NEJM original articles

Background. Whether successful catheter ablation for atrial fibrillation eliminates the need for long-term oral anticoagulant therapy is unknown.

Methods. We conducted an international, open-label, randomized, blinded-outcome-assessment trial involving 1284 patients who had undergone successful catheter ablation for atrial fibrillation at least 1 year earlier and had a CHA₂DS₂-VASc score (scores range from 0 to 9, with higher scores indicating a higher risk of stroke) of 1 or more (or ≥2 for women or for patients in whom vascular disease was a risk factor). Patients were randomly assigned to receive either aspirin (at a dose of 70 to 120 mg daily, depending on availability in the local jurisdiction) or rivaroxaban (at a dose of 15 mg) and followed for 3 years. Magnetic resonance imaging (MRI) of the head was performed after enrollment and at 3 years. The primary outcome was a composite of stroke, systemic embolism, or new covert embolic stroke (defined by ≥1 new infarct measuring ≥15 mm on MRI) at 3 years.

Results. A total of 641 patients were assigned to the rivaroxaban group and 643 to the aspirin group. A primary-outcome event occurred in 5 patients (0.31 events per 100 patient-years) in the rivaroxaban group and in 9 patients (0.66 events per 100 patient-years) in the aspirin group (relative risk, 0.56; 95% confidence interval [CI], 0.19 to 1.65; absolute risk difference at 3 years, -0.6 percentage points; 95% CI, -1.8 to 0.5; P = 0.28). New cerebral infarcts measuring less than 15 mm occurred in 22 of 568 patients (3.9%) in the rivaroxaban group and in 26 of 590 patients (4.4%) in the aspirin group (relative risk, 0.89; 95% CI, 0.51 to 1.55). Fatal or major bleeding (the composite primary safety outcome) had occurred in 10 patients (1.6%) with rivaroxaban and in 4 patients (0.6%) with aspirin (hazard ratio, 2.51; 95% CI, 0.79 to 7.95) at 3 years.

Conclusions. Among patients who had had successful catheter ablation for atrial fibrillation at least 1 year earlier and had risk factors for stroke, treatment with rivaroxaban did not result in a significantly lower incidence of a composite of stroke, systemic embolism, or new covert embolic stroke than treatment with aspirin. (Funded by Bayer and others; OCEAN ClinicalTrials.gov number, NCT02168829.).

Background. In the CheckMate 238 trial, patients with resected stage IIIB-C or stage IV melanoma who were treated with nivolumab had longer recurrence-free survival than those who received ipilimumab. Data were needed on longer-term survival.

Methods. We randomly assigned patients in a 1:1 ratio to receive an intravenous infusion of nivolumab (at a dose of 3 mg per kilogram of body weight every 2 weeks) or ipilimumab (at a dose of 10 mg per kilogram every 3 weeks for four doses, then every 12 weeks) for up to 1 year or until disease recurrence or the occurrence of unacceptable toxic effects. Randomization was stratified according to disease stage and status with respect to programmed cell death ligand 1. The primary end point was recurrence-free survival; secondary end points included overall and distant metastasis-free survival and safety.

Results. At a minimum follow-up of nearly 9 years (107 months), the median duration of recurrence-free survival was 61.1 months with nivolumab and 24.2 months with ipilimumab (hazard ratio for recurrence or death, 0.76; 95% confidence interval [CI], 0.63 to 0.90); 9-year recurrence-free survival was 44% and 37%, respectively. The median duration of distant metastasis-free survival in patients with stage III melanoma was more than 9 years with nivolumab and 83.8 months with ipilimumab, with 9-year survival of 54% and 48%, respectively (hazard ratio for distant metastasis or death, 0.81; 95% CI, 0.65 to 1.00). The median overall survival was more than 9 years in both trial groups, with 9-year survival of 69% in the nivolumab group and 65% in the ipilimumab group (hazard ratio for death, 0.88; 95.03% CI, 0.69 to 1.11). The rates of death from melanoma at 9 years were 26% with nivolumab and 30% with ipilimumab (hazard ratio, 0.87; 95% CI, 0.67 to 1.13). Subsequent systemic therapy was administered to fewer patients in the nivolumab group than in the ipilimumab group (37.3% vs. 44.6%). No new late adverse events were reported.

Conclusions. The 9-year final data support a sustained finding of longer recurrence-free survival with nivolumab than with ipilimumab. (Funded by Bristol Myers Squibb and Ono Pharmaceutical; CheckMate 238 ClinicalTrials.gov number, NCT02388906; Eudra-CT number, 2014-002351-26.).

Background. Both tobevibart (a monoclonal antibody) and elebsiran (a small interfering RNA) target hepatitis B virus surface antigen (HBsAg). Their efficacy and safety in the treatment of chronic hepatitis D virus (HDV) infection are unknown.

Methods. In this ongoing, phase 2, open-label trial, we randomly assigned participants to receive tobevibart plus elebsiran every 4 weeks or tobevibart monotherapy every 2 weeks. The primary end point was a combined response, defined by an HDV RNA level below the limit of detection or a decrease in the HDV RNA level of at least 2 log₁₀ IU per milliliter from baseline (virologic response) and normalization of the alanine aminotransferase (ALT) level, at week 24.

Results. At week 24, a combined response was observed in 47% of participants (15 of 32) who received tobevibart plus elebsiran and in 70% of participants (23 of 33) who received tobevibart, with a virologic response in 100% (32 of 32) and 82% (27 of 33), respectively, and normalization of the ALT level in 47% (15 of 32) and 76% (25 of 33). At week 48, a combined response was observed in 56% of participants (18 of 32) with tobevibart plus elebsiran and 61% of participants (20 of 33) with tobevibart; undetectable HDV RNA (also known as target not detected, or TND; no amplification during reverse-transcriptase-polymerase-chain-reaction assay) in 66% (21 of 32) and 48% (16 of 33), respectively; normalization of the ALT level in 56% (18 of 32) and 61% (20 of 33); and an HBsAg level below 10 IU per milliliter in 91% (29 of 32) and 21% (7 of 33). No ALT flares were observed in participants starting tobevibart and elebsiran simultaneously or receiving tobevibart monotherapy. Through week 48, a total of 81% of participants who received tobevibart plus elebsiran and 94% of those who received tobevibart had at least one adverse event, primarily influenza-like illness and chills.

Conclusions. In this phase 2 trial, tobevibart plus elebsiran as well as tobevibart monotherapy decreased HDV RNA and ALT levels through week 48. Treatment with tobevibart plus elebsiran was associated with a high incidence of undetectable HDV RNA and of a decrease in the HBsAg level. (Funded by Vir Biotechnology; ClinicalTrials.gov number, NCT05461170.).

Background. Triple-negative breast cancer is an aggressive breast cancer subtype, and there remains an unmet need to improve outcomes in patients with previously untreated, programmed death ligand 1 (PD-L1)-positive, locally advanced unresectable or metastatic triple-negative breast cancer.

Methods. In this phase 3, open-label, international trial, we randomly assigned patients in a 1:1 ratio to receive sacituzumab govitecan plus pembrolizumab or chemotherapy plus pembrolizumab. The primary end point was progression-free survival as assessed by blinded independent central review. Secondary end points included overall survival, objective response (complete or partial response) and duration of response as assessed by blinded independent central review, and safety.

Results. A total of 443 patients were randomly assigned to receive sacituzumab govitecan plus pembrolizumab (221 patients) or chemotherapy plus pembrolizumab (222 patients). The median progression-free survival was 11.2 months (95% confidence interval [CI], 9.3 to 16.7) with sacituzumab govitecan plus pembrolizumab and 7.8 months (95% CI, 7.3 to 9.3) with chemotherapy plus pembrolizumab (hazard ratio for disease progression or death, 0.65; 95% CI, 0.51 to 0.84; two-sided P<0.001). Data for overall survival were immature. The percentage of patients with an objective response was 60% (95% CI, 53 to 66) with sacituzumab govitecan plus pembrolizumab and 53% (95% CI, 46 to 60) with chemotherapy plus pembrolizumab; among patients with a response, the median duration of response was 16.5 months (95% CI, 12.7 to 19.5) and 9.2 months (95% CI, 7.6 to 11.3), respectively. Adverse events of grade 3 or higher occurred in 71% of the patients receiving sacituzumab govitecan plus pembrolizumab and in 70% of those receiving chemotherapy plus pembrolizumab; the incidence of treatment discontinuation due to adverse events was 12% and 31%, respectively. Adverse events leading to death occurred in 3% of the patients in each group.

Conclusions. Sacituzumab govitecan plus pembrolizumab led to significantly longer progression-free survival than chemotherapy plus pembrolizumab among patients with previously untreated, PD-L1-positive, advanced triple-negative breast cancer. (Funded by Gilead Sciences; ASCENT-04/KEYNOTE-D19 ClinicalTrials.gov number, NCT05382286.).