Nivolumab with or without ipilimumab in patients with recurrent or metastatic cervical cancer (CheckMate 358): a phase 1-2, open-label, multicohort trial.

BACKGROUND: In preliminary findings from the recurrent or metastatic cervical cancer cohort of CheckMate 358, nivolumab showed durable anti-tumour responses, and the combination of nivolumab plus ipilimumab showed promising clinical activity. Here, we report long-term outcomes from this cohort. METHODS: CheckMate 358 was a phase 1-2, open-label, multicohort trial. The metastatic cervical cancer cohort enrolled patients from 30 hospitals and cancer centres across ten countries. Female patients aged 18 years or older with a histologically confirmed diagnosis of squamous cell carcinoma of the cervix with recurrent or metastatic disease, an Eastern Cooperative Oncology Group performance status of 0 or 1, and up to two previous systemic therapies were enrolled into the nivolumab 240 mg every 2 weeks group, the randomised groups (nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks [NIVO3 plus IPI1] or nivolumab 1 mg/kg every 3 weeks plus ipilimumab 3 mg/kg every 3 weeks for four cycles then nivolumab 240 mg every 2 weeks [NIVO1 plus IPI3]), or the NIVO1 plus IPI3 expansion group. All doses were given intravenously. Patients were randomly assigned (1:1) to NIVO3 plus IPI1 or NIVO1 plus IPI3 via an interactive voice response system. Treatment continued until disease progression, unacceptable toxicity, or consent withdrawal, or for up to 24 months. The primary endpoint was investigator-assessed objective response rate. Anti-tumour activity and safety were analysed in all treated patients. This study is registered with ClinicalTrials.gov (NCT02488759) and is now completed. FINDINGS: Between October, 2015, and March, 2020, 193 patients were recruited in the recurrent or metastatic cervical cancer cohort of CheckMate 358, of whom 176 were treated. 19 patients received nivolumab monotherapy, 45 received NIVO3 plus IPI1, and 112 received NIVO1 plus IPI3 (45 in the randomised group and 67 in the expansion group). Median follow-up times were 19·9 months (IQR 8·2-44·8) with nivolumab, 12·6 months (7·8-37·1) with NIVO3 plus IPI1, and 16·7 months (7·2-27·5) with pooled NIVO1 plus IPI3. Objective response rates were 26% (95% CI 9-51; five of 19 patients) with nivolumab, 31% (18-47; 14 of 45 patients) with NIVO3 plus IPI1, 40% (26-56; 18 of 45 patients) with randomised NIVO1 plus IPI3, and 38% (29-48; 43 of 112 patients) with pooled NIVO1 plus IPI3. The most common grade 3-4 treatment-related adverse events were diarrhoea, hepatic cytolysis, hyponatraemia, pneumonitis, and syncope (one [5%] patient each; nivolumab group), diarrhoea, increased gamma-glutamyl transferase, increased lipase, and vomiting (two [4%] patients each; NIVO3 plus IPI1 group), and increased lipase (nine [8%] patients) and anaemia (seven [6%] patients; pooled NIVO1 plus IPI3 group). Serious treatment-related adverse events were reported in three (16%) patients in the nivolumab group, 12 (27%) patients in the NIVO3 plus IPI1 group, and 47 (42%) patients in the pooled NIVO1 plus IPI3 group. There was one treatment-related death due to immune-mediated colitis in the NIVO1 plus IPI3 group. INTERPRETATION: Nivolumab monotherapy and nivolumab plus ipilimumab combination therapy showed promise in the CheckMate 358 study as potential treatment options for recurrent or metastatic cervical cancer. Future randomised controlled trials of nivolumab plus ipilimumab or other dual immunotherapy regimens are warranted to confirm treatment benefit in this patient population. FUNDING: Bristol Myers Squibb and Ono Pharmaceutical.

Probiotics in septic acute kidney injury, a double blind, randomized control trial.

INTRODUCTION: During acute kidney injury (AKI) due to sepsis, the intestinal microbiota changes to dysbiosis, which affects the kidney function recovery (KFR) and amplifies the injury. Therefore, the administration of probiotics could improve dysbiosis and thereby increase the probability of KFR. METHODS: In this double-blind clinical trial, patients with AKI associated with sepsis were randomized (1:1) to receive probiotics or placebo for 7 consecutive days, with the objectives of evaluate the effect on KFR, mortality, kidney replacement therapy (KRT), urea, urine volume, serum electrolytes and adverse events at day 7. RESULTS: From February 2019 to March 2022, a total of 92 patients were randomized, 48 to the Probiotic and 44 to Placebo group. When comparing with placebo, those in the Probiotics did not observe a higher KFR (HR 0.93, 0.52-1.68, p = 0.81), nor was there a benefit in mortality at 6 months (95% CI 0.32-1.04, p = 0.06). With probiotics, urea values decreased significantly, an event not observed with placebo (from 154 to 80 mg/dl, p = 0.04 and from 130 to 109 mg/dl, p = 0.09, respectively). Urinary volume, need for KRT, electrolyte abnormalities, and adverse events were similar between groups. (ClinicalTrial.gov NCT03877081) (registered 03/15/2019). CONCLUSION: In AKI related to sepsis, probiotics for 7 consecutive days did not increase the probability of KFR, nor did other variables related to clinical improvement, although they were safe.

A randomized phase 3 trial comparing pemetrexed/carboplatin and docetaxel/carboplatin as first-line treatment for advanced, nonsquamous non-small cell lung cancer.

INTRODUCTION: This study compared survival without toxicity in patients with advanced, nonsquamous non-small cell lung cancer who were treated with first-line pemetrexed/carboplatin or docetaxel/carboplatin. METHODS: This multicenter, open-label, parallel-group, phase 3 trial comprised patients randomized (1:1) to pemetrexed/carboplatin (n = 128) or docetaxel/carboplatin (n = 132). Patients received treatment on day 1 of each 21-day cycle (maximum of six cycles). Treatment included carboplatin (area under the curve = 5 mg/ml × min) and pemetrexed (500 mg/m(2)) or docetaxel (75 mg/m(2)). The primary outcome measure, survival without treatment-emergent grade 3/4 toxicity, was defined as the time from randomization to the first treatment-emergent grade 3/4 adverse event or death and was analyzed using a log-rank test. The analysis population included 106 patients in the pemetrexed/carboplatin (Pem/Carb) group and 105 patients in the docetaxel/carboplatin (Doc/Carb) group. RESULTS: Survival without treatment-emergent grade 3/4 toxicity was significantly longer in the Pem/Carb versus the Doc/Carb group (log-rank p < 0.001; median survival without treatment-emergent grade 3/4 toxicity: 3.2 versus 0.7 months; adjusted hazard ratio = 0.45 [95% confidence interval: 0.34-0.61]). Overall survival was similar in the Pem/Carb versus the Doc/Carb group (log-rank p = 0.934; median survival: 14.9 versus 14.7 months; adjusted hazard ratio = 0.93 [95% confidence interval: 0.66-1.32]). Compared with the Doc/Carb group, fewer patients in the Pem/Carb group experienced grade 3/4 drug-related, treatment-emergent neutropenia, leukopenia, or febrile neutropenia, and more patients experienced anemia and thrombocytopenia. There were three study drug-related deaths during treatment in each group. CONCLUSIONS: The favorable benefit-to-risk profile of pemetrexed/carboplatin suggests that pemetrexed/carboplatin is an appropriate first-line treatment option for chemonaïve patients with advanced, nonsquamous non-small cell lung cancer.