NEJM original articles

Background. Patients are at increased risk for recurrent ischemic events after an acute coronary syndrome event. Milvexian, an oral factor XIa inhibitor, may reduce the risk of major adverse clinical events with minimal bleeding risk.

Methods. In this phase 3, randomized, placebo-controlled trial, we evaluated the efficacy and safety of milvexian when added to standard antiplatelet therapy within 7 days after an acute coronary syndrome event. Patients were assigned in a 1:1 ratio to receive oral milvexian (25 mg twice daily) or matched placebo. The primary efficacy outcome was a composite of cardiovascular death, myocardial infarction, or ischemic stroke as evaluated in a time-to-event analysis. The principal safety outcome was Bleeding Academic Research Consortium (BARC) type 3c or 5 bleeding (intracranial or intraocular bleeding that compromises vision or fatal bleeding).

Results. After a planned interim analysis that was based on 556 adjudicated efficacy end points, the trial was terminated for futility. A total of 14,194 patients had been enrolled, with 7094 assigned to receive milvexian and 7100 to receive placebo. After a median follow-up of 12.2 months, a primary efficacy outcome event had occurred in 384 patients (5.4%) in the milvexian group and in 365 patients (5.1%) in the placebo group (hazard ratio, 1.05; 95% confidence interval, 0.91 to 1.21; P = 0.50). BARC type 3c or 5 bleeding occurred in 23 patients (0.3%) in the milvexian group and in 22 patients (0.3%) in the placebo group (P = 0.88).

Conclusions. Among patients with a recent acute coronary syndrome event, milvexian did not decrease the risk of cardiovascular death, myocardial infarction, or ischemic stroke but did not increase the risk of intracranial or fatal bleeding, as compared with placebo. (Funded by Janssen Research and Development and Bristol Myers Squibb; LIBREXIA ACS ClinicalTrials.gov number, NCT05754957.).

Background. Sjögren's disease is a complex, systemic autoimmune disease with no approved targeted therapies. Ianalumab is an IgG1 monoclonal antibody with a dual mechanism of action, depleting B cells through antibody-dependent cellular cytotoxicity and inhibiting B-cell activation and survival through blockade of B-cell activating factor receptor.

Methods. We conducted two 52-week, double-blind, randomized, placebo-controlled trials involving patients with active Sjögren's disease. Patients in the NEPTUNUS-1 trial were assigned in a 1:1 ratio to receive subcutaneous ianalumab (300 mg monthly) or placebo; patients in the NEPTUNUS-2 trial were assigned in a 1:1:1 ratio to receive 300 mg of ianalumab monthly or every 3 months or placebo. The primary end point was the change from baseline in the score on the European Alliance of Associations for Rheumatology (EULAR) Sjögren's Syndrome Disease Activity Index (ESSDAI) at week 48 (scores range from 0 to 123, with higher scores indicating greater disease activity). The first key secondary end point in the hierarchical plan for the NEPTUNUS-1 trial was an ESSDAI response (≥5-point reduction) at week 48; for the NEPTUNUS-2 trial, it was the change from baseline in the score on the Sjögren's Syndrome Symptom Diary (SSSD) or EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) at week 48.

Results. Overall, 275 patients underwent randomization in the NEPTUNUS-1 trial (ianalumab monthly, 137 patients; placebo, 138 patients) and 504 in the NEPTUNUS-2 trial (ianalumab monthly, 168 patients; ianalumab every 3 months, 167 patients; and placebo, 169 patients). In both trials, ianalumab monthly led to a significantly greater decrease in the ESSDAI score at week 48 than placebo, with a between-group difference of -1.3 points (95% confidence interval [CI], -2.6 to 0.0; P = 0.0496) in NEPTUNUS-1 and -1.0 points (95% CI, -2.0 to 0.0; P = 0.04) in NEPTUNUS-2. No significant differences in the incidence of an ESSDAI response or in the change from baseline in SSSD or ESSPRI scores were observed at week 48. The incidence of serious adverse events was similar with ianalumab and placebo. Nonserious local injection-site and systemic injection-related reactions were more common in the ianalumab groups.

Conclusions. In these two trials involving patients with active Sjögren's disease, ianalumab at a dose of 300 mg monthly resulted in a significantly greater decrease in disease activity at week 48 than placebo, although there were no significant differences in the incidence of an ESSDAI response or in the change from baseline in SSSD or ESSPRI symptom scores. (Funded by Novartis Pharma; NEPTUNUS-1 and NEPTUNUS-2 ClinicalTrials.gov numbers, NCT05350072 and NCT05349214, respectively.).

Background. In patients with infective endocarditis on the left side of the heart, the current recommendation of up to 6 weeks of antibiotic therapy is based largely on expert consensus opinion. Whether a clinical response-tailored antibiotic management strategy can shorten treatment duration without compromising safety is unclear.

Methods. In this international, open-label, randomized trial, we assigned adults in stable condition with infective endocarditis caused by Staphylococcus aureus, Enterococcus faecalis, or streptococcus species to receive either response-tailored or standard-duration antibiotic therapy. Before randomization, all the patients received at least the prespecified 2 to 4 weeks of therapy and met criteria for clinical stabilization. After randomization, patients in the tailored-therapy group discontinued antibiotics and those in the standard-therapy group continued standard treatment (total duration, 4 to 6 weeks). The primary efficacy end point was days alive without antibiotic treatment for infective endocarditis or bacteremia within 6 months after randomization (tested for superiority). The primary safety end point was a composite of death from any cause, unplanned cardiac surgery, or symptomatic embolic events within 6 months after randomization (tested for noninferiority; margin, 7.5 percentage points). Relapse of bacteremia or infective endocarditis was a key secondary end point.

Results. A total of 508 patients underwent randomization, with 255 assigned to response-tailored therapy and 253 to standard-duration therapy. The median time alive without antibiotic treatment was 183 days (interquartile range, 181 to 183) with tailored therapy and 169 days (interquartile range, 166 to 171) with standard therapy (Hodges-Lehmann estimated difference, 13 days; 95% confidence interval [CI], 12 to 13; P<0.001 for superiority). A primary safety end-point event occurred in 21 patients (8.2%) with tailored therapy and in 27 patients (10.7%) with standard therapy (absolute between-group difference, -2.4 percentage points; 95% CI, -7.7 to 2.7; P<0.001 for noninferiority), indicating noninferiority. Relapse occurred in 13 patients (5.1%) with tailored therapy and in 4 patients (1.6%) with standard therapy (P = 0.04).

Conclusions. Among patients with infective endocarditis on the left side of the heart, the use of a response-tailored antibiotic strategy resulted in a longer time alive without antibiotic therapy than standard-duration therapy and met the criterion for noninferiority with respect to safety but was associated with a higher incidence of relapse of bacteremia or infective endocarditis. (Funded by Sygeforsikringen "danmark" and others; POET II ClinicalTrials.gov number, NCT03851575.).

Background. Tambotatug pelitecan (known as Tam-Peli, a new antibody-drug conjugate that targets the immune-checkpoint molecule B7-H3) showed promising clinical efficacy in patients with relapsed extensive-stage small-cell lung cancer in early-phase trials.

Methods. In this phase 3, multicenter, open-label, randomized trial, we assigned eligible patients with small-cell lung cancer that had progressed after first-line platinum-based therapy in a 1:1 ratio to receive tambotatug pelitecan or topotecan. The primary end point was overall survival. The key secondary end points were progression-free survival and objective response as assessed by investigators. Here, we report the results from the prespecified interim analysis.

Results. A total of 451 patients underwent randomization: 225 were assigned to receive tambotatug pelitecan and 226 to receive topotecan. Overall survival was significantly longer with tambotatug pelitecan than with topotecan - a median of 13.3 months (95% confidence interval [CI], 12.1 to could not be estimated), as compared with 9.4 months (95% CI, 7.7 to 10.5); the stratified hazard ratio for death was 0.46 (95% CI, 0.35 to 0.62; P<0.001). Treatment with tambotatug pelitecan also resulted in significantly longer progression-free survival than treatment with topotecan (median, 7.4 months [95% CI, 6.1 to 7.6] vs. 2.8 months [95% CI, 1.8 to 3.0]; stratified hazard ratio, 0.29 [95% CI, 0.23 to 0.37]; P<0.001). A confirmed objective response occurred in 59.1% of the patients in the tambotatug pelitecan group, as compared with 9.7% of those in the topotecan group (P<0.001). The overall incidence of adverse events of grade 3 or higher was lower with tambotatug pelitecan than with topotecan (55.4% vs. 77.9%).

Conclusions. Among patients with relapsed small-cell lung cancer after platinum-based therapy, treatment with tambotatug pelitecan resulted in longer overall survival, longer progression-free survival, and a higher percentage of patients with an objective response than treatment with topotecan, with a lower incidence of adverse events of grade 3 or higher. (Funded by the Innovative Drug Research and Development National Science and Technology Major Project and MediLink Therapeutics; TAISHAN-302 ClinicalTrials.gov number, NCT06612151.).