PubMed：

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

Filters applied: from 2026/05/01 - 2026/05/31.

1. Cell. 2026 May 19:S0092-8674(26)00505-2. doi: 10.1016/j.cell.2026.04.038.

Nociceptive innervation limits tertiary lymphoid structures to promote lung cancer.

Sensory innervation regulates lung physiology and pathology, but its role in lung cancer is poorly understood. We show that lung adenocarcinoma (LUAD) progression locally amplifies nociceptive sensory innervation and activation, which drives the release of a major sensory neuropeptide, calcitonin gene-related peptide (CGRP). CGRP acts on a subset of macrophages, thereby impairing the recruitment of CXCL13+ fibroblasts and blocking tertiary lymphoid structure (TLS) assembly, a key predictor of LUAD prognosis. Local sensory denervation restores TLS formation, enhances B and T cell-dependent immunity, and suppresses tumor growth. Cigarette smoke extract (CSE) further activates this neural circuit to accelerate LUAD progression. In CSE-exposed animals, pharmacologic CGRP blockade sensitizes tumors to immunotherapy and prolongs survival. Together, our findings uncover a neuroimmune axis linking nociceptive neurons, TLS, and LUAD and identify neurogenic inflammation as a mechanism by which smoking promotes lung tumorigenesis independent of somatic mutagenesis.

PMID: 42161272

2. Lancet. 2026 May 29:S0140-6736(26)00968-2. doi: 10.1016/S0140-6736(26) 00968-2.

Sacituzumab tirumotecan plus pembrolizumab versus pembrolizumab in PD-L1-positive advanced non-small-cell lung cancer (OptiTROP-Lung05): interim analysis of a randomised, open-label, phase 3 trial.

BACKGROUND: Sacituzumab tirumotecan (sac-TMT), a trophoblast cell-surface antigen 2-targeting antibody-drug conjugate, combined with programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitors, has shown promising antitumour activity as first-line therapy for non-small-cell lung cancer (NSCLC) in early-phase studies. Our aim was to evaluate the efficacy and safety of sac-TMT plus pembrolizumab as first-line treatment for patients with PD-L1-positive advanced NSCLC without targetable genomic alterations.

METHODS: In this randomised, open-label, phase 3 trial (OptiTROP-Lung05) conducted across 68 hospitals in China, eligible patients had locally advanced or metastatic NSCLC without targetable genomic alterations and a PD-L1 tumour proportion score (TPS) of 1% or greater. Patients were randomly assigned (1:1) to receive sac-TMT (4 mg/kg on days 1, 15, and 29) plus pembrolizumab (400 mg fixed dose on day 1), or pembrolizumab alone, administered intravenously every 6 weeks. The primary endpoint was progression-free survival, as assessed by blinded independent central review in the intention-to-treat population. This trial was registered with ClinicalTrials.gov (NCT06448312). Recruitment is complete, with the trial ongoing and the final analysis to be reported later.

FINDINGS: Between June 7, 2024, and March 27, 2025, 741 patients were screened and 413 eligible patients were randomly assigned to receive sac-TMT plus pembrolizumab (n=208) or pembrolizumab alone (n=205). At the prespecified interim analysis, conducted after a median follow-up of 10·5 months (IQR 8·7-12·5), median progression-free survival was significantly longer with sac-TMT plus pembrolizumab than with pembrolizumab alone (not reached vs 5·7 months; stratified hazard ratio [HR] 0·35 [95% CI 0·26-0·47]; p<0·0001). The progression-free survival benefit was broadly consistent across subgroups, including patients with PD-L1 TPS of 1-49% (HR 0·28 [95% CI 0·19-0·41]) and those with PD-L1 TPS of 50% or greater (HR 0·47 [0·29-0·77]). Grade 3 or higher treatment-emergent adverse events occurred in 115 (55%) of 208 patients in the sac-TMT plus pembrolizumab group and 64 (31%) of 204 patients in the pembrolizumab group.

INTERPRETATION: Among patients with PD-L1-positive advanced NSCLC without targetable genomic alterations, first-line treatment with sac-TMT plus pembrolizumab significantly prolonged progression-free survival compared with pembrolizumab alone. Therefore, sac-TMT plus pembrolizumab has the potential to redefine first-line treatment for patients with PD-L1-positive advanced NSCLC without targetable genomic alterations.

PMID: 42214392

3. N Engl J Med. 2026 May 31. doi: 10.1056/NEJMoa2602628. Online ahead of print.

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

BACKGROUND: Selpercatinib, a highly selective, potent, and central nervous system-penetrant rearranged during transfection (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, 0.17; 95% CI, 0.06 to 0.49; 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

4. Cell. 2026 May 14;189(10):2845-2856.e20. doi: 10.1016/j.cell.2026.02.013. Epub 2026 Mar 11.

Respiratory viral infections prime accelerated lung cancer growth.

The COVID-19 pandemic has highlighted the long-term consequences of viral pneumonia, yet its impact on cancer development remains unclear. Here, we show that patients previously hospitalized with severe COVID-19 have an increased risk of subsequent lung cancer. Across multiple murine models, severe respiratory viral infections accelerated lung cancer growth, whereas vaccination mitigated infection-enhanced tumor progression. Mechanistically, prior viral pneumonia reprogrammed the lung into a pro-tumor microenvironment marked by the sustained accumulation of tumor-associated neutrophils and heightened immunosuppression. We observed persistent chromatin remodeling at key cytokine loci in immune and structural cells, linking inflammatory memory to tumor-promoting signals. Therapeutically, combined blockade of neutrophil recruitment and programmed death-ligand 1 (PD-L1) restored CD8+ T cell function and suppressed tumor growth. Together, these findings establish a causal link between prior viral pneumonia and lung tumorigenesis, underscoring the need for enhanced surveillance and targeted interventions to reduce post-COVID cancer risk.

PMID: 41819102 [Indexed for MEDLINE]

5. Nat Med. 2026 May;32(5):1927-1934. doi: 10.1038/s41591-026-04294-w.

Long-term risk of death after tuberculosis diagnosis and treatment.

Tuberculosis (TB) remains a major societal burden, yet data on long-term mortality following TB diagnosis and treatment are limited. We conducted a nationwide Brazilian cohort study using linked data (2004-2018) to quantify long-term mortality (up to 14 years) following TB. We matched: (i) individuals diagnosed with TB or (ii) individuals who had completed TB treatment to TB-free individuals. We used competing risk methods to analyze natural causes (that is, defined as deaths excluding TB, HIV and external causes) and cause-specific mortality. In the diagnosed cohort (185,921 pairs), the risk of 14-year natural cause mortality was significantly higher (risk ratio (RR) = 2.16, 95% confidence interval = 1.96-2.37); RRs were significantly elevated for deaths due to cancer, cardiovascular, endocrine, respiratory and external causes. The treated cohort (111,871 pairs) presented elevated natural cause mortality risk (RR = 1.77,1.55-2.03), with similarly increased RRs across specific causes. We showed that TB survivors, even after treatment, faced a significantly elevated, prolonged risk of death from various causes up to 14 years later. This finding highlights the need for long-term monitoring to reduce the burden of TB.

PMID: 41857197 [Indexed for MEDLINE]

6. Lancet Infect Dis. 2026 May 29:S1473-3099(26)00143-X. doi: 10.1016/S1473-3099(26)00143-X. Online ahead of print.

Efficacy and safety of a 4-month quabodepistat, delamanid, and bedaquiline regimen for drug-susceptible pulmonary tuberculosis: a multicentre, open-label, randomised, proof-of-concept, non-inferiority, phase 2b/c trial.

BACKGROUND: Combined therapy with delamanid, bedaquiline, and quabodepistat (DBQ) showed potent early bactericidal activity and was well tolerated in a phase 2a, 14-day early bactericidal activity trial in participants with drug-susceptible pulmonary tuberculosis. This subsequent proof-of-concept trial evaluated the efficacy and safety of a 4-month, three-dose level regimen of DBQ in participants with drug-susceptible pulmonary tuberculosis compared with 6 months of the standard of care.

METHODS: This open-label, randomised, proof-of-concept, non-inferiority, phase 2b/c trial was conducted at six clinical research sites in South Africa. Adults aged 18-65 years with newly diagnosed, drug-susceptible pulmonary tuberculosis were recruited by research sites from community tuberculosis clinics. Participants were randomly assigned (1:2:2:1) by balanced block randomisation (block size six) to receive oral delamanid (300 mg once a day) and bedaquiline (400 mg once a day for 2 weeks then 200 mg three times a week) plus quabodepistat at once-daily doses of 10 mg (DBQ10 group), 30 mg (DBQ30 group), or 90 mg (DBQ90 group) for 4 months; or 6 months of RHEZ (rifampicin, isoniazid, ethambutol, and pyrazinamide for 8 weeks followed by 18 weeks of rifampin and isoniazid). All drugs were administered orally. Masking procedures were not used, although microbiology laboratory staff were masked to treatment assignment. The primary endpoints were the proportion of participants reaching sputum culture conversion by the end of the treatment period in the modified intention-to-treat (mITT) analysis set and safety in the safety analysis set. Non-inferiority, with a margin of 12%, was assessed for the primary endpoint in the mITT analysis set, comparing the pooled DBQ group and the RHEZ group using a two-sided 80% CI. This study was registered at ClinicalTrials.gov, NCT05221502, and is complete.

FINDINGS: Between April 12, 2022, and May 19, 2024, 306 individuals were screened, of whom 122 were enrolled and randomly assigned: 20 to the DBQ10 group, 42 to the DBQ30 group, 39 to the DBQ90 group, and 21 to the RHEZ group. 121 participants received at least one dose of study drug and comprised the mITT analysis set. At the end of the treatment period, the proportion of participants with sputum culture conversion was 100·0% (95% CI 83·2-100·0, all 20 participants) in the DBQ10 group, 92·9% (80·5-98·5, 39 of 42 participants) in the DBQ30 group, 97·4% (86·2-99·9, 37 of 38 participants) in the DBQ90 group, 96·0% (90·1-98·9, 96 of 100 participants) in the pooled DBQ group, and 100·0% (83·9-100·0, all 21 participants) in the RHEZ group. The comparison between the pooled DBQ group and the RHEZ group met non-inferiority for the primary endpoint (difference -4·0% [80% CI -7·4 to 3·4]). Adverse events were mostly mild to moderate, with no serious adverse events or discontinuations attributed to trial medications. Rates of adverse events of grade 3 or higher were 20% (four of 20 participants) in the DBQ10 group, 14% (six of 42 participants) in the DBQ30 group, 11% (four of 38 participants) in the DBQ90 group, and 5% (one of 21 participants) in the RHEZ group. One participant (in the DBQ90 group) died after worsening pulmonary tuberculosis with pneumonia, which was assessed as not related to study treatment. 105 (87%) of 121 participants had at least one treatment-emergent adverse event: 17 (85%) of 20 in the DBQ10 group, 37 (88%) of 42 in the DBQ30 group, 30 (79%) of 38 in the DBQ90 group, and all 21 (100%) participants in the RHEZ group. The most common treatment-emergent adverse events in the total population of 121 participants were upper respiratory tract infection (n=36, 30%), headache (n=24, 20%), and diarrhoea (n=12, 10%).

INTERPRETATION: In this proof-of-concept study, 4 months of DBQ showed a promising end-of-treatment non-inferiority signal versus 6 months of RHEZ and was generally well tolerated. Our results support further studies of quabodepistat as a potential component of new treatment-shortening regimens for tuberculosis.

PMID: 42214407

7.Lancet Infect Dis. 2026 May 6:S1473-3099(26)00133-7. doi: 10.1016/S1473-3099(26)00133-7. Online ahead of print.

Expanding Xpert MTB/RIF Ultra and lateral flow urine lipoarabinomannan testing for diagnosis of tuberculosis among adults living with HIV admitted to hospitals in Tanzania and Mozambique (EXULTANT): a randomised controlled trial.

BACKGROUND: Tuberculosis is the main cause of death among hospitalised people living with HIV. Non-sputum-based diagnostics could improve patient outcomes. The EXULTANT trial aims to evaluate an expanded tuberculosis screening strategy among people with HIV in two African countries with a high tuberculosis and HIV burden.

METHODS: This pragmatic, individually randomised controlled superiority trial was conducted across 11 hospitals in Tanzania and Mozambique. We consecutively enrolled adults living with HIV (aged ≥18 years) without an existing tuberculosis diagnosis or recent tuberculosis treatment, within 24 h of admission. The intervention group underwent Xpert MTB/RIF Ultra (Xpert Ultra) testing from sputum, stool, and urine, plus lateral flow urine lipoarabinomannan (LF-LAM) testing (Determine TB LAM Ag assay), irrespective of symptoms. The control group followed standard-of-care, symptom-based, WHO-recommended sputum Xpert Ultra and LF-LAM testing. The primary endpoint was the proportion of participants with microbiologically confirmed tuberculosis starting treatment within 72 h. Secondary endpoints included 8-week all-cause mortality and time to tuberculosis diagnosis. The trial is registered at ClinicalTrials.gov (NCT04568967) and is completed.

FINDINGS: From Sept 25, 2022, to March 15, 2024, we screened 1534 participants, and randomly assigned 1172 (76·6%) to either the intervention group (n=582) or the control group (n=590). At admission, 715 participants (61·0%) were female, 845 (75·4%) were on antiretroviral therapy (ART), and median CD4 count was 232 cells per μL (IQR 87-490). In the control group, 505 (85·6%) had tuberculosis-compatible symptoms and were eligible for sputum Xpert Ultra testing (306 of them [60·6%] provided a sample) and 538 (91·2%) met WHO criteria for LF-LAM testing. In the intention-to-treat analysis, 93 (16·0%) of 582 participants in the intervention group and 90 (15·3%) of 590 in the control group had microbiologically confirmed tuberculosis and started treatment within 72 h (difference 0·7%, 95% CI -3·4 to 4·8, p=0·73). 8-week all-cause mortality was 25·8% (150 of 582) in the intervention group and 28·8% (170 of 590) in the control group (hazard ratio 0·86, 95% CI 0·69 to 1·07, p=0·18). Median time to tuberculosis treatment initiation was 0·98 days (IQR 0·83-1·92) and 0·92 days (0·79-1·86) in the intervention and control groups, respectively (hazard ratio 1·05, 95% CI 0·82 to 1·33, p=0·72).

INTERPRETATION: An expanded screening strategy among people living with HIV admitted to hospital did not increase the proportion of individuals with microbiologically confirmed tuberculosis starting treatment or reduce 8-week mortality.

PMID: 42105779

8. Nat Immunol. 2026 Jun;27(6):1104-1118. doi: 10.1038/s41590-026-02529-z. Epub 2026 May 18.

The host immune response to Mycobacterium tuberculosis determining protection or disease progression.

Tuberculosis (TB) remains a global health issue and leading cause of death. Understanding the immune response to Mycobacterium tuberculosis infection is critical to advance TB control. Although immune factors involved in protection against TB have long been identified, these cannot predict the efficacy of TB vaccines, nor which individuals will control the infection or progress to active TB disease. This is especially challenging given the complexity of M. tuberculosis infection states and the breadth of TB disease severities, which is increasingly apparent from basic, clinical and translational research. Here, we discuss the evolving spectrum of M. tuberculosis infection outcomes and TB disease, how the host immune response determines and unfolds across this spectrum and how the natural diversity of M. tuberculosis contributes to this complexity. Integration of these new concepts with fast-evolving systems immunology approaches holds great potential to inform the design of novel strategies to control TB.

PMID: 42151479

9. Lancet. 2026 May 31:S0140-6736(26)00966-9. doi: 10.1016/S0140-6736(26) 00966-9. Online ahead of print.

Ivonescimab plus chemotherapy versus tislelizumab plus chemotherapy in advanced squamous non-small-cell lung cancer (HARMONi-6): interim overall survival analysis of a randomised, double-blind, phase 3 trial in China.

BACKGROUND: Bispecific antibodies targeting programmed death 1 (PD-1) and vascular endothelial growth factor (PD1-VEGF) have shown promising efficacy in non-small-cell lung cancer (NSCLC). In our previous report of the HARMONi-6 study, we aimed to evaluate the efficacy and safety of ivonescimab plus chemotherapy versus tislelizumab plus chemotherapy as a first-line therapy for patients with advanced squamous NSCLC. Ivonescimab combined with chemotherapy significantly prolonged progression-free survival compared with tislelizumab plus chemotherapy. Here we report the prespecified interim overall survival analysis.

METHODS: HARMONi-6 is a double-blind, randomised, phase 3 trial, which was conducted at 50 hospitals across China. Patients aged 18-75 years with previously untreated, pathologically confirmed, unresectable stage IIIB, IIIC, or stage IV squamous NSCLC and an Eastern Cooperative Oncology Group performance status score of 0 or 1 were eligible for inclusion. Eligible patients were randomly assigned in a 1:1 ratio to receive ivonescimab or tislelizumab, in combination with paclitaxel and carboplatin for four cycles, followed by maintenance ivonescimab or tislelizumab monotherapy. The primary endpoint was progression-free survival assessed by the independent radiographic review committee as per Response Evaluation Criteria in Solid Tumours guidelines (version 1.1) in all randomly assigned patients. Overall survival was a key secondary endpoint; an interim analysis was planned when approximately 225 overall survival events were observed, but it was triggered after 204 overall survival events to meet regulatory deadlines. Safety, defined as adverse events and serious adverse events related to treatment, as well as adverse events related to immunity or VEGF blockade, were analysed in all randomly assigned patients who received at least one dose of the assigned study treatment. This study is registered at ClinicalTrials.gov (NCT05840016), has completed enrolment, and is ongoing for treatment and follow-up.

FINDINGS: From Aug 17, 2023, to Jan 21, 2025, 761 patients were assessed for eligibility, and after 229 exclusions a total of 532 patients were randomly allocated (266 per group). 494 (93%) of patients were male and 38 (7%) of patients were female. The median age was 64 years (IQR 59-69). At data cutoff (Feb 27, 2026), 204 deaths had occurred: 84 (32%) patients in the ivonescimab plus chemotherapy group and 120 (45%) in the tislelizumab plus chemotherapy group. With a median follow-up of 21·4 months (95% CI 20·27-21·91), the median overall survival was 27·9 months (95% CI 27·89-not evaluable [NE]) with ivonescimab versus 23·7 months (20·11-NE) with tislelizumab (hazard ratio for death 0·66 [95% CI 0·50-0·87]; pone-sided=0·0017), meeting the prespecified boundary (p<0·0049). The overall survival benefit with ivonescimab plus chemotherapy was consistent across key subgroups. Treatment-related adverse events of grade 3 or higher occurred in 184 (69%) of 266 patients in the ivonescimab group and 156 (59%) of 265 patients in the tislelizumab group. The incidence of grade 3 or higher haemorrhage was seven (3%) of 266 and two (1%) of 265, respectively.

INTERPRETATION: Ivonescimab plus chemotherapy demonstrated a statistically significant and clinically meaningful improvement in overall survival compared with tislelizumab plus chemotherapy in previously untreated patients with advanced squamous NSCLC. This regimen could provide a novel treatment option as first-line treatment in this patient group.

PMID: 42218899

10. Cancer Discov. 2026 May 1;16(5):895-910. doi: 10.1158/2159-8290.CD-25-1346.

Preclinical Characterization and Clinical Activity of RNK08954, a Highly Selective and Orally Bioavailable KRASG12D Inhibitor.

KRAS G12D is the most prevalent subtype of KRAS mutation across solid tumors, but no drug is available in the clinic. RNK08954 is a potent and selective KRASG12D inhibitor that inhibits proliferation of KRASG12D-mutant cells and demonstrates significant tumor regressions in mouse xenograft models while inhibiting KRAS-mediated signaling. The in vivo effects of RNK08954 are explained by its unique pharmacokinetic (PK) profile and significantly prolonged retention time in tumor tissues. RNK08954 shows synergy with immune checkpoint blockade (ICB). In a phase Ia study, the median follow-up was 4.85 months for 36 evaluable patients. In patients with non-small cell lung cancer (NSCLC), the objective response rate (ORR; unconfirmed) was 58.33%, and in patients with pancreatic ductal adenocarcinoma (PDAC), the ORR (unconfirmed) was 33.33% in the 1,000- to 1,200-mg cohort. This study supports the clinical potential of RNK08954 in patients with KRASG12D mutation either as a single agent or in combination.

SIGNIFICANCE: RNK08954 is potentially the first orally bioavailable KRASG12D inhibitor, distinguished by unique PK properties, preclinical efficacy, preliminary clinical activity with encouraging results in patients with NSCLC and PDAC, and synergistic potential with ICB. RNK08954 may address a critical unmet need by targeting the most prevalent KRAS mutation across solid tumors.

PMID: 41557983

11. Lancet Infect Dis. 2026 May 14:S1473-3099(26)00168-4. doi: 10.1016/S1473-3099(26)00168-4. Online ahead of print.

Understanding and exploiting superspreading to disrupt Mycobacterium tuberculosis transmission.

Tuberculosis remains a persistent threat to global public health. Ultimately, future progress towards tuberculosis elimination is contingent on our ability to interrupt Mycobacterium tuberculosis transmission between individuals who are infectious and their susceptible contacts. This Personal View examines individual heterogeneity in M tuberculosis infectiousness and secondary transmission and focuses specifically on M tuberculosis superspreading, ie, the observation that most secondary M tuberculosis infections and tuberculosis clinical cases are attributable to transmission from a relatively small number of individuals. Reviewing both historical and contemporary data, we argue that superspreading is not only an important, ubiquitous feature of tuberculosis epidemiology, but also represents a potential opportunity for disruptive, strategic interventions with potentially outsized impacts on M tuberculosis transmission.

PMID: 42134384

12. Lancet Glob Health. 2026 May;14(5):e817-e828. doi: 10.1016/S2214-109X(25) 00540-6.

Untangling the complex relationship between HIV-exposure and tuberculosis in children: a narrative review.

With the remarkable success of antiretroviral programmes for the prevention of vertical HIV transmission, there has been a notable reduction in the proportion of children born with HIV and, subsequently, a corresponding increase in the population of children who are HIV-exposed but uninfected (CHEU). There is growing appreciation for the increased risk of childhood morbidity and mortality among CHEU compared with children who are HIV-unexposed, particularly from infectious diseases. Given the high prevalence of tuberculosis in populations with high HIV prevalence, the effect of HIV exposure on tuberculosis is therefore of particular interest. In this Review, we contextualise and reflect on the existing literature for CHEU with regard to prevention, prevalence, and outcomes of tuberculosis infection and tuberculosis disease. In so doing, we identify gaps in reported knowledge on CHEU to guide future research.

PMID: 41999718 [Indexed for MEDLINE]

13. Lancet Glob Health. 2026 May 11:S2214-109X(26)00065-3. doi: 10.1016/S2214-109X(26)00065-3. Online ahead of print.

Global, regional, and national estimates of tuberculosis incidence averted by eliminating undernutrition in adults: a modelling study.

BACKGROUND: Current efforts to reduce global tuberculosis incidence have proved insufficient, highlighting that urgent action is needed to address underlying modifiable risk factors such as undernutrition. We aimed to estimate the global impact of eliminating undernutrition on tuberculosis incidence among adults, accounting for varying nutritional status by country, sex, and age, in addition to incorporating the continuous, non-linear relationship between BMI and tuberculosis risk.

METHODS: For this modelling study, we used a continuous risk framework to consider the population-level implications of BMI distributions for tuberculosis incidence in adults aged 15 years or older in 2023. We generated BMI distributions for each country, sex, and age group, and applied a bilinear model for the logarithmic relative risk of tuberculosis incidence at different BMI values. We assessed the impact of eliminating moderate-to-severe undernutrition (BMI<17 kg/m2) or all undernutrition (BMI <18·5 kg/m2) on tuberculosis incidence by constructing counterfactual BMI distributions that redistributed those with low BMI to high BMI, proportional to the remaining density.

FINDINGS: We estimated that eliminating moderate-to-severe undernutrition could avert 1·4 million (95% uncertainty interval 1·1-1·7) tuberculosis episodes globally, representing 14·6% (12·6-16·6) of global adult incidence in 2023, while eliminating all undernutrition could avert 2·3 million (1·8-2·7) episodes, representing a reduction in global tuberculosis incidence of 23·7% (20·9-26·5). The largest proportional reductions in tuberculosis incidence could be achieved by eliminating undernutrition in the WHO African, South-East Asia, and Eastern Mediterranean regions; in females; and in adolescents or older adults.

INTERPRETATION: Almost a quarter of global tuberculosis incidence in adults could be averted by eliminating undernutrition, approximately two-and-a-half times higher than current estimates. These findings highlight the urgent need to scale up population-level nutritional interventions, which could have myriad social and health benefits beyond tuberculosis, alongside research to establish optimal implementation strategies and impacts.

PMID: 42114532

14. Lancet Glob Health. 2026 May;14(5):e690-e701. doi: 10.1016/S2214-109X(26) 00008-2. Epub 2026 Feb 2.

Impact of two decades of humanitarian and development assistance and the projected mortality consequences of current defunding to 2030: retrospective evaluation and forecasting analysis.

BACKGROUND: Official development assistance (ODA) accounts for the majority of humanitarian and development assistance in the world's most vulnerable countries and has played a pivotal role in advancing global health. We aimed to comprehensively evaluate the impact of ODA funding on mortality across the past two decades, and to project the potential consequences of current defunding trends.

METHODS: We conducted an integrated retrospective evaluation and forecasting analysis using longitudinal panel data from 93 low-income and middle-income countries (LMICs). First, we estimated the association between ODA per-capita funding and mortality outcomes from 2002 to 2021 using a two-ways fixed-effects multivariable Poisson regression model with robust standard errors, adjusted for all relevant demographic, socioeconomic, and health-system covariates. We then assessed age-specific and cause-specific effects, performing extensive sensitivity and triangulation analyses to test the robustness and causal interpretation of results. Finally, we integrated the retrospective impact estimates into validated country-level microsimulation models to forecast mortality under three defunding scenarios up to 2030: a business-as-usual trajectory, a severe defunding scenario, and a mild defunding scenario.

FINDINGS: Higher ODA funding levels were associated with a 23% reduction in age-standardised all-cause mortality (rate ratio [RR] 0·77; 95% CI 0·70-0·85) and a 39% reduction in under-5 mortality (0·61; 0·49-0·75). ODA funding was associated with large mortality declines in major communicable diseases: 70% for HIV/AIDS (RR 0·30; 95% CI 0·24-0·39), 56% for malaria (0·44; 0·35-0·56), 56% for nutritional deficiencies (0·44; 0·30-0·65), and 54% for neglected tropical diseases (0·46; 0·36-0·59). Significant reductions were also observed in mortality from tuberculosis, diarrhoeal diseases, lower respiratory infections, and maternal and perinatal causes. Forecasting analyses projected that ongoing reductions in ODA funding could, under a severe defunding scenario, result in 22·6 million (95% uncertainty interval [UI] 16·3-29·3) additional deaths across all ages by 2030, including 5·4 million (4·1-6·8) among children younger than 5 years. Under a mild defunding scenario-defined as a continuation of current downward trends-the projected excess deaths would be 9·4 million (95% UI 6·2-12·6) overall and 2·5 million (1·8-3·2) among children younger than 5 years.

INTERPRETATION: ODA funding has played a decisive role in reducing preventable mortality across LMICs over the past two decades, and the abrupt withdrawal of this support threatens to cause millions of avoidable deaths, reversing decades of progress in global health.

PMID: 41643687 [Indexed for MEDLINE]

15. Am J Respir Crit Care Med. 2026 May 13:aamag107. doi: 10.1093/ajrccm/ aamag107. Online ahead of print.

Post-Tuberculosis Lung Disease in Treated Extra-Pulmonary Tuberculosis.

BACKGROUND: Post-tuberculosis lung disease is a well-recognized sequela of pulmonary tuberculosis (PTB). Extra-pulmonary tuberculosis (EPTB) accounts for a quarter of the global tuberculosis 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 (≥18 years) with drug-sensitive PTB and EPTB recruited from outpatient clinics in India. Adult household contacts without current tuberculosis disease underwent spirometry at enrolment and served as non-tuberculosis controls. Logistic and linear regression was used to measure the association of treated EPTB with ventilatory defects and persistence of impaired lung function during post-treatment follow-up, respectively.

RESULTS: We enrolled 775 tuberculosis survivors, 275 (35%) of whom were treated for EPTB, and 502 non-tuberculosis controls. Compared to controls, EPTB was associated with lower z-scores for FEV1 (-0.37, 95%CI -0.54 to -0.20, p < 0.001) and FVC (-0.46, 95%CI -0.65 to -0.26, p < 0.001), and higher odds of airflow obstruction (aOR=1.58, 95%CI 0.95 to 2.61, p = 0.066) and restrictive spirometry (aOR=2.16, 95%CI 1.48 to 3.15, p < 0.001) at treatment completion. Lung function deficits in EPTB survivors persisted during the 1.5 years of post-treatment 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 was lower.

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

PMID: 42128261

16. Am J Respir Crit Care Med. 2026 May 1;212(5):1005-1016. doi: 10.1093/ajrccm/ aamag063.

Clinical and transcriptomic risk factors for post-tuberculosis lung disease in a cohort of Kenyan adults.

RATIONALE: Post-tuberculosis lung disease (PTLD), which includes restrictive and obstructive patterns of impairment, develops in 50% or more of survivors of tuberculosis (TB), yet mechanisms and associated risk factors are poorly understood.

OBJECTIVES: We sought to identify clinical and transcriptomic risk factors for PTLD phenotypes.

METHODS: In a prospective, observational, cohort study, we enrolled adults (month 0) with newly diagnosed pulmonary TB in Nairobi, Kenya, and evaluated clinical and transcriptomic risk factors for PTLD. Participants completed 6 months of standard anti-TB therapy. PTLD was defined as abnormal spirometry at month 12 (ie, 6 months posttreatment) with either a restrictive or obstructive pattern.

MEASUREMENTS AND MAIN RESULTS: We enrolled 205 participants, of whom 103 (50.2%) had PTLD, including 60 with restrictive PTLD and 43 obstructive PTLD. Participants with PTLD had lower mid-upper arm circumference (MUAC) and cough peak flow. In multivariable analyses, having more lung quadrants involved on radiograph at diagnosis was a risk factor for both restrictive PTLD (adjusted odds ratio [aOR], 2.1; P <.001) and obstructive PTLD (aOR, 2.2; P <.001). Prior TB was associated with obstructive PTLD (aOR, 5.4; P <.001). Gene expression improved clinical predictive models. In transcriptomic analyses, restrictive PTLD was associated with upregulation of IL-6/JAK/STAT3 and TNF-α signaling at diagnosis (false discovery rate [FDR]<0.2). In contrast, obstructive PTLD was associated with transcriptomic upregulation of IFN-α and IFN-γ signaling responses (FDR <0.2) at month 6.

CONCLUSIONS: Despite common clinical risk factors (lower MUAC, radiographic lung involvement), PTLD phenotypes have unique transcriptional signatures. Restrictive PTLD is marked by early profibrotic inflammation. In contrast, obstructive PTLD is characterized by persistent inflammation at treatment completion.

PMID: 41738226 [Indexed for MEDLINE]

17. Lancet Microbe. 2026 May;7(5):101362. doi: 10.1016/j.lanmic.2026.101362.

Molecular diagnostic tests for isoniazid-resistant tuberculosis: a scoping review.

The paucity of diagnostic tests for isoniazid-resistant tuberculosis is concerning, given its status as the most common form of drug-resistant tuberculosis and a gateway to multidrug-resistant diseases. Molecular drug-susceptibility testing has improved access to timely diagnosis of rifampicin-resistant tuberculosis, but testing for isoniazid-resistant tuberculosis still remains rare. In this Review, we assessed the characteristics of molecular drug-susceptibility testing for detection of isoniazid-resistant tuberculosis, referencing the WHO target product profiles. 9243 citations were screened to select 238 studies published between 2000 and 2024. The diagnostics options have expanded rapidly since 2020, with 27 nucleic acid amplification tests, eight line probe assays, five DNA microarrays, two targeted next-generation sequencing platforms, and two whole-genome sequencing platforms. Most of the evaluated molecular drug-susceptibility tests met diagnostic performance targets but were often complex and costly. Although a few low-complexity nucleic acid amplification tests met key target product profile criteria, additional field validation and greater efforts are needed to ensure optimal feasibility and affordability for low-resource settings.

PMID: 41871590 [Indexed for MEDLINE]

18. Lancet Microbe. 2026 May 14:101330. doi: 10.1016/j.lanmic.2025.101330.

Multicountry assessment of tongue swabs for tuberculosis using a common protocol for Xpert MTB/RIF Ultra testing: a prospective diagnostic accuracy study.

BACKGROUND: Despite advancements in tuberculosis diagnostics, many cases remain unconfirmed because of challenges in conventional sputum-based testing. This study aimed to evaluate the diagnostic accuracy of tongue swab sampling as a non-invasive alternative for tuberculosis diagnosis using Xpert MTB/RIF Ultra (Ultra).

METHODS: We conducted a large-scale, multicountry, prospective diagnostic accuracy study of Ultra using tongue swabs in people with presumptive pulmonary tuberculosis. Participants were enrolled consecutively at primary health centres and hospitals across eight countries from June 26, 2023, to Feb 15, 2024, and the study was coordinated by three consortia. Eligible participants were individuals aged 12 years or older or 18 years or older, according to the consortium involved, with presumptive pulmonary tuberculosis or at least one risk factor for tuberculosis and a positive tuberculosis screening test at the select consortia. Standardised tongue swab collection and processing protocols were used in all countries. Sensitivity and specificity with 95% CI values were calculated against sputum liquid or solid culture (primary) and sputum Ultra (secondary) reference standards using Wilson's score method. Fisher's exact tests were used for subgroup comparisons, with p values < 0·05 considered statistically significant.

FINDINGS: Among the 1844 participants included in the analysis, 389 tested positive and 1455 tested negative for pulmonary tuberculosis based on the primary sputum culture reference standard. 871 (47·2%) participants were female and 973 (52·7%) were male, with a mean age of 43 years (range 12-90). Among the 1844 participants, 399 (21·7%) were enrolled in Viet Nam, 166 (9·0%) in India, 427 (23·2%) in South Africa, 271 (14·7%) in the Philippines, 138 (7·5%) in Nigeria, 102 (5·5%) in Zambia, 175 (9·5%) in Uganda, and 166 (9·0%) in Peru. Tongue swab Ultra testing showed a sensitivity of 65·6% (95% CI 60·6-70·3) and specificity of 98·5% (95% CI 97·7-99·1) against the culture-based reference standard. Sensitivity estimates varied across collection centres and were higher in individuals without HIV than in those living with HIV (68·4% vs 50·0%; absolute difference 18·4 percentage points [95% CI 3·3-33·4]). When sputum Ultra was used as the reference standard, sensitivity was 75·4% (95% CI 69·0-78·8). Tongue swab Ultra showed higher sensitivity than sputum smear microscopy. Invalid or error result rates were variable and high at certain sites (range 0-16%).

INTERPRETATION: Tongue swabs are a promising sample type for rapid diagnostic tests for tuberculosis, with moderate sensitivity and high specificity when Ultra was used as the reference standard. However, further research is needed to optimise protocols for Ultra testing and develop assays tailored to tongue swab specimens. Adoption of tongue swab-based molecular testing could expand tuberculosis diagnostics access, especially for populations unable to produce sputum, thus supporting global tuberculosis elimination goals.

PMID: 42134368

19. Cell Mol Immunol. 2026 May 28. doi: 10.1038/s41423-026-01431-w.

Mycobacterium tuberculosis MEM39 (Rv1977) hijacks host aldolase A (ALDOA) to subvert immunometabolism to facilitate bacterial intracellular survival.

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), is the leading cause of infectious disease-related death. As a major intracellular pathogen, Mtb can escape clearance by the immune system, but the underlying molecular mechanisms remain incompletely elucidated. Specific genomic regions of deletion (RD)-encoded proteins in virulent Mtb H37Rv have been implicated in modulating pathogenicity and immunity. Here, we report a novel RD15-encoding protein, Rv1977 (a mycobacterial cell wall protein with a size of 39 kDa, named MEM39), which facilitates Mtb survival in macrophages. The survival of the Mtb H37Rv MEM39-deficient strain is reduced in both macrophage and murine infection models. Furthermore, the mycobacterial MEM39 protein binds fructose-diphosphate aldolase A (ALDOA), a key enzyme of glycolysis, thereby impairing ALDOA enzyme activity, disrupting macrophage metabolite flux, and reducing lactate production. The MEM39-ALDOA interaction also suppresses lysosomal acidification; reduces NLRP3 inflammasome activation and the production of proinflammatory cytokines (TNF-α, IL-6 and IL-1β); and thereby promotes bacterial survival within macrophages. Disruption of the interaction between MEM39-ALDOA and a cell-penetrating synthetic peptide (VLARYASICQ) significantly suppressed Mtb survival by restoring lactate production, lysosome acidification and proinflammatory cytokine production in both macrophage and mouse infection models. These findings revealed that mycobacterial MEM39 negatively regulates host immune defense through reprogramming ALDOA-mediated glycolysis in macrophages, thereby forming a "mycobacterial MEM39 virulence factor-glycolysis metabolism-immunity" regulatory axis. Targeting MEM39 or the MEM39-ALDOA interaction interface holds promise as a new therapeutic strategy against tuberculosis.

PMID: 42209765

20. Nat Immunol. 2026 Jun;27(6):1268-1281. doi: 10.1038/s41590-026-02515-5. Epub 2026 May 12.

Epigenetic reprogramming of T cell metabolism restores function and enhances anti-tumor immunity in lung cancer.

T cell exhaustion represents a critical target for immunotherapy in cancer. Nevertheless, T cells exhibit diminished responsiveness to immune checkpoint inhibitors once they transition to a terminally exhausted state. Here we used an epigenetic drug screen and identified bromodomain and extra-terminal motif inhibitors (BETis) as enhancers of effector functions in primary exhausted T cells (TEX) from malignant pleural effusions in patients with lung cancer. Transcriptomics, metabolomics and ATAC-seq analyses revealed that BETis reinvigorate TEX cells by activating the polyamine biosynthesis pathway, expanding intracellular polyamine pools and altering chromatin accessibility. Genetic and pharmacological inhibition of ornithine decarboxylase (ODC1), a key enzyme in this pathway, abolished BETi-mediated immunopotentiation. Single-cell RNA-seq demonstrated that BETis reduced terminal TEX while promoting progenitor TEX through activation of the MYC-ODC axis. BETi treatment or adoptive transfer of BETi-treated T cells suppressed malignant pleural effusion formation in a syngeneic lung cancer model. These findings highlight an epigenetic-metabolic approach to enhance TEX plasticity and offer insights for novel cancer immunotherapies.

PMID: 42120791

21. J Clin Oncol. 2026 May 22:JCO2503026. doi: 10.1200/JCO-25-03026.

Overcoming Primary and Acquired Resistance to Immunotherapy in Non-Small Cell Lung Cancer: Mechanisms, Challenges, and Emerging Strategies.

Acquired resistance (AR) to immune checkpoint inhibitors (ICIs) remains a major obstacle to durable clinical benefit in non-small cell lung cancer (NSCLC). Emerging after initial responses, AR reflects tumor evolution, immune escape, and metabolic reprogramming. Key mechanisms may include impaired antigen presentation (β2-microglobulin, human leukocyte antigen mutations), T-cell exhaustion, and remodeling of the tumor microenvironment (TME). In this review, we summarize the current understanding of ICIs resistance and highlight therapeutic strategies under investigation to overcome it. Novel approaches include next-generation ICIs targeting TIGIT and LAG-3, epigenetic modulators (HDAC, DNMT inhibitors), and metabolic agents relevant to STK11 and KEAP1 mutations. Additional strategies aim to reprogram the TME through AXL or multikinase inhibition, tumor-treating fields, and cytokine- and/or gene-based therapies. Cellular immunotherapies (tumor-infiltrating lymphocytes, T-cell receptors, chimeric antigen receptor-T), antibody-drug conjugates, and vaccines offer complementary means to restore antitumor immunity. Advancing the field will require biomarker-driven patient selection and rational combinations to overcome AR and achieve more durable, personalized immunotherapy outcomes in

NSCLC.

PMID: 42172565

22. Nat Med. 2026 May;32(5):1817-1826. doi: 10.1038/s41591-026-04292-y.

Implementation of the NHS England Lung Cancer Screening Programme over 5 years.

Lung cancer screening with low-dose computed tomography has been proven to reduce lung-cancer-specific and all-cause mortality. The UK launched the NHS England Targeted Lung Health Check Programme in 2019, which has now become the national Lung Cancer Screening Programme, with full coverage expected by 2030. Here we present the progress and outcomes of the program. People aged 55-74 were offered low-dose computed tomography of the thorax if they had ever smoked and if risk thresholds, as determined by multivariable models, were met. Delivery of the program is through regionally federated clinical infrastructure and leadership, with national strategic, clinical and economic frameworks. The program has invited over two million people, with 7,193 lung cancers diagnosed-63.1% at tumor, node, metastasis stage 1 and 12.6% stage 2-to March 2025. This has increased the early-stage proportion of lung cancer in England over 5 years, particularly in socioeconomically deprived regions. The NHS England Programme exemplifies how large-scale implementation can be achieved at speed through centralized protocols and effective project management. The program has demonstrated feasibility and scalability in reaching high-risk and underserved populations, but needs to further address inequalities in participation. These findings support adoption of lung cancer screening across the UK and globally, and offer practical tools for international adaptation.

PMID: 41872602 [Indexed for MEDLINE]

23. Nat Rev Clin Oncol. 2026 May;23(5):374-389. doi: 10.1038/s41571-026-01131-4.

Innovative approaches for lung cancer screening and interception.

Lung cancer remains the leading cause of cancer-related deaths worldwide, partly because many patients are diagnosed at late stages, highlighting the urgent need for effective early detection and intervention strategies. Low-dose computed tomography (LDCT)-based screening reduces lung cancer mortality in high-risk populations defined by age and smoking history; however, the uptake of LDCT remains low among eligible individuals. Compounding this issue, modelling studies estimate that nearly half of lung cancers occur in individuals who do not meet eligibility criteria for LDCT-based lung cancer screening under current guidelines. Moreover, LDCT-based screening has inherent limitations, including a high rate of false-positive results that can lead to unnecessary invasive procedures, as well as substantial costs that limit scalability. Major efforts have been made to identify novel biomarkers such as radiomic features and liquid biopsy assays to enhance the accuracy of lung cancer risk prediction. Furthermore, the increasing detection of pulmonary nodules by LDCT or diagnostic CT scans has highlighted the importance of therapeutic interventions that can enable interception of high-risk precancerous nodules and halt their progression to invasive disease. In this Review, we summarize the current state of lung cancer screening, the disparities and infrastructural considerations for optimal implementation, and future directions in the development of biomarkers and design of precancer interception strategies that could transform both lung cancer prevention and early intervention.

PMID: 41731061 [Indexed for MEDLINE]

24. J Clin Oncol. 2026 Jun;44(16):1540-1552. doi: 10.1200/JCO-25-01958. Epub 2026 May 5.

Metastatic Trajectories in Non-Small Cell Lung Cancer Guide Local and Systemic Therapies.

Advances in systemic therapy have improved outcomes for metastatic non-small cell lung cancer (NSCLC), yet resistance and progression remain nearly universal. Local therapies such as radiotherapy, surgery, and image-guided ablation can extend disease control in selected patients, but existing classifications-including dynamic models of oligometastatic disease-assign a single state per patient and do not capture lesion-level heterogeneity. We introduce the concept of metastatic trajectories-the spatiotemporal dynamics of response and progression across lesions, organs, and patients-as a framework to characterize intrapatient heterogeneity and inform adaptive treatment strategies. Dimensions of metastatic trajectories include the magnitude and homogeneity of response, mechanisms of resistance, organotropism, and the pattern, site, extent, and pace of progression. This framework shifts the focus from overall disease states to individual lesion behavior over time, enabling reactive strategies based on observed trajectories and anticipatory strategies based on predicted ones. We review the biological foundations of intrapatient heterogeneity-including genomic diversification, nongenetic plasticity, and tumor-microenvironmental adaptation-that drive divergent lesion evolution and treatment response. Emerging biomarkers such as circulating tumor DNA and radiomic signatures, together with integrative genomic and functional imaging approaches, may allow tracking and prediction of trajectory evolution. Standardized reporting parameters are proposed to ensure consistent documentation and facilitate validation across studies. Integrating trajectory-based assessment into clinical practice could refine patient selection for local and systemic therapy, enable biology-informed adaptation of treatment timing and intensity, and provide a foundation for next-generation clinical trials aimed at precision management of metastatic NSCLC.

PMID: 42085620 [Indexed for MEDLINE]

25. Lancet Respir Med. 2026 May;14(5):453-462. doi: 10.1016/S2213-2600(26) 00051-2.

Consensus definition of stage III non-small-cell lung cancer technical resectability to standardise inclusion criteria for clinical trials: a multisocietal EORTC-Lung Cancer Group collaboration.

The decision regarding resectability in stage III non-small-cell lung cancer (NSCLC) is complex. To improve consistency in eligibility criteria in clinical trials, the European Organisation for Research and Treatment of Cancer (EORTC) initiated a Delphi study to establish a standardised definition of technical resectability for stage III NSCLC. 36 experts from the EORTC, European Respiratory Society, International Association for the Study of Lung Cancer, European Society for Radiotherapy and Oncology, European Thoracic Oncology Platform and International Breast Cancer Study Group, European Society of Thoracic Surgeons, and European Society of Pathology formulated 34 consensus statements on the definition of resectability. Consensus was defined as 75% agreement. After three Delphi rounds there was unanimous consensus that the decision on resectability should be made by experienced thoracic surgeons within the context of a multidisciplinary team. Initial assessments should include PET-CT, brain MRI, and invasive mediastinal staging. Stage IIIA was generally classified as resectable. Tumours with N2 involvement might be resectable depending on the nature of lymph node involvement (ie, single or multi-station, bulky or non-bulky, and invasive or non-invasive). Stage IIIB might be considered resectable, depending on lymph node characteristics: N2single mostly resectable; N2multi mostly unresectable; N2bulky mostly unresectable; and N2invasive or N3 unresectable. Stage IIIC was classified as unresectable. The proposed definitions aim to standardise inclusion criteria for clinical trials facilitating a more consistent evaluation of multimodal treatments for stage III NSCLC. Further data collection, especially on the nature of N2 disease, is needed to refine the definition.

PMID: 41895314 [Indexed for MEDLINE]

26. J Clin Oncol. 2026 May 14:JCO2502536. 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

27. JAMA Oncol. 2026 May 14:e261199. doi: 10.1001/jamaoncol.2026.1199.

Temporal Trends in Lung Cancer Cases Diagnosed at Early Stage.

IMPORTANCE: Since December 2013, the US Preventive Services Task Force has recommended lung cancer screening for adults at high risk of developing lung cancer because of their age and smoking history. Increased uptake in lung cancer screening may be reflected in changes in the stage at which lung cancer is diagnosed.

OBJECTIVE: To examine the percentage of lung cancer cases diagnosed at an early stage, visualizing temporal patterns with heat maps.

DESIGN, SETTING, AND PARTICIPANTS: This descriptive surveillance study used US Cancer Statistics incidence data to identify US adults who were diagnosed with malignant lung cancer from 2003 to 2022. Data were analyzed from November 14 to November 30, 2025.

MAIN OUTCOMES AND MEASURES: Percentage of lung cancers diagnosed at early stage, stratified by year of diagnosis, age at diagnosis, and state of residence.

RESULTS: From 2003 to 2022, 4 363 687 new lung cancer cases were reported in the US. The percentage diagnosed at early stage increased slowly from 17.6% (95% CI, 17.5%-17.8%) in 2003 to 20.2% (95% CI, 20.0%-20.4%) in 2014, increased sharply from 21.4% (95% CI, 21.2%-21.6%) in 2015 to 24.6% (95% CI, 24.4%-24.8%) in 2016, then increased steadily to 30.1% (95% CI, 29.9%-30.3%) in 2022. The percentage diagnosed at early stage increased in all states, beginning around 2016 in most states. In 2003, the percentage diagnosed at early stage ranged from 11.2% (95% CI, 8.5%-14.6%) to 24.0% (95% CI, 22.7%-25.4%); by 2022, this range was 22.0% (95% CI, 18.9%-25.5%) to 40.2% (95% CI, 36.7%-43.9%).

CONCLUSIONS AND RELEVANCE: This descriptive surveillance study showed that since lung cancer screening was recommended in 2013, more people with lung cancer are being diagnosed early, when treatment is more effective and more treatment options are available. Population-based survey data indicate that fewer than 1 in 5 eligible persons reported being up to date with lung cancer screening in 2024. Strengthening awareness about the benefits of lung cancer screening and supporting uptake remain important strategies for cancer prevention and control.

PMID: 42133301

28. JAMA Oncol. 2026 May 7:e261080. doi: 10.1001/jamaoncol.2026.1080.

Rates of Systemic Treatment for Metastatic Non-Small Cell Lung Cancer Among Older Adults.

IMPORTANCE: Metastatic non-small cell lung cancer (mNSCLC) has very high mortality rates, and comprises approximately half of new cases of lung cancer; however, highly effective and better tolerated treatments have become available in recent decades. Nevertheless, population-level treatment of mNSCLC is poorly characterized in the era of rapid treatment advances.

OBJECTIVE: To characterize treatment rates, trends, and factors associated with treatment of mNSCLC.

DESIGN, SETTING, AND PARTICIPANTS: This population-based study used linked Surveillance Epidemiology and End Results (SEER) and Medicare claims data and the analysis included patients 65 years and older diagnosed with mNSCLC from January 2006 to December 2021. Data were analyzed from October 2025 to February 2026.

EXPOSURES: Sociodemographic variables, comorbidity burden, histologic type, referral to subspecialist, enrollment in Medicare Part D, and biomarker testing.

MAIN OUTCOMES: The primary outcome was receipt of systemic treatment. Statistical analyses included summary statistics and a competing risk proportional hazards model for receipt of systemic treatment.

RESULTS: Of 254 611 patients with mNSCLC, the cohort median (IQR) age was 73 (68-80) years, with 133 635 (52.5%) male individuals; a total of 9512 (3.7%) were Asian, 26 546 (10.4%) were Black, 4553 (1.8%) were Hispanic, 205 381 (80.7%) were White, and 8619 (3.4%) were another or unknown race. A total of 119 197 patients (46.8%) ever received systemic treatment. Of the 100 367 (39.8%) who died within 90 days of diagnosis, 13.2% were treated compared with 69% of those surviving more than 90 days. The treated proportion increased only slightly between 2006 and 2021. In a competing risk model, referral to oncology specialists was associated with treatment (hazard ratio [HR], 2.5; 95% CI, 2.41-2.67; P < .001) which corresponded to a 30.3% greater cumulative incidence of treatment at 180 days (CIF180) compared with those without a referral. Similarly, those with biomarker testing had a 17.8% greater CIF180, whereas those older than 80 years had a 15.4% lower CIF180 compared to those aged 65 to 69 years. Patients with NSCLC not otherwise specified histologic findings had a 12.8% lower CIF180 compared with those with adenocarcinoma histologic findings. Other factors associated with significant but smaller differences in receipt of treatment included comorbidity burden, marital status, Medicare Part C or Part D coverage, rurality, and race and ethnicity.

CONCLUSIONS AND RELEVANCE: In this cohort study of older adults with mNSCLC, despite advances in therapy in recent decades, almost half of patients never received systemic therapy, and the proportion treated only minimally improved over time. Approximately one-fifth of those with the most favorable clinical profiles did not receive systemic therapy.

PMID: 42096214

29. JAMA Oncol. 2026 May 1;12(5):506-516. doi: 10.1001/jamaoncol.2026.0392.

Combination of Radiotherapy and Immunotherapy in Advanced Non-Small Cell Lung Cancer.

IMPORTANCE: The optimal sequencing of radiotherapy (RT) combined with immunotherapy (iRT) and the value of chemotherapy remain undefined for advanced non-small cell lung cancer (NSCLC), where randomized data are limited.

OBJECTIVE: To compare real-world overall survival (OS) between sequential and concurrent iRT in newly diagnosed advanced NSCLC, assess the effect of immune checkpoint inhibitor (ICI) maintenance after RT in refractory disease, and evaluate the association of chemotherapy with survival.

DESIGN, SETTING, AND PARTICIPANTS: This is a territory-wide study (OCEANUS) based on the Hong Kong Hospital Authority Clinical Data Analysis and Reporting System (more than 90% population coverage). Patients with NSCLC diagnosed from January 1, 2010, to December 31, 2021, who subsequently received iRT for advanced or refractory disease were included. Overlap weighting was the primary propensity score-weighted method, with inverse probability of treatment weighting used for sensitivity analysis. Data were analyzed from December 2024 to April 2025.

EXPOSURES: Sequential vs concurrent iRT for newly diagnosed advanced NSCLC; RT with vs without ICI maintenance for refractory NSCLC; receipt of chemotherapy. MAIN OUTCOMES AND MEASURES: The primary outcome was real-world OS after landmark, estimated with weighted Kaplan-Meier and Cox models. When proportional hazards were violated (per Schoenfeld residuals), treatment effects were summarized using restricted mean survival time.

RESULTS: Of 3522 patients who received ICIs, 335 received RT, including 155 with newly diagnosed advanced and 180 with refractory NSCLC. Of these, 247 (73.7%) were male, and the median (range) age was 64 (34-90) years. In newly diagnosed NSCLC, patients treated with sequential iRT had significant longer real-world OS than those treated with concurrent iRT (median, 20.3 months [95% CI, 13.3 to not reached] vs 16.0 months [95% CI, 8.3-30.0]; adjusted hazard ratio, 0.68; 95% CI, 0.47-0.99; P = .045). Chemotherapy was also associated with longer survival in patients with newly diagnosed advanced NSCLC. In refractory NSCLC, RT with ICI maintenance was associated with a numerically longer median real-world OS (11.2 months [95% CI, 7.9-20.6] vs 6.7 months [95% CI, 4.4-17.4]; P = .20). Addition of chemotherapy was not significant for real-world OS. Inverse probability of treatment weighting analyses produced similar estimates.

CONCLUSIONS AND RELEVANCE: In this cohort study, sequential iRT was associated with longer survival than concurrent iRT in patients with newly diagnosed advanced NSCLC, and chemotherapy was associated with longer survival. In patients with refractory NSCLC who survived at least 90 days, RT with ICI maintenance resulted in nonsignificantly longer survival and an unclear association with chemotherapy. These findings are hypothesis generating and support prospective randomized studies to define optimal sequencing of iRT and use of systemic treatment partners.

PMID: 41885834 [Indexed for MEDLINE]

30. JAMA. 2026 May 18:e268044. doi: 10.1001/jama.2026.8044. Online ahead of print.

Biomarker-Based Eligibility for Lung Cancer Screening: Validation of the Protein-Based INTEGRAL-Risk Model.

IMPORTANCE: Screening by low-dose computed tomography can reduce lung cancer mortality among high-risk individuals, but many lung cancers occur among individuals with a smoking history who are not eligible for screening.

OBJECTIVE: To develop and validate the protein-based Integrative Analysis of Lung Cancer Risk and Etiology (INTEGRAL)-Risk model in individuals with a smoking history from the general population.

DESIGN, SETTING, AND PARTICIPANTS: Cohorts in the Lung Cancer Cohort Consortium recruited research participants in the US, Europe, Asia, and Australia between 1985 and 2009, who were followed up for lung cancer and other health outcomes until 2021. Fourteen case cohorts of 3695 participants with a smoking history within the Lung Cancer Cohort Consortium, including 2305 randomly sampled participants and 1390 patients diagnosed with lung cancer within 3 years after blood sample collection, were designed. Plasma or serum samples from each participant were assayed using the INTEGRAL protein panel in 2022. The INTEGRAL-Risk model was trained using 7 predefined case cohorts (training set; n = 1951) to estimate absolute risk of being diagnosed with lung cancer based on age, smoking history, and 13 proteins. The validity of the INTEGRAL-Risk model was assessed in 7 independent case cohorts (testing set; n = 1744) at 1, 2, and 3 years after blood collection.

EXPOSURE: Absolute risk estimates from the protein-based INTEGRAL-Risk model.

MAIN OUTCOMES AND MEASURES: The primary outcome was the validity of the INTEGRAL-Risk model in the testing set with respect to discrimination (area under the curve [AUC]) and calibration (ratio of expected-to-observed cases [E/O]).

RESULTS: A total of 3695 participants were included, with 1951 participants (including 807 with lung cancer) in the training set and 1744 participants (including 583 with lung cancer) in the testing set. In the combined 14 training and testing sets, after application of statistical weights, 323 570 participants were represented (185 016 [57%] female; median [IQR] age, 60 [51-67] years). In the independent testing set, discrimination of the INTEGRAL-Risk model was highest at 1 year of follow-up and exceeded that of the questionnaire-based PLCOm2012 (Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial) model (INTEGRAL-Risk AUC of 0.88 [95% CI, 0.85-0.91] vs PLCOm2012 AUC of 0.79 [95% CI, 0.75-0.83]; P value for difference <.001). Using a risk threshold to achieve the same specificity as US Preventive Services Task Force (USPSTF) 2021 criteria, the INTEGRAL-Risk model captured 85% of lung cancer cases compared with 63% by USPSTF 2021 and 70% by PLCOm2012. Discrimination of the INTEGRAL-Risk model decreased with longer prediction horizons, with a 2-year AUC of 0.84 (95% CI, 0.81-0.86) and 3-year AUC of 0.81 (95% CI, 0.79-0.83). The model was well calibrated (E/O over 3 years, 0.87 [95% CI, 0.69-1.14]).

CONCLUSIONS AND RELEVANCE: Compared with questionnaire-based approaches, the protein-based INTEGRAL-Risk model improved short-term prediction of lung cancer in people with a smoking history. This model has potential to improve selection of high-risk individuals who are most likely to benefit from lung cancer creening.

PMID: 42149699

31. J Clin Oncol. 2026 May;44(13):1190-1197. doi: 10.1200/JCO-25-01489.

Final Efficacy and Safety Data From the Phase I/II ARROW Study of Pralsetinib in Patients With Advanced RET Fusion-Positive Non-Small Cell Lung Cancer.

RET fusions appear in 1%-2% of non-small cell lung cancers (NSCLCs). The results from the ARROW study (ClinicalTrials.gov identifier: NCT03037385) supported US Food and Drug Administration approval of pralsetinib, an oral selective RET inhibitor, for metastatic RET-altered NSCLC and RET fusion-positive thyroid cancers. ARROW was a phase I/II open-label study of pralsetinib 400 mg once daily in RET fusion-positive NSCLCs. Coprimary end points were overall response rate (ORR) and safety. Key secondary end points included duration of response, progression-free survival, and overall survival (OS). At data lock (May 20, 2024), 281 patients initiated pralsetinib (median treatment duration, 15.0 months). ORR (measurable disease patients; n = 259) was 78% (95% CI, 69 to 86) for treatment-naïve patients and 63% (95% CI, 54 to 71) for prior platinum-based chemotherapy patients. Median OS was 44.3 months (95% CI, 30.9 to 53.1), 50.1 months (95% CI, 28.3 to not reached) in treatment-naïve patients, and 39.7 months (95% CI, 27.8 to 53.2) in prior platinum patients. Common grade ≥3 treatment-related adverse events were anemia (21%), hypertension (15%), and decreased neutrophils (13%). Three treatment-related deaths occurred (pneumonia, n = 2; interstitial lung disease and rhabdomyolysis, n = 1 each). Safety was consistent with previous ARROW reports; no hypersensitivity was reported in patients receiving prior immunotherapies. Pralsetinib produced robust, durable responses with manageable safety in treatment-naïve and previously treated patients with RET fusion-positive NSCLCs, confirming previous findings with longer follow-up.

PMID: 41886723 [Indexed for MEDLINE]

32. J Clin Oncol. 2026 May 26:JCO2600842. doi: 10.1200/JCO-26-00842.

Therapy for Stage IV Non-Small Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline, 2026.3.1.

Living guidelines are developed for selected topic areas with rapidly evolving evidence that drives frequent change in recommended clinical practice. Living guidelines are updated on a regular schedule by a standing expert panel that systematically reviews the health literature on a continuous basis, as described in the ASCO Guidelines Methodology Manual. ASCO Living Guidelines follow the ASCO Conflict of Interest Policy Implementation for Clinical Practice Guidelines. Living Guidelines and updates are not intended to substitute for independent professional judgment of the treating clinician and do not account for individual variation among patients. See appendix for disclaimers and other important information (Appendix 1 and Appendix 2, online only). Updates are published regularly and can be found at https://ascopubs.org/nsclc-non-da-living-guideline.

PMID: 42190141

33. Cancer Discov. 2026 May 1;16(5):911-930. doi: 10.1158/2159-8290.CD-25-1483.

Circulating Tumor Cells Predict Response to the DLL3-Targeting Bispecific Antibody Tarlatamab.

The bispecific antibody tarlatamab recruits T cells to cancers expressing the neuroendocrine epitope delta-like ligand 3 (DLL3). Tarlatamab is effective in small cell lung cancer (SCLC), but clinical outcomes vary, and no biomarkers enable patient selection. Single-cell RNA sequencing of SCLC biopsies identifies heterogeneity in DLL3 expression, and analysis of circulating tumor cells (CTC) distinguishes individual patients as predominantly DLL3Pos or DLL3Low. In a prospective cohort of 20 patients, pretreatment DLL3 expression on CTCs predicts tarlatamab clinical benefit (85% sensitivity and 100% specificity). Necrotic CTC clusters in blood accompany treatment-induced tumor lysis. Acquired resistance to tarlatamab is associated in some cases with loss of DLL3 expression but persistence of other targetable neuroendocrine epitopes; in other patients, DLL3 is retained on CTCs but accompanied by systemic markers of T-cell dysfunction. Quantitation of DLL3-positive CTCs identifies patients likely to benefit from tarlatamab, and longitudinal monitoring may guide therapeutic decision-making at the time of acquired resistance.

SIGNIFICANCE: CTCs are abundant in SCLC, allowing noninvasive quantitation of epitopes targeted by immune therapies. Patients with at least 25% DLL3-positive CTCs derive clinical benefit from a bispecific antibody targeting this epitope; those with a lower fraction rarely respond. CTC scoring may thus enable stratification of patients for antibody-mediated therapeutics.

PMID: 41532856 [Indexed for MEDLINE]

34. Cancer Cell. 2026 May 11;44(5):983-994.e5. doi: 10.1016/j.ccell.2026.03.018.

JYP0322, a highly selective and brain-penetrant ROS1 inhibitor, overcomes ROS1(G2032R) resistance mutation in NSCLC: The first-in-human phase 1 trial.

Targeted therapies against ROS1-rearrangements face limitations due to resistance mutations, brain metastases, and central nervous system toxicities. We have developed a next-generation, brain-penetrant ROS1 inhibitor, JYP0322, that can overcome resistance mutations (e.g., ROS1G2032R) while minimizing off-target inhibition. In preclinical studies, JYP0322 demonstrated >130-fold selectivity over TRKA, potent antitumor activity in ROS1 re-arrangement and ROS1G2032R tumor models, and effective brain penetration (CSF/plasma AUC ratio 0.893). In a phase I trial (NCT06128148) enrolling 89 non-small cell lung cancer (NSCLC) patients with ROS1-fusion (36% with brain metastases), JYP0322 was well tolerated with low TRK-related neurologic events (dizziness: 6.7%; headache: 3.4%). Among 80 efficacy-evaluable patients, the objective response rate (ORR) was 95.7% in TKI-naive, 57.1% in those with ≥2 prior TKIs, and 77.8% in ROS1G2032R-mutant patients. Intracranial ORR was 55.6% among brain-metastatic patients. These findings highlight JYP0322 as a promising therapy for heavily pretreated NSCLC patients, including those with brain metastases or ROS1G2032R mutations.

PMID: 42030931 [Indexed for MEDLINE]

35. N Engl J Med. 2026 May 29. doi: 10.1056/NEJMoa2604461. Online ahead of print.

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