NEJM original articles

Background. Limited evidence exists to support the simultaneous initiation of sodium-glucose cotransporter-2 inhibitors and finerenone, a nonsteroidal mineralocorticoid receptor antagonist, in persons with chronic kidney disease and type 2 diabetes.

Methods. We randomly assigned participants with chronic kidney disease (estimated glomerular filtration rate [eGFR], 30 to 90 ml per minute per 1.73 m² of body-surface area), albuminuria (a urinary albumin-to-creatinine ratio of 100 to ≤5000 [with albumin measured in milligrams and creatinine measured in grams]), and type 2 diabetes, who were already taking a renin-angiotensin system inhibitor, in a 1:1:1 ratio to receive finerenone (with empagliflozin-matching placebo) at a dose of 10 or 20 mg per day, empagliflozin at a dose of 10 mg per day (with finerenone-matching placebo), or a combination of finerenone and empagliflozin. The primary outcome was the relative change in the log-transformed mean urinary albumin-to-creatinine ratio from baseline to 180 days. Safety was assessed.

Results. At baseline, the urinary albumin-to-creatinine ratio was similar among the participants in the three groups; the median value was 579 (interquartile range, 292 to 1092) among those with available data (265 in the combination-therapy group, 258 in the finerenone group, and 261 participants in the empagliflozin group). At day 180, the reduction in the urinary albumin-to-creatinine ratio with combination therapy was 29% greater than that with finerenone alone (least-squares mean ratio of the difference in the change from baseline, 0.71; 95% confidence interval [CI], 0.61 to 0.82; P<0.001) and 32% greater than that with empagliflozin alone (least-squares mean ratio of the difference in the change from baseline, 0.68; 95% CI, 0.59 to 0.79; P<0.001). Neither agent, alone or in combination, led to unexpected adverse events. Symptomatic hypotension, acute kidney injury, and hyperkalemia leading to drug discontinuation were uncommon.

Conclusions. Among persons with both chronic kidney disease and type 2 diabetes, initial therapy with finerenone plus empagliflozin led to a greater reduction in the urinary albumin-to-creatinine ratio than either treatment alone. (Funded by Bayer; CONFIDENCE ClinicalTrials.gov number, NCT05254002.).

Background. Plague is a high-consequence infectious disease with epidemic potential. Current treatment guidelines are based on weak evidence.

Methods. We enrolled persons (excluding pregnant persons) in Madagascar who had clinically suspected bubonic plague during 2020-2024. Using an open-label noninferiority design, we compared two treatments included in the national plague guidelines: oral ciprofloxacin for 10 days (ciprofloxacin monotherapy) or injectable aminoglycoside for 3 days followed by oral ciprofloxacin for 7 days (aminoglycoside-ciprofloxacin). The primary end point was treatment failure on day 11, with treatment failure defined as death, fever, secondary pneumonic plague, or alternative or prolonged plague treatment. To show noninferiority of ciprofloxacin monotherapy among patients with laboratory-confirmed or probable infections, the upper boundary of the 95% confidence interval around the risk difference had to be less than 15 percentage points.

Results. A total of 933 patients underwent screening; 450 patients with suspected bubonic plague were enrolled and underwent randomization. A total of 220 patients (110 per group) had confirmed infection, and 2 (1 per group) had probable infection. Of the patients who underwent randomization, 53.2% were male, and the median age was 14 years (range, 2 to 72). Ciprofloxacin monotherapy was noninferior to aminoglycoside-ciprofloxacin therapy: among the patients with confirmed or probable infection, treatment failure occurred in 9.0% (10 of 111 patients) in the ciprofloxacin monotherapy group and 8.1% (9 of 111 patients) in the aminoglycoside-ciprofloxacin group (difference, 0.9 percentage points; 95% confidence interval, -6.0 to 7.8). Noninferiority was consistent in other prespecified analysis populations. A total of 5 patients in the ciprofloxacin monotherapy group and 4 patients in the aminoglycoside-ciprofloxacin group died, and secondary pneumonic plague developed in 3 patients in each group. The incidence of adverse events among patients with confirmed or probable infections was similar in the two groups - 18.0% in the ciprofloxacin monotherapy group and 18.9% in the aminoglycoside-ciprofloxacin group had adverse events, and 7.2% and 5.4%, respectively, had serious adverse events.

Conclusions. Oral ciprofloxacin monotherapy for 10 days was noninferior to an aminoglycoside-ciprofloxacin sequential combination for the treatment of patients with bubonic plague. (Funded by the U.K. Foreign, Commonwealth, and Development Office and Wellcome; IMASOY ClinicalTrials.gov number, NCT04110340.).

Background. Vepdegestrant is an oral proteolysis-targeting chimera (PROTAC) estrogen receptor (ER) degrader that directly harnesses the ubiquitin-proteasome system.

Methods. In this phase 3, open-label, randomized trial, we enrolled patients with ER-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer who had received one previous line of cyclin-dependent kinase 4 and 6 inhibitor therapy plus one line of endocrine therapy (and up to one additional line of endocrine therapy). Patients were randomly assigned in a 1:1 ratio to receive vepdegestrant at a dose of 200 mg orally once every day of each 28-day cycle or fulvestrant at a dose of 500 mg, administered intramuscularly, on day 1 and day 15 of cycle 1 and on day 1 of subsequent cycles, with randomization stratified according to ESR1-mutation status and presence or absence of visceral disease. The primary end point was progression-free survival as assessed by blinded independent central review among the patients with ESR1 mutations and among all the patients who underwent randomization. Progression-free survival was estimated with Kaplan-Meier methods and hazard ratios with a stratified Cox proportional-hazards model.

Results. A total of 624 patients underwent randomization; 313 were assigned to receive vepdegestrant, and 311 to receive fulvestrant. Among the 270 patients with ESR1 mutations, the median progression-free survival was 5.0 months (95% confidence interval [CI], 3.7 to 7.4) with vepdegestrant and 2.1 months (95% CI, 1.9 to 3.5) with fulvestrant (hazard ratio, 0.58 [95% CI, 0.43 to 0.78]; P<0.001). Among all the patients, the median progression-free survival was 3.8 months (95% CI, 3.7 to 5.3) with vepdegestrant and 3.6 months (95% CI, 2.6 to 4.0) with fulvestrant (hazard ratio, 0.83 [95% CI, 0.69 to 1.01]; P = 0.07). Adverse events of grade 3 or higher occurred in 23.4% of the patients in the vepdegestrant group and in 17.6% of the patients in the fulvestrant group. Adverse events led to treatment discontinuation in 2.9% and 0.7% of the patients, respectively.

Conclusions. Among patients with ER-positive, HER2-negative advanced breast cancer, vepdegestrant was associated with significantly longer progression-free survival than fulvestrant in the subgroup with ESR1 mutations but not in the full patient population. (Funded by Pfizer and Arvinas Estrogen Receptor; VERITAC-2 ClinicalTrials.gov number, NCT05654623.).

Background. Mutations in ESR1 are the most common mechanism of acquired resistance to treatment with an aromatase inhibitor plus a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor for advanced breast cancer. Camizestrant, a next-generation selective estrogen-receptor (ER) degrader and complete ER antagonist, has shown antitumor activity in ER-positive advanced breast cancer.

Methods. We tested patients with advanced breast cancer with ER-positive, human epidermal growth factor receptor 2 (HER2)-negative tumors for ESR1 mutations in circulating tumor DNA (ctDNA) once every 2 to 3 months. All the patients had received at least 6 months of first-line therapy with an aromatase inhibitor plus a CDK4/6 inhibitor (palbociclib, ribociclib, or abemaciclib). Patients who were found to have an ESR1 mutation and did not have radiologic progression were assigned in a 1:1 ratio to switch to camizestrant (75 mg once daily) with a continued CDK4/6 inhibitor plus placebo in place of an aromatase inhibitor or to continue to receive an aromatase inhibitor plus a CDK4/6 inhibitor plus placebo in place of camizestrant. The primary outcome was investigator-assessed progression-free survival.

Results. A total of 3256 patients were tested for an ESR1 mutation. The 315 eligible patients were assigned to switch to camizestrant (157 patients) or to continue to receive an aromatase inhibitor (158 patients). At an interim analysis at a median follow-up of 12.6 months, the median progression-free survival was 16.0 months (95% confidence interval [CI], 12.7 to 18.2) in the camizestrant group and 9.2 months (95% CI, 7.2 to 9.5) in the aromatase-inhibitor group (hazard ratio for progression or death, 0.44; 95% CI, 0.31 to 0.60; P<0.0001). The median time until a deterioration in the patient-reported global health status and quality of life occurred was 21.0 months with camizestrant and 6.4 months with an aromatase inhibitor (hazard ratio, 0.54; 95% CI, 0.34 to 0.84). The frequency of discontinuation because of adverse events was 1.3% with camizestrant and 1.9% with an aromatase inhibitor.

Conclusions. In patients with ER-positive, HER2-negative advanced breast cancer with an ESR1 mutation that emerged during treatment, those who were switched to camizestrant with continuation of a CDK4/6 inhibitor during first-line therapy had significantly longer progression-free survival than those who maintained the aromatase-inhibitor combination. (Funded by AstraZeneca; SERENA-6 ClinicalTrials.gov number, NCT04964934.).