PubMed：

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

Filters applied: from 2026/09/01 - 2026/09/30.

1. N Engl J Med. 2026 Sep 3;395(9):882-893. doi: 10.1056/NEJMoa2504059.

Daraxonrasib for Previously Treated RAS-Mutant Non-Small-Cell Lung Cancer.

BACKGROUND: RAS mutations, as a group, are the most common oncogenic drivers of non-small-cell lung cancer (NSCLC), and they occur in approximately 30% of patients. Whether daraxonrasib (RMC-6236) - an oral RAS(ON) multiselective, tri-complex inhibitor of guanosine triphosphate-bound mutant and wild-type RAS protein isoforms - is safe and effective in patients with RAS-mutant NSCLC is unknown.

METHODS: In this phase 1-2, multicenter, dose-escalation and dose-expansion study of daraxonrasib, we enrolled patients with previously treated advanced RAS-mutant NSCLC and administered daraxonrasib in doses of 10 to 400 mg orally once daily in 21-day cycles. The primary end point was safety. Secondary end points included investigator-assessed objective response (complete or partial response) and the duration of response, with response assessed according to Response Evaluation Criteria in Solid Tumors, version 1.1.

RESULTS: As of the data-cutoff date of July 21, 2025, a total of 136 patients with NSCLC who had been enrolled and treated with daraxonrasib at doses of 300 mg or less had been evaluated for safety and efficacy. Adverse events of any grade occurring with a dose of 300 mg or less, regardless of attribution, were reported in 99% of the patients, with rash, diarrhea, nausea, vomiting, and mucositis or stomatitis occurring in at least 30% of patients. Adverse events of grade 3 or higher were reported in 54% of the patients, with pneumonia (in 10%), diarrhea (in 9%), rash (in 8%), and anemia (in 5%) occurring in at least 5% of patients; four grade 5 adverse events occurred. The percentage of patients who had an objective response was 31% with daraxonrasib at a dose of 120 mg or less, 34% at doses of 160 to 220 mg, and 37% at a dose of 300 mg.

CONCLUSIONS: Among patients with previously treated metastatic RAS-mutant NSCLC receiving daraxonrasib at a dose of 300 mg or less daily, 54% had adverse events of grade 3 or higher, and antitumor activity was reported in more than 30%. (Funded by Revolution Medicines; RMC-6236-001 ClinicalTrials.gov number, NCT05379985.).

PMID: 42685317 [Indexed for MEDLINE]

2. Science. 2026 Sep 17;393(6817):eaec0473. doi: 10.1126/science.aec0473.

Germline EGFR T790M mutation and lung cancer risk.

Most lung cancers are tobacco related, with genetic factors influencing smoking behavior identified through genome-wide association studies. However, inherited risk in familial and non-smoking-related lung cancers, including risk in carriers of EGFR T790M, remains poorly understood. Here, in more than 3.3 million individuals, the EGFR T790M germline variant is significantly associated with lung cancer risk, with no increased risk for 17 other cancers and no interaction with polygenic risk. This risk exceeds that conferred by smoking and is several-fold higher in never-smokers. Global geographic and ancestry analyses show higher T790M prevalence in the US than in British- and Irish-descendant populations, reflecting a Southern Appalachian founder event about 200 to 225 years ago, increasing regional prevalence and affecting those of British, Irish, and African descent. Recognition of high-risk carriers may inform targeted genetic testing and screening strategies.

PMID: 42752144 [Indexed for MEDLINE]

3. Lancet. 2026 Oct 3;408(10562):1313-1325. doi: 10.1016/S0140-6736(26)01655-7. Epub 2026 Sep 6.

Induction and consolidation atezolizumab with stereotactic body radiation

BACKGROUND: Stereotactic body radiation therapy (SBRT) is the standard of care for early-stage, medically inoperable non-small-cell lung cancer (NSCLC). We aimed to test the addition of neoadjuvant, concurrent, and adjuvant atezolizumab with SBRT for early-stage NSCLC.

METHODS: In this multicentre, open-label, phase 3, randomised controlled trial, eligible patients from 146 institutions across the USA who had T1-T3N0M0 NSCLC ≤7 cm, and were medically inoperable or declined surgery, and had at least one risk factor suggestive of increased risk of recurrence, were included in the study. Patients underwent open-label equal and stratified randomisation to SBRT over three to eight fractions with or without up to eight cycles of neoadjuvant, concurrent, and adjuvant atezolizumab 1200 mg intravenously every 21 days for up to eight cycles, with SBRT initiated with cycle three. The primary objective was to compare overall survival between the two groups. The group sequential design included four interim analyses. Target accrual was 480 patients (432 eligible). The trial is registered with ClinicalTrials.gov (NCT04214262) and is closed to new participants.

FINDINGS: Between March 25, 2020, and Sept 9, 2024, 417 patients were enrolled and randomly assigned to atezolizumab plus SBRT (n=210) or SBRT alone (n=207). 402 were eligible and made up the modified intention-to-treat population (201 per group). The median age was 72·8 years (IQR 67·4-78·4), 218 (54%) of 402 participants were female, and 184 (46%) were male. Accrual closed at the first interim analysis of all randomly assigned participants for futility with 76 progression-free survival (PFS) events and 41 deaths among 400 eligible participants (200 per group). An updated analysis was performed with 140 PFS events, 92 deaths, and a median of 24·8 months (range 0·1-64·9; IQR 18·6-36·0) of follow-up among living patients. The overall survival hazard ratio was 1·04 (95% CI 0·69-1·58; one-sided p=0·58). Estimated 2-year overall survival was 82% in both groups (95% CI 75-87). Grade 3 or higher adverse event rates were 12% with atezolizumab plus SBRT and 3% with SBRT. Two grade 5 respiratory events occurred in the atezolizumab plus SBRT group.

INTERPRETATION: In the first fully reported phase 3 cooperative group trial to assess immunotherapy in inoperable early-stage NSCLC, we observed no improvement in overall survival with atezolizumab plus SBRT, and more grade 3 or higher adverse events were reported with atezolizumab combined with SBRT.

PMID: 42702214 [Indexed for MEDLINE]

4. CA Cancer J Clin. 2026 Sep-Oct;76(5):e70100. doi: 10.3322/caac.70100.

Early stage nonsmall cell lung cancer: Toward a risk-adaptive paradigm in the era of biologic precision.

The clinical landscape of early stage nonsmall cell lung cancer is at transformative crossroads. Driven by the widespread adoption of low-dose computed tomography screening, the frequent detection of ground-glass opacities, and a rising incidence among never-smokers, the diagnostic center of gravity has shifted toward earlier, potentially curable disease. This shift has been accompanied by equally important therapeutic advances, including parenchyma-sparing surgical techniques, minimally invasive platforms enhanced by digital navigation, and the transformative integration of perioperative immunotherapy and targeted agents. Concurrently, noninvasive monitoring approaches, such as liquid biopsy, have emerged as powerful tools to guide precision management. Despite this progress, substantial barriers to achieving a universal cure persist. Clinicians continue to face uncertainty in the management of ground-glass opacities, the anatomy-based TNM staging system fails to capture the biologic heterogeneity of early tumors, and global disparities in access to innovation remain unresolved. To address these challenges, the authors propose a shift toward a risk-adaptive management paradigm that harnesses artificial intelligence-driven analytics and multi-omics profiling to tailor treatment intensity according to each patient's biologic risk. Such an approach would enable appropriate escalation for high-risk individuals while permitting safe de-escalation for those at low risk. This holistic, lifespan-oriented strategy must be embraced to deliver equitable and durable cures for patients with early stage nonsmall cell lung cancer.

PMID: 42713910 [Indexed for MEDLINE]

5. Lancet Respir Med. 2026 Sep 18:S2213-2600(26)00219-5. doi: 10.1016/S2213-2600(26)00219-5. Online ahead of print.

Duration of effectiveness of tuberculosis preventive treatment across various tuberculosis burden settings: a systematic review and individual-participant meta-analysis.

BACKGROUND: Millions of individuals at risk of tuberculosis are given tuberculosis preventive treatment (TPT) annually. However, questions remain regarding the duration of protection from TPT and potential variability across populations and settings with disparate tuberculosis risk. We aimed to assess the effect of TPT on time to tuberculosis among close contacts of individuals with tuberculosis and with evidence of Mycobacterium tuberculosis infection across high-burden, medium-burden, and low-burden settings.

METHODS: In this systematic review and individual-participant meta-analysis, we searched MEDLINE, PubMed, Web of Science, BIOSIS, and Embase for cohort studies and randomised controlled trials published between Jan 1, 1998, and Aug 28, 2023. Studies were eligible if they included individuals (of any age) with household or close exposure to a person with microbiologically or clinically diagnosed tuberculosis (contacts); had at least 6 months of contact follow-up from baseline; and reported start and end of follow-up dates or days of follow-up. We pooled individual-participant data from included cohorts, including contact and index patient characteristics and setting. Analyses were restricted to participants who tested positive for M tuberculosis infection at baseline and stratified by background tuberculosis burden (low burden was defined as a country-level annual incidence of<20 per 100 000 population, medium as 20-100 per 100 000 population, and high as >100 per 100 000 population). The primary outcome was incident tuberculosis, which was defined as tuberculosis diagnosed more than 90 days after baseline. We calculated incidence rates by TPT status, generated Nelson-Aalen cumulative hazard plots, and estimated adjusted hazard ratios (HRs) using mixed-effects Cox models with a time interaction. This study is registered with PROSPERO, CRD42018087022.

FINDINGS: Of 466 523 participants from 47 studies, we included 84 128 individuals from 44 cohort studies across 24 countries. TPT was highly protective within the first year but declined over the course of follow-up in all settings, with greater effects observed in low-burden and medium-burden settings. At 1 year, the adjusted HR was 0·57 (95% CI 0·31-1·07) in high-burden settings, 0·14 (0·09-0·21) in medium-burden settings, and 0·21 (0·17-0·26) in low-burden settings. The protective effect persisted up to the end of follow-up in medium-burden settings (adjusted HR at 8 years 0·15 [95% CI 0·07-0·33]) and up to 13 years in low-burden settings (0·65 [0·43-1·00]). In medium-burden and low-burden settings, participants who completed TPT initially had lower risk of tuberculosis than those who did not complete TPT (adjusted HR at 1 year 0·59 [95% CI 0·36-0·95]); within 2 years, these groups were not statistically different (adjusted HR at 2 years 0·72 [0·41-1·26]) and both showed strong protection for at least 8 years.

INTERPRETATION: Among close contacts with evidence of M tuberculosis infection, we found that the initial protection from TPT eroded relatively quickly in high-burden settings, but was sustained long-term in medium-burden and low-burden settings. In medium-burden and low-burden settings, completing TPT provided greater initial protection, but TPT non-completers had similar long-term tuberculosis risk.

PMID: 42759526

6. Lancet Glob Health. 2026 Sep 14:104012. doi: 10.1016/j.langlo.2026.104012.

Online ahead of print.

External validation of a treatment decision algorithm for tuberculosis in children living with HIV: a diagnostic cohort study.

BACKGROUND: Tuberculosis is the leading cause of death in children living with HIV, and is challenging to diagnose owing to the limitations of microbiological approaches. The Pediatric Asian African Network for Tuberculosis and HIV Research (PAANTHER) treatment decision algorithm (TDA) was previously developed to improve the diagnosis of tuberculosis in children living with HIV, but has not yet been validated. We aimed to externally validate this TDA in a prospective cohort of children from four countries in Africa.

METHODS: The TB-Speed HIV study was a prospective diagnostic cohort study conducted in seven tertiary hospitals: two in Côte d'Ivoire, two in Mozambique, one in Uganda, and two in Zambia. Eligible participants were children living with HIV, aged 1 month to 14 years, with presumptive tuberculosis. Children who were currently receiving tuberculosis treatment, or who had received treatment within the past 3 months, were excluded. At enrolment, children were evaluated for suggestive tuberculosis symptoms (fever for >2 weeks, unremitting cough, haemoptysis and/or weight loss in the past 4 weeks, and tachycardia) and underwent Xpert MTB/RIF Ultra testing on respiratory and stool samples, chest radiography, and abdominal ultrasonography. Children were given a PAANTHER TDA score, with a score of less than 100 defined as negative and a score of 100 or higher defined as positive and prompting the initiation of treatment. At the end of the study, children were retrospectively classified by an endpoint review committee as having confirmed, unconfirmed, or unlikely tuberculosis, forming the composite reference standard against which diagnostic accuracy was assessed. The primary outcome was the proportion of children with missed tuberculosis (false negatives) among those who were not initiated on treatment as per the PAANTHER TDA. We assessed the diagnostic accuracy (sensitivity, specificity, and negative and positive predictive values) and feasibility (uptake and time to treatment initiation) of the PAANTHER TDA. The protocol-defined negative predictive value threshold for validation was 75%. This study is registered at ClinicalTrials.gov, NCT04121026, and is complete.

FINDINGS: From Oct 2, 2019, to Dec 31, 2021, 1706 children were prescreened for eligibility, of whom 713 children living with HIV were screened for tuberculosis symptoms; 423 were eligible for the study and 277 were enrolled. Of these 277 children, 272 (98%) had a complete TDA evaluation: 215 (79%) had a score of 100 or higher, including 24 (9%) with a positive Xpert MTB/RIF Ultra test. Treatment was initiated in 185 (86%) of 215 children with a positive score and 12 (20%) of 60 children with a negative score, at a median of 1 day [IQR 0-4] after inclusion. After assessment by the endpoint review committee, the proportion of children with tuberculosis in the classifiable study population (n=273) was 56·8% (95% CI 50·9-62·5), with 131 having unconfirmed tuberculosis and 24 having confirmed tuberculosis. Four (7%) of the 60 children with a negative score were subsequently classified as having tuberculosis by the endpoint review committee (missed tuberculosis). The TDA had a negative predictive value of 93·3% (95% CI 84·1-97·4), a positive predictive value of 70·9% (95% CI 64·5-76·6), a sensitivity of 97·4% (95% CI 93·6-99·0), and a specificity of 47·5% (95% CI 38·7-56·4).

INTERPRETATION: The PAANTHER TDA was externally validated in a cohort of children living with HIV as per the study protocol. The high sensitivity of this TDA and its potential to enable rapid treatment initiation could contribute to the reduction of mortality in children living with HIV.

PMID: 42735691

7. Lancet Glob Health. 2026 Sep;14(9):103971. doi: 10.1016/j.langlo.2026.103971.

Phone-based screening versus home-based screening after tuberculosis in India (TB Aftermath): a multicentre, open-label, randomised, controlled, non-inferiority trial.

BACKGROUND: Tuberculosis survivors and their household contacts are at increased risk for tuberculosis even after treatment completion; however, effective strategies for post-tuberculosis screening remain untested. We aimed to assess whether phone-based screening is non-inferior to home-based screening for tuberculosis after treatment completion in India.

METHODS: In this multicentre, open-label, randomised, controlled, non-inferiority trial, we enrolled tuberculosis survivors (aged >18 years) within 60 days of completing treatment for any form of tuberculosis from six public clinics in Maharashtra, India. Household contacts were enumerated at baseline (all ages). Survivors were randomly assigned (1:1) to receive phone-based or home-based symptom screening at 6 months and 12 months. The trial was powered to identify a difference in the tuberculosis detection rate per 100 person-years among survivors and contacts together (primary outcome), comparing screening groups during the 12 months after survivor treatment completion. We conducted an intention-to-treat analysis with a rate difference non-inferiority margin of 1·70 per 100 person-years based on the upper bound of the 95% CI. We adjusted for household-level clustering of tuberculosis by fitting a multilevel Poisson model. We also conducted a subgroup analysis of detection rates among survivors and contacts separately. This study is registered with ClinicalTrials.gov, NCT04333485 and is completed.

FINDINGS: We enrolled 1076 tuberculosis survivors (537 in the phone-based screening group and 539 in the home-based screening group) and enumerated 3309 contacts (1638 in the phone-based screening group and 1671 in the home-based screening group) between Jan 21, 2021, and Sept 4, 2023. In the 12-month post-treatment period, tuberculosis was detected in 75 (7%) tuberculosis survivors and 30 (1%) contacts: 41 events in the phone-based screening group (rate 1·19 [95% CI 0·82-1·71]) compared with 64 events in the home-based screening group (1·92 [1·37-2·45]). Non-inferiority was reached (rate difference 0·73 [95% CI 0·05-1·41]). Among tuberculosis survivors, the recurrence detection rate was 4·36 (95% CI 2·87-6·34) in the phone-based screening group compared with 8·00 (5·90-10·60) in the home-based screening group (p=0·01). Among contacts, the tuberculosis detection rate was 0·61 (95% CI 0·32-1·07) in the phone-based screening group compared with 0·70 (0·39-1·20) in the home-based screening group (p=0·70).

INTERPRETATION: Risk of tuberculosis remains high for households with a tuberculosis survivor. For detecting tuberculosis among survivors and their household contacts together, phone-based screening was non-inferior to home-based screening. For survivors, the recurrence detection rate was higher in the home-based screening group. Countries with a high burden of recurrence should consider home-based screening among tuberculosis survivors.

PMID: 42392121 [Indexed for MEDLINE]

8. Ann Intern Med. 2026 Sep;179(9):ITC129-ITC144. doi: 10.7326/ANNALS-26-03002.

Tuberculosis.

Tuberculosis (TB) is the leading cause of infection-related mortality in the world, and cases in the United States are increasing. Prompt diagnosis, isolation, and treatment improve patient outcomes and reduce onward transmission. Screening of contacts and high-risk persons for asymptomatic TB infection and treatment of those testing positive reduces progression to disease. TB disease should be suspected in persons with compatible symptoms, risk factors, and consistent imaging. Microbiological confirmation requires an acid-fast smear, nucleic acid amplification test, and culture. Treatment, guided by drug sensitivity testing, requires multiple antibiotics given for 4 to 9 months and monitoring for drug toxicity and clinical response.

PMID: 42704895 [Indexed for MEDLINE]

9. N Engl J Med. 2026 Sep 12. doi: 10.1056/NEJMoa2610229.

Tambotatug Pelitecan in Small-Cell Lung Cancer after Platinum-Based Therapy.

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

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

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

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

PMID: 42734213

10. JAMA. 2026 Sep 8;336(10):838-847. 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 26.1months 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.

PMID: 42574006 [Indexed for MEDLINE]

11. J Clin Oncol. 2026 Sep 14:JCO2600556. doi: 10.1200/JCO-26-00556.

P-Loop/αC-Helix Compressing Mutations and Exon 20 Insertions in EGFR-Mutant NSCLC: A Rapidly Evolving Therapeutic Landscape.

PURPOSE: A structure-function classification has defined epidermal growth factor receptor (EGFR) P-loop/αC-helix compressing (PACC) mutations and exon 20 insertions (ex20ins) as distinct subsets of kinase domain EGFR alterations. Lung cancers harboring those mutations display reduced sensitivity to EGFR tyrosine kinase inhibitors (TKIs) currently approved for EGFR classical sensitizing mutations and have often been managed with chemotherapy.

METHODS: This narrative review describes structural biology, clinical trial data, and real-world evidence on PACC and ex20ins EGFR-mutant non-small cell lung cancer, with a focus on current treatment options, emerging resistance mechanisms, and the potential treatment sequencing.

RESULTS: For EGFR PACC variants such as G719X, S768I, E709X, and L747X, second-generation TKIs such as afatinib provide the most consistent activity, whereas common-plus-PACC compound mutations often derive greater benefit from third-generation TKIs, including osimertinib. Emerging mutant-selective inhibitors, including firmonertinib and enozertinib, are now being explored as dedicated options for PACC mutations. For EGFR ex20ins, amivantamab and mutant-selective TKIs such as sunvozertinib, zipalertinib, and firmonertinib have demonstrated clinically meaningful activity, with WU-KONG28 establishing first-line superiority of sunvozertinib over platinum-pemetrexed. Across both these subsets, resistance remains heterogeneous, encompassing on-target mutations, including C797S and E709K, as well as MET and other bypass track pathways.

CONCLUSION: EGFR PACC and ex20ins are established subgroups of kinase domain mutations, distinct from classical mutations, due to structure and responsiveness to available TKIs.

PMID: 42735369

12. JAMA Oncol. 2026 Sep 1;12(9):965-972. doi: 10.1001/jamaoncol.2026.2330.

Consolidative Thoracic Radiotherapy With Atezolizumab Maintenance in Extensive-Stage Small Cell Lung Cancer: The Phase 2 TREASURE Randomized Clinical Trial (AIO-TRK-0320).

IMPORTANCE: Chemoimmunotherapy followed by immunotherapy maintenance is the standard first-line treatment for extensive-stage small cell lung cancer (ES-SCLC), yet data regarding efficacy and safety of consolidative thoracic radiotherapy (TRT) are lacking.

OBJECTIVE: To determine whether combining consolidative TRT with immunotherapy maintenance in ES-SCLC is safe and improves patients' overall survival (OS) and progression-free survival (PFS).

DESIGN, SETTINGS, AND PARTICIPANTS: This was a multicenter open-label phase 2 randomized clinical trial recruiting patients from September 2020 to August 2022 in Germany and Austria, with the last follow-up visit in September 2024. Eligible patients had ES-SCLC with at least stable disease after induction chemoimmunotherapy (carboplatin-etoposide-atezolizumab). Although the database was locked in April 2025, a post hoc survival update was performed in April 2026. Data were analyzed from April 2025 to April 2026.

INTERVENTIONS: Randomized (1:1) to either atezolizumab maintenance combined with consolidative TRT (30 Gy in 10 fractions) (arm A) or atezolizumab maintenance alone (arm B).

MAIN OUTCOME AND MEASURE: OS (time from randomization to death due to any cause).

RESULTS: Of 96 patients assessed for eligibility, 68 patients were randomized; recruitment was prematurely terminated due to safety concerns. Median OS in the combination arm was numerically shorter compared to atezolizumab only (6.7 months [95% CI, 5.1-9.0] vs 13.4 months [95% CI, 10.7-17.5]; HR, 1.55 [95% CI, 0.90-2.69]; P = .34), while median PFS was similar (2.4 months [95% CI, 1.3-3.9] vs 2.6 months [95% CI, 1.2-3.9]; HR, 0.92 [95% CI, 0.54-1.55]; P = .85). TRT plus atezolizumab was accompanied by higher frequency of severe adverse events (SAEs) (19 patients [61.3%] vs 6 patients [18.2%]; P < .001) and fatal outcomes (6 patients [19.4%] vs 1 patient [3.0%]; P = .04). Safety analysis revealed predominance of infection and respiratory disorder-related SAEs, possibly facilitated by a depletion of lymphocytes observed specifically in patients after TRT, and by a lower single breath diffuse capacity of the lungs for carbon monoxide in patients with fatal AEs in arm A. No further risk factors were identified, given that baseline characteristics were well balanced between both arms and between patients with and without SAEs, including fatal SAEs.

CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, TRT combined with immunotherapy increased toxic effects in unselected patients with ES-SCLC without survival benefit, presumably due to radiation-induced lymphocyte depletion facilitating infections. Cautious patient selection and further investigation to identify those who may benefit without undue risk are required.

PMID: 42424047 [Indexed for MEDLINE]

13. Cell Host Microbe. 2026 Sep 9;34(9):1795-1813.e7. doi: 10.1016/j.chom. 2026.07.019. Epub 2026 Aug 25.

Host eicosanoid signals define a granuloma fibroblast population that coordinates mycobacterial containment.

Genetic variation at the leukotriene A4 hydrolase (LTA4H) locus is associated with tuberculosis (TB) severity and outcome. Here, we define a unique population of peripheral fibroblasts at the mycobacterial granuloma, the central immune structure in TB, whose recruitment and functions are coordinated by lta4h-dependent signals. Using single-cell profiling of zebrafish mycobacterial infections, we identify a layer of lta4h-dependent recruited fibroblasts at the granuloma's edge with mesenchymal and stem-like expression signatures, including aldh1a3 expression. Ablation of these cells compromises bacterial containment at the structure's periphery. Similarly, genetic disruption of apolipoprotein D, produced specifically in granuloma-associated fibroblasts, results in an altered eicosanoid balance, decreased inflammation, and increased dissemination of infection. In humans, this granuloma-associated fibroblast population is distinct from myofibroblasts, interacts with LTA4H-expressing macrophages, and is prominent across diverse TB granuloma types. These results link a host genetic susceptibility locus to the recruitment and function of a specialized fibroblast population that limits bacterial dissemination.

PMID: 42641606 [Indexed for MEDLINE]

14. Adv Sci (Weinh). 2026 Sep;13(49):e23921. doi: 10.1002/advs.202523921.

SERS Facemask for Rapid and Portable Sensing Mycobacterium Tuberculosis Antigens for TB Screening.

Rapid and sensitive diagnostic strategies are crucial for the prevention and control of tuberculosis (TB). Unlike the invasive TB diagnostic strategy in the clinic, here we introduce a convenient, portable, and non-invasive system that is constructed by Ag@Au nanoflower (NF) array-based sensing facemask and catalytic/plasmonic urchin-shaped Au─Ag embedded covalent organic framework (U@COF) sensor. This system detects TB antigen ESAT-6/CFP-10 complex in droplet or sputum samples from a variety of clinical settings. Practical analysis of clinical samples demonstrates this assay is capable of classifying the negative (N = 12) and positive (N = 17) TB patients with satisfactory sensitivity (76.5%) and specificity (100%), among whom two TB-infected patients (TB3 and TB5) missed by droplet analysis are successfully identified by sputum analysis. More importantly, two cases with abnormally elevated ESAT-6/CFP-10 levels are screened out from close contacts of TB patients (N = 6), which is highly suggestive of TB infection (Close contacts 3 and 4). This portable mask is suitable for rapid diagnosis of TB infection in patients with cough, particularly for screening of TB close contacts.

PMID: 42318745 [Indexed for MEDLINE]

15. Cell Host Microbe. 2026 Sep 9;34(9):1716-1728.e6. doi: 10.1016/j.chom. 2026.07.014.

Strong, sustained type I IFN signaling acts cell intrinsically to impair IFNγ responses and cause tuberculosis susceptibility.

Mycobacterium tuberculosis (Mtb) causes over one million deaths annually, but most infected individuals never exhibit symptoms. Type I interferons (IFNs) have emerged as a major factor driving susceptibility to Mtb, but how type I IFNs impair immunity to Mtb is a key unresolved question. Here, we show that an early effect of type I IFN during Mtb infection is the cell-intrinsic impairment of IFNγ signaling. IFNγ signaling is selectively impaired in the subset of infected macrophages experiencing high and sustained levels of type I IFN signaling. Genetic elimination of regulated stimulator of interferon via stabilization of transcript (RESIST), a recently described positive regulator of type I IFN production, specifically eliminates the high and sustained type I IFN response, fully restores IFNγ signaling, and rescues susceptibility to Mtb without affecting basal type I IFN responses. Our results demonstrate that strong and sustained type I IFN responses specifically and cell intrinsically impair responsiveness to IFNγ to cause susceptibility to Mtb.

PMID: 42600620 [Indexed for MEDLINE]

16. Am J Respir Crit Care Med. 2026 Sep 1;212(9):2211-2225. doi: 10.1093/ajrccm/aa- mag156.

Blood transcriptomic signatures predict poor outcomes in drug-susceptible pulmonary tuberculosis in Brazil.

RATIONALE: Non-sputum biomarkers to monitor tuberculosis treatment and predict poor outcomes are lacking.

OBJECTIVES: To evaluate host-blood transcriptomic signatures for treatment monitoring and prognosis of death, treatment failure, and recurrence in adults with pulmonary tuberculosis.

METHODS: Adults with culture-confirmed, drug-susceptible pulmonary tuberculosis were enrolled at 5 Brazilian sites. Whole-blood PAXgene samples were collected at baseline, month 2 (M2), and end of treatment (EoT). Treatment failure was defined as sputum culture positivity at month 5 or later. Participants were followed for 24 months from treatment initiation for clinical or microbiological tuberculosis recurrence. Unfavorable outcomes were matched ∼1:3 to recurrence-free cure. Twenty-two published blood transcriptomic signatures were measured by microfluidic RT-qPCR and benchmarked against the WHO Target Product Profile (TPP) criteria.

MEASUREMENTS AND MAIN RESULTS: We matched 263 participants with recurrence-free cure to 33 with treatment failure, 24 who died (tuberculosis/unknown cause), and 9 with recurrence. Signature scores generally declined from baseline to EoT. Multiple signatures measured at baseline and M2 predicted recurrence (AUC range 0.71-0.91), with waning performance when measured at EoT (AUC range 0.42-0.89). Against the WHO TPP, 2/22 signatures met minimum criteria at baseline, 13/22 at M2, and none at EoT. Prediction of treatment failure was poor across timepoints (AUC < 0.70). In contrast, several signatures measured at baseline predicted death during treatment or follow-up (AUC ≥ 0.80).

CONCLUSIONS: Blood transcriptomic signatures tracked treatment response and predicted recurrence and death, meeting WHO TPP benchmarks at baseline and M2. These findings support prospective, biomarker-guided trials to individualize tuberculosis therapy-shortening regimens for early responders and intensifying care for high-risk patients.

PMID: 42085241 [Indexed for MEDLINE]

17. Nat Microbiol. 2026 Sep;11(9):2647-2665. doi: 10.1038/s41564-026-02412-5.

Identification of chemical features for improved outer membrane permeation in mycobacteria using machine learning.

The ability of compounds to permeate and accumulate in bacterial cells is a critical determinant of antibiotic efficacy. Better therapeutics are urgently needed for the human pathogen Mycobacterium tuberculosis, yet the cell envelope, including the mycobacterial outer membrane, represents a significant barrier for drug entry, and the chemical features governing permeation remain poorly understood. Here we used the bioorthogonal click chemistry-based PAC-MAN assay to profile mycomembrane permeation of 1,572 azide-tagged compounds in M. tuberculosis and the model organism M. smegmatis. Cheminformatics and machine learning identified chemical features associated with mycomembrane permeation, which in turn had predictive value in three molecule series. Chemical predictors of mycomembrane permeation include nitrogen-containing aromatic scaffolds, such as indole, which in some cases were associated with increased anti-M. tuberculosis activity. Our data suggest a rational framework for improving mycomembrane permeation and whole-cell activity of antibiotics targeting M. tuberculosis.

PMID: 42380282 [Indexed for MEDLINE]

18. Sci Transl Med. 2026 Sep 16;18(867):eaef2648. doi: 10.1126/scitranslmed.aef2648.

A rapid CRISPR-based nanodroplet assay enables direct clinical identification of mycobacteria species.

The global incidence and mortality of nontuberculous mycobacterial infections have risen sharply with population aging. In some regions, they are now surpassing Mycobacterium tuberculosis complex infections, imposing a substantial clinical and economic burden. Because nontuberous mycobacteria exhibit species-level heterogeneity and require prolonged culture for identification, their diagnosis remains slow and is frequently inaccurate. Here, we describe a multiplexed clustered regularly interspaced short palindromic repeats (CRISPR)-assisted nanodroplet differential identification (CANDI) diagnostic platform that integrates species-agnostic target amplification with species-specific CRISPR-associated protein 12a (Cas12a) detection in fluorescence-barcoded nanodroplets. By spatially compartmentalizing CRISPR reactions into color-encoded nanodroplets, CANDI overcomes the multiplexing limitations of conventional CRISPR diagnostics and enables simultaneous interrogation of multiple mycobacterial targets in a single assay. We designed a 16-plex panel that distinguishes 15 clinically relevant Mycobacterium species and subspecies. CANDI achieved high analytical sensitivity and accurate discrimination in samples containing coinfections with multiple species or subspecies. When applied to 230 clinical specimens, including sputum, tracheal aspirates, and other respiratory fluids, CANDI delivered subspecies-level results within 3.5 hours, achieving 97.08% sensitivity and 99.7% specificity relative to culture-based identification. By combining multiplexed, high-specificity CRISPR detection with scalable droplet-based engineering, CANDI has the potential to overcome the culture dependency of current diagnostics and enable species- and subspecies-level identification across the genetically complex Mycobacterium genus, offering a clinically adaptable framework for rapid, precision diagnosis of mycobacterial infections.

PMID: 42748215 [Indexed for MEDLINE]

19. 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]

20. Cancer Cell. 2026 Sep 18:S1535-6108(26)00392-2. doi: 10.1016/j.ccell. 2026.08.015.

γδ T cells modulate anti-tumor immunity in small cell lung cancer.

Small cell lung cancer (SCLC) is a highly aggressive neoplasm with limited sensitivity to anti-PD-(L)1 blockade, which is likely caused by the epigenetic silencing of MHC-I. Elucidating MHC-I-independent immune recognition mechanisms is therefore crucial for enhancing treatment responses and improving clinical outcomes in a greater number of patients. Leveraging single-cell approaches, we discovered γδ T cell infiltration in biospecimens from patients with SCLC. Despite PD-1 expression, γδ T cells maintained a cytotoxic transcriptional profile, suggesting an anti-tumor role. Indeed, high γδ T cell infiltration in two practice-changing clinical trials predicted improved response to anti-PD-L1 immunotherapy in patients with SCLC. Moreover, using preclinical models, we demonstrated that γδ T cells are effective at tarlatamab (delta-like ligand 3 [DLL3]-CD3 bispecific T cell engager [BiTE])-redirected SCLC killing and that zoledronate, an FDA-approved compound, can sensitize SCLC cells to γδ T cell-mediated killing. Thus, our findings suggest that engaged γδ T cells are potentially valuable targets for SCLC therapy.

PMID: 42759517

21. Lancet Respir Med. 2026;14(10):894-913. doi: 10.1016/S2213-2600(26)00221-3.

Epub 2026 Sep 6.

Early-stage non-small-cell lung cancer: emerging treatments and evolving challenges.

The treatment of early-stage non-small-cell lung cancer (NSCLC) has evolved substantially in recent years. For decades, curative-intent surgery followed by platinum-based chemotherapy remained the standard of care (SOC), despite delivering only modest gains in long-term survival. Current evidence from randomised trials incorporating immunotherapy as a neoadjuvant or perioperative approach, along with targeted therapies, have defined a new SOC treatment approach for patients with resectable early-stage NSCLC. However, these advances have introduced uncertainties regarding optimal sequencing, treatment duration, patient selection, and the role of treatment escalation or de-intensification with immunotherapy and targeted therapies. The advances and uncertainties are discussed in this Series paper, along with the role of radiotherapy in this setting.

PMID: 42702210 [Indexed for MEDLINE]

22. Cancer Cell. 2026 Sep 14;44(9):1832-1846.e2. doi: 10.1016/j.ccell.2026.07.012.

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 [Indexed for MEDLINE]

23. Nat Rev Clin Oncol. 2026 Sep;23(9):712-729. doi: 10.1038/s41571-026-01174-7.

Improving neoadjuvant and perioperative therapy in non-small-cell lung cancer.

Neoadjuvant chemoimmunotherapy, comprising an anti-PD-(L)1 antibody and platinum-doublet chemotherapy, given alone or as part of a perioperative regimen with the addition of adjuvant anti-PD-(L)1 therapy, has become the standard of care for patients with early-stage, resectable non-oncogene-driven non-small-cell lung cancer (NSCLC). This approach has demonstrated substantial increases in pathological response rates and improvements in long-term outcomes, including overall survival. However, these advances have largely been achieved through uniform treatment application across biologically heterogeneous tumours. As a result, a central challenge in contemporary perioperative management is how to identify which patients require escalation or de-escalation of treatment following surgery and which individuals could safely avoid unnecessary treatment. In this Review, we summarize current evidence supporting pathological response, and particularly pathological complete response (pCR), as a robust and clinically meaningful surrogate for durable benefit in patients with NSCLC. We then consider how complementary tools, including circulating tumour DNA, radiomics and metabolic imaging approaches, and baseline molecular and immune biomarkers, can be integrated to refine patient selection and dynamically adapt perioperative strategies. Finally, we describe potential therapeutic strategies to intensify perioperative treatment in biologically high-risk populations, with the dual objective of increasing the likelihood of a pCR and improving disease control in patients with an insufficient pathological response.

PMID: 42380613 [Indexed for MEDLINE]

24. Lancet Respir Med. 2026 ;14(10):914-934. doi: 10.1016/S2213-2600(26)00253-5.

Epub 2026 Sep 6.

Targeted therapies in advanced non-small-cell lung cancer: new biomarkers and treatment strategies.

Precision oncology has changed the management of advanced non-small-cell lung cancer (NSCLC). Biomarker-matched therapies now improve outcomes in an increasing number of molecularly defined subgroups. In this second paper in a Series on therapeutics in lung cancer, we summarise recent advances in NSCLC with established alterations, including EGFR, ALK, ROS1, KRAS, BRAF, RET, HER2, MET, and NTRK, and discuss emerging targets, such as NRG1 fusions, MTAP loss, and SMARCA4 deficiency. Newer generations of tyrosine kinase inhibitors, the introduction of bispecific antibodies, and antibody-drug conjugates have improved response durability, intracranial disease control, and in some settings, overall survival. However, durable benefit can remain limited by acquired resistance, tumour heterogeneity, lineage plasticity, and off-target escape, supporting repeat tissue biopsy and circulating-tumour DNA profiling to guide subsequent treatment. With several options available such as monotherapy and combination approaches, individualised treatment selection is becoming increasingly complex. We discuss these choices, including the management of CNS disease and oligoprogression, and long-term tolerability. As drug development extends beyond canonical drivers to rarer alterations and adverse co-mutations, the range of targetable disease is increasing. Further progress will depend on more effective and adaptive treatment strategies together with equitable access to comprehensive molecular profiling, timely biomarker testing, and next-generation targeted therapies.

PMID: 42702211 [Indexed for MEDLINE]

25. Cancer Discov. 2026 Sep 18:OF1. doi: 10.1158/2159-8290.CD-NW2026-0090.

Phase III Trials Test First-Line Options in Advanced NSCLC.

Presented at the 2026 World Conference on Lung Cancer, two phase III trials-PAPILLON and REZILIENT3-established amivantamab and zipalertinib combination therapies as effective first-line strategies for advanced NSCLC with EGFR exon 20 insertions, with significantly improved progression-free survival, although high crossover rates prevented them demonstrating an overall survival benefit. Separately, HARMONi-2 showed that the bispecific antibody ivonescimab improved overall survival versus pembrolizumab in PD-L1-positive NSCLC, supporting its use as standard of care in China while larger global trials continue.

PMID: 42755291

26. J Clin Oncol. 2026 Sep;44(25):2400-2408. doi: 10.1200/JCO-25-02777.

SKYSCRAPER-01: Tiragolumab in Combination With Atezolizumab in Previously Untreated PD-L1-High, Locally Advanced, Unresectable or Metastatic Non-Small Cell Lung Cancer.

PURPOSE: Tiragolumab plus atezolizumab has shown encouraging survival outcomes in metastatic non-small cell lung cancer (NSCLC), primarily in patients with PD-L1-high tumors. We further evaluated the combination of tiragolumab plus atezolizumab in the phase III SKYSCRAPER-01 study.

METHODS: Patients with untreated, locally advanced unresectable/metastatic PD-L1-high (by central laboratory testing) NSCLC were randomly assigned 1:1 to receive either tiragolumab (600 mg) plus atezolizumab (1,200 mg) or placebo plus atezolizumab (1,200 mg) intravenously in 21-day cycles until disease progression, loss of clinical benefit, or unacceptable toxicity. Primary end points were investigator-assessed progression-free survival (INV-PFS) and overall survival (OS) in the primary analysis set (PD-L1-high per 22C3 assay).

RESULTS: Five hundred twenty-one patients were randomly assigned to either the tiragolumab plus atezolizumab group (n = 262) or the placebo plus atezolizumab group (n = 259). At the primary PFS analysis (Mar 12, 2022; median follow-up 9.9 months [IQR, 6.2-13.8]), median INV-PFS was 7.0 months (95% CI, 5.6 to 9.8) with tiragolumab plus atezolizumab and 5.6 months (95% CI, 4.4 to 7.0) with placebo plus atezolizumab (hazard ratio [HR], 0.78 [95% CI, 0.63 to 0.97]; P = .02 [nonsignificant]). At the final OS analysis (Sept 24, 2024; median follow-up 17.9 months [IQR, 6.7-39.0]), median OS was 23.1 months (95% CI, 17.7 to 28.8) with tiragolumab plus atezolizumab and 16.9 months (95% CI, 14.6 to 21.3) with placebo plus atezolizumab (HR, 0.87 [95% CI, 0.7 to 1.1]; P = .22 [nonsignificant]). Overall, 41.2% (n = 110/267) and 33.8% (n = 89/263) of patients experienced grade 3-4 adverse events with tiragolumab plus atezolizumab and placebo plus atezolizumab, respectively. Four and two treatment-related deaths occurred in each group, respectively.

CONCLUSION: Tiragolumab plus atezolizumab did not demonstrate a statistically significant INV-PFS or OS benefit over atezolizumab in patients with previously untreated PD-L1-high NSCLC.

PMID: 42507968 [Indexed for MEDLINE]

27. Lancet Oncol. 2026;27(10):1260-1270. doi: 10.1016/S1470-2045(26)00305-0.

Epub 2026 Sep 11.

Patient-reported symptom monitoring in patients with lung cancer (SYMPRO-Lung trial): long-term, post-hoc survival results of a multicentre, stepped-wedged, cluster-randomised clinical trial.

BACKGROUND: Patient-reported outcome (PRO) symptom monitoring has been shown to improve overall survival. Yet, available evidence largely derives from resource-intensive studies limited to patients with advanced cancer. We aimed to assess the effect of PRO symptom monitoring on overall and progression-free survival in patients with stage I-IV lung cancer in a real-world clinical setting, with follow-up extending to 5 years.

METHODS: The SYMPRO-Lung trial was a multicentre, stepped-wedged, cluster-randomised clinical trial across 14 medical centres in the Netherlands. Patients were eligible for inclusion if they were aged 18 years or older with stage I-IV lung cancer (new-onset or recurrent; cytologically or histologically confirmed or radiological suspected) and were starting new treatment. All hospitals started with a control period (standard of care) and, according to randomisation by a computer-generated allocation sequence, crossed over at predefined timepoints to the intervention period (completing weekly online symptom assessments for 1 year). The primary outcome for SYMPRO-Lung trial was health-related quality of life, which has been previously reported. In this post-hoc analysis, we assessed long-term survival outcomes of overall survival and progression-free survival, with overall survival as the primary outcome. Survival analyses in the intention-to-treat population was performed using Cox mixed-effects modelling, adjusted for age, sex, stage, histology, Eastern Cooperative Oncology Group performance status, systemic treatment line, and a random effect for site clustering. The study is registered with Netherlands Trial Register, NL7897, and is complete.

FINDINGS: Of the 515 patients initially enrolled to the SYMPRO-Lung trial between Oct 24, 2019, and Sept 16, 2021, 446 (87%) patients were included in this post-hoc analysis (230 [52%] male; 216 [48%] female). 235 (53%) were assigned to the pooled intervention group and 211 (47%) patients to the control group. 69 (13%) of 515 patients were excluded due to the absence of informed consent for the use of their data in follow-up research or because linkage to the Netherlands Cancer Registry could not be established. At a median follow-up 50 months (IQR 46-55), median overall survival was 26 months in the intervention group (IQR 9-not reached, 95% CI 21-33) compared with 21 months (IQR 10-54, 95% CI 17-26) in the control group. Analyses adjusting for confounders showed that PRO symptom monitoring might be associated with improved overall survival (hazard ratio [HR] 0·80, 95% CI 0·63-1·00, p=0·049). Analyses adjusting for confounders showed that PRO symptom monitoring showed no significant difference in progression-free survival between groups (0·86, 0·70-1·07; p=0·18).

INTERPRETATION: Weekly PRO symptom monitoring was associated with meaningful improvement in long-term overall survival among patients with stage I-IV lung cancer. Median overall survival was 5 months longer in the intervention group than in the control group. These findings underscore the value of implementing PRO symptom monitoring within routine care for patients with lung cancer.

PMID: 42727592 [Indexed for MEDLINE]

28. Lancet Respir Med. 2026 Sep;14(9):775-785. doi: 10.1016/S2213-2600(26)00142-6.

Ifebemtinib plus garsorasib as first-line treatment for KRAS(G12C)-mutated non-small-cell lung cancer in China: a multicentre, single-arm expansion cohort from a phase 1b/2 trial.

BACKGROUND: Ifebemtinib, a potent selective oral inhibitor of FAK, has shown preclinical synergistic activity with KRASG12C inhibitors. Garsorasib is a novel KRASG12C inhibitor approved in China for patients with KRASG12C-mutated non-small-cell lung cancer (NSCLC). This study aimed to evaluate the safety and efficacy of ifebemtinib plus garsorasib in KRASG12C-mutated solid tumours.

METHODS: This multicentre study had a phase 1b component to establish the recommended phase 2 dose and a phase 2 multitumour expansion. Here, we report the results of the single-arm, Simon's two-stage cohort of first-line KRASG12C-mutated NSCLC from phase 2 expansion. The study was conducted at eight sites in China. Eligible patients were adults with pathologically confirmed locally advanced or metastatic NSCLC who were harbouring a KRASG12C mutation, were treatment-naive, and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Enrolled patients received ifebemtinib (100 mg orally once a day) in combination with garsorasib (600 mg orally twice a day) in a 21-day cycle until disease progression, intolerable toxicity, withdrawal of consent, initiation of new therapies, or death. The primary endpoint was objective response rate (ORR), as assessed by investigators, in all patients who received at least one dose of study treatment. The same population was included in safety analyses. This study is registered with ClinicalTrials.gov (NCT06166836 and NCT05379946) and is active but not recruiting.

FINDINGS: Between April 21, 2023, and Dec 27, 2023, 33 first-line patients with NSCLC (two [6%] female and 31 [94%] male) were enrolled and received at least one dose of ifebemtinib plus garsorasib. As of Sept 16, 2025, median follow-up duration was 21·5 months (IQR 21·0-23·9). Confirmed ORR was 82% (27 of 33 patients; 95% CI 64·5-93·0). All 33 (100%) patients reported treatment-emergent adverse events, with 11 (33%) patients experiencing grade 3 or 4 events, of which eight (24%) were related to study drugs. The most frequent treatment-emergent adverse events of grade 3-4 were grade 3 proteinuria, diarrhoea, anaemia, hypertension, and pneumonia, each occurring in two (6%) of 33 patients. Serious adverse events occurred in nine (27%) of 33 patients, with intracranial haemorrhage and pneumonia being the only events reported in at least two patients (two [6%] each). No treatment-related deaths were reported.

INTERPRETATION: The dual-oral chemotherapy-free regimen of ifebemtinib plus garsorasib had encouraging efficacy with a manageable safety profile as first-line treatment for KRASG12C-mutated NSCLC. A randomised phase 3 study has been initiated to further validate these findings against standard-of-care in the first-line setting (NCT07174908).

PMID: 42413526 [Indexed for MEDLINE]

29. Cancer Discov. 2026 Sep 17:OF1. doi: 10.1158/2159-8290.CD-NW2026-0088.

Anti-B7-H3 ADCs Take Center Stage against SCLC at WCLC.

Separate phase III trials of the anti-B7-H3 antibody-drug conjugates tambotatug pelitecan and risvutatug rezetecan significantly improved overall survival, progression-free survival, and objective response rates compared with topotecan in patients with relapsed small-cell lung cancer. In a third trial, the combination of the investigational PD-L1 x VEGF-A bispecific antibody pumitamig plus the anti-B7-H3 ADC elfetabart drozuntecan showed encouraging early efficacy in SCLC across lines of therapy and doses. The studies were presented at the 2026 World Congress on Lung Cancer in Seoul, Republic of Korea.

PMID: 42751833

30. Lancet Oncol. 2026 Oct;27(10):1304-1313. doi: 10.1016/S1470-2045(26)00295-0.

Epub 2026 Sep 15.

Long-term exposure to wildfire-related PM(2·5) and overall survival of older patients with lung cancer: a retrospective, registry-based cohort study.

BACKGROUND: Fine particulate matter (PM2·5) has been identified as a key risk factor for lung cancer incidence and survival. PM2·5 from wildfire smoke is an increasingly important contributor to total PM2·5 in the USA, driven by climate change, and potentially more toxic than non-wildfire PM2·5 due to its smaller particle size and higher toxic contents. However, the effects of wildfire-related PM2·5 on the overall survival of patients with lung cancer remain unclear.

METHODS: This retrospective cohort study included patients aged 65 years or older with histologically confirmed primary small-cell lung cancer or non-small-cell lung cancer (as defined by the International Classification of Diseases for Oncology, Third Edition) from the Surveillance, Epidemiology, and End Results (SEER)-Medicare database between Jan 1, 2006, and Dec 31, 2019, for whom residential zip code-based estimates of wildfire-related PM2·5 and non-wildfire PM2·5 were available. Individuals diagnosed at the in situ stage, without continuous enrolment in Medicare Parts A and B, or with missing exposure or covariate data were excluded. Participants were followed up annually from diagnosis until death, loss to follow-up, or the end of the study in 2019, whichever came first. Daily estimates of ambient wildfire-related PM2·5 and total PM2·5 across the contiguous USA (from 2006 to 2019) were obtained from previously developed and validated models and spatially aggregated to zip code level. Non-wildfire PM2·5 was calculated as the difference between total PM2·5 and wildfire-related PM2·5, and negative values were excluded. The main outcome was all-cause mortality. A time-varying Cox proportional hazards model was applied to estimate the primary exposure of interest of the long-term effects of 3-year moving averages of wildfire-related PM2·5 and non-wildfire PM2·5 concentrations on overall survival.

FINDINGS: Between Jan 1, 2008, and Dec 31, 2019 (the analysis period), 414 016 patients with lung cancer contributed 1 211 490 person-years of follow-up, with a median follow-up of 2 years (IQR 1-4). Of these, 208 468 (50·4%) patients were female, 205 548 (49·6%) were male, 356 356 (86·1%) were White, 36 914 (8·9%) were Black, 18 982 (4·6%) were Asian or Pacific Islander, and 1269 (0·3%) were American Indian or Alaska Native; race or ethnicity was unknown for 495 patients (0·1%). The median concentrations of PM2·5 were 0·28 μg/m3 (IQR 0·21-0·39) for wildfire-related PM2·5 and 8·11 μg/m3 (6·84-9·47) for non-wildfire PM2·5. Each 1-SD increase in wildfire-related PM2·5 or non-wildfire PM2·5 was associated with an increased risk of death for patients with lung cancer (HR 1·0229, 95% CI 1·0189-1·0270; p<0·0001 for wildfire-related PM2·5 and HR 1·0384, 1·0335-1·0432; p<0·0001 for non-wildfire PM2·5). The HR per 1-μg/m3 increase in PM2·5 concentration was 1·0782 (1·0641-1·0924; p<0·0001) for wildfire-related PM2·5 and 1·0171 (1·0149-1·0192; p<0·0001) for non-wildfire PM2·5. Overall, 696 (95% CI 576-814) average annual excess deaths in this cohort were attributable to wildfire-related PM2·5 and 3465 (3061-3864) were attributable to non-wildfire PM2·5.

INTERPRETATION: Wildfire-related PM2·5 showed greater toxicity per unit exposure than non-wildfire PM2·5. As wildfire-related PM2·5 is the fastest-growing contributor to ambient air pollution, there is an urgent need for updated strategies to manage wildfires and mitigate their effects.

PMID: 42743939 [Indexed for MEDLINE]

31. Cancer Discov. 2026 Sep 17:OF1. doi: 10.1158/2159-8290.CD-NW2026-0089.

How a Rare Inherited Lung Cancer Mutation Took Root in Appalachia.

A rare inherited EGFR mutation took root in Southern Appalachia after being carried to the United States by European settlers in the 1700s. Mapping the distribution of this germline EGFRT790M variant could help clinicians identify people at elevated risk of lung cancer and target them for genetic testing and closer surveillance.

PMID: 42752783

32. Lancet Oncol. 2026 Sep;27(9):1110-1119. doi: 10.1016/S1470-2045(26)00283-4.

Adjuvant alectinib versus chemotherapy in resected ALK-positive non-small-cell lung cancer (ALINA): health-related quality-of-life and safety outcomes from a randomised, open-label, phase 3 trial.

BACKGROUND: For patients with resected, ALK-positive non-small-cell lung cancer (NSCLC), adjuvant alectinib significantly improved disease-free survival versus platinum-based chemotherapy in the global, phase 3, open-label, randomised ALINA trial. We report safety and health-related quality-of-life (HRQoL) outcomes from the ALINA trial.

METHODS: Eligible patients aged 18 years or older with resected, ALK-positive, stage IB (≥4 cm)-IIIA NSCLC (per the American Joint Committee on Cancer and the Union for International Cancer Control Cancer Staging Manual 7th edition) and an Eastern Cooperative Oncology Group performance status of 0-1 were randomly assigned (1:1) via a block-stratified randomisation method to receive oral alectinib (600 mg twice daily) for 24 months or intravenous platinum-based chemotherapy for four 3-week cycles. Randomisation was stratified according to disease stage and race. The primary endpoint, previously reported, was disease-free survival. Safety was a secondary endpoint and HRQoL was an exploratory endpoint. Safety was assessed by the investigator as per the National Cancer Institute Common Terminology Criteria for Adverse Events version 5·0 until 28 days after the last alectinib dose or chemotherapy cycle. HRQoL was assessed via the Short-Form 36-item health survey version 2 (SF-36v2) questionnaire at baseline, every 3 weeks to week 12, then every 12 weeks until disease recurrence, consent withdrawal, death, or week 96. Norm-based scoring was applied; clinically meaningful changes were defined using the SF-36v2 manual. Safety was assessed in the safety-evaluable population and HRQoL in the intention-to-treat population. This study is registered with ClinicalTrials.gov (NCT03456076) and is ongoing.

FINDINGS: Between Aug 16, 2018, and Dec 8, 2021, 257 patients were assigned to receive alectinib (n=130) or chemotherapy (n=127). 123 (48%) patients were male and 134 (52%) were female; 143 (56%) were Asian. The safety-evaluable population comprised 128 patients who received alectinib and 120 patients who received chemotherapy; median duration of safety follow-up was 24·8 months (IQR 22·0-24·9) in the alectinib group and 3·7 months (IQR 3·7-3·8) in the chemotherapy group. The safety of adjuvant alectinib was generally consistent with its known profile. The most common grade 3-4 adverse events were blood creatine phosphokinase increased (eight [6%] of 128), alanine aminotransferase increased (two [2%] of 128), and blood bilirubin increased (two [2%] of 128) in the alectinib group, and neutrophil count decreased (12 [10%] of 120), neutropenia (ten [8%] of 120), and nausea (five [4%] of 120) in the chemotherapy group. Serious treatment-related adverse events occurred in two (2%; one each with appendicitis and pneumonitis) of 128 patients in the alectinib group and eight (7%) of 120 patients in the chemotherapy group ( most common were gastrointestinal disorders in three [3%] patients). No deaths due to adverse events were reported in either group. There were fewer discontinuations due to adverse events with alectinib (seven [5%]) versus chemotherapy (15 [13%]). A clinically meaningful difference in improvement from baseline was seen at week 12 for bodily pain, role physical, mental health, social functioning, and vitality SF-36v2 domains with alectinib; improvements in physical and mental HRQoL were maintained over 2 years of active treatment (at week 96, mean Mental Component Summary score: 49·9 [SD 10·4]; mean Physical Component Summary score: 48·8 [SD 7·2]) and reached levels similar to the general population (population norm: 50).

INTERPRETATION: For patients with resected ALK-positive NSCLC, adjuvant alectinib had a manageable safety profile; HRQoL improved and was maintained over 2 years of active treatment. Together with the disease-free survival benefit seen in ALINA, these data support adjuvant alectinib as an important new standard-of-care for patients with resected ALK-positive NSCLC.

PMID: 42636834 [Indexed for MEDLINE]

33. Lancet Oncol. 2026 Sep;27(9):1094-1109. doi: 10.1016/S1470-2045(26)00282-2.

Ivonescimab plus chemotherapy versus placebo plus chemotherapy in patients with advanced EGFR-mutated non-small-cell lung cancer after disease progression on EGFR tyrosine kinase inhibitor therapy (HARMONi): a multicentre, randomised, double-blind, phase 3 trial.

BACKGROUND: Ivonescimab has shown clinical efficacy in non-small-cell lung cancer (NSCLC). We aimed to assess the efficacy and safety of ivonescimab plus chemotherapy versus placebo plus chemotherapy in patients with advanced EGFR-mutated NSCLC whose disease progressed after third-generation EGFR tyrosine kinase inhibitor (TKI) therapy.

METHODS: HARMONi is a randomised, placebo-controlled, double-blind, phase 3 trial done at 114 cancer centres and hospitals across Asia, Europe, and North America. Eligible patients were aged at least 18 years (upper limit: 75 years in Asia) with stage IIIB/IIIC or IV non-squamous EGFR-mutated NSCLC, disease progression after treatment with a third-generation EGFR-TKI, and an Eastern Cooperative Oncology Group performance status score of 0 or 1. Patients were randomly assigned (1:1) via a centralised interactive voice response system or interactive web response system to receive ivonescimab (20 mg/kg) or placebo plus pemetrexed (500 mg/m2) and carboplatin (target area under the curve 5 mg/mL per min) intravenously every 3 weeks. Randomisation was stratified by brain metastases status at enrolment and geographical region. The primary endpoints were progression-free survival by blinded independent radiology review committee and overall survival in the intention-to-treat population. Safety was assessed in patients who received at least one dose of trial treatment. This study is registered with ClinicalTrials.gov (NCT06396065), has completed enrolment, and is ongoing for treatment and follow-up.

FINDINGS: From Jan 25, 2022, to Oct 1, 2024, 660 individuals were screened for eligibility; of these, 438 were enrolled and randomly assigned to receive ivonescimab plus chemotherapy or placebo plus chemotherapy (219 per group). Of enrolled patients, 257 (59%) were female and 181 (41%) were male; 306 (70%) reported race as Asian, and 105 (24%) as White. At a median follow-up of 22·3 months (95% CI 21·5-23·0), 275 progression or death events had occurred in 345 patients (129 events among 172 patients in the ivonescimab plus chemotherapy group and 146 events among 173 patients in the placebo plus chemotherapy group). Median progression-free survival was 6·8 months (95% CI 5·7-7·1) in the ivonescimab plus chemotherapy group versus 4·4 months (4·1-5·5) in the placebo plus chemotherapy group (hazard ratio [HR] 0·52; 95% CI 0·41-0·66; p<0·0001). At a median follow-up of 29·7 months (95% CI 27·7-31·0), 262 deaths occurred in 438 patients (122 in the ivonescimab plus chemotherapy group and 140 in the placebo plus chemotherapy group). Median overall survival was 16·8 months (14·3-19·0) in the ivonescimab plus chemotherapy group versus 14·0 months (12·8-15·7) in the placebo plus chemotherapy group (HR 0·79; 0·62-1·01). The most common grade 3-4 treatment-related adverse events in the ivonescimab plus chemotherapy versus the placebo plus chemotherapy group were decreased neutrophil count (42 [19%] of 218 vs 36 [17%] of 218), decreased white blood cell count (28 [13%] vs 24 [11%]), decreased platelet count (27 [12%] vs 14 [6%]), and anaemia (22 [10%] vs 27 [12%]). Serious treatment-related adverse events occurred in 61 (28%) patients in the ivonescimab plus chemotherapy group and 33 (15%) patients in the placebo plus chemotherapy group. Treatment-related adverse events led to death in four patients (disease progression, multiple organ dysfunction syndrome, and hepatic failure, each in one patient; gastrointestinal haemorrhage and pulmonary embolism in one patient) in the ivonescimab plus chemotherapy group and five patients (pneumonitis, myocardial infarction, cerebrovascular accident, cognitive disorder, and embolic stroke, each in one patient) in the placebo plus chemotherapy group.

INTERPRETATION: Ivonescimab plus chemotherapy showed a clinically meaningful and statistically significant progression-free survival benefit in patients with EGFR-mutated NSCLC after progression on EGFR-TKI therapy. The clinical benefit and lack of new safety signals of ivonescimab with chemotherapy support the potential for the combination as a new treatment option in this patient population.

PMID: 42636833 [Indexed for MEDLINE]

34. Cancer Cell. 2026 Sep 14;44(9):1815-1831.e11. doi: 10.1016/j.ccell.2026.07.001.

Tumor-infiltrating plasma cell profiling after PD-1 blockade reveals tumor-specific antibodies.

The role of tumor-infiltrating B cells (TIL-Bs) in shaping anti-tumor responses in the context of immune checkpoint blockade remains incompletely understood. Here, we interrogate the humoral response in resected lung tumors from patients with non-small cell lung cancer (NSCLC) treated with neoadjuvant PD-1 blockade. We find that tumors orchestrate tertiary lymphoid structures with CD138+ plasma cells, from which we clone recombinant monoclonal antibodies (mAbs) using B cell receptors (BCRs) exhibiting somatic hypermutation and class switching. Several mAbs bind cell-surface citrullinated proteins, characteristic of cancer cells. Chimeric antigen receptor (CAR) T redirected with the soluble chain fragment variable (scFv) of our lead candidate antibody (PC-1) specifically target tumor cells and tumor-promoting myeloid cells in vivo without off-target activity. Moreover, ablation of the citrullination enzyme PADI2 in tumor-bearing mice eliminates reactivity to PC-1 and cytotoxic killing by the CAR. Our results implicate a therapeutic potential for tumor-infiltrating plasma cells that may be harnessed for cancer treatment.

PMID: 42508408 [Indexed for MEDLINE]

35. Nat Med. 2026 Sep;32(9):3235-3247. doi: 10.1038/s41591-026-04488-2.

Clinical usability of an explainable AI decision support tool and evaluation of multimodal models in NSCLC.

Despite a decade in, immunotherapy (IO) treatment selection in non-small cell lung cancer (NSCLC) remains largely guided by subgroup analyses and imperfect programmed death ligand 1 (PD-L1) and clinical scores. To our knowledge, I3LUNG ( NCT05537922 ) is currently the largest international, real-world, multimodal, artificial intelligence (AI)-based study, enrolling 2,396 patients. We integrated real-world clinical and blood (CB) data, computed tomography (CT) images, digital pathology (DP), and genomics into machine learning early fusion (MLEF) and deep learning intermediate fusion (DLIF) models. Machine learning (ML) and deep learning (DL) CB-only models achieved consistent performance across outcomes with area under the curve (AUC) up to 0.77 in the test (TEST) set. Performance drop in external validation (EXVAL) likely reflects population differences (AUC range: 0.55-0.72). AI models significantly surpassed PD-L1, Eastern Cooperative Oncology Group performance status (ECOG PS), neutrophil-to-lymphocyte ratio (NLR), lactate dehydrogenase (LDH) and Lung Immune Prognostic Index (LIPI) score in the independent TEST set. The clinical usability study showed that lung expert and nonexpert physicians improved their prediction with the explainable AI (XAI) ML CB-only based tool. Although multimodal integration with MLEF (CB+CT+DP) was associated with higher performance, its incremental benefit remains uncertain, not translated in TEST and EXVAL. The I3LUNG project is a pioneering framework showing the clinical usefulness of AI tools. A prospective validation of the decision support system (both CB and multimodal) is currently undergoing in more than 2,000 patients.

PMID: 42733093 [Indexed for MEDLINE]