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Sunitinib alone was not inferior to nephrectomy followed by sunitinib in patients with metastatic renal-cell carcinoma who were classified as having intermediate-risk or poor-risk disease. (Funded by Assistance Publique-Hôpitaux de Paris and others; CARMENA ClinicalTrials.gov number, NCT00930033 .).

Larynx preservation, progression-free interval, and overall survival were similar in both arms, as were acute and late toxic effects.

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Background Poor-prognosis germ-cell tumours (GCT) are associated with only a 50% cure rate. Our hypothesis was that treatment intensification based on an early tumour marker decline will improve progression-free survival (PFS). Methods In this phase III, multicentre, international trial (NCT00104676 ; EU-20502), after patients with poor-prognosis GCT defined according to the International Germ-Cell Cancer Consensus Group (IGCCCG) had received one cycle of cisplatin (20 mg/m2/day × 5 days), etoposide (100 mg/m2/day × 5 days), and bleomycin (30 mg/week) (BEP), AFP and hCG were assessed between day 18 and 21: 1) patients with a favourable decline continued BEP (Fav-BEP); 2) patients with an unfavourable decline were randomised to receive either BEP (Unfav-BEP) or a dose-dense regimen (Unfav-dose-dense), consisting of paclitaxel (175 mg/ m2 day 1)-BEP plus oxaliplatin (130 mg/ m2 day 10) (2 cycles), followed by cisplatin (100 mg/ m2 day 1), ifosfamide (2 g/ m2 on days 10, 12, 14 + mesna), and bleomycin (25 units/day, by continuous infusion × 5 days on day 10 to 14) (2 cycles), with G-CSF support. Centrally blocked randomisation stratified by centre was used. The primary endpoint was PFS and the efficacy analysis was conducted on an intention-to-treat basis i.e. it included all randomised patients. The planned trial accrual was completed in May 2012 and follow-up is ongoing. Results 263 patients were enrolled and 203 had an unfavourable tumour marker decline (randomised: 105 Unfav-dose-dense arm, 98 Unfav-BEP arm). The 3-year PFS rate was 59% [95% Confidence Interval (CI): 49–68] in the Unfav-dose-dense arm versus 48% [95% CI: 38–59] in the Unfav-BEP arm (p=0.05; HR: 0.66 [95% CI: 0.44–1.00]). The 3-year PFS rate was 70% [95% CI: 57%–81%] for patients in the Fav-BEP arm (p=0.01 for PFS compared with the Unfav-BEP arm). More grade 3–4 neurotoxicity (7 [7%] vs 1 [1%]) and greater haematotoxicity occurred in the dose-dense arm, with no excess febrile neutropenia (18 [17%] vs 18 [18%]) or toxic deaths (1 each arm). Salvage high-dose chemotherapy + a stem-cell transplant were required in 6 [6%] in the Unfav-dose-dense arm and 16 [16%] patients in the Unfav-BEP arm (p=0.015). Conclusion Personalising treatment with chemotherapy intensification reduces the risk of progression or death in patients with poor-prognosis GCT and an unfavourable tumour marker decline.

Both regimens produced similar results in terms of favorable response rates. As the trial was underpowered for survival analyses, conclusive data would require a larger randomized trial. Unless such a study is done, 3BE500P is the treatment of choice for metastatic NSGCT patients.

PURPOSE Nivolumab is standard of care for patients with metastatic clear cell renal cell carcinoma (ccRCC) after failure of antiangiogenic therapies, but its activity on brain metastases from ccRCC remains unknown, because these patients were excluded from pivotal studies. We aimed to assess the activity of nivolumab in this population. METHODS The GETUG-AFU 26 NIVOREN phase II trial assessed the activity and safety of nivolumab in patients with metastatic ccRCC who failed vascular endothelial growth factor–directed therapies ( ClinicalTrials.gov identifier: NCT03013335 ). Patients with asymptomatic brain metastases were prospectively identified and underwent dedicated brain evaluation. Two cohorts were constituted: cohort A comprised patients with previously untreated brain metastases, and cohort B comprised patients whose brain metastases underwent prior therapy. The primary end point was intracranial response rate in cohort A. RESULTS Seventy-three patients with brain metastases were included: 39 in cohort A and 34 in cohort B. Intracranial response rate was 12% in cohort A; no objective response was reported in patients with brain lesions that were multiple or larger than 1 cm. Median intracranial progression-free survival was 2.7 months (95% CI, 2.3 to 4.6 months) in cohort A and 4.8 months (95% CI, 3.0 to 8.0 months) in cohort B, with adjusted hazard ratio of 2.04 (95% CI, 1.08 to 3.83). Overall survival rate at 12 months was 67% (95% CI, 49.6% to 79.1%) in cohort A and 59% (95% CI, 40.6% to 73.2%) in cohort B. Most patients in cohort A (72%) needed subsequent focal brain therapy. Nivolumab was well tolerated, with no unexpected toxicity. CONCLUSION Nivolumab activity is limited in patients with untreated brain metastases from ccRCC. Brain imaging and focal therapy should be considered before immune checkpoint inhibitors in patients with metastatic ccRCC.

Purpose Both concurrent chemoradiotherapy (CT-RT) and cetuximab radiotherapy (cetux-RT) have been established as the standard of care for the treatment of locally advanced squamous cell carcinoma of the head and neck. It was not known whether the addition of induction chemotherapy before cetux-RT could improve outcomes compared with standard of care CT-RT. Patients and Methods The current trial was restricted to patients with nonmetastatic N2b, N2c, or N3 squamous cell carcinoma of the head and neck and fit for taxotere, cisplatin, fluorouracil (TPF). Patients were randomly assigned to receive three cycles of TPF followed by cetux-RT versus concurrent carboplatin fluorouracil and RT as recommended in National Comprehensive Cancer Network guidelines. The trial was powered to detect a hazard ratio (HR) of 0.66 in favor of TPF plus cetux-RT for progression-free survival at 2 years. The inclusion of 180 patients per arm was needed to achieve 80% power at a two-sided significance level of .05. Results Between 2009 and 2013, 370 patients were included. All patients and tumors characteristics were well balanced between arms. There were more cases of grade 3 and 4 neutropenia in the induction arm, and the induction TPF was associated with 6.6% treatment-related deaths. With a median follow-up of 2.8 years, 2-year progression-free survival was not different between both arms (CT-RT, 0.38 v TPF + cetux-RT, 0.36; HR, 0.93 [95% CI, 0.73 to 1.20]; P = .58). HR was 0.98 (95% CI, 0.74 to 1.3; P = .90) for locoregional control and 1.12 (95% CI, 0.86 to 1.46; P = .39) for overall survival. These effects were observed regardless of p16 status. The rate of distant metastases was lower in the TPF arm (HR, 0.54 [95% CI, 0.30 to 0.99]; P = .05). Conclusion Induction TPF followed by cetux-RT did not improve outcomes compared with CT-RT in a population of patients with advanced cervical lymphadenopathy.