Rossignol J., Terriou L., Robu D., Willekens C., Hivert B., Pascal L., Guieze R., Trappe R., Baillet C., Huglo D., Morschhauser F.   Radioimmunotherapy (Y-90-Ibritumomab Tiuxetan) for Posttransplant Lymphoproliferative Disorders After Prior Exposure to Rituximab.  Am. J. Transplant..  2015 ;15 :1976-1981

Posttransplantation lymphoproliferative disorders (PTLDs) are life-threatening complications after solid organ and hematopoietic stem cell transplantation. Only half of CD20-positive PTLDs respond to rituximab monotherapy, and outcomes remain poor for patients with relapsed/refractory disease, especially those who do not qualify for an anthracycline containing regimen due to frailty or comorbidities. Radioimmunotherapy (RIT) might be an option in this particular setting. We report a panel of eight patients with rituximab refractory/relapsed CD20-positive PTLDs including three ineligible for subsequent CHOP-like chemotherapy who received (90) Y-Ibritumomab tiuxetan as a single agent (n = 7) or combined to chemotherapy (n = 1). Five out of eight patients were kidney transplant recipients, while 2/8 had a liver transplant and 1/8 had a heart transplant. Patients received a median of two previous therapies. Overall response rate was 62.5%. Importantly, all responders achieved complete response. At a median follow-up of 37 months [5; 84], complete response was ongoing in four patients. Toxicity was predominantly hematological and easily manageable. No graft rejection was noticed concomitantly or following RIT administration despite immunosuppression reduction after diagnosis of PTLDs. This report emphasizes the potential efficiency of salvage RIT for early rituximab refractory PTLDs without any unexpected toxicity.

Robert C., Schachter J., Long G. V., Arance A., Grob J. J., Mortier L., Daud A., Carlino M. S., McNeil C., Lotem M., Larkin J., Lorigan P., Neyns B., Blank C. U., Hamid O., Mateus C., Shapira-Frommer R., Kosh M., Zhou H., Ibrahim N., Ebbinghaus S., Ribas A.   Pembrolizumab versus Ipilimumab in Advanced Melanoma.  N. Engl. J. Med..  2015 ;372 :2521-2532

BACKGROUND: The immune checkpoint inhibitor ipilimumab is the standard-of-care treatment for patients with advanced melanoma. Pembrolizumab inhibits the programmed cell death 1 (PD-1) immune checkpoint and has antitumor activity in patients with advanced melanoma. METHODS: In this randomized, controlled, phase 3 study, we assigned 834 patients with advanced melanoma in a 1:1:1 ratio to receive pembrolizumab (at a dose of 10 mg per kilogram of body weight) every 2 weeks or every 3 weeks or four doses of ipilimumab (at 3 mg per kilogram) every 3 weeks. Primary end points were progression-free and overall survival. RESULTS: The estimated 6-month progression-free-survival rates were 47.3% for pembrolizumab every 2 weeks, 46.4% for pembrolizumab every 3 weeks, and 26.5% for ipilimumab (hazard ratio for disease progression, 0.58; P<0.001 for both pembrolizumab regimens versus ipilimumab; 95% confidence intervals [CIs], 0.46 to 0.72 and 0.47 to 0.72, respectively). Estimated 12-month survival rates were 74.1%, 68.4%, and 58.2%, respectively (hazard ratio for death for pembrolizumab every 2 weeks, 0.63; 95% CI, 0.47 to 0.83; P=0.0005; hazard ratio for pembrolizumab every 3 weeks, 0.69; 95% CI, 0.52 to 0.90; P=0.0036). The response rate was improved with pembrolizumab administered every 2 weeks (33.7%) and every 3 weeks (32.9%), as compared with ipilimumab (11.9%) (P<0.001 for both comparisons). Responses were ongoing in 89.4%, 96.7%, and 87.9% of patients, respectively, after a median follow-up of 7.9 months. Efficacy was similar in the two pembrolizumab groups. Rates of treatment-related adverse events of grade 3 to 5 severity were lower in the pembrolizumab groups (13.3% and 10.1%) than in the ipilimumab group (19.9%). CONCLUSIONS: The anti-PD-1 antibody pembrolizumab prolonged progression-free survival and overall survival and had less high-grade toxicity than did ipilimumab in patients with advanced melanoma. (Funded by Merck Sharp & Dohme; KEYNOTE-006 ClinicalTrials.gov number, NCT01866319.).

Robert C., Long G. V., Brady B., Dutriaux C., Maio M., Mortier L., Hassel J. C., Rutkowski P., McNeil C., Kalinka-Warzocha E., Savage K. J., Hernberg M. M., Lebbe C., Charles J., Mihalcioiu C., Chiarion-Sileni V., Mauch C., Cognetti F., Arance A., Schmidt H., Schadendorf D., Gogas H., Lundgren-Eriksson L., Horak C., Sharkey B., Waxman I. M., Atkinson V., Ascierto P. A.   Nivolumab in Previously Untreated Melanoma without BRAF Mutation.  N. Engl. J. Med..  2015 ;372 :320-330

BACKGROUND: Nivolumab was associated with higher rates of objective response than chemotherapy in a phase 3 study involving patients with ipilimumab-refractory metastatic melanoma. The use of nivolumab in previously untreated patients with advanced melanoma has not been tested in a phase 3 controlled study. METHODS: We randomly assigned 418 previously untreated patients who had metastatic melanoma without a BRAF mutation to receive nivolumab (at a dose of 3 mg per kilogram of body weight every 2 weeks and dacarbazine-matched placebo every 3 weeks) or dacarbazine (at a dose of 1000 mg per square meter of body-surface area every 3 weeks and nivolumab-matched placebo every 2 weeks). The primary end point was overall survival. RESULTS: At 1 year, the overall rate of survival was 72.9% (95% confidence interval [CI], 65.5 to 78.9) in the nivolumab group, as compared with 42.1% (95% CI, 33.0 to 50.9) in the dacarbazine group (hazard ratio for death, 0.42; 99.79% CI, 0.25 to 0.73; P<0.001). The median progression-free survival was 5.1 months in the nivolumab group versus 2.2 months in the dacarbazine group (hazard ratio for death or progression of disease, 0.43; 95% CI, 0.34 to 0.56; P<0.001). The objective response rate was 40.0% (95% CI, 33.3 to 47.0) in the nivolumab group versus 13.9% (95% CI, 9.5 to 19.4) in the dacarbazine group (odds ratio, 4.06; P<0.001). The survival benefit with nivolumab versus dacarbazine was observed across prespecified subgroups, including subgroups defined by status regarding the programmed death ligand 1 (PD-L1). Common adverse events associated with nivolumab included fatigue, pruritus, and nausea. Drug-related adverse events of grade 3 or 4 occurred in 11.7% of the patients treated with nivolumab and 17.6% of those treated with dacarbazine. CONCLUSIONS: Nivolumab was associated with significant improvements in overall survival and progression-free survival, as compared with dacarbazine, among previously untreated patients who had metastatic melanoma without a BRAF mutation. (Funded by Bristol-Myers Squibb; CheckMate 066 ClinicalTrials.gov number, NCT01721772.).

Robert C., Lebbe C., Ricard S., Saiag P., Grange F., Mortier L., Lhomel C., Sassolas B.   Personal vs. intrinsic melanoma risk awareness: results of the EDIFICE Melanoma survey.  J. Eur. Acad. Dermatol. Venereol..  2015 ;29 :31-34

BACKGROUND: The efficiency of skin cancer prevention programmes is strongly correlated with the information dispensed, and with the level of risk awareness, of the overall population on one hand, and on the other, of specific sub-populations, according to their risk profiles. OBJECTIVES: The primary objective of this analysis was to establish a correlation between individual perceptions of the risk of developing a melanoma, and the recognized intrinsic risk factors for a given individual. Secondary objectives were to assess factors that are potentially associated with acceptable, high or low perception of melanoma risk. METHODS: The EDIFICE Melanoma survey was conducted in 2011 via telephone interviews of a representative sample of 1502 individuals aged 18 and older in the French population. RESULTS: Although most respondents (73%) had a true estimation of their intrinsic risk for melanoma, those who did not (underestimation, 17%; overestimation, 10%) had an attitude towards environmental risk factors (sun exposure, sun protection, sunbed use) that did not compensate for this misplaced perception. CONCLUSIONS: Skin cancer prevention messages need to be reinforced, new methods of evaluating understanding of the messages need to be implemented, and both need to be included into personal risk assessment.

Robert C., Karaszewska B., Schachter J., Rutkowski P., Mackiewicz A., Stroyakovskiy D., Lichinitser M., Dummer R., Grange F., Mortier L., Chiarion-Sileni V., Drucis K., Krajsova I., Hauschild A., Mookerjee B., Legos J., Schadendorf D.   Two year estimate of overall survival in COMBI-v, a randomized, open-label, phase III study comparing the combination of dabrafenib (D) and trametinib (T) with vemurafenib (Vem) as first-line therapy in patients (pts) with unresectable or metastatic BRAF .  Eur. J. Cancer.  2015 ;51 :S663-S664
Robert C., Karaszewska B., Schachter J., Rutkowski P., Mackiewicz A., Stroiakovski D., Lichinitser M., Dummer R., Grange F., Mortier L., Chiarion-Sileni V., Drucis K., Krajsova I., Hauschild A., Lorigan P., Wolter P., Long G. V., Flaherty K., Nathan P., Ribas A., Martin A. M., Sun P., Crist W., Legos J., Rubin S. D., Little S. M., Schadendorf D.   Improved Overall Survival in Melanoma with Combined Dabrafenib and Trametinib.  N. Engl. J. Med..  2015 ;372 :30-39

BACKGROUND: The BRAF inhibitors vemurafenib and dabrafenib have shown efficacy as monotherapies in patients with previously untreated metastatic melanoma with BRAF V600E or V600K mutations. Combining dabrafenib and the MEK inhibitor trametinib, as compared with dabrafenib alone, enhanced antitumor activity in this population of patients. METHODS: In this open-label, phase 3 trial, we randomly assigned 704 patients with metastatic melanoma with a BRAF V600 mutation to receive either a combination of dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) or vemurafenib (960 mg twice daily) orally as first-line therapy. The primary end point was overall survival. RESULTS: At the preplanned interim overall survival analysis, which was performed after 77% of the total number of expected events occurred, the overall survival rate at 12 months was 72% (95% confidence interval [CI], 67 to 77) in the combination-therapy group and 65% (95% CI, 59 to 70) in the vemurafenib group (hazard ratio for death in the combination-therapy group, 0.69; 95% CI, 0.53 to 0.89; P=0.005). The prespecified interim stopping boundary was crossed, and the study was stopped for efficacy in July 2014. Median progression-free survival was 11.4 months in the combination-therapy group and 7.3 months in the vemurafenib group (hazard ratio, 0.56; 95% CI, 0.46 to 0.69; P<0.001). The objective response rate was 64% in the combination-therapy group and 51% in the vemurafenib group (P<0.001). Rates of severe adverse events and study-drug discontinuations were similar in the two groups. Cutaneous squamous-cell carcinoma and keratoacanthoma occurred in 1% of patients in the combination-therapy group and 18% of those in the vemurafenib group. CONCLUSIONS: Dabrafenib plus trametinib, as compared with vemurafenib monotherapy, significantly improved overall survival in previously untreated patients with metastatic melanoma with BRAF V600E or V600K mutations, without increased overall toxicity. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT01597908.).

Rizk J., Ouzzane A., Flamand V., Fantoni J. C., Puech P., Leroy X., Villers A.   Long term biochemical recurrence free survival after radical prostatectomy for cancer: Comparative analysis according to surgical approach and clinicopathological stage.  Prog. Urol..  2015 ;25 :157-168

OBJECTIVE: To assess long term biochemical recurrence free survival after radical prostatectomy according to open, laparoscopic and robot-assisted surgical approach and clinicopathological stage. MATERIAL AND METHODS: A cohort study of 1313 consecutive patients treated by radical prostatectomy for localized or locally advanced prostate cancer between 2000 and 2013. Open surgery (63.7%), laparoscopy (10%) and robot-assisted laparoscopy (26.4%) were performed. Biochemical recurrence was defined by PSA>0,1ng/mL. The biochemical recurrence free survival was described by Kaplan Meier method and prognostic factors were analysed by multivariable Cox regression. RESULTS: Median follow-up was 57 months (IQR: 31-90). Ten years biochemical recurrence free survival was 88.5%, 71.6% and 53.5% respectively for low, intermediate and high-risk D'Amico groups. On multivariable analysis, the worse prognostic factor was Gleason score (P<0.001). Positive surgical margins rate was 53% in pT3 tumours and 24% in pT2 tumours (P<0.001). Biochemical recurrence free survival (P=0.06) and positive surgical margins rate (P=0.87) were not statistically different between the three surgical approaches. CONCLUSION: Biochemical recurrence free survival in our study does not differ according to surgical approach and is similar to published series. Ten years biochemical recurrence free survival for high-risk tumours without hormone therapy is 54% justifying the role of surgery in the therapeutic conversations in this group of tumours. LEVEL OF EVIDENCE: 3.

Rischmann P., Crouzet S., Villers A., Pasticier G., Petit J., Surga N., Bugel H., Bondil P., Mallick S., Toledano H., Jung J., Gelet A.   [Not Available].  Prog. Urol..  2015 ;25 :834
Ribas A., Schachter J., Long G. V., Arance A., Grob J. J., Mortier L., Daud A., Carlino M. S., McNeil C., Lotem M., Larkin J., Lorigan P., Neyns B., Blank C. U., Hamid O., Kosh M., Zhou H. H., Ibrahim N., Ebbinghaus S., Robert C.   Phase III study of pembrolizumab (MK-3475) versus ipilimumab in patients with ipilimumab-naive advanced melanoma.  Cancer Res..  2015 ;75 :CT101-CT101
Ramirez D., Flammand V., Villers A., Kaouk J. H.   NOVEL ROBOTIC SYSTEM FOR SINGLE PORT PARTIAL NEPHRECTOMY: INITIAL EXPERIENCE AND TECHNIQUE.  J. Urol..  2015 ;193 :E777-E778