PubMed：

(tuberculosis[Title/Abstract]) OR (lung cancer [Title/ Abstract])

Filters applied: from 2026/08/01 - 2026/08/31.

1. Nature. 2026 Aug 12. doi: 10.1038/s41586-026-10925-6. Online ahead of print.

Biomarkers of nivolumab benefit in resectable non-small cell lung cancer.

Perioperative nivolumab significantly improved event-free survival (EFS) compared with placebo in patients with resectable non-small cell lung cancer (NSCLC) in the CheckMate 77T study (ClinicalTrials.gov NCT04025879 )1. Here, after randomization, 98 out of 229 patients who received nivolumab and 92 out of 232 patients who received placebo had evaluable biomarkers (41% of randomized patients). Of the 98 patients receiving nivolumab, 83 (85%) had detectable circulating tumour DNA (ctDNA) before initiating neoadjuvant treatment and 90 (92%) at neoadjuvant treatment completion. Of the 92 placebo-treated patients, 75 (82%) had detectable ctDNA at the treatment start and 78 (85%) at completion. Among the 98 nivolumab-treated patients, 76 (78%) had detectable and evaluable ctDNA before and after neoadjuvant treatment, and 50 of them (66%) had pre-surgical ctDNA clearance, and 25 out of 50 (50%) had pathologic complete response (pCR). For the placebo-treated group, these values were 64 out 92 (70%) for detectable and evaluable ctDNA before and after neoadjuvant treatment, and 24 out of 64 (38%) had pre-surgical ctDNA clearance, and 3 out of 24 (12%) had pCR. Furthermore, 4 out of 48 (8%) patients in the nivolumab group and 9 out of 44 (20%) in the placebo group who were negative for molecular residual disease (MRD) after surgery and before adjuvant treatment initiation became positive during the adjuvant treatment period; all had disease recurrence. EFS seemed to be prolonged with nivolumab (n = 60) versus placebo (n = 45) in patients with single or co-alterations in any of the KEAP1, STK11, CDKN2A and/or SMARCA4 driver genes (hazard ratio, 0.48; 95% confidence interval, 0.28-0.83). In a machine-learning model trained using biomarker-evaluable patients, top predictors of prolonged EFS included pre-surgical ctDNA clearance, non-N2 NSCLC, pCR, squamous tumour histology and nivolumab treatment. These findings provide insights into predictive markers for outcomes with perioperative nivolumab in resectable NSCLC.

PMID: 42587156

2. N Engl J Med. 2026 Aug 13;395(7):660-670. doi: 10.1056/NEJMoa2602628.

Selpercatinib in Early-Stage RET Fusion-Positive Non-Small-Cell Lung Cancer.

BACKGROUND: Selpercatinib, a highly selective, potent, and central nervous system-penetrant RET inhibitor, is approved for RET fusion-positive advanced or metastatic non-small-cell lung cancer (NSCLC). The efficacy and safety of selpercatinib in early-stage NSCLC are unknown.

METHODS: We conducted a phase 3, double-blind trial involving patients with RET fusion-positive NSCLC who had received definitive therapy with curative intent (surgery or radiotherapy with adjuvant systemic anticancer therapy, if applicable). Patients were randomly assigned to receive adjuvant selpercatinib or placebo for up to 3 years. The primary end point was investigator-assessed event-free survival in patients with stage II or IIIA disease. Secondary end points were investigator-assessed event-free survival in patients with stage IB, II, or IIIA disease; event-free survival as assessed by blinded independent central review; overall survival; and safety.

RESULTS: A total of 151 patients were assigned to receive selpercatinib (75 patients) or placebo (76 patients). Median follow-up was 24 months and 27 months in the respective groups. Among 109 patients with stage II or IIIA disease, 2-year investigator-assessed event-free survival was 92% with selpercatinib and 61% with placebo (hazard ratio for disease recurrence, progression, or death, 0.17; 95% confidence interval [CI], 0.06 to 0.51; P<0.001). Event-free survival as assessed by blinded independent central review was consistent with investigator-assessed event-free survival. Among the 151 patients with stage IB, II, or IIIA NSCLC, investigator-assessed event-free survival at 2 years was 94% with selpercatinib and 70% with placebo (hazard ratio for disease recurrence, progression, or death, 0.16; 95% CI, 0.06 to 0.48; P<0.001). The most common adverse events during the treatment period were increased levels of alanine aminotransferase and aspartate aminotransferase (grade ≥3 in 17% and 19% of patients, respectively, in the selpercatinib group). Three deaths occurred, all in the placebo group, owing to disease progression.

CONCLUSIONS: Among patients with stage II or IIIA RET fusion-positive NSCLC, event-free survival was significantly longer with adjuvant selpercatinib than with placebo. (Funded by Lilly; LIBRETTO-432 ClinicalTrials.gov number, NCT04819100.).

PMID: 42223087 [Indexed for MEDLINE]

3. N Engl J Med. 2026 Aug 20;395(8):765-775. doi: 10.1056/NEJMoa2604461.

First-Line Sunvozertinib in NSCLC with EGFR Exon 20 Insertion Mutations.

BACKGROUND: Sunvozertinib received accelerated approval for use in later lines of therapy for patients with advanced non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations. Data are needed on the efficacy and safety of sunvozertinib as a first-line treatment for NSCLC.

METHODS: In this phase 3, international trial, we randomly assigned, in a 1:1 ratio, patients with advanced nonsquamous NSCLC with EGFR exon 20 insertions to receive sunvozertinib or chemotherapy (carboplatin-pemetrexed). The primary end point was progression-free survival as assessed by blinded independent central review. Crossover to the sunvozertinib group was allowed after disease progression was confirmed. Secondary end points included overall survival, investigator-assessed progression-free survival, objective response (complete or partial response), change in tumor size, and duration of response.

RESULTS: A total of 324 patients were randomly assigned to receive sunvozertinib (163 patients) or chemotherapy (161 patients). Treatment with sunvozertinib led to significantly longer median progression-free survival than chemotherapy (10.3 vs. 7.5 months; hazard ratio for disease progression or death, 0.65; 95% confidence interval, 0.50 to 0.85; P<0.001). At 12 months, progression-free survival was reported in 46.1% of the patients in the sunvozertinib group and in 26.7% of those in the chemotherapy group; the data for overall survival were immature (38.9% maturity). The percentage of patients with an objective response was 58.9% in the sunvozertinib group and 31.1% in the chemotherapy group; the median best percentage change in tumor size was -42.1% and -24.7% respectively, and the median duration of response was 11.2 and 7.1 months. Grade 3 or higher adverse events were reported in 75.5% of the patients in the sunvozertinib group and in 56.7% of those in the chemotherapy group. In the sunvozertinib group, the most common adverse events of grade 3 or higher included increased serum creatine kinase levels, diarrhea, and anemia. No deaths were attributed to adverse events considered by the investigators to be related to sunvozertinib.

CONCLUSIONS: The efficacy of sunvozertinib was superior to that of chemotherapy as first-line treatment for advanced NSCLC with EGFR exon 20 insertions. (Funded by Dizal Pharmaceuticals; WU-KONG28 ClinicalTrials.gov number, NCT05668988.).

PMID: 42212913 [Indexed for MEDLINE]

4. JAMA. 2026 Aug 10:e2610599. doi: 10.1001/jama.2026.10599.

Osimertinib With or Without Chemotherapy in Advanced Non-Small Cell Lung Cancer With EGFR and Concurrent TP53 Mutations: A Randomized Clinical Trial.

IMPORTANCE: Combination therapy has emerged as a promising therapeutic approach for patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). However, its clinical benefit-risk profile remains a focus of ongoing debate. Identifying patients most likely to derive benefit from such regimens remains an unmet clinical need.

OBJECTIVE: To prospectively compare the efficacy and safety of first-line osimertinib plus chemotherapy with osimertinib monotherapy for patients with EGFR-mutated advanced NSCLC harboring concurrent TP53 mutations.DESIGN, SETTING, AND PARTICIPANTS: A multicenter, randomized, open-label, phase 3 study conducted at 17 sites in China. Between March 25, 2021, and July 11, 2024, a total of 294 eligible patients with treatment-naive, stage IV or recurrent nonsquamous NSCLC harboring concurrent TP53 and EGFR-sensitizing mutations were enrolled.

INTERVENTIONS: Patients were randomized (1:1) to receive osimertinib plus chemotherapy (pemetrexed and carboplatin every 3 weeks for 4 cycles, followed by maintenance therapy of osimertinib plus pemetrexed; n = 146) or osimertinib monotherapy (n = 148).

MAIN OUTCOMES AND MEASURES: The primary end point was investigator-assessed progression-free survival. Secondary end points included overall survival, response, safety, and quality of life.

RESULTS: Among 294 enrolled patients, the median age was 57 years (range, 26-79 years), and 159 (54.1%) were female. The data cutoff date was November 11, 2025. At a median follow-up of 25.1 months for the osimertinib-chemotherapy group and 26.1 months for the osimertinib monotherapy group, median progression-free survival was significantly longer with osimertinib plus chemotherapy than with osimertinib monotherapy (34.0 vs 15.6 months; difference, 18.4 months [95% CI, 9.9-22.3]; hazard ratio, 0.44 [95% CI, 0.32-0.60]; P < .001). This benefit was consistent across prespecified subgroups, including those with brain metastases and L858R mutations. The overall survival data remained immature (30.6% maturity); however, a trend toward overall survival benefit with combination therapy was observed. The incidence of grade 3 or higher treatment-related adverse events was higher in the combination group, with no new safety signal identified.

CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, osimertinib plus chemotherapy significantly increased progression-free survival among patients with EGFR-mutated advanced NSCLC harboring concurrent TP53 mutations. These findings provided a clinical rationale for individualized combination strategies in the management of patients with EGFR-mutated NSCLC.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04695925.

PMID: 42574006

5. Immunity. 2026 Aug 11;59(8):2122-2141.e9. doi: 10.1016/j.immuni.2026.05.017.

Monocytic niches escape T cell surveillance and promote Mycobacterium tuberculosis persistence in lymph nodes.

Lung-draining mediastinal lymph nodes (medLNs) are critical for Mycobacterium tuberculosis (Mtb) pathogenesis, serving both as sites of T cell priming and, paradoxically, reservoirs for long-term bacterial persistence. To understand this dichotomy, we examined myeloid and CD4+ T cell dynamics in medLNs after aerosol Mtb infection. Early bacterial dissemination occurred via monocytes and interleukin (IL)-12-producing conventional dendritic cells (cDCs), which initiated T helper 1 (Th1) cell priming within the T cell zone. Over time, cDC migration and T cell activation declined, and medLNs became dominated by heavily infected monocyte-derived aggregates that persisted into late infection. Despite inducing proinflammatory and bactericidal pathways, these aggregates escaped recognition by Mtb-specific T cells and failed to clear Mtb, thereby forming an immunologically "blind" niche. Bacille Calmette-Guérin (BCG) vaccination reduced Mtb burden and niche establishment without altering myeloid trafficking or T cell priming. Thus, Mtb persists in medLNs within monocytic niches, eliciting classical antimicrobial programs that are insufficient for sterilizing control.

PMID: 42335893 [Indexed for MEDLINE]

6. BMJ. 2026 Aug 6;394:e100195. doi: 10.1136/bmj-2026-100195.

Evaluation of patient centred digital adherence technology for tuberculosis treatment outcomes: pragmatic randomised controlled trial.

OBJECTIVE: To evaluate the effectiveness of Tuberculosis Treatment Support Tools (TB-TST), a patient centred digital adherence technology, in improving treatment outcomes among individuals with drug susceptible tuberculosis in Argentina.

DESIGN: Pragmatic, two arm, parallel randomised controlled trial.

SETTING: Four public reference hospitals in Buenos Aires, Argentina.

PARTICIPANTS: 555 patients aged ≥16 years with newly diagnosed drug susceptible tuberculosis, recruited between November 2020 and July 2023, randomised to standard of care (n=278) or standard of care plus TB-TST (n=277).

INTERVENTION: A mobile application that enabled daily adherence reporting, bidirectional messaging with treatment supporters, educational content, and a weekly urine based isoniazid test for verification of adherence. Participants and care givers were aware of their group assignment, but data collectors and data analysts were masked.

MAIN OUTCOME MEASURES: The primary outcome was treatment success (cure or treatment completion). Secondary outcomes included loss to follow-up. Analyses used intention-to-treat and per protocol approaches.

RESULTS: 525 participants (94.6% of the enrolled population) were included in the analysis after exclusion of 30 individuals who deviated from the protocol. In the intention-to-treat analysis, treatment success was higher in the intervention group (208/255; 82%) than in the control group (201/270; 74%). The risk difference was 7.1% (95% confidence interval 1.1% to 14.1%), and the risk ratio was 1.10 (1.00 to 1.20; P=0.04). Loss to follow-up was lower in the intervention group (17% v 24%; risk ratio 0.70, 0.50 to 0.98; P=0.04). Greater benefit was observed among female participants and those aged under 35 years.

CONCLUSIONS: A multifaceted, interactive digital adherence tool improved tuberculosis treatment outcomes, particularly among younger participants and women, showing feasibility and effectiveness in supporting adherence to tuberculosis treatment in low resource settings. Future research should evaluate the impact of app engagement, context factors such as the covid-19 pandemic, cost effectiveness, and use of the tool beyond tuberculosis in the management of chronic diseases. AI powered features and integrated mental health support may enhance the scalability and personalisation of care.

TRIAL REGISTRATION: ClinicalTrials.gov NCT04221789; International Registered Report Identifier DERR1-10.2196/28094.

PMID: 42562413 [Indexed for MEDLINE]

7. Lancet Infect Dis. 2026 Aug 14:S1473-3099(26)00359-2. doi: 10.1016/S1473-3099(26)00359-2. Online ahead of print.

Guiding principles for pragmatic randomised trials of tuberculosis treatments.

Tuberculosis remains a major global health challenge, despite recent advances in drug and regimen development. Pragmatic randomised trials are needed to evaluate the effectiveness, safety, and tolerability of new tuberculosis treatments under routine care conditions to appropriately inform practice guidelines and facilitate uptake. In this Review, we propose guiding principles for pragmatic tuberculosis treatment trials. Using the PRECIS-2 framework, we address eligibility, recruitment, setting, organisation of care, adherence support, outcomes, follow-up, primary analysis, data collection, and monitoring. Pragmatic trials should maximise generalisability through broad inclusion criteria, integration within routine health systems, and flexible delivery approaches while maintaining appropriate standards for participant safety and data reliability. We discuss considerations for individually randomised and cluster-randomised designs, outcome definitions, risk-proportionate monitoring, and streamlined data collection. Adoption of these principles will improve the generation of real-world evidence and facilitate global implementation of effective tuberculosis treatments.

PMID: 42600623

8. Am J Respir Crit Care Med. 2026 Aug 1;212(8):1806-1814. doi: 10.1093/ajrccm/ aamag107.

Post-tuberculosis lung disease in treated extra-pulmonary tuberculosis.

BACKGROUND: Post-tuberculosis lung disease is a well-recognized sequela of pulmonary tuberculosis (PTB). Extra-PTB (EPTB) accounts for a quarter of the global TB burden; yet pulmonary sequelae in people treated for EPTB are unknown.

METHODS: We performed spirometry at successful treatment completion and semi-annually thereafter for 1.5 years, among adults (aged 18 years and older) with drug-sensitive PTB and EPTB recruited from outpatient clinics in India. Adult household contacts without current TB disease underwent spirometry at enrollment and served as non-TB controls. Logistic and linear regression was used to measure the association of treated EPTB with ventilatory defects and persistence of impaired lung function during posttreatment follow-up, respectively.

RESULTS: We enrolled 775 TB survivors; 275 (35%) of whom were treated for EPTB and 502 non-TB controls. Compared to controls, EPTB was associated with lower z scores for FEV1 (-0.37; 95% CI, -0.54 to -0.20; P < .001) and FVC (-0.46; 95% CI, -0.65 to -0.26; P < .001) and higher odds of airflow obstruction (adjusted odds ratio [aOR] = 1.58; 95% CI, 0.95-2.61; P = .066) and restrictive spirometry (aOR = 2.16; 95% CI, 1.48-3.15; P < .001) at treatment completion. Lung function deficits in EPTB survivors persisted during the 1.5 years of posttreatment follow-up and were associated with respiratory symptoms. Findings were consistent in sensitivity analyses accounting for misclassified EPTB and unmeasured confounders. Ventilatory defects in treated EPTB were phenotypically comparable to those seen in treated PTB, however their burden, severity, and likelihood of respiratory symptoms were lower.

CONCLUSION: People treated for EPTB have persistent ventilatory defects and respiratory symptoms and should be screened for post-TB lung disease.

PMID: 42128261 [Indexed for MEDLINE]

9. JAMA. 2026 Aug 10. doi: 10.1001/jama.2026.13898. Online ahead of print.

Liquid Biopsies for Cancer: A Translational Science Review.

IMPORTANCE: Circulating tumor DNA (ctDNA) evaluation, in which fragments of tumor DNA circulating in a patient's bloodstream are extracted and analyzed, can be used to monitor cancer progression, detect residual cancer after treatment, and identify genetic changes within cancer cells that could affect treatment response.

OBSERVATIONS: ctDNA sequencing identifies cancer cell gene variants that inform the selection of molecularly directed therapies in several types of cancer, including non-small cell lung cancer, colorectal cancer, and breast cancer. Increases or decreases in ctDNA levels can indicate treatment response (ctDNA decrease) or cancer cell resistance and recurrence (ctDNA increase). Detecting ctDNA after curative intent therapy correlates strongly with cancer recurrence and poorer survival. In a meta-analysis of 1725 patients undergoing treatment for urothelial carcinoma, higher ctDNA levels were associated with poorer survival outcomes (hazard ratio for disease-free survival, 20.69 [95% CI, 9.63-44.43]; P < .001). This association was also observed in adjuvant settings (hazard ratio for disease-free survival, 4.51 [95% CI, 3.04-6.69]; P < .001) and in patients undergoing systemic therapy for metastatic disease (hazard ratio for overall survival, 2.0 [95% CI, 1.25-3.38]; P = .004; absolute rates not available). ctDNA detection may indicate minimal residual disease, defined as cancer cells detectable only by highly sensitive testing (eg, detection of 1 cancer cell in a population of 1 million normal cells) before disease progression is identified with imaging. Detecting an early increase in ctDNA and/or a novel sequence variation that may confer resistance to standard treatment can guide therapeutic decisions, such as changing to a new treatment, before tumor progression is detectable with conventional imaging. In a prospective cohort study of 130 patients with colorectal cancer, molecular relapse of disease was detected approximately 8.7 months earlier compared with standard-of-care imaging surveillance (5.5 months vs 14.2 months; P < .001). Similarly, patients with undetectable ctDNA levels may be able to discontinue therapy and be monitored, preventing potentially unnecessary exposure to chemotherapy that may have substantial adverse effects. However, the optimal timing of ctDNA testing, management of positive results in the absence of radiographic disease, and the cost-effectiveness of serial monitoring remain unclear.

CONCLUSIONS AND RELEVANCE: ctDNA, consisting of small DNA fragments from cancer cells that can be analyzed in human blood, can help clinicians monitor cancer progression, detect minimal residual cancer, and identify genetic variants that may help guide treatment decisions. Use of ctDNA may help select best treatment and timing of therapy for a patient with cancer, but optimal clinical applications remain unclear.

PMID: 42574031

10. Nat Med. 2026 Aug;32(8):2983-2990. doi: 10.1038/s41591-026-04448-w.

Biological aging and generational shifts in early-onset cancer risk.

Incidence of early-onset cancer is rising globally in recent generations, which underscores the need to elucidate the influence of emerging generational risk factors. Systemic and organ-specific aging reflects the cumulative impact of exposures and may provide an integrative and complementary approach to understand early-onset cancer risk. Here among 154,169 young adults from the United Kingdom Biobank, systemic aging measured by PhenoAge increased across birth cohorts, with 23% s.d. increase for those born 1965-1974 versus 1950-1954, and was associated with early-onset solid cancer risk (hazard ratio (HR)per s.d. 1.08; 95% confidence interval (CI), 1.03-1.13), driven by lung, gastrointestinal and uterine cancers, independent of genetic risks of aging and cancer. Patterns were consistent using alternative systemic aging measures, including the Klemera-Doubal method-defined age gap and metabolomic-based age gap. These findings were validated partially among 10,262 participants in the United States All of Us Research Program. Proteomics-based organ-specific aging analyses linked immune aging with early-onset lung cancer (HRper s.d. 1.89; CI, 1.20-2.97) and adipose tissue aging to early-onset colorectal cancer (HR 1.60; CI, 1.11-2.32). Greater age gap, reflecting more advanced biological aging relative to chronological age, may serve as a driver associated with risk of early-onset solid cancers, highlighting the importance of uncovering underlying mechanisms to guide effective prevention strategies.

PMID: 42332142 [Indexed for MEDLINE]

11. JAMA. 2026 Aug 11;336(6):484-495. doi: 10.1001/jama.2026.8717.

Lung Transplant for Refractory Lung-Limited Stage IV Non-Small Cell Lung Cancer.

IMPORTANCE: Patients with medically refractory, lung-limited, stage IV non-small cell lung cancer (NSCLC) often die of progressive respiratory failure. Although lung transplant offers the possibility of organ-level disease extirpation, the surgery has historically not been offered to such patients due to concerns of poor oncological outcomes.

OBJECTIVE: To describe outcomes among patients who underwent lung transplant and examine survival associated with lung transplant compared with medical management alone.

DESIGN, SETTING, AND PARTICIPANTS: This prospective, single-center, registry study included 404 adults. Of 98 adults with medically refractory, lung-limited, stage IV NSCLC, 17 underwent lung transplant and 81 met transplant eligibility criteria but did not undergo transplant due to nonbiologic barriers and were treated with medical management alone. There were 306 adults without cancer who underwent lung transplant for end-stage pulmonary disease. All who underwent lung transplant had respiratory failure. The study was conducted from September 1, 2021, through June 30, 2025; the last day of extended follow-up was January 31, 2026.

EXPOSURES: Lung transplant after contemporary staging and a dissemination-minimizing operative technique was used.

MAIN OUTCOMES AND MEASURES: The primary outcome was overall survival from eligibility evaluation completion in patients with NSCLC who underwent lung transplant vs those with NSCLC who were treated with medical management alone. The secondary outcome was 1-year posttransplant survival (organ stewardship comparison) in patients with NSCLC who underwent lung transplant vs those without cancer who underwent lung transplant.

RESULTS: Among the 98 patients with stage IV NSCLC, the median follow-up from eligibility evaluation completion through June 30, 2025, was 343 (IQR, 191-768) days for the 17 lung transplant recipients (median age, 61.0 [IQR, 48.0-64.0] years; 10 [59%] were women) and the median follow-up was 221 (IQR, 68-386) days for the 81 patients who received medical management alone (median age, 63.4 [IQR, 56.7-68.1] years; 42 [52%] were women). Among the 306 lung transplant recipients without cancer, the median follow-up from transplant was 200 (IQR, 126-496) days (median age, 63.0 [IQR, 55.0-68.8] years; 112 [37%] were women). The Kaplan-Meier estimated 1-year overall survival was 100.0% (95% CI, 63.1%-100.0%) (0 deaths) among the lung transplant recipients with NSCLC vs 40.8% (95% CI, 29.6%-53.1%) (52 deaths) among those with NSCLC who received medical management alone (absolute difference, 59.2 [95% CI, 46.2-71.7] percentage points). The 1-year posttransplant survival was 100% (95% CI, 63.1%-100%) among patients with NSCLC vs 88.1% (95% CI, 83.7%-91.4%) among patients without cancer (absolute difference, 11.9 [90% CI, 9.1-15.5] percentage points). At the extended follow-up (January 31, 2026), 2 of the transplant recipients with stage IV NSCLC had died.

CONCLUSIONS AND RELEVANCE: Among selected patients with medically refractory, lung-limited, stage IV NSCLC and respiratory failure who underwent lung transplant, early survival was favorable. Longer-term follow-up and quality-of-life assessment are needed.

PMID: 42418196 [Indexed for MEDLINE]

12. JAMA Oncol. 2026 Aug 1;12(8):810-818. doi: 10.1001/jamaoncol.2026.1645.

First-Line Serplulimab in Extensive-Stage Small Cell Lung Cancer: Secondary Analysis of the ASTRUM-005 Phase 3 Randomized Clinical Trial.

IMPORTANCE: The ASTRUM-005 phase 3 randomized clinical trial showed substantial survival benefit from adding serplulimab to chemotherapy for previously untreated extensive-stage small cell lung cancer (ES-SCLC). However, the long-term outcomes are unclear.

OBJECTIVE: To investigate the efficacy, safety, patient-reported outcomes (PROs), and exploratory biomarker findings from ASTRUM-005 at an extended follow-up.

DESIGN, SETTING, AND PARTICIPANTS: This international, double-blind, phase 3 randomized clinical trial enrolled patients from September 12, 2019, to April 27, 2021 in China, Russia, Ukraine, Poland, Turkey, and Georgia. Eligible patients had histologically or cytologically confirmed ES-SCLC with no prior systemic therapy. Patients were followed up through May 7, 2024, and the data analysis of this prespecified, secondary analysis lasted from August to September 2024. The median follow-up duration was 42.4 months (range, 0.2-55.2).

EXPOSURES: Patients were randomized in a 2:1 ratio to receive intravenous serplulimab (4.5 mg/kg; serplulimab group) or placebo (placebo group), which was combined with up to 4 cycles of carboplatin and etoposide every 3 weeks.

MAIN OUTCOMES AND MEASURES: The primary end point was overall survival (OS). Secondary end points included other efficacy end points, safety, and PROs.

RESULTS: A total of 585 patients (median [range] age was 63 [28-76] years in the serplulimab group and 62 [31-83] years in the placebo group) with previously untreated ES-SCLC, and 389 (66.5%) were randomly assigned to the serplulimab group and 196 (33.5%) to the placebo group. Baseline characteristics were balanced across treatment groups. At data cutoff, 280 OS events (72.0%) in the serplulimab group and 166 (84.7%) in the placebo group were observed. Compared with the placebo group, the serplulimab group showed more favorable efficacy (median OS, 15.8 [95% CI, 13.9-17.4] vs 11.1 [95% CI, 10.0-12.4] months; hazard ratio, 0.60; 95% CI, 0.49-0.73; P < .001). The serplulimab group showed improved OS rates at 4 years compared with the placebo group (21.9% vs 7.2%). Grade 3 or higher serplulimab-related or placebo-related treatment-emergent adverse events occurred for 136 (35.0%) and 57 patients (29.1%) in the respective groups. A PRO analysis revealed consistent trends of improved overall health, dyspnea, and pain in both groups and faster recovery from alopecia in the serplulimab group.

CONCLUSIONS AND RELEVANCE: This secondary analysis of a randomized clinical trial demonstrated long-term benefit from adding serplulimab to chemotherapy for previously untreated patients with ES-SCLC, supporting this therapy as a first-line standard of care for this patient population.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04063163.

PMID: 42240984 [Indexed for MEDLINE]

13. Nat Immunol. 2026 Aug;27(8):1653-1665. doi: 10.1038/s41590-026-02545-z.

mRNA-based tuberculosis vaccines BNT164a1 and BNT164b1 are immunogenic, well tolerated and efficacious in rodent models.

We designed and preclinically tested two mRNA-lipid-nanoparticle-based vaccinecandidates to protect against tuberculosis. BNT164a1 and BNT164b1 encode thesame eight Mycobacterium tuberculosis antigens expressed across differentinfection stages: Ag85A, Hrp1, ESAT-6, RpfD, RpfA, HbhA, M72 and VapB47.BNT164a1 utilizes nucleoside-unmodified mRNA, whereas BNT164b1 utilizesN1-methylpseudouridine-modified mRNA. Prime-boost immunization with BNT164candidates elicited antibody and/or T cell responses against all antigens inthree mouse strains (C57BL/6, BALB/c and HLA-A2.1/DR1 humanized mice). Thecandidates demonstrated favorable safety profiles in a rat toxicity study andsignificantly reduced bacterial burdens of two M. tuberculosis strains in murineaerosol challenge models. BNT164 protection was correlated with granulomainfiltration by CD8+ T cells with memory precursor phenotypes. In conclusion,BNT164a1 and BNT164b1 were immunogenic, well tolerated and efficacious inpreclinical models and have entered phase 1/2 clinical trials ( NCT05537038 ,NCT05547464 ).

PMID: 42286358 [Indexed for MEDLINE]

14. Lancet Infect Dis. 2026 Aug;26(8):e314-e318. doi: 10.1016/S1473-3099(26)003-4.

The looming crisis of bedaquiline-resistant tuberculosis and a promising way forward.

Drug-resistant tuberculosis is entering a new and dangerous phase. Bedaquiline and other newer drugs have transformed drug-resistant tuberculosis treatment, yet resistance to these agents is now being reported across high-burden settings. In some regions, baseline bedaquiline resistance is substantial, treatment outcomes for extensively drug-resistant tuberculosis remain poor and mortality is unacceptably high. At the same time, the tuberculosis drug pipeline is stronger than it has been in decades, with several promising investigational compounds advancing to late-stage trials. However, regulatory approval remains years away, leaving people with few or no effective treatment options to wait-and often die-while drugs with potential benefit remain inaccessible. Here, we argue that the central barrier to addressing complex drug-resistant tuberculosis is not scientific, but moral and organisational. Drawing on lessons from earlier pre-approval access programmes for bedaquiline and delamanid, we propose the establishment of compassionate-use support platforms (CUSPs): coordinated, global mechanisms to facilitate equitable access to investigational tuberculosis drugs before formal approval. Well designed CUSPs could balance urgency with safety, share responsibility across stakeholders, strengthen diagnostic and pharmacovigilance capacity, and ensure that people with the most difficult-to-treat tuberculosis are not excluded from scientific progress.

PMID: 41713477 [Indexed for MEDLINE]

15. Nat Immunol. 2026 Aug;27(8):1577-1589. doi: 10.1038/s41590-026-02544-0.

Airway immune signatures of protection and disease progression in recent human tuberculosis household contacts.

The local immune factors dictating whether individuals who have been infected with Mycobacterium tuberculosis remain healthy or progress to active tuberculosis (TB) have not been defined. Here we interrogated the airway immune response at single-cell resolution in bronchoalveolar lavage from positron emission and computed tomography-characterized recent TB household contacts, who either controlled the infection or progressed to TB disease, as well as of patients with active TB at diagnosis. Single-cell RNA sequencing revealed type I IFN-dependent and IFN-independent neutrophil signatures in bronchoalveolar lavage from patients with active TB and TB progressors. We report an inverse relationship between airway neutrophils and T cells, with T cells showing signatures of exhaustion, cytotoxicity and cell death in progressors and patients with active TB with a neutrophil-dominated airway profile. Conversely, we identified T cell signatures of protection in nonprogressor contacts dominated by genes related to regulation, quiescence and a stem-like profile. Our findings from early human airway responses in TB contacts reveal genes, pathways and cell states that may dictate infection outcome and inform strategies for developing effective host-directed therapies and vaccines.

PMID: 42343006 [Indexed for MEDLINE]

16. Lancet Infect Dis. 2026 Aug 18:S1473-3099(26)00354-3. doi: 10.1016/S1473-3099(26)00354-3. Online ahead of print.

Congenital tuberculosis presenting as acute cervical lymphadenitis in a 28-week preterm infant.

Congenital tuberculosis is a rare infection in infants with extremely low birthweight. We report the case of an infant born at 28 weeks' gestation who developed isolated, cervical lymphadenitis at age 84 days. Despite the infant's continuous hospitalisation in the neonatal intensive care unit and a negative maternal history, Mycobacterium tuberculosis was identified through culture and molecular testing of surgical drainage fluid. The diagnosis was substantially delayed due to several factors: a low index of clinical suspicion based on the infant's isolation from external sources, the presence of concurrent cytomegalovirus infection, and the masking effect of empirical linezolid therapy. A review of 20 case reports suggests a recurrent pattern of association between maternal urogenital or endometrial tuberculosis and localised neonatal infection in the head and neck. Congenital tuberculosis in extremely preterm infants can present atypically as late-onset, localised suppuration. To avoid diagnostic delays in the neonatal intensive care unit, clinicians should consider tuberculosis disease when managing localised, antibiotic-refractory infections. Particularly following in-vitro fertilisation, such clinical presentations should prompt an immediate evaluation for occult maternal pelvic tuberculosis.

PMID: 42612669

17. Am J Respir Crit Care Med. 2026 Aug 1;212(8):1793-1805. doi: 10.1093/ajrccm/ aamag163.

Cost-effectiveness of community tuberculosis screening in South Africa.

RATIONALE: The World Health Organization recommends community-based tuberculosis active case finding using digital chest radiography with computer-aided detection (dCXR/CAD) and/or molecular diagnostics, but clinical and economic outcomes are unclear.

OBJECTIVE: To evaluate the cost-effectiveness of community-based tuberculosis screening strategies in South Africa.

METHODS: Using a microsimulation model, we evaluated 3 symptom-agnostic screening strategies among adult people without HIV (PWoH) and people with HIV (PWH): (1) No Screening; (2) sputum Xpert Ultra (Xpert); and (3) dCXR/CAD followed by confirmatory sputum Xpert (dCXR + Xpert). Base case tuberculosis prevalence was 0.64%-1.23%. Sensitivity/specificity/cost for dCXR/CAD were 77%-90%/65%-73%/$3.55; for Xpert Ultra, they were 69%-91%/98%-99%/$15.24. Model outcomes included life-years, costs, and incremental cost-effectiveness ratios (ICERs) (<$3000/year-of-life saved [YLS] considered cost-effective). We conducted sensitivity analysis around key parameters, including test sensitivity, specificity, and cost.

MEASUREMENTS AND MAIN RESULTS: In the base case, Xpert identifies the most individuals with tuberculosis but produces the most false positives and highest costs. Compared to Xpert, dCXR + Xpert identifies ∼13% fewer individuals with tuberculosis while decreasing screening costs by ∼45%. Given base case performance characteristics, at the lifetime horizon, dCXR + Xpert is cost-effective (ICER $610/YLS) whereas Xpert is not (ICER $3460/YLS). dCXR + Xpert remains cost-effective relative to No Screening, unless tuberculosis prevalence (PWoH/PWH) is ≤0.15%/0.45%, dCXR/CAD sensitivity is (PWoH/PWH) ≤ 20%/10%, dCXR/CAD cost is ≥$34.00, Xpert Ultra cost is ≥$135.00, or linkage to tuberculosis care is ≤15%.

CONCLUSION: Digital chest radiography with computer-aided detection followed by confirmatory sputum Xpert Ultra would likely be a cost-effective strategy for tuberculosis screening in South Africa.

PMID: 42085271 [Indexed for MEDLINE]

18. Lancet Infect Dis. 2026 Aug;26(8):858-870. doi: 10.1016/S1473-3099(26)00114-3.

Diagnostic and prognostic accuracy of the Mycobacterium tuberculosis host response 3-gene cartridge among tuberculosis household contacts in Mozambique, Tanzania, and Zimbabwe: a prospective, longitudinal, diagnostic and prognostic accuracy cohort study.

BACKGROUND: Tuberculosis elimination is constrained by symptom-based and sputum-dependent diagnostic strategies, which miss asymptomatic disease and are difficult to deploy in community settings. Household contacts of people with tuberculosis are a priority population for screening and preventive therapy, but existing tests have poor prognostic ability. We aimed to evaluated host-response assays for screening and prognostic use in household contacts of people with tuberculosis.

METHODS: In this prospective, longitudinal, diagnostic and prognostic accuracy study, we recruited people aged 10 years and older who lived with a person diagnosed with tuberculosis in Mozambique, Tanzania, or Zimbabwe. Household contacts who had taken antimycobacterial antibiotics within the past 4 weeks were excluded. Participants had real-time Cepheid Xpert Mycobacterium tuberculosis Host Response (MTB-HR) testing and clinical, radiological, and microbiological tuberculosis screening every 6 months for up to 24 months. The primary outcomes were the diagnostic accuracy of MTB-HR obtained within 30 days of a confirmed or likely tuberculosis diagnosis at any baseline or follow-up visit, and the prognostic ability of MTB-HR for incident tuberculosis using MTB-HR results obtained 1-6 months, 6-12 months, and 1-12 months before incident tuberculosis diagnosis. Tuberculosis diagnoses were established by an endpoint review committee and we assessed discrimination using the area under the receiver operating characteristic (AUROC) curve. The study was registered with ClinicalTrials.gov (NCT04781257) and is completed.

FINDINGS: Between March 8, 2021, and March 23, 2023, we screened 2109 household contacts and enrolled 2079 for analysis (1294 [62·2%] female and 785 [37·8%] male). In the diagnostic analysis (41 household contacts with tuberculosis), the AUROC was 0·86 (95% CI 0·79-0·92). The prognostic analysis included 29 people with incident tuberculosis during the 1-6-month interval, 19 people for the 6-12-month interval, and 39 people for the 1-12-month interval, yielding AUROCs of 0·80 (0·71-0·89), 0·64 (0·53-0·76), and 0·71 (0·62-0·79), respectively, at optimised cutoffs. For the 6-month prediction at the optimised cutoff, the positive predictive value was 7·5% (95% CI 4·9-11·4).

INTERPRETATION: MTB-HR did not meet the 2025 WHO target product profile criteria for screening or prognostic use; however, its positive predictive value for incident tuberculosis was higher than that of currently used tests. These findings support a potential role for MTB-HR in screening and prevention strategies.

FUNDING: The second European and Developing Countries Clinical Trials Partnership (EDCTP2) programme.

PMID: 42026013 [Indexed for MEDLINE]

19. Lancet Infect Dis. 2026 Aug 18:S1473-3099(26)00374-9. doi: 10.1016/S1473-3099(26)00374-9. Online ahead of print.

Comparison of VPM1002 with BCG in the prevention of tuberculosis in newborn infants: a multicentre, double-blind, randomised, phase 3, non-inferiority trial.

BACKGROUND: Although BCG provides protection against severe forms of tuberculosis in children, its efficacy against pulmonary tuberculosis in adolescents and adults is highly variable, and it offers limited and inconsistent protection against infection and transmission. VPM1002 is a recombinant BCG vaccine that showed manageable toxicity and immunogenicity in phase 1 trials in adults and in phase 2 trials in South African newborns. We compared VPM1002 with BCG for the prevention of Mycobacterium tuberculosis infection in infants.

METHODS: This double-blind, randomised, active-controlled, phase 3 trial was conducted at ten main sites and four satellite sites in sub-Saharan Africa, ranging from rural to urban settings, with experience in tuberculosis trials. Healthy newborn infants, aged 0-14 days and with a birthweight of at least 2·3 kg, were randomly assigned (1:1) to receive single 0·05 mL doses of either VPM1002 or BCG, administered intradermally. Follow-up was extended from 36 months up to 48 months (due to the lower than expected event rate) or until 632 cases of M tuberculosis had accrued. The randomisation was done centrally through an interactive web response system and allocation was stratified by maternal HIV status at a 1:10 ratio, using a permuted block design with variable block sizes. Only the site personnel involved in preparation and administration of the vaccines were not masked to the trial. Mothers were aged 18 years or older, free from active tuberculosis, and without household contact with an individual with tuberculosis within the 3 months before enrolment. Neonates were excluded for any fever, acute or chronic illness, congenital malformation, substantial skin lesion or infection at the site of injection, or previous receipt of routine BCG vaccination. The primary endpoint was non-inferiority of VPM1002 versus BCG for prevention of M tuberculosis infection, defined by incident QuantiFERON-TB Gold Plus (QFT; an interferon-γ release assay [IGRA]) conversion, assessed every 6 months from month 6 until the final visit and more frequently in suspected cases of tuberculosis. In the time-to-event efficacy analysis, participants with missing event occurrence data were censored at the last timepoint for which there was no clear evidence of the event occurrence. The primary efficacy analysis was in the per-protocol population (randomly assigned, vaccinated participants with at least one post-vaccination result and no major efficacy-relevant protocol deviations) with a supportive intention-to-treat analysis of all randomly assigned participants; both were analysed as assigned. As estimates were concordant, intention-to-treat results are presented. Safety was analysed as treated in all vaccinated participants. Non-inferiority required the upper bound of the 95% CI for the hazard ratio (HR) to be less than 1·25. The trial was registered on ClinicalTrials.gov (NCT04351685) and PACTR (PACTR202007868402718) and is complete.FINDINGS: Between Nov 9, 2020, and June 21, 2022, we enrolled 6950 infants. The trial was terminated early in October, 2024, due to a lower than expected QFT conversion rate. After the withdrawal of ten infants, 6940 were randomly assigned to treatment, including 720 infants born to mothers living with HIV and 6220 HIV-unexposed infants. Overall, 3449 male and 3491 female infants were included in the intention-to-treat population. 6897 infants received vaccination (3452 received VPM1002 and 3445 received BCG). Median follow-up was 35 months (IQR 30-38). QFT conversion occurred in 184 (5·3%) of 3471 infants in the VPM1002 group and 150 (4·3%) of 3469 infants in the BCG group. Cox proportional hazards regression analysis (VPM1002 vs BCG) revealed VPM1002 was not non-inferior to BCG, with an HR of 1·23 (95% CI 0·99-1·53). Adverse event profiles, including serious adverse events and deaths, were similar between groups; no vaccine-related serious adverse events were reported.

INTERPRETATION: VPM1002 did not show non-inferiority to BCG on the primary endpoint of QFT conversion. Because fewer infections occurred than expected (334 of 632 planned events, despite extending the duration to 48 months), the trial did not have sufficient statistical certainty to definitively compare the two vaccines. Moreover, discordance between the QFT surrogate and confirmed tuberculosis endpoints, approximately 33·0% higher household tuberculosis exposure in the VPM1002 group, and violation of the proportional hazards assumption when tuberculosis exposure was included as a covariate (that is, the effect of tuberculosis exposure on QFT conversion was not constant over time, precluding reliable HR estimation without penalised modelling) collectively add to this uncertainty. Both vaccines showed similar adverse event profiles. These findings highlight challenges in using IGRA-defined infection endpoints in infant vaccine trials.

FUNDING: European and Developing Countries Clinical Trials Partnership 2 (EDCTP2) programme (RIA2016V-1645-priMe), supported by the European Union and co-funded by Deutsches Zentrum für Luft- und Raumfahrt (DLR) and the European Investment Bank (EIB).

PMID: 42612668

20. Nat Immunol. 2026 Sep;27(9):1899-1912. doi: 10.1038/s41590-026-02607-2.

A novel CAF population coordinates hyper-suppressive regulatory T cell recruitment and localization in lung cancer.

Across many solid tumor types, cancer-associated fibroblasts (CAFs) are abundant and heterogeneous, with distinct subpopulations exerting immunomodulatory functions. Here we identify a novel population of immunomodulatory CAFs (imCAFs) in primary lung adenocarcinoma and pulmonary metastases, characterized by cell adhesion molecule L1-like (CHL1) expression and enriched in immune regulation and chemokine signaling programs. Through single-cell and spatial transcriptomics, we demonstrate that imCAFs are spatially colocalized with CXCR3+ regulatory T (Treg) cells, a hyper-suppressive subset accumulating at the tumor border. imCAFs produce CXCL9, driving CXCR3+ Treg cell recruitment and promoting an immunosuppressive microenvironment. CXCR3+ Treg cells display enhanced proliferative and suppressive capacity and are transcriptionally distinct from CXCR3- counterparts. Genetic ablation of Cxcr3 in Treg cells or Cxcl9 in stromal cells reduces Treg cell accumulation, enhances CD8+ T cell activation and decreases tumor burden. Analogous CHL1+ imCAF-like fibroblasts in human non-small cell lung cancer colocalize with Treg cells, and elevated CHL1 expression is associated with reduced cytotoxicity and decreased progression-free survival, highlighting the imCAF-CXCL9-CXCR3+ Treg axis as a promising therapeutic target.

PMID: 42581185 [Indexed for MEDLINE]

21. Cancer Discov. 2026 Aug 3;16(8):OF1. doi: 10.1158/2159-8290.CD-NW2026-0070.

Blood Protein Test Predicts Lung Cancer Years before Diagnosis.

A 14-protein blood test can identify people at high risk of lung cancer more than 5 years before a tumor becomes detectable on imaging, including never-smokers who falloutside current screening criteria. In a retrospective analysis, the test also identified individuals most likely to benefit from the anti-IL-1β drug canakinumab, which roughly halved lung cancer incidence in the high-risk group but not in low-risk participants.

PMID: 42299102 [Indexed for MEDLINE]

22. Cancer Cell. 2026 Aug 13:S1535-6108(26)00350-8. doi: 10.1016/j.ccell.2026.07. 012. Online ahead of print.

SYS6010, epidermal growth factor receptor-targeting antibody-drug conjugate for advanced non-small cell lung cancer: A phase 1 trial.

SYS6010 is an antibody-drug conjugate targeting epidermal growth factor receptor (EGFR). We report the results of a phase 1 trial (ChiCTR2300072141) of SYS6010 in patients with non-small cell lung cancer (NSCLC). A total of 236 patients were treated. One dose-limiting toxicity occurred at 6.4 mg/kg; therefore, 4.2, 4.5, and 4.8 mg/kg were selected for cohort expansion. Treatment-related adverse events (TRAEs; any/grade ≥ 3) occurred in 99.6%/57.2% of patients. Common grade ≥3 TRAEs included neutropenia (30.9%), leukopenia (25.0%), and thrombocytopenia (17.4%). Objective response rate was 34.7% in EGFR-mutant NSCLC treated with EGFR tyrosine kinase inhibitors (TKIs) and platinum chemotherapy, 45.7% in EGFR-mutant NSCLC treated with EGFR TKIs, 20.0% in EGFR wild-type squamous NSCLC, and 35.7% in EGFR wild-type non-squamous NSCLC. Median progression-free survival and overall survival were 7.6 and 19.4 months, respectively, in EGFR-mutant NSCLC treated with EGFR TKIs and platinum chemotherapy. Overall, SYS6010 shows a manageable safety profile and encouraging antitumor activity in previously treated, advanced NSCLC.

PMID: 42594871

22. Cancer Discov. 2026 Aug 3;16(8):1529-1549. doi: 10.1158/2159-8290.CD-25-1454.

Blockade of Tumor-Intrinsic TGFβ Signaling Drives Hyperprogression in Small Cell Lung Cancer.

Stromal immunosuppressive pathways are key modulators of response to immune checkpoint inhibitors, but the tumor-intrinsic consequences of blocking these pathways remain incompletely defined. We conducted a clinical trial of bintrafusp alfa, a bifunctional PD-L1/TGFβ inhibitor, in small cell lung cancer (SCLC). Among 34 evaluable patients, 18% had partial responses, 20% stable disease, and 62% progressive disease; 38% of progressors met the criteria for hyperprogressive disease (HPD). HPD was also observed across other tumor types (n = 450), in higher frequencies with bintrafusp alfa than PD-(L)1 blockade alone. Blood and tumor profiling showed that HPD correlated with systemic immune suppression and elevated TGFβ signaling. Functional studies demonstrated that tumor-intrinsic TGFβ signaling restrains proliferation in a subset of SCLC; pathway blockade triggers hyperproliferation. External validation across cell lines and tumor samples confirmed a tumor-intrinsic TGFβ-high transcriptional state associated with inferior survival. These findings identify a context-dependent, growth-constraining function of TGFβ and support tumor-intrinsic biomarker guidance while targeting stromal immunosuppressive pathways.

SIGNIFICANCE: This study identifies tumor-intrinsic TGFβ signaling as a context-dependent growth restraint in SCLC and a driver of HPD following TGFβ blockade. A reproducible TGFβ-high mesenchymal state is linked to inferior survival, supporting biomarker-guided use of TGFβ-targeted immunotherapy.

PMID: 42018154 [Indexed for MEDLINE]

23. Cancer Cell. 2026 Aug 13:S1535-6108(26)00344-2. doi: 10.1016/j.ccell.2026. 07.006. Online ahead of print.

EGFR-targeting ADCs: From oncogene addiction to antigen-guided drug delivery.

In this issue of Cancer Cell, Li et al. report a first-in-human phase 1 study of SYS6010, an epidermal growth factor receptor (EGFR)-targeting antibody-drug conjugate, in advanced solid tumors. The study highlights how EGFR-directed therapy moves beyond kinase inhibition toward antigen-guided cytotoxic delivery in non-small cell lung cancer.

PMID: 42594872

24. Cancer Discov. 2026 Aug 3;16(8):1573-1589. doi: 10.1158/2159-8290.CD-25-1936.

The Oncogenic EGFR-SHC1 Fusion Confers Insensitivity to EGFR-TKIs via Dual Activation of N-EGFR Kinase Domain and C-SHC1 Phosphorylation Sites in Lung Cancer.

Although epidermal growth factor receptor (EGFR) fusions in non-small cell lung cancer (NSCLC) typically show sensitivity to tyrosine kinase inhibitors (TKI), we identified an EGFR-SHC1 fusion subtype that exhibits intrinsic resistance to EGFR-TKI monotherapy through a dual-activation mechanism in the preclinical and clinical settings. EGFR-SHC1 fusion protein comprises of N-terminal EGFR and C-terminal SHC1. We demonstrated that EGFR-SHC1 simultaneously activates the EGFR kinase domain (KD) and SRC-mediated phosphorylation of the SHC1 fusion partner, thereby driving ERK/AKT pathway activation and tumorigenesis independent of KD inhibition. Structural modeling coupled with domain-specific mutagenesis revealed that SHC1 phosphorylation establishes a kinase-independent bypass mechanism. Notably, dual-targeted inhibition using afatinib (EGFR-TKI) in combination with dasatinib (SRC-TKI) induced marked tumor regression in a TKI-refractory patient with NSCLC with EGFR-SHC1. This study illustrates a cooperative oncogenesis between kinases and scaffold proteins in fusions, providing a clinically actionable strategy for overcoming TKI resistance in patients with these oncogenic fusions.

SIGNIFICANCE: This study identifies a previously unrecognized mode of oncogenic signaling in receptor tyrosine kinase (RTK) fusions, in which a non-kinase fusion partner actively drives tumorigenesis through kinase-independent mechanisms. By challenging the classical kinase-centric model of RTK fusions, it provides a framework for understanding intrinsic resistance to TKIs and for developing rational combination therapies. See related commentary by Le and Wolf, p. 1480.

PMID: 41874451 [Indexed for MEDLINE]

25. J Clin Oncol. 2026 Aug 28:JCO2502659. doi: 10.1200/JCO-25-02659.

Perioperative Durvalumab for Resectable Non-Small Cell Lung Cancer: Updated Outcomes From the Phase III AEGEAN Trial.

In AEGEAN, perioperative durvalumab plus neoadjuvant chemotherapy, versus neoadjuvant chemotherapy alone, significantly improved event-free survival (EFS) and pathologic complete response in patients with resectable non-small cell lung cancer (R-NSCLC), with a safety profile consistent with the individual agents. We report EFS from a second planned interim analysis, interim disease-free survival (DFS) and overall survival (OS), and safety, after all patients completed/discontinued treatment. In this phase III, double-blind, placebo-controlled study, patients with treatment-naïve R-NSCLC (stage II-IIIB [N2]) were randomly assigned (1:1) to neoadjuvant platinum-based chemotherapy plus durvalumab/placebo (once every 3 weeks, four cycles) presurgery and then adjuvant durvalumab/placebo (once every 4 weeks, 12 cycles). Efficacy was analyzed in the modified intention-to-treat population (n = 740; for DFS, its resected subpopulation), which excluded patients with documented EGFR/ALK aberrations. As of May 10, 2024 (median follow-up, 25.9 months [censored patients]), EFS benefit favoring the durvalumab arm remained consistent (hazard ratio [HR], 0.69 [95% CI, 0.55 to 0.88]). Numerical improvement in DFS (HR, 0.66 [95% CI, 0.47 to 0.92]) and OS (HR, 0.89 [95% CI, 0.70 to 1.14]) favored the durvalumab arm. Maximum grade 3/4 adverse events occurred in 15.4% and 10.6% of the durvalumab and placebo arms, respectively, during adjuvant treatment. These results further support perioperative durvalumab plus neoadjuvant chemotherapy as a new treatment option.

PMID: 42664473

26. J Clin Oncol. 2026 Aug;44(22):2087-2097. doi: 10.1200/JCO-25-02536.

Multicenter Cohort Study of Original or Substitute Systemic Therapy With or Without Brain Radiotherapy for Extensive-Stage Small Cell Lung Cancer With Brain-Only Progression After First-Line Treatment.

PURPOSE: The optimal second-line strategy for patients with extensive-stage small cell lung cancer (ES-SCLC) developing brain-only progression (BOP) after first-line therapy remains undefined. We aimed to evaluate the efficacy of continuing the original systemic therapy versus switching strategies.

METHODS: This multicenter cohort study screened 889 patients with ES-SCLC. A total of 203 patients developing BOP were assigned to 3 second-line strategies: continuation of original systemic therapy plus brain radiotherapy (OTP + BRT), substitution therapy plus BRT (ST + BRT), or substitution therapy alone (ST). Inverse probability of treatment weighting was used to balance baseline characteristics. The primary end point was overall survival from second-line initiation (OS2).

RESULTS: In the inverse probability of treatment weighting-weighted analysis of 203 BOP patients, OTP + BRT demonstrated significantly superior median OS2 (14.7 months) compared with ST (10.2 months; hazard ratio [HR], 1.68; P = .028) and ST + BRT (9.8 months; HR, 1.67; P = .023). OTP + BRT also yielded improved median second-line progression-free survival (PFS) (8.0 months) versus ST (4.0 months; P = .024). Multivariable analysis confirmed OTP + BRT as an independent prognostic factor for improved survival. The benefit was most pronounced in patients with prior immunotherapy and longer initial PFS (≥7.5 months). No significant survival differences were observed among radiotherapy modalities (whole-brain radiotherapy v stereotactic radiosurgery).

CONCLUSION: For ES-SCLC patients with BOP, continuing the original systemic regimen plus BRT yields superior survival compared with switching systemic therapy. This supports a site-of-progression-directed strategy, effectively controlling the CNS sanctuary while maintaining an effective systemic backbone.

PMID: 42133905 [Indexed for MEDLINE]

27. Ann Oncol. 2026 Aug 18:S0923-7534(26)01458-4. doi: 10.1016/j.annonc. 2026.08.004.

Therapeutic targeting of RAS-mediated resistance in oncogene-driven lung cancer.

BACKGROUND: Despite the dramatic activity of next generation targeted therapies, most patients with oncogene-driven lung cancers eventually relapse. Novel inhibitors are particularly active against on-target resistance, fostering the emergence of off-target resistance mechanisms. The current clinical development of RAS inhibitors hints at their potential role in overcoming off-target resistance mediated by RAS alterations.

PATIENTS AND METHODS: Using tissue and liquid biopsies, we assessed resistance mechanisms to first-line osimertinib in patients with EGFR-mutant lung cancer, and to ALK-, MET-, ROS1-, and RET- inhibitors, for a total of 590 patients. We established two patient-derived models with acquired KRAS mutations obtained at osimertinib progression, enabling in vitro and in vivo functional experiments.

RESULTS: Among 312 patients progressing on first-line osimertinib, we observed a major complementary role of tissue and liquid biopsies in identifying resistance mechanisms. We identified RAS alterations in 35 of 312 patients (11.2%), with an enrichment in KRAS G12D (n = 10) and a paucity of KRAS G12C (n = 1) mutations. In patients with ALK-positive disease (n = 148), RAS alterations were more common at resistance to lorlatinib compared to second-generation inhibitors (14.7% vs 5%, p = 0.0444). Across MET-, ROS1-, and RET-driven lung cancers at progression to targeted agents, RAS alterations were detected in 7-16% of the cases. In the two patient-derived models established at osimertinib resistance with acquired KRAS mutations (G12D and G12R, respectively), we tested the combinatorial effect of osimertinib with either the selective KRAS G12D inhibitor zoldonrasib or the pan-RAS inhibitor daraxonrasib. Both combinations demonstrated marked synergistic activity in vitro and in vivo.

CONCLUSIONS: RAS alterations mediate resistance to targeted agents in approximately 10% of oncogene-driven lung cancer. Rational combinations with novel RAS inhibitors are effective in preclinical models, providing the basis for their clinical investigation and extending the paradigm of precision oncology.

PMID: 42612796

28. Ann Intern Med. 2026 Aug;179(8):1094-1106. doi: 10.7326/ANNALS-25-03816.

Performance of Lung Cancer Risk Prediction Models in Different Racial and Ethnic Groups in the United States: Results From the Lung Cancer Cohort Consortium.

BACKGROUND: Racial and ethnic disparities are a concern in lung cancer

screening.

OBJECTIVE: To investigate the performance of risk prediction models to define screening eligibility across 4 U.S. racial and ethnic groups.

DESIGN: Cohort study.

SETTING: United States, Lung Cancer Cohort Consortium.

PARTICIPANTS: 641 830 participants aged 50 to 80 years with a smoking history from 12 U.S. cohorts, including 6390 Asian, 9781 Hispanic, 39 872 non-Hispanic Black, and 585 787 non-Hispanic White participants.

MEASUREMENTS: Calibration and discrimination were quantified for 16 lung cancer prediction models. Then, screening-related metrics were calculated after applying model thresholds to select the same number of eligible participants as the 2021 criteria from the U.S. Preventive Services Task Force (USPSTF-2021). These included eligibility, sensitivity, and efficiency measured as estimated number needed to screen (NNS; the ratio between participants and lung cancer cases) for each strategy or prediction model in each racial and ethnic group.

RESULTS: General patterns across the 16 models included substantial underestimation of lung cancer risk in non-Hispanic Black participants (expected-observed ratio < 0.75 for 11 of 16 models), lower discrimination in Asian participants than all other groups (13 of 16 models), and lower discrimination in non-Hispanic Black than non-Hispanic White participants (15 of 16 models). When a same-sized screening-eligible population as USPSTF-2021 (38.0%) was enforced, all risk-based strategies achieved better average estimated screening efficiency and reduced racial and ethnic differences in efficiency compared with USPSTF-2021. The Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial Model 2012 (PLCOm2012) and Life Years gained From Screening-Computed Tomography model (LYFS-CT) performed best (mean estimated NNS, 36.5 [SD, 8.8] and 40.1 [SD, 8.2], respectively). However, no strategy could simultaneously optimize eligibility, sensitivity, and efficiency while also reducing racial and ethnic differences.

LIMITATION: Smaller sample for Asian and Hispanic participants.

CONCLUSION: To optimize efficiency and minimize its variation across racial and ethnic groups, risk-based strategies were superior to USPSTF criteria. Further optimization of prediction models for the diverse U.S. population is needed.

PRIMARY FUNDING SOURCE: U.S. National Cancer Institute, Lung Cancer Research Foundation, and Cancer Research UK.

PMID: 42372272 [Indexed for MEDLINE]

29. JAMA Intern Med. 2026 Aug 10:e263666. doi: 10.1001/jamainternmed.2026.3666.

Health Communication and Stepped Reminders Interventions for Lung Cancer Screening: A Randomized Clinical Trial.

IMPORTANCE: For more than 10 years, the US Preventive Services Task Force has recommended annual lung cancer screening (LCS), but adherence to annual screening remains low.

OBJECTIVE: To test 2 multilevel, patient-centered interventions to increase adherence to guideline-concordant annual LCS.

DESIGN, SETTING, AND PARTICIPANTS: A pragmatic 2 × 2 factorial randomized clinical trial was conducted at Kaiser Permanente Washington among patients who completed LCS with normal findings from November 21, 2022, to April 5, 2024. The date of last follow-up was July 4, 2025. Data were analyzed from July to December 2025.

INTERVENTIONS: The 4 arms included usual care, health communication, Stepped Reminders, or both interventions. The health communication intervention addressed patient screening knowledge barriers with print and video messaging. The Stepped Reminders intervention pended LCS scan orders for primary care physicians (PCPs) and sent outreach to patients to remind them to schedule scans. Both interventions were facilitated by a system-level LCS coordinator with electronic health record registry to deliver interventions.

MAIN OUTCOMES AND MEASURES: The primary outcome was completion of screening low-dose computed tomography (LDCT) or chest CT 9 to 15 months after index LDCT. All participants eligible for annual screening were included in the modified intent-to-treat analysis. Participants were censored due to lung cancer diagnosis, death, early LDCT or chest CT, or disenrollment from the health plan.

RESULTS: Among 1837 trial participants, the mean (SD) age was 66.3 (6.5) years; 897 (48.8%) were female and 940 (51.2%) were male; 17 (1.0%) were American Indian or Alaska Native, 47 (2.7%) were Asian, 55 (3.1%) were Black, 10 (0.6%) were Native Hawaiian or Other Pacific Islander, 1560 (88.7%) were White, 37 (2.1%) were multiracial, and 32 (1.8%) were another race; and 875 (47.6%) were currently using tobacco. A total of 459 were randomized to the usual care group, 460 to the health communication group, 460 to the Stepped Reminders group, and 458 to the both interventions group. Adherence to annual screening was 4.7 percentage points lower in those who received the health communication intervention relative to those who did not (59.2% [476 of 804] vs 63.3% [516 of 815]; relative risk, 0.93; 95% CI, 0.86-1.00; P = .04) and 27.7 percentage points higher in those who received the Stepped Reminders intervention relative to those who did not (75.5% [604 of 800] vs 47.4% [388 of 819]; relative risk, 1.59; 95% CI, 1.47-1.72; P < .001). The Stepped Reminders intervention improved screening rates significantly more among participants currently using tobacco (received Stepped Reminders, 281 [73.0%]; did not receive Stepped Reminders, 160 [41.2%]; risk difference, 32.3 percentage points; 95% CI, 25.9-38.8) compared with former users (received Stepped Reminders, 323 [77.8%]; did not receive Stepped Reminders, 228 [52.9%]; risk difference, 24.1 percentage points; 95% CI, 18.1-30.0) (P for interaction = .03).

CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, appropriately timed multilevel reminders directed to PCPs to order and patients to schedule LDCT scans were effective at improving annual LCS adherence in programs led by PCPs.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05747443.

PMID: 42574003

30. Lancet Respir Med. 2026 Aug 25:S2213-2600(26)00192-X. doi: 10.1016/S2213-2600(26)00192-X. Online ahead of print.

Crizotinib versus observation or placebo for surgically resected early-stage ALK-positive non-small-cell lung cancer (Eastern Cooperative Oncology Group-American College of Radiology Imaging Network E4512): a phase 3 trial.

BACKGROUND: Crizotinib is an established first-generation anaplastic lymphoma kinase (ALK) inhibitor approved for the treatment of advanced ALK-positive non-small-cell lung cancer (NSCLC). E4512 aimed to evaluate the effect of adjuvant crizotinib on disease-free survival (DFS) in patients with resected, early-stage ALK-positive NSCLC.

METHODS: In this randomised, controlled, phase 3 trial conducted in 1618 sites across the USA, Guam, and Puerto Rico, patients were randomly assigned 1:1 by computer-generated sequence to receive crizotinib 250 mg orally twice daily or observation (changed from initial double-blind placebo) for up 2 years. Eligible patients had resected NSCLC tumours that were 4 cm or larger in diameter or lymph node-positive, negative surgical margins, no neoadjuvant therapy, ALK positivity by local or central testing, and an Eastern Cooperative Oncology Group performance status of 0-1. Adjuvant chemotherapy was allowed but not required. Stratification factors were stage, previous radiation therapy, and sex. The primary endpoint was disease-free survival (DFS) in the centrally tested ALK-positive intention-to-treat population and presented as hazard ratio with 90% and 95% CI. The trial was registered at ClinicalTrials.gov (NCT02201992) and is completed. Safety was assessed in all patients whose tumours tested ALK-positive and who received the study drug.

FINDINGS: Between Aug 18, 2014, and May 10, 2024, 166 patients (of 168 planned) were enrolled (85 to crizotinib and 81 to observation). Accrual was stopped when the US Food and Drug Administration approved adjuvant alectinib for resected ALK-positive NSCLC. Overall, 153 (92%) patients had centrally confirmed ALK-positive tumours. Among these 153 individuals, 99 (65%) were female, 54 (35%) were male, and 121 (79%) were White. After a median follow-up of 65·7 months (IQR 37·5-85·6), median DFS was 74·6 (95% CI 71·2 to not assessable) months in the crizotinib group and 106·2 (67·8 to NA) months in the observation group (HR 1·08 [90% CI 0·67-1·73; 95% CI 0·61-1·90; p=0·80). In the crizotinib group, 46 (58%) patients had grade 3 or higher adverse events of any attribution (most commonly diarrhoea, in eight [10%] patients; oedema, in four [5%] patients; and hypertension, in four [5%] patients), including one death that was not deemed treatment-related. 21 (27%) patients had serious adverse events, most commonly dyspnoea (three [4%] patients), abdominal pain (two [3%] patients), thromboembolic event (two [3%] patients), diarrhoea (two [3%] patients), dehydration (two [3%] patients), and hypertension (two [3%] patients).

INTERPRETATION: Adjuvant crizotinib does not prolong DFS in patients with surgically resected ALK-positive NSCLC. These findings suggest that crizotinib should not be recommended as an adjuvant therapy for patients with resected ALK-positive NSCLC.

FUNDING: National Cancer Institute of the US National Institutes of Health.

PMID: 42641639

31. Lancet Oncol. 2026 Aug;27(8):1043-1056. doi: 10.1016/S1470-2045(26)00191-9.

Differential impact of proton pump inhibitors and antibiotics on immunotherapy efficacy after chemoradiotherapy in locally advanced non-small-cell lung cancer: a post-hoc analysis of the PACIFIC trial.

BACKGROUND: Baseline exposure to antibiotics and proton pump inhibitors has been associated with reduced efficacy of immune checkpoint inhibitors in patients with advanced tumours, possibly through gut microbiome disruption. Whether this outcome extends to those with earlier-stage disease remains unclear. We aimed to assess the association of baseline antibiotics and proton pump inhibitors with progression-free survival and overall survival in patients with unresectable stage III non-small cell lung cancer (NSCLC).

METHODS: PACIFIC was a randomised, double-blind, placebo-controlled phase 3 trial done in patients aged 18 years or older with unresectable stage III squamous or non-squamous NSCLC, WHO performance status 0-1, and no progression after two or more cycles of concurrent chemoradiotherapy. Patients were randomly assigned (2:1) to durvalumab 10 mg/kg intravenously every 2 weeks for up to 12 months or placebo, starting 1-42 days after chemoradiotherapy; patients were stratified by age, sex, and smoking history. This post-hoc analysis was based on the final 5-year data cutoff date of the completed trial and included the treated population with consent for exploratory analyses. Co-primary endpoints were progression-free survival and overall survival, assessed according to baseline exposure to proton pump inhibitors and systemic antibiotics. This trial is registered on ClinicalTrials.gov (NCT02125461).

FINDINGS: Between May 9, 2014, and April 22, 2016, 713 patients were randomly assigned; 660 were included in this post-hoc analysis, of whom 449 received durvalumab and 211 received placebo; 203 (30·8%) were female and 453 (68·6%) were male. Race was reported as Asian in 153 (23·1%) patients, Black or African American in five (0·7%), White in 424 (64·2%), and unknown in 78 (11·8%). Baseline proton pump inhibitor exposure was recorded in 263 (40%) of 660 patients and antibiotic exposure was recorded in 69 (10%). Median follow-up in the pooled population was 62·4 (IQR 61·9-63·2) months. In the durvalumab group baseline exposure to proton pump inhibitors was associated with shorter progression-free survival (9·4 months [95% CI 7·6-13·7] vs 17·2 months [15·4-23·2]; hazard ratio [HR] 1·57 [95% CI 1·28-1·93]; p<0·0001) and overall survival (33·0 months [95% CI 21·9-46·7] vs 57·9 months [48·7-not computable (NC)]; HR 1·66 [95% CI 1·30-2·13]; p<0·0001) compared to no exposure to proton pump inhibitors, while baseline exposure to antibiotics was associated with shorter progression-free survival (9·2 months [95% CI 4·9-18·1] vs 15·6 months [13·6-17·6]; HR 1·50 [95% CI 1·08-2·10]; p=0·016) compared to no exposure to antibiotics, but there was no significant change in overall survival (37·7 months [95% CI 18·8-NC; 28 events] vs 49·2 months [39·7-57·3]; HR 1·33 [95% CI 0·90-1·97]; p=0·16). In the placebo group, neither proton pump inhibitor exposure nor antibiotic exposure was associated with changes in progression-free survival and overall survival. Interactions between treatment and proton pump inhibitors for progression-free survival (p=0·023) and overall survival (p<0·0001) were significant, but not for antibiotics.

INTERPRETATION: Baseline exposure to proton pump inhibitors and antibiotics was associated with inferior outcomes with durvalumab, but not with placebo, consistent with potential attenuation of the benefit of durvalumab with proton pump inhibitors and antibiotics in patients with unresectable stage III NSCLC.

PMID: 42398520

32. Ann Oncol. 2026 Aug;37(8):1030-1048. doi: 10.1016/j.annonc.2026.04.014.

Lung cancer brain metastases management at the dawn of personalized medicine: are we ready to break the barriers?

Brain metastases occur in nearly half of patients with lung cancer and significantly impair survival and quality of life. Historically, limited blood-brain barrier penetration and low intracranial efficacy of systemic therapies restricted treatment options. However, advances in immune checkpoint inhibitors and next-generation central nervous system-penetrant targeted therapies have reshaped the therapeutic landscape, improving intracranial control and patient outcomes. In parallel, stereotactic radiotherapy has emerged as a precise and effective local treatment with a more favorable safety profile than whole-brain radiotherapy. The integration of systemic and local approaches, guided by personalized medicine, offers new opportunities to optimize central nervous system disease control. Nevertheless, these advances raise key challenges regarding treatment sequencing, patient selection, and risk-adapted strategies. This review summarizes the evolving management of lung cancer brain metastases and highlights future directions for clinical trial design, emphasizing the integration of clinical, biological, and radiological tools to guide individualized treatment strategies.

PMID: 42061818 [Indexed for MEDLINE]

33. Ann Oncol. 2026 Aug 21:S0923-7534(26)01462-6. doi: 10.1016/j.annonc. 2026.08.005. Online ahead of print.

Five-Year Outcomes of Perioperative Pembrolizumab for Early-Stage Non-Small-Cell Lung Cancer From the Randomized KEYNOTE-671 Study.

BACKGROUND: Adding perioperative pembrolizumab to neoadjuvant chemotherapy significantly improved survival outcomes compared with neoadjuvant chemotherapy and surgery alone in participants with early-stage non-small-cell lung cancer (NSCLC) in the phase 3, randomized KEYNOTE-671 study. We report results from KEYNOTE-671 after 5 years of follow-up.

PATIENTS AND METHODS: Eligible participants with previously untreated, resectable stage II, IIIA, or IIIB (N2) NSCLC were randomized 1:1 to 4 cycles of pembrolizumab 200 mg or placebo every 3 weeks, plus platinum-doublet chemotherapy, followed by surgery then adjuvant pembrolizumab or placebo every 3 weeks for up to 13 cycles. Dual primary endpoints were event-free survival (EFS) per RECIST v1.1 by investigator assessment and overall survival (OS).

RESULTS: 797 participants were randomized to pembrolizumab (n=397) or placebo (n=400). Median time from randomization to data cutoff (July 3, 2025) was 60.4 (range, 42.6‒85.8) months. Five-year EFS was 49.9% (95% CI, 44.6‒55.0) in the pembrolizumab arm and 26.5% (95% CI, 21.7‒31.5) in the placebo arm (HR, 0.58; 95% CI, 0.48‒0.69); 5-year OS was 64.6% (95% CI, 59.5‒69.2) and 53.6% (95% CI, 48.3‒58.6), respectively (HR, 0.74; 95% CI, 0.59‒0.92). No detriment to health-related quality of life was identified in the pembrolizumab versus placebo arm with longer follow-up. Safety was consistent with the known profiles of each treatment.

CONCLUSIONS: After 5 years of follow-up, EFS was nearly double with perioperative pembrolizumab plus neoadjuvant chemotherapy, along with continued improvement in OS compared with neoadjuvant chemotherapy and surgery alone. The durable and clinically meaningful benefits observed support use of this treatment as a standard of care for patients with resectable early-stage NSCLC (ClinicalTrials.gov, NCT03425643).

PMID: 42628840

34. Nat Med. 2026 Aug;32(8):2898-2908. doi: 10.1038/s41591-026-04452-0.

SEZ6-targeting antibody-drug conjugate ABBV-706 in advanced small cell lung cancer and solid tumors: a phase 1 trial.

Seizure-related homolog 6 (SEZ6) is expressed in small cell lung cancer (SCLC) and neuroendocrine neoplasms. In an open label, phase 1 trial, ABBV-706, an antibody-drug conjugate with a SEZ6-directed antibody linked to topoisomerase-1 inhibitor (Top1i), was administered intravenously every 3 weeks (Q3W) to 288 patients with advanced solid tumors; 240 received monotherapy, including 124 with relapsed/refractory (R/R) SCLC. Primary objectives of dose escalation (part 1, advanced solid tumors), dose optimization and expansion (part 2, R/R SCLC only) and dose expansion (part 4, central nervous system tumors and high-grade neuroendocrine neoplasms only) were to evaluate the safety, tolerability, pharmacokinetics (PK), immunogenicity and antitumor activity of ABBV-706 monotherapy and, from parts 1 and 2, to determine the recommended phase 2 dose (RP2D) of ABBV-706 in R/R SCLC. In the monotherapy cohort (N = 240), the most common treatment-related adverse events (TRAEs) at any grade were anemia (61%) and fatigue (38%). Grade 3 or higher TRAEs occurred in 61% of patients and were dose dependent (39% at 1.8 mg kg-1 and 70% at 2.5 mg kg-1). In the R/R SCLC monotherapy cohort (n = 124), any-grade and grade 3 or higher TRAEs occurred in 93% and 61% of patients, respectively. ABBV-706 demonstrated promising preliminary efficacy in patients with R/R SCLC, with an objective response rate (ORR) of 52% (65/124). In patients with R/R SCLC receiving monotherapy in dose optimization and expansion part 2, ORR was similar between 1.8 mg kg-1 and 2.5 mg kg-1 doses (56% (23/41) and 59% (23/39), respectively), with a duration of response that was highest at the 1.8 mg kg-1 dose and with most patients achieving rapid and durable tumor reduction. Although exploratory, long-term efficacy measures were an important consideration in the RP2D determination, and in R/R SCLC monotherapy, overall survival (OS) was highest at the 1.8 mg kg-1 dose, with amedian OS of 12.4 months. Based on the totality of available data, including, but not limited to, safety, preliminary efficacy measures and PK, 1.8 mg kg-1 Q3W was confirmed as the optimal RP2D for patients with R/R SCLC.

PMID: 42225988 [Indexed for MEDLINE]

35. JAMA. 2026 Aug 11;336(6):464-472. doi: 10.1001/jama.2026.8992.

Adjuvant Nivolumab vs Observation in Resected Non-Small Cell Lung Cancer: A Randomized Clinical Trial.

IMPORTANCE: Preoperative and perioperative nivolumab improve event-free survival in resectable non-small cell lung cancer. The role of adjuvant nivolumab after upfront surgery is unknown.

OBJECTIVE: To determine whether adjuvant nivolumab improves disease-free survival and overall survival in patients with resected non-small cell lung cancer with any tumor programmed death-ligand 1 (PD-L1) expression and in those with at least 50% PD-L1 expression.

DESIGN, SETTING, AND PARTICIPANTS: This open-label, randomized phase 3 study enrolled participants from May 2016 through September 2019, with median follow-up of 72.6 months at the data cutoff in December 2025. The study was conducted at 378 centers in the US National Clinical Trials Network. Patients were identified through a screening trial. Those with resected tumors at least 4 cm and/or who were lymph node positive (N1/N2) were eligible for inclusion after completion of planned standard adjuvant therapy if the tumor was adenocarcinoma without sensitizing sequence variants in EGFR and ALK or squamous cell carcinoma.

INTERVENTION: Patients were randomized in a 1:1 ratio to receive nivolumab 480 mg intravenously every 4 weeks for up to 1 year or standard care observation.

MAIN OUTCOMES AND MEASURES: Co-primary end points were disease-free survival in the intention-to-treat population and in those with tumoral PD-L1 expression at least 50%. Overall survival was examined if the corresponding test of disease-free survival was statistically significant.

RESULTS: A total of 466 patients (median age, 66 years; 241 [52%] male) were assigned to receive nivolumab and 469 (median age, 67 years; 245 [52%] male) to undergo standard care observation. The median duration of follow-up was 72.6 months. The trial was stopped for futility at 75% information. In the intention-to-treat population, median disease-free survival was 71.3 months with nivolumab and 68.8 months with observation (hazard ratio for progression or death, 0.97 [97% CI, 0.79-1.20]; [95% CI, 0.81-1.17]; 1-sided P = .39). In the subset of participants with PD-L1 of at least 50%, median disease-free survival was 89.8 months with nivolumab and 78.5 months with observation (hazard ratio for progression or death, 0.86 [98% CI, 0.55-1.34]; [95% CI, 0.59-1.25]; 1-sided P = .22).

CONCLUSIONS AND RELEVANCE: Adjuvant nivolumab was not associated with improved disease-free survival in patients with resected non-small cell lung cancer without sensitizing EGFR and ALK alterations when given after planned adjuvant chemotherapy and/or radiotherapy.

TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT02595944.

PMID: 42224490 [Indexed for MEDLINE]