin, Diego Salas Benito, Bishoy Hanna, Henry Chang, Xin Wei, Marta Ocejo Garcia, Pilar Lardelli, Tania Sánchez, Josep Lluís Parra Palau, Zariana Nikolova, Emiliano Calvo. CC-95775, a reversible, oral bromodomain and extra-terminal (BET) inhibitor in patients with advanced solid tumors (STs): Results of a phase 1 study [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P033.

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.

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

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.

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 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: A novel combination of vemurafenib (VM), a selectif inhibitor of BRAF V600 mutated protein + oral palbociclib (Palbo) a highly selective reversible oral inhibitor of cyclin-dependent kinases (CDK) 4 and 6, could provide a synergistic antitumor activity in patients with metastatic melanoma harbouring BRAF V600 mutation and CDKN2A loss. VM has been shown to be an inductor of CYP3A4 which is also mainly involved in Palbo metabolism. In this study we investigated the potential pharmacokinetic (PK) drug-drug interactions (DDI) related to the association of VM and Palbo. Methods: metastatic melanoma harbouring BRAF V600 mutation and CDKN2A loss patients were treated with a 14 days on followed by 7 days off dosing schedule of Palbo + continuous bid dosing of VM. Dose levels [DL, Palbo (mg/day)/VM (mg/bid)] ranged from 25/720 to 200/960. For PK analysis, 7 time point samples were collected on D1C1, D21C1, and D7C2, for Palbo and VM assays. Plasma concentrations of Palbo and VM, were measured using ultra high performance liquid chromatography (UHPLC) coupled with tandem mass spectrometry validated methods. Population PK (PPK) was modeled using a non linear mixed effect model program (Monolix version 2018r) by computing the maximum likelihood estimator of the parameters without any approximation of the model (no linearization). The following parameters were calculated absorption constant (Ka); apparent distribution volume (V/F); apparent clearance (CL/F) Results: A total of 18 patients were treated by the combination of Palbo + VM. VM and palbo plasma concentrations were measured in 236 and 275 blood samples respectively. A one-compartment open model with linear elimination adequately described Palbo concentration-time courses. The inter-individual variabilities (ISV) could be well estimated for all stuctural parameters. The PPK parameters obtained for the structural model were: Ka = 0.791 h-1, CL/F=76.0L/h, V1/F=2830 L. Albuminemia had a significant impact on palbo CL. A one-compartment model adequately fitted the VM plasma concentration-time data. The PPK parameters were CL/F=0.133 L/h, V/F=83.6 L and Ka has been fixed at 0.2 h-1. Body weight (BW) was the best size descriptor when VM CL and V terms were normalized to a mean BW of 70 Kg according to an allometric scaling rule. Conclusions: The PPK modeling satisfactorily described the plasma Plabo and VM time-concentration curves in patients. The main covariate effect was related to BW and albuminemia. There is no significant evidence for drug-drug PK interaction between Palbo and VM. PK-PD modeling will be performed. Citation Format: Samuel Huguet, Thierry Lesimple, Arthur Geraud, Mouna Amini-Adle, Caroline Dutriaux, Laetitia Da Meda, Florence Capelle, Zineb Ghrieb, Samia Mourah, Olivier Madar, Didier Bouton, Mathieu Resche-Rigon, Celest Lebbe, Keyvan Rezai. A phase I-II pharmacokinetic drug-drug interaction evaluation of oral palbociclib in combination with vemurafenib in patients suffering metastatic melanoma with BRAF V600 mutated and CDKN2A loss & expression of Rb [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3895.

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.

9520Background: Brain metastasis commonly occur in patients with metastatic melanoma (MM) and are managed with surgery or stereotactic radiosurgery (SRS) and/or systemic treatment based on BRAF sta...

e21536Background: Melanoma’s incidence is increasing, and elderly people could be significantly impacted since more than 50% of melanoma arise in > 65 years-old (yo). Combined BRAF and MEK targeted...

Purpose Thymosin α 1 (Tα1) is an immunomodulatory polypeptide that enhances effector T-cell responses. In this large randomized study, we evaluated the efficacy and safety of combining Tα1 with dacarbazine (DTIC) and interferon alfa (IFN-α) in patients with metastatic melanoma. Patients and Methods Four hundred eighty-eight patients were randomly assigned to five treatment groups: DTIC+IFN-α+Tα1 (1.6 mg); DTIC+IFN-α+Tα1 (3.2 mg); DTIC+IFN-α+Tα1 (6.4 mg); DTIC+Tα1 (3.2 mg); DTIC+IFN-α (control group). The primary end point was best overall response at study end (12 months). Secondary end points included duration of response, overall survival (OS), and progression-free survival (PFS). Patients were observed for up to 24 months. Results Ten and 12 tumor responses were observed in the DTIC+IFN-α+Tα1 (3.2 mg) and DTIC+Tα1 (3.2 mg) groups, respectively, versus four in the control group, which was sufficient to reject the null hypothesis that P0 ≤ .05 (expected response rate of standard therapy) in these two arms. Duration of response ranged from 1.9 to 23.2 months in patients given Tα1 and from 4.4 to 8.4 months in the control group. Median OS was 9.4 months in patients given Tα1 versus 6.6 months in the control group (hazard ratio = 0.80; 9% CI, 0.63 to 1.02; P = .08). An increase in PFS was observed in patients given Tα1 versus the control group (hazard ratio = 0.80; 95% CI, 0.63 to 1.01; P = .06). Addition of Tα1 to DTIC and IFN-α did not lead to any additional toxicity. Conclusion These results suggest Tα1 has activity in patients with metastatic melanoma and provide rationale for further clinical evaluation of this agent.

Improving glioblastoma multiforme (GBM) treatment with radio-chemotherapy remains a challenge. Topotecan is an attractive option as it exhibits growth inhibition of human glioma as well as brain penetration. The present study assessed the combination of radiotherapy (60 Gy/30 fractions/40 days) and topotecan (0.9 mg/m(2)/day on days 1-5 on weeks 1, 3 and 5) in 50 adults with histologically proven and untreated GBM. The incidence of non-hematological toxicities was low and grade 3-4 hematological toxicities were reported in 20 patients (mainly lymphopenia and neutropenia). Partial response and stabilization rates were 2% and 32%, respectively, with an overall time to progression of 12 weeks. One-year overall survival (OS) rate was 42%, with a median OS of 40 weeks. Topotecan in combination with radiotherapy was well tolerated. However, while response and stabilization concerned one-third of the patients, the study did not show increased benefits in terms of survival in patients with unresectable GBM.

Purpose The PRAME tumour antigen is expressed in several tumour types but in few normal adult tissues. A dose-escalation phase I/II study (NCT01149343) assessed the safety, immunogenicity and clinical activity of the PRAME immunotherapeutic (recombinant PRAME protein (recPRAME) with the AS15 immunostimulant) in patients with advanced melanoma. Here, we report the phase I dose-escalation study segment. Patients and methods Patients with stage IV PRAME-positive melanoma were enrolled to 3 consecutive cohorts to receive up to 24 intramuscular injections of the PRAME immunotherapeutic. The RecPRAME dose was 20, 100 or 500 µg in cohorts 1, 2 and 3, respectively, with a fixed dose of AS15. Adverse events (AEs), including predefined dose-limiting toxicity (DLT) and the anti-PRAME humoral response (ELISA), were coprimary end points. Cellular immune responses were evaluated using in vitro assays. Results 66 patients were treated (20, 24 and 22 in the respective cohorts). AEs considered by the investigator to be causally related were mostly grade 1 or 2 injection site symptoms, fatigue, chills, fever and headache. Two DLTs (grade 3 brain oedema and proteinuria) were recorded in two patients in two cohorts (cohorts 2 and 3). All patients had detectable anti-PRAME antibodies after four immunisations. Percentages of patients with predefined PRAME-specific-CD4+T-cell responses after four immunisations were similar in each cohort. No CD8+ T-cell responses were detected. Conclusions The PRAME immunotherapeutic had an acceptable safety profile and induced similar anti-PRAME-specific humoral and cellular immune responses in all cohorts. As per protocol, the phase II study segment was initiated to further evaluate the 500 µg PRAME immunotherapeutic dose. Trial registration number NCT01149343, Results.

Epithelioid hemangioendothelioma (EHE) is an uncommon vascular neoplasm. Its intracranial occurrence is rare, and the literature review revealed only 23 cases (14 adults and 9 children). To our knowledge, this is the first case of EHE arising in the infundibular-hypothalamic region. A 53-year-old man presented with headaches and loss of libido. Magnetic resonance imaging revealed a supra-sellar mass, which homogeneously absorbed the contrast agent. A trans-sphenoidal craniotomy and a biopsy were performed. Adjuvant radiotherapy was administered due to intolerance to interferon. Epithelioid hemangioendothelioma is a hemorrhagic tumor. Total resection is mandatory where possible, otherwise radiotherapy seems necessary. The prognosis of intracranial location has not yet been well defined, despite the favorable outcome noted in the majority of cases.

Treating patients with anthracycline- and taxane-pretreated metastatic breast cancer (MBC) represents a significant challenge to oncologists. The tumour-activated oral fluoropyrimidine, capecitabine, is the only treatment approved for these patients. Our study evaluated the efficacy, safety and impact on quality of life (QOL) of capecitabine in this setting. Patients (n=126) with anthracycline- and taxane-pretreated metastatic breast cancer received capecitabine 1250 mg/m 2 twice daily, days 1–14, followed by a 7-day rest period. Median time to progression was 4.9 months (95% Confidence Interval (CI): 4.0–6.4). Thirty-five patients (28%) achieved an objective response (95% CI: 20–36%), including five (4%) complete responses. Median overall survival was 15.2 months (95% CI: 13.5–19.6 months). Capecitabine demonstrated a favourable safety profile, with a low incidence of treatmentrelated grade 3/4 adverse events. The most common adverse events were hand–foot syndrome and gastrointestinal effects. QOL assessment showed that capecitabine treatment was associated with an increase in mean Global Health Score. Capecitabine is active, well tolerated and improves the QOL of patients with anthracycline- and taxane-pretreated metastatic breast cancer. Based on the consistently high activity demonstrated in clinical trials, capecitabine has become the reference treatment in this setting. # 2003 Elsevier Ltd. All rights reserved.

The objective of this study was to examine and compare two core measures of Quality Of Life (QOL) used in cancer clinical trials: the European Organisation for Research and Treatment of Cancer QOL Core Questionnaire 30 (EORTC QLQ-30) and the Functional Assessment of Chronic Illness Therapy (FACIT), in order to identify which one patients have the strongest preference for using. 68 patients suffering from Carcinomas of an Unknown Primary site (CUP) were recruited in a multicentric study; all of them completed both questionnaires, administered in a randomised manner. The criteria were the percentage of preferences, and four indicators of acceptability. The results indicated that an equal proportion of patients preferred the QLQ-C30 (19%) and FACIT (19%). 54% of patients felt both questionnaires were acceptable. All the indicators of acceptability favoured the QLQ-C30. Analysis of open-ended questions shed light on the difficulties encountered by the patients. As no significant preference was observed for one of the questionnaires, the QLQ-C30 was chosen on the basis of its significantly better acceptability criteria.

A phase I study was performed to determine the maximum tolerated dose and the recommended dose of continuous intravenous infusion of topotecan in combination with radiotherapy (RT) in patients with previously untreated glioblastoma multiforme (GBM). Twenty patients with histologically proven GBM and 1 with rhabdoid tumor were enrolled. After surgery or stereotactic biopsy, patients received cranial RT (60 Gy/30 fractions/40 days) and 3 cycles of topotecan as continuous infusion (CIV) from day 1 to 5 on weeks 1, 3, and 5 during RT. The dose of topotecan was escalated from 0.6 to 1.0 mg/m2/day. Four dose levels were tested. One grade 4 thrombocytopenia was seen at level 1 (topotecan dose 0.6 mg/m2/day; 6 patients). No dose-limiting toxicity was seen at level 2 (0.8 mg/m2/day; 3 patients) or an intermediate level of 2 bis (0.9 mg/m2/day; 6 patients). Six patients were included at level 3 (1.0 mg/m2/day), 4 of whom experienced dose-limiting toxicities, including 3 episodes of grade 4 thrombocytopenia, 1 platelet transfusion, 1 febrile neutropenia, and 1 grade 4 neutropenia of more than 7 days. Eighty percent of patients with GBM were alive at 12 months. The dose-limiting toxicity of topotecan administered as CIV for 5 days every 2 weeks is hematological. The maximum tolerated dose is 1.0 mg/m2/day and the recommended dose is 0.9 mg/m2/day. A phase II trial using the recommended dose of topotecan is ongoing.

Purpose: To evaluate the efficacy and toxicity of novel chemotherapy combinations including cisplatin with gemcitabine (GC) or irinotecan (IC) for patients with carcinomas of an unknown primary site. Patients and Methods: Eighty patients were randomly assigned to receive GC or IC. In the GC arm, chemotherapy consisted of cycles combining gemcitabine 1,250 mg/m2 intravenously (IV) on days 1 and 8, and cisplatin 100 mg/m2 IV on day 1 at 3-week intervals. Patients in the IC arm originally received 3-week cycles of irinotecan 200 mg/m2 IV on day 1 and cisplatin 80 mg/m2 IV on day 1. After the inclusion of 15 patients in that arm, the toxicity profile required the irinotecan doses to be reduced to 150 mg/m2 per cycle. Independent histologic and radiologic reviews were done. Results: A total of 78 patients were assessable for efficacy and toxicity. The median number of cycles was four in each arm. Objective responses were observed in 21 patients (55%) in the GC arm (95% CI, 34% to 66%) and in 15 patients (38%) in the IC arm (95% CI, 23% to 54%). Treatment had to be stopped because of toxicity in seven patients in the GC arm and in eight patients in the IC arm. With a median follow-up of 22 months, the median survivals were 8 and 6 months in the GC and IC arms, respectively. Conclusion: This study demonstrates the activity of both the GC and IC regimens. There was toxicity associated with both regimens. Additional studies of combination chemotherapy regimens are required.

Carcinomas of unknown primary site are metastatic malignant epithelial tumours whose primary site cannot be identified during pretreatment assessment. They are characterised by their slow local development and their high metastatic potential. The primary site remains unknown in 20–50% of the patients, but the results from autopsies show that the primary tumours are most often located in the pancreas, lung, gut or kidney. In France, the incidence of carcinomas of unknown primary site is eight out of 100 000 per year, corresponding to between 5 and 7% of the solid tumours in adults. The average age at detection is 60 years old, with slightly more men being affected. The median survival time is only a few months. The heterogeneity of carcinoma of unknown primary site is due to the different histopathological types and anatomical localisations, making this a difficult topic to cover. In this document, we present the diagnostic strategy based on these two parameters, with the first entry point being the histopathological type. The therapeutic strategies to be used depend on the prognostic factors: specific anatomoclinical entities (neuroendocrine tumours, cervical lymph node metastases from squamous cell carcinoma, axillary lymph node metastases from an adenocarcinoma in women, undifferentiated carcinoma of the mediastinum in young men) and other nonspecific situations. Although primary papillary serous carcinoma is no longer included in the classification of peritoneum carcinomas of unknown primary site, we covered the management in women here in an attempt to be exhaustive.

9551 Background: With increasing armamentarium in advanced melanoma management, the impact of various strategies remains to be determined including the importance of time to switch from one treatment to another. We report the impact of time to IPI/APD non-planned switch on APD efficacy in real life patients within MelBase (MB). Methods: MB is a French multicentric biobank dedicated to the prospective follow-up (FU) of unresectable stage III or IV melanoma with 1102 patients included since March 2013. Data were collected (Sept.2016) and analyzed (demography, overall survival (OS), progression-free survival (PFS), response rate, multivariate analysis, safety). Results: 71 patients were treated with IPI/APD sequence. 72% received 4 IPI injections. The median time to switch was 1.7 months (0.36-3). The characteristics at the initiation of APD are: mean age 64 yrs, PS 0-1 80%, elevated LDH 34%, BRAF WT 90%, brain metastasis 25%, ≥ 3 metastatic organ sites (MOS) 49%, median FU 11.9 months, OS 20 months (95%CI:12.6-NR), PFS 3.5 months (95%CI:2.9-6.2). The best overall response was 25%, disease control rate was 54% with a low toxicity profile (17% grade 3/4). In a multivariable analysis, longer time to switch was significantly associated with better OS (adjusted HR 0.38 per 1 more month, 95%CI:0.14-0.93), as well as ECOG 0-1 (aHR 3.11, 95%CI:0.99-9.72) and LDH < ULN (aHR 3.32, 95%CI:1.26-8.75). In addition, the association of time to switch with OS vary significantly according to the number of MOS ( < 3 MOS aHR 0.25, 95%CI:0.10-0.62; ≥3 MOS aHR 0.99 95%CI:0.41-2.39) and AJCC stage (M0/1a/1b aHR 0.06, 95%CI:0.01-0.43 ; M1c aHR 0.77, 95%CI:0.39-1.54). Conclusions: In patients who failed IPI treatment, longer survival after APD was associated to time to switch only in patients with favorable baseline factors. Such results are probably more related to the slow kinetics of the disease than to the delay itself. Our results are different from Blank et al.(ESMO 2016) who tested a planned switch, immediately after 2 IPI perfusions, and showed overall response rate close to IPI+APD association. We are currently conducting a similar study on the reverse sequence (APD/IPI) and the role on IPI efficacy.

9538 Background: In the past decade, the prognosis of advanced melanoma has been greatly improved by new therapeutic agents such as immune and targeted therapies, which are now being evaluated as adjuvant therapies. Although the kinetic of metastatic disease is correlated to patient survival, the unfolding of the dormant disease remains hardly predictable and data from the literature on the topic is controversial (Karakousis, Francken). We hypothesized that the course of the advanced disease could be predicted from time to distant recurrence. Methods: Melbase is a French multicentric cohort dedicated to the prospective follow-up of adults with unresectable stage III or IV melanoma. Date of primary excision, time to recurrence, progression free survival (PFS) and overall survival (OS) of 298 patients treated in first line by immune therapies (IT, n = 148), targeted therapies (TT, n = 68) or within clinical trials (n = 73) were collected on September 5th, 2016. Patients with unknown primary or de novo metastatic melanoma were not included. Time to distant recurrence was analyzed as a continuous variable and as a categorical variable ( < 12 months; 12 to 24 months; ≥ 24 months). Results: Patients’ characteristics at baseline are: mean age 62 years, PS 0-1 84%, elevated LDH 32%, BRAF mutated 39%, brain metastases 18%. Time to recurrence studied as a continuous variable was not correlated to PFS (HR = 0.96; 95%CI: 0.85-1.07) or OS (HR = 0.89; 95%CI: 0.77-1.03). These results remained insignificant after stratification upon treatment or even when time to recurrence was analyzed as a categorized variable. Conclusions: Our data showed no correlation between the time from primary to distant recurrence and PFS or OS in patients treated with TT or IT. Therefore, kinetics of advanced disease cannot be predicted by the history of dormant disease. Dormancy and metastasis proliferation are thus probably driven by different molecular and cellular mechanisms.

Background Mutations of BRAF, NRAS and c-KIT oncogenes are preferentially described in certain histological subtypes of melanoma and linked to specific histopathological features. BRAF-, MEK- and KIT-inhibitors led to improvement in overall survival of patients harbouring mutated metastatic melanoma. Objectives To assess the prevalence and types of BRAF, NRAS, c-KIT and MITF mutations in cutaneous and mucous melanoma and to correlate mutation status with clinicopathological features and outcome. Methods Clinicopathological features and mutation status of 108 samples and of 98 consecutive patients were, respectively, assessed in one retrospective and one prospective study. Clinicopathological features were correlated with mutation status and the predictive value of these mutations was studied. Results This work identified significant correlations between BRAF mutations and melanoma occurring on non-chronic sun-damaged skin and superficial spreading melanoma (P < 0.05) on one hand, and between NRAS mutations and nodular melanoma (P < 0.05) on the other hand. Younger age (P < 0.05), microscopic (P < 0.05) and macroscopic (P < 0.05) lymphatic involvement at diagnosis of primary melanoma were significantly linked to BRAF mutations. A mutated status was a positive predictive factor of a response to BRAF inhibitors (OR = 3.44). Mutated melanoma showed a significantly (P = 0.038) higher objective response rate to cytotoxic chemotherapy (26.3%) than wild-type tumours (6.7%). Conclusion Clinical and pathological characteristics of the primary melanoma differed between wild-type and BRAFor NRAS-mutated tumours. Patients with BRAF-mutated tumours were younger at diagnosis of primary melanoma. Patients carrying mutations showed better responses better to specific kinase inhibitors and interestingly also to systemic cytotoxic chemotherapy.

Purpose: We have previously reported a clinical trial on the intravenous injection of autologous activated macrophages (AAM) in 15 patients with renal carcinoma [11]. The present paper concerns scintigraphic investigations performed in 11 of these patients after injection of 111indium oxinate-radiolabeled AAM. Methods: AAM were prepared from mononuclear cells (MNC) collected by apheresis from patients treated simultaneously with granulocyte–macrophage colony-stimulating factor (GM-CSF). MNC were cultured for 6 days in the presence of GM-CSF and exposed for 18 h to gamma-interferon, the AAM were then separated by elutriation and injected. Results: After intravenous infusion, radiolabeled AAM were transiently retained in the lungs, where they predominated in the first hour. Later on, radioactivity accumulated in liver and spleen and then decreased from the first and second day, respectively. In one patient, two foci of radioactivity were detected in the lungs 1 h after injection, and persisted thereafter. Their association with tumor lesions was uncertain. This observation possibly resulted from the presence of granulocytes in the radiolabeled AAM populations of this patient. It seems that MNC collected from GM-CSF-treated patients and cultured in the presence of GM-CSF enables the differentiation of granulocytes. Conclusions: A series of 11 investigations confirms the previously reported distribution pattern of intravenously injected AAM. It is possible that in patients treated with hematopoietic cell-mobilizing agents, granulocytes develop in cultures designed to produce monocyte-derived antigen-presenting cells.