NEJM original articles

Background. Until recently, no first-line targeted treatment options were available for patients with human epidermal growth factor receptor 2 (HER2)-mutant non-small-cell lung cancer (NSCLC). Zongertinib is an oral, irreversible tyrosine kinase inhibitor that selectively inhibits HER2 while sparing wild-type epidermal growth factor receptor (EGFR), thereby minimizing associated toxic effects.

Methods. We conducted a phase 1a-1b, multicohort trial to assess zongertinib in patients with advanced or metastatic nonsquamous HER2-mutant NSCLC. Here, we evaluated zongertinib at a dose of 120 mg once daily in patients who had not previously received treatment (cohort 2). The primary end point was objective response as assessed by blinded independent central review. Secondary end points included duration of response and progression-free survival. In addition, zongertinib was evaluated in patients with active brain metastases (exploratory cohort 4).

Results. In cohort 2, a total of 74 previously untreated patients received zongertinib at a dose of 120 mg. As of August 21, 2025, the percentage of patients with a confirmed objective response was 76% (95% confidence interval [CI], 65 to 84); the median duration of response was 15.2 months (95% CI, 9.8 to not evaluable), and the median progression-free survival was 14.4 months (95% CI, 11.1 to not evaluable). Adverse events of any grade occurred in 73 patients (99%), including events of grade 3 or higher in 33 patients (45%). Treatment-related adverse events occurred in 67 patients (91%), including events of grade 3 or higher in 14 patients (19%). In cohort 4, a total of 30 patients with active brain metastases received zongertinib at a dose of 120 mg; of these, 47% (95% CI, 30 to 64) had a confirmed intracranial objective response according to Response Assessment in Neuro-Oncology Brain Metastases criteria. In this cohort, treatment-related adverse events of grade 3 or higher occurred in 5 patients (17%).

Conclusions. Zongertinib showed sustained efficacy in previously untreated patients with advanced or metastatic HER2-mutant NSCLC. Treatment-related adverse events were predominantly low-grade. (Funded by Boehringer Ingelheim; Beamion LUNG-1 ClinicalTrials.gov number, NCT04886804.).

Background. Maternal infection and sepsis are major causes of maternal death and severe illness worldwide, particularly in low- and middle-income countries. Inconsistent implementation of evidence-based recommendations for infection prevention and management and delays in detection and treatment of maternal sepsis contribute to the number of preventable deaths.

Methods. We conducted a cluster-randomized trial to assess a multicomponent intervention, the Active Prevention and Treatment of Maternal Sepsis (APT-Sepsis) program. This program was designed to support health care providers in achieving three goals: adherence to World Health Organization (WHO) hand-hygiene standards; adoption of evidence-based practices for maternal infection prevention and management; and early detection of sepsis and use of the FAST-M (fluids, antibiotics, source control, transfer if required, and monitoring) treatment bundle. Usual care was provided in the control group, along with dissemination of guidelines. The primary outcome was a composite of infection-related maternal death, infection-related near-miss event (events in which women survived a life-threatening complication), or severe infection-related illness (deep surgical-site, deep perineal, or body-cavity infection) among women who were pregnant or had recently been pregnant.

Results. We randomly assigned 59 health facilities (where 431,394 women gave birth during the trial) in Malawi and Uganda to the intervention group (30 clusters) or the usual-care group (29 clusters). A primary-outcome event occurred in 1.4% of the patients in the intervention group and in 1.9% of those in the usual-care group (risk ratio, 0.68; 95% confidence interval, 0.55 to 0.83; P<0.001). This effect was generally consistent between countries and among facilities of difference sizes and was sustained over time.

Conclusions. Implementation of the APT-Sepsis program led to a significantly lower risk of a composite of infection-related maternal death, infection-related near-miss event, or severe infection-related illness than usual care. (Funded by the Joint Global Health Trials scheme and others; APT-Sepsis ISRCTN number, ISRCTN42347014.).

Background. Mim8 (denecimig), a bispecific antibody mimicking activated factor VIII, was developed for bleeding prophylaxis in patients with hemophilia A with or without factor VIII inhibitors.

Methods. In this phase 3, randomized trial, we assigned patients 12 years of age or older with hemophilia A with or without inhibitors to receive subcutaneous Mim8 once weekly or once monthly at a dose tiered according to body weight and given in a fixed injection volume (0.8 ml). Patients who had been receiving on-demand treatment before the trial were assigned in a 1:1:1 ratio to continue on-demand treatment (group 1) or receive Mim8 once weekly (group 2a) or once monthly (group 2b). Patients who had been receiving clotting factor concentrates during a run-in phase were assigned in a 1:1 ratio to receive Mim8 once weekly (group 3) or once monthly (group 4). The first primary end point was the annualized rate of treated bleeding events (those treated with a coagulation factor product) in an evaluation of Mim8 in group 2a and Mim8 in group 2b as compared with on-demand treatment in group 1. The second was the annualized rate of treated bleeding events in an intrapatient evaluation of Mim8 in group 3 and Mim8 in group 4 as compared with clotting factor concentrate prophylaxis during the run-in phase.

Results. Of the 58 patients in the pretrial on-demand treatment cohort, 17 were assigned to group 1, 21 to group 2a, and 20 to group 2b. The estimated mean annualized rate of treated bleeding events was 0.57 (95% confidence interval [CI], 0.25 to 1.30) in group 2a and 0.20 (95% CI, 0.06 to 0.71) in group 2b, as compared with 15.76 (95% CI, 10.70 to 23.20) in group 1 (relative decrease, 96.4% and 98.7%, respectively; P<0.001 for both comparisons). Of the 196 patients in the pretrial prophylaxis cohort, 98 each were assigned to group 3 or group 4. The estimated mean annualized rate of treated bleeding events was 2.25 (95% CI, 1.37 to 3.71) in group 3, as compared with 4.90 (95% CI, 3.65 to 6.56) during the run-in phase (relative decrease, 54.0%; P = 0.006), and 1.78 (95% CI, 1.18 to 2.71) in group 4, as compared with 3.12 (95% CI, 2.25 to 4.32) (relative decrease, 42.8%; P = 0.006). Injection-site reactions were reported in 103 of 4005 injections (2.6%). No patient was reported to have a thromboembolic event or clinical evidence of neutralizing anti-Mim8 antibodies.

Conclusions. Among patients with hemophilia A with or without inhibitors, Mim8 prophylaxis was superior to on-demand treatment and clotting factor concentrate prophylaxis regarding the annualized rate of treated bleeding events. (Funded by Novo Nordisk; FRONTIER2 ClinicalTrials.gov number, NCT05053139.).

Background. Improved diagnostic tools for tuberculosis that are suitable for use in peripheral health centers are essential for reducing the persistent gap between estimated and notified cases. The diagnostic accuracy and usability of the MiniDock MTB test for detecting pulmonary tuberculosis is unknown.

Methods. We conducted a prospective, cross-sectional study at outpatient centers in India, Nigeria, the Philippines, South Africa, Uganda, Vietnam, and Zambia. Patients 12 years of age or older with presumptive pulmonary tuberculosis were enrolled between September 12, 2024, and March 31, 2025. Assessment with MiniDock MTB was performed with sputum swabs and tongue swabs. Diagnostic accuracy was evaluated against a sputum-culture-based reference and as compared with sputum-smear microscopy and Xpert MTB/RIF Ultra assay. Usability was assessed with a system usability scale and direct observation.

Results. A total of 1380 participants were enrolled; 255 (18.5%) had human immunodeficiency virus infection and 226 (16.4%) had culture-confirmed tuberculosis. MiniDock MTB sensitivity was 85.7% (95% confidence interval [CI], 80.4 to 90.0) with sputum and 79.6% (95% CI, 73.8 to 84.7) with tongue swabs; specificity was greater than 97.5% for both. Results of sputum tests with MiniDock MTB closely matched those with Xpert MTB/RIF Ultra for sensitivity (difference, -2.8 percentage points; 95% CI, -6.0 to 0.5). MiniDock MTB had greater sensitivity than smear microscopy for tests of sputum (difference, 24.3 percentage points; 95% CI, 17.9 to 30.7) and tongue swabs (difference, 18.3 percentage points; 95% CI, 12.0 to 24.7). The test showed diagnostic accuracy that was consistent with World Health Organization (WHO) accuracy targets for near-point-of-care tuberculosis diagnostics (≥85% sensitivity for sputum and ≥75% for nonsputum and ≥98% specificity for both). The median score on the system usability scale (range, 0 to 100, with higher scores indicating better perceived usability) was 75 (interquartile range, 65 to 80), which indicated good usability. No adverse events related to the index test were reported.

Conclusions. MiniDock MTB met WHO targets for diagnostic accuracy and usability for tuberculosis detection across diverse clinical settings. (Funded by the National Institutes of Health and others; Rapid Research in Diagnostics Development for TB Network and Assessing Diagnostics at Point-of-Care for Tuberculosis ClinicalTrials.gov numbers, NCT04923958 and NCT05941052.).