Adjunction of a MEK inhibitor to Vemurafenib in the treatment of metastatic melanoma results in a 60% reduction of acute kidney injury

International audienceA combined therapy MEK inhibitor, Cobimetinib (CB) and BRAF inhibitor, Vemurafenib (VMF), results in an improvement in progression-free survival among patients with BRAF V600-mutated metastatic melanoma. VMF skin adverse effects attributed to ERK paradoxical activation are decreased by the adjunction of CB. The aim of this study was to determine if this combination also improved the renal side effects of VMF. To investigate the incidence of acute kidney injury (AKI), we conducted a retrospective observational monocentric study in Lyon Sud University Hospital in France. We included 38 patients with metastatic BRAF-mutated melanomas treated by VMF and CB between March 2015 and June 2016. According to the NCI-CTCAE classification, AKI was defined as an increase in serum creatinine exceeding the baseline concentration by 1.5-fold. Serum creatinine was measured before treatment, then on a monthly basis during treatment, and 1 month after treatment discontinuation. Patients were divided into two main groups: AKI-positive (AKI+) and AKI-negative (AKI-), and further subdivided into three groups according to AKI severity (stage 1-5). Of 38 patients, 29 (76%) were AKI-, and all 9 AKI+ patients (24%) were diagnosed within the first trimester of treatment. Three-quarters of AKI (n = 7, 77%) had stage 1 AKI and the remaining 23% stage 2 AKI. Pre-treatment renal function was significantly better in AKI+ group: 105 vs. 80 ml/min/1.73mA(2) AKI-, p = 0.009. Compared to previous results, the AKI incidence under the combined VMF-CB vs. VMF monotherapy was reduced by 60%. We reported a reduced incidence and severity of nephrotoxicity of the association inhibitors of BRAF and MEK compared to a BRAF inhibitor monotherapy

Older and younger patients treated with immune checkpoint inhibitors have similar outcomes in real-life setting

International audienceBACKGROUND: Age-related immune dysfunction might impair the efficacy of immune checkpoint inhibitors (ICIs) in older patients. We aimed to evaluate the impact of age on clinical outcomes and tolerance of ICIs in a real-life setting. METHODS: All patients receiving a single-agent ICI (cytotoxic T-lymphocyte-associated protein 4 [CTLA-4] or programmed death(ligand)1 [PD(L)-1] inhibitors) for the standard treatment of a locally advanced or metastatic cancer were included in this retrospective multicentric series. The primary end-point was overall survival (OS). Progression-free survival (PFS) and immune-related adverse events (irAEs) were secondary end-points. The impact of age was assessed using the threshold of 70 years. RESULTS: A total of 410 patients were included, for 435 lines of treatment, including 150 lines (34%) given to patients aged 70 years or older. The primary tumour types were lung cancer (n = 304, 74%), melanoma (n = 79, 19%) and urologic cancer (n = 27, 7%). Most of the administered treatments were PD(L)-1 inhibitors (n = 356, 82%). Median follow-up reached 46 months in the CTLA-4 cohort, and 20 months in the PD(L)-1 cohort. In both treatment cohorts, age did not impact OS (respectively, HR = 0.82, 95% CI 0.5-1.4; log-rank P = 0.49 and HR = 0.9, 95% CI 0.7-1.1; log-rank P = 0.27) or PFS (HR = 0.7, 95% CI 0.4-1.1; log-rank P = 0.13 and HR = 0.9, 95% CI 0.7-1.1; log-rank P = 0.19). Grade 3-4 irAEs rates were not statistically different between older and younger patients (11% vs 12%, P = 0.87). CONCLUSION: In a large real-world series of patients treated by ICI monotherapy, the long-term clinical outcomes were not statistically different between older or younger patients, with no increased immune-related toxicity

New insights into renal toxicity of the B-RAF inhibitor, vemurafenib, in patients with metastatic melanoma

International audiencePURPOSE: Vemurafenib (VMF) is a B-RAF inhibitor used in the treatment of B-RAF-V600-mutant metastatic melanomas. Reports of acute kidney injury (AKI) in patients treated with VMF are scarce. METHODS: To investigate the incidence and severity of AKI, we conducted a retrospective, observational, monocentric study in the Lyon Sud Hospital University, France, which included 74 patients with metastatic B-RAF-mutated melanomas treated with VMF, between June 2011 and August 2014. According to the Kidney Disease Improving Global Outcomes Guidelines, AKI is defined as an increase in serum creatinine concentration exceeding the baseline concentration by 1.5 fold. Serum creatinine was thus determined before treatment, on a monthly basis during treatment, and 3 months after treatment discontinuation. Patients were divided into two main groups: AKI-positive (AKI+) and AKI-negative (AKI-) and further subdivided into three groups according to AKI severity (stage 1, 2 or 3). To visualize the tissue damage caused by VMF, kidney biopsies were performed for two stage 1 AKI+ patients. RESULTS: Of the 74 patients, 30 (40.5 %) were AKI-, and of the 44 AKI+ patients (59.5 %), 29 (66 %) were diagnosed within the first three months of treatment. There were significantly more men in the AKI+ group: n = 33 (75 %) versus n = 12 (40 %) women, p = 0.004 with an odds ratio for developing AKI of 4.6 (95 % CI 1.48-14.23). Most AKI + cases were considered as stage 1 (n = 40; 91 %) and the remaining four (9 %) as stage 2 AKI. Kidney biopsies revealed interstitial fibrosis and acute focal tubular damage. However, renal failure was reversible in 80 % of patients within 3 months of VMF discontinuation. CONCLUSIONS: We observed frequent, reversible, moderately severe AKI with some histological evidence of tubular and interstitial damage in VMF-treated patients, suggesting that renal function should be carefully monitored in male patients, especially during the first 3 months

Dermoscopic features in BRAF and NRAS primary cutaneous melanoma: association with peppering and blue‐white veil

International audiencePURPOSE MYC rearrangement ( MYC-R) occurs in approximately 10% of diffuse large B-cell lymphomas (DLBCLs) and has been associated with poor prognosis in many studies. The impact of MYC-R on prognosis may be influenced by the MYC partner gene (immunoglobulin [IG] or a non-IG gene). We evaluated a large cohort of patients through the Lunenburg Lymphoma Biomarker Consortium to validate the prognostic significance of MYC-R (single-, double-, and triple-hit status) in DLBCL within the context of the MYC partner gene. METHODS The study cohort included patients with histologically confirmed DLBCL morphology derived from large prospective trials and patient registries in Europe and North America who were uniformly treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone therapy or the like. Fluorescence in situ hybridization for the MYC, BCL2, BCL6, and IG heavy and light chain loci was used, and results were correlated with clinical outcomes. RESULTS A total of 5,117 patients were identified of whom 2,383 (47%) had biopsy material available to assess for MYC-R. MYC-R was present in 264 (11%) of 2,383 patients and was associated with a significantly shorter progression-free and overall survival, with a strong time-dependent effect within the first 24 months after diagnosis. The adverse prognostic impact of MYC-R was only evident in patients with a concurrent rearrangement of BCL2 and/or BCL6 and an IG partner (hazard ratio, 2.4; 95% CI, 1.6 to 3.6; P < .001). CONCLUSION The negative prognostic impact of MYC-R in DLBCL is largely observed in patients with MYC double hit/triple-hit disease in which MYC is translocated to an IG partner, and this effect is restricted to the first 2 years after diagnosis. Our results suggest that diagnostic strategies should be adopted to identify this high-risk cohort, and risk-adjusted therapeutic approaches should be refined further

ZEB1-mediated melanoma cell plasticity enhances resistance to MAPK inhibitors

International audienceTargeted therapies with MAPK inhibitors (MAPKi) are faced with severe problems of resistance in BRAF-mutant melanoma. In parallel to the acquisition of genetic mutations, melanoma cells may also adapt to the drugs through phenotype switching. The ZEB1 transcription factor, a known inducer of EMT and invasiveness, is now considered as a genuine oncogenic factor required for tumor initiation, cancer cell plasticity, and drug resistance in carcinomas. Here, we show that high levels of ZEB1 expression are associated with inherent resistance to MAPKi in BRAFV600-mutated cell lines and tumors. ZEB1 levels are also elevated in melanoma cells with acquired resistance and in biopsies from patients relapsing while under treatment. ZEB1 overexpression is sufficient to drive the emergence of resistance to MAPKi by promoting a reversible transition toward a MITFlow/p75high stem-like and tumorigenic phenotype. ZEB1 inhibition promotes cell differentiation, prevents tumorigenic growth in vivo, sensitizes naive melanoma cells to MAPKi, and induces cell death in resistant cells. Overall, our results demonstrate that ZEB1 is a major driver of melanoma cell plasticity, driving drug adaptation and phenotypic resistance to MAPK