e16110 Background: Long-term outcomes of neoadjuvant chemoradiotherapy (nCRT) for locally advanced esophageal squamous cancer (LA-ESCC) are unsatisfactory. The short-term efficacy of concurrent nCRT and immunotherapy isn’t superior to that of nCRT. The use of total neoadjuvant therapy (TNT), which includes sequential chemotherapy and chemoradiation, is increasing in other malignancies and promises enhanced systemic disease control. The purpose of this study is to assess the efficacy and safety of the integration of tislelizumab, a PD-1 inhibitor with TNT (iTNT) in LA-ESCC. Here, we report our interim results. Methods: This is a prospective, single center, randomized, phase 2 trial. Eligible patients with thoracic LA-ESCC (cT1b-3N1-3M0 or cT3N0M0) were randomized in a 1:1:1 ratio into each of the three treatment arms and then surgery. All patients received nCRT (40Gy/20f with concurrent nab-paclitaxel and cisplatin). Arm A: nCRT followed by consolidation immunochemotherapy (ICT); Arm B: induction ICT followed by nCRT; Arm C: nCRT alone. The ICT regimen consisted of two 3-week cycles of tislelizumab plus nab-paclitaxel and cisplatin. The primary endpoint is the pathological complete response (pCR) rate, the secondary endpoints are R0 resection rate, 1-year and 2-year disease-free survival and overall survival and safety. Results: From February 2025 to December 2025, 90 patients were enrolled. At the time of writing, 65 patients (Arm A n = 19, Arm B n = 21, Arm C n = 25) completed neoadjuvant therapy and accepted surgery in per protocol set (PPS). One patient was inoperatable because of disease progression (Arm A), 9 patients are awaiting surgery; 15 patients remain on neoadjuvant treatment. Among the 65 patients who have received surgery, the incidence of grade ≥3 treatment-related adverse events during neoadjuvant treatment was 36.8% (7/19) for Arm A, 42.9% (9/21) for Arm B and 20.0% (5/25) for Arm C. No grade 5 TRAEs were reported. In Arm A, Arm B and Arm C groups, the rates of surgical complications of any grade were 63.2% (12/19), 47.6% (10/21) and 44.0% (11/25), respectively. Among these, the proportions of Clavien-Dindo grade 3-4 complications were 21.1% (4/19), 14.3% (3/21) and 8.0% (2/25), respectively. There was no postoperative 30-day mortality. All 65 patients achieved R0 resection. The pCR rate was 63.2% (12/19) in arm A, 76.2% (16/21) in arm B and 24.0% (6/25) in arm C (Table 1). The pCR rate was 70.0% (28/40) in the iTNT group (arm A + arm B). Conclusions: Immunotherapy-based TNT has achieved an encouraging pCR rate and a tolerable safety profile. Clinical trial information: ChiCTR2500098409. Pathological outcomes. Arm A (n=19) Arm B (n=21) Arm C (n=25) pCR 63.2% 76.2% 24.0% ypT0 63.2% 76.2% 40.0% ypN0/N1/N2-3 84.2% / 10.5% / 5.3% 90.5% / 0.0% / 9.5% 56.0% / 24.0% / 20.0%

Despite the lack of predictive biomarkers and a prognostic stratification strategy, immune checkpoint inhibitor (ICI) has shown promise in improving outcomes for patients with limited-stage small cell lung cancer (LS-SCLC). We evaluated the potential of circulating tumor DNA (ctDNA) to dynamically predict outcomes in patients with LS-SCLC receiving concurrent chemoradiotherapy (CCRT) with or without consolidation ICI. We analyzed 490 serial samples collected from 144 LS-SCLC patients at baseline (t0), post-induction chemotherapy and pre-thoracic radiotherapy (t1), post-radiotherapy (t2), and progressive disease (t3). For 44 patients receiving consolidation ICI with serplulimab, an investigational PD-1 inhibitor, ctDNA dynamics during consolidation ICI were also assessed at multiple time points. Patients with undetectable ctDNA after CCRT had good outcomes with or without consolidation ICI, whereas ctDNA-positive patients at t2, indicating poor response to CCRT, derived survival benefit from consolidation ICI. Notably, ctDNA status at t1 appeared more predictive than at t2. A three-level risk stratification strategy integrating t1 ctDNA status with radiological tumor shrinkage identified a high-risk subgroup of patients who achieved significantly improved progression-free survival (PFS) (hazard ratio [HR], 0.24; 95% confidence interval [CI], 0.08-0.75; p = 0.014) and overall survival (OS) (HR, 0.06; 95% CI, 0.00-0.42; p = 0.001) from consolidation ICI, prioritizing CCRT plus consolidation ICI. Furthermore, maintaining ctDNA negativity during consolidation ICI was associated with favorable outcomes. These data provide valuable insights into the individualized management of LS-SCLC in the era of immunotherapy.

ABSTRACT Objectives To evaluate the prognosis of patients with nonsmall cell lung cancer (NSCLC) who did not undergo surgery after neoadjuvant chemotherapy combined with immunotherapy (NACI). Patients were grouped according to subsequent treatment: radiotherapy (RT) or nonradiotherapy (non‐RT), and the prognostic importance of positron emission tomography/computed tomography (PET/CT) was further assessed. Materials and Methods This retrospective study included NSCLC patients who received NACI between November 2020 and September 2024 at the Cancer Hospital, Chinese Academy of Medical Sciences, and Peking Union Medical College. Not all patients underwent surgery and subsequently received either RT or non‐RT treatment. Patients were stratified by whether PET/CT was performed and by their SUV‐max values before RT or non‐RT. Progression‐free survival (PFS) and overall survival (OS) were calculated from the start of neoadjuvant therapy using the Kaplan–Meier method. Results A total of 73 eligible patients were enrolled: 21 (28.8%) in the non‐RT group (nRTG) and 52 (71.2%) in the RT group (RTG). The median follow‐up time for all patients in the group was 18 months. The results show no significant difference in PFS (p = 0.653) or OS (p = 0.742) between RTG and nRTG. Among the patients who did not undergo PET/CT examination, the results showed a significant difference in PFS (p = 0.022), but no difference in OS (p = 0.320). Among the patients undergoing PET/CT examinations, in terms of PFS, compared to nRTG + SUV‐max ≤ 4 g/mL, there is no significant difference in RTG + SUV‐max ≤ 4 g/mL (p = 0.584), and RTG + SUV‐max > 4, < 8 g/mL (p = 0.156). However, RTG + SUV‐max ≥ 8 shows a statistical difference (p = 0.005). Conclusion Among NSCLC patients who did not undergo surgery following NACI, no significant differences in OS or PFS were observed between the RTG and nRTG groups. For patients who did not receive PET/CT evaluation, radiotherapy remains a key therapeutic option. In patients with a PET/CT SUVmax ≤ 4, radiotherapy may be safely omitted. In comparison, patients with a PET/CT SUVmax > 4 should be managed with a comprehensive treatment strategy that includes radiotherapy as the main component. PET/CT plays a critical role in guiding subsequent treatment selection.

Introduction: The high mortality of non-small cell lung cancer (NSCLC) is influenced by pre-treatment individual variability, yet reliable prognostic biomarkers are lacking, hindering precision therapy. Objectives: This study aimed to identify plasma metabolite biomarkers for predicting prognosis in stage III NSCLC patients using a targeted quantitative metabolomics approach. Methods: Plasma samples from 113 stage III NSCLC patients with long-term follow-up and 57 healthy controls were analyzed via LC-MS/MS-based targeted metabolomics. Patients were stratified into favorable and poor prognosis groups based on three-year survival. Differential metabolites were identified, and their association with overall survival was evaluated using Kaplan-Meier analysis. Results: Several metabolites differed between NSCLC patients and controls. Survival analysis revealed that elevated glutathione (GSH) levels were significantly associated with improved overall survival (p = 0.0013). Conversely, higher levels of glutamylglutamine (Glu-Gln) (p = 0.0117) and lysophosphatidylcholine 18:3 (LPC 18:3) (p = 0.0119) were correlated with poorer overall survival. Conclusion: This study identifies GSH and LPC 18:3 as promising prognostic biomarkers for stage III NSCLC. These findings provide new insights into patient stratification and the development of personalized treatment strategies.

PurposeThis study aimed to quantify the statistical cure in patients with unresectable locally advanced esophageal squamous cell carcinoma (LA-ESCC) treated with definitive radiotherapy (RT)-based strategies and to explore the independent prognostic factors of cure.Methods and MaterialsThis retrospective study analyzed 801 patients with unresectable LA-ESCC at Affiliated Cancer Hospital of Zhengzhou University from 2014 to 2023. All patients received definitive RT and were stratified into chemoradiotherapy (CRT, n=689) or CRT combined with immunity checkpoint inhibitors (CRT+ICIs, n=112) based on treatment received. A relative survival (RS)-based mixture cure modeling methodology was used to estimate the cure fraction and cure point. The model was externally validated using a dataset of 5,000 matched patients from the SEER database.ResultsOur model estimated a cure fraction of 10.4% and a cure point of 6.7 years. Subset analysis indicated that patients treated with CRT+ICIs had a higher cure fraction than those treated with CRT (30.6% vs 10.9%), with a shorter time to cure (3.9 vs 7.1 years). Validation with the SEER dataset showed a comparable cure fraction (10.8%) but a longer cure point (9.3 years). Multivariable analysis suggested that the favorable independent prognostic factors of statistical cure included a higher BMI (β, 0.10; 95% CI, 0.01 to 0.19; p=0.039) and the CRT+ICIs regimen (β, 2.18; 95% CI, 0.91 to 3.44; p<0.001). Factors associated with a lower probability of cure were age ≥65 years (β -0.04; 95% CI, -0.09 to 0.00; p=0.032) and chronic comorbidities (β, -1.10; 95% CI, -2.14 to -0.05; p=0.040).ConclusionsStatistical cure is achievable in unresectable LA-ESCC patients receiving RT-based regimens. However, the traditional 5-year overall survival (OS) insufficiently reflects long-term survival, indicating that follow-up in the CRT group should be at least 7 years. Incorporation of ICIs facilitated curative potential and shortened cure point, supporting a 4-year OS surrogate endpoint for CRT+ICIs. These findings emphasize the value of integrating cure models into clinical practice to optimize individualized treatment and surveillance strategies.

Purpose Immune checkpoint inhibitors (ICIs) have improved outcomes for patients with unresectable locally advanced non-small cell lung cancer (LA-NSCLC). However, reliable biomarkers for predicting response to immunotherapy remain limited. Among circulating immune cells, PD-1⁺CD8⁺ T cells represent an activated subset that directly responds to PD-1 blockade. Profiling the T-cell receptor (TCR) repertoire within this population may reflect antitumor immune activity and holds promise as noninvasive, blood-based biomarker. Methods and Materials We prospectively enrolled 63 patients with unresectable LA-NSCLC who underwent chemoradiation therapy. Peripheral blood PD-1⁺CD8⁺ T cells were isolated from peripheral blood mononuclear cells obtained by density gradient centrifugation at 3 time points: before radiation therapy, during radiation therapy (on-RT, approximately at the 20th fraction), and after radiation therapy (post-RT), yielding a total of 141 blood samples. TCR sequencing was performed to assess repertoire diversity. Dynamic changes in TCR diversity metrics across time points were analyzed and correlated with progression-free survival (PFS). Results A higher D50 index on-RT was significantly associated with improved median PFS (not reached vs 21.95 months; P = .0246), regardless of the timing of immunotherapy. Patients with more stable TCR diversity and clonality on-RT experienced significantly longer PFS. Specifically, patients with low D50 index variation between on-RT and post-RT had a median PFS that was not reached (95% CI, 30.72-NA), compared with 21.95 months (95% CI, 17.84-NA; P = .018) in the high-variation group. Similarly, patients with low clonality variation demonstrated longer PFS from pre-RT to on-RT (30.72 vs 21.95 months; P = .0425) and from on-RT to post-RT (not reached vs 22.21 months; P = .0331). Clonal tracking analyses revealed that patients with short-PFS exhibited a higher proportion of markedly decreased TCR clones, particularly among high-frequency clones, suggesting impaired antitumor immune responses. Conclusions Peripheral PD-1⁺CD8⁺ TCR diversity and its dynamic changes on-RT are associated with PFS in patients with LA-NSCLC. These findings suggest that TCR repertoire profiling of circulating PD-1⁺CD8⁺ T cells may serve as a noninvasive biomarker to identify patients less likely to benefit from consolidation immunotherapy. Further validation in larger, prospective cohorts is warranted.

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.

BACKGROUND:In the phase III LAURA study, osimertinib, a third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor demonstrated statistically significant improvement in progression-free survival (PFS) versus placebo in patients with unresectable stage III EGFR-mutated non-small cell lung cancer (NSCLC) without progression during/after definitive chemoradiotherapy (CRT); PFS hazard ratio 0.16; 95 % confidence interval (CI): 0.10-0.24; p < 0.001. Here we report pre-specified exploratory efficacy and safety analyses in the LAURA China cohort (which was a stratification factor). METHODS:Adults with unresectable stage III EGFR-mutated (exon 19 deletion/L858R) NSCLC without progression during/after CRT were randomized 2:1 to receive osimertinib 80 mg once daily or placebo until disease progression (per Response Evaluation Criteria in Solid Tumours version 1.1) or discontinuation. The primary endpoint was PFS by blinded independent central review (BICR). Secondary endpoints included overall survival, objective response rate (ORR), duration of response and safety. RESULTS:Of 216 patients randomized globally, 40 (19 %) were enrolled in mainland China, comprising the China cohort (osimertinib n = 27; placebo n = 13). Baseline characteristics were generally well-balanced between treatment arms. Median (95 % CI) BICR-assessed PFS was not reached (17.4-not calculable) versus 3.7 months (1.8-7.7) with osimertinib versus placebo, respectively. ORR (95 % CI) was 63 % (42-81) and 15 % (2-45), respectively. The majority of adverse events (AEs) were grade 1 or 2 in severity and did not lead to treatment discontinuation. No AEs led to dose reductions or death. CONCLUSIONS:Osimertinib after definitive CRT demonstrated PFS benefit over placebo and a manageable safety profile in the China cohort, consistent with findings in the global LAURA population. The results support the use of osimertinib after definitive CRT as the new standard of care, globally and in China, for patients with unresectable stage III EGFR-mutated NSCLC.

Purpose Accurate quantitative survival prediction in advanced non-small cell lung cancer (NSCLC) remains an unmet clinical need. While liquid biopsy is widely used, single circulating tumor DNA (ctDNA) shows limited predictive power. We developed an interpretable deep-learning model to quantitatively predict outcomes. Methods/patients We integrated data from 1373 advanced NSCLC patients profiled by two ultra-deep ctDNA sequencing assays (MSK-ACCESS and ctDx Lung). Features associated with overall survival (OS) were incorporated into a deep-learning network (DeepSurv), which estimates time-to-event survival probabilities. Model performance was evaluated by time-dependent area under the curve (AUC). SHapley Additive exPlanations (SHAP) were employed to interpret model output. Results A total of 1373 patients were analyzed, with 1012 using MSK-ACCESS (discovery) and 361 using ctDx Lung (validation). Among over 40 clinicopathological features, ctDNA status, cell-free DNA (cfDNA) concentration, age, blood-based TP53, EGFR, PIK3CA, ARID1A, STK11 and MET mutations significantly predicted OS. In ctDNA-positive patients, TP53/PIK3CA/ARID1A/STK11/MET-mutated patients had significantly inferior OS compared with wildtype patients (P < 0.001). Using above variables, DeepSurv was trained and tested in the MSK-ACCESS cohort (12-month AUC = 0.75), outperforming single cfDNA (AUC = 0.66) or ctDNA (AUC = 0.59), and externally validated in the ctDx Lung cohort. Compared with high-risk patients, DeepSurv-identified low-risk patients had significantly longer OS in both discovery (12-month OS 87.8% vs 53.8%, HR 0.32, P < 0.001) and validation cohorts (73.2% vs 48.4%, HR 0.42, P < 0.001). SHAP revealed TP53 and cfDNA concentration > 4.8 ng/mL had the most important contributions. Conclusions The interpretable DeepSurv model, integrating multimodal features, enables quantitative survival prediction and risk stratification in advanced NSCLC, facilitating personalized decision-making.

PurposeThe purpose of this study was to evaluate the effect of consolidation immunotherapy on patients with stage III non-small cell lung cancer (NSCLC) who received induction chemoimmunotherapy before chemoradiotherapy (CRT).Materials and methodsPatients with stage III NSCLC who received induction chemoimmunotherapy before CRT with or without consolidation immunotherapy at 4 hospitals between February 2018 and December 2022 were retrospectively analyzed. The patients were divided into two groups on the basis of whether they received consolidation immunotherapy (Ind+Con group) or not (Ind group). Progression-free survival (PFS) and overall survival (OS) were assessed from the initiation of treatment and were estimated using the Kaplan–Meier method. One-to-one propensity score matching (PSM) was used to further minimize confounding effects.ResultsA total of 196 eligible patients were enrolled, with 124 (63.3%) in the Ind group and 72 (36.7%) in the Ind+Con group. The median follow-up was 24.6 months, and the median PFS and OS for the whole cohort were 24.8 months and 46.0 months, respectively. The median PFS was 25.5 months in the Ind group vs. 24.0 months in the Ind+Con group, with 2-year PFS rates of 52.2% vs. 47.7% (P = 0.472). The median OS was 46.0 months in the Ind group vs. not reached (NR) in the Ind+Con group, with 2-year OS rates of 78.0% vs. 83.8% (P = 0.578). After 1:1 PSM, the median PFS was 30.2 months vs. 24.0 months, with 2-year PFS rates of 55.4% vs. 47.7% (P = 0.261). The median OS was 46.0 months vs. NR, with 2-year OS rates of 80.8% vs. 83.8% (P = 0.960).ConclusionThe effect of consolidation immunotherapy on patients with stage III NSCLC who receive induction chemoimmunotherapy before CRT needs to be further studied.

Objective To compare the efficacy and safety of a sequential combination of chemoradiotherapy (CRT) with immune checkpoint inhibitors (ICIs) administered as induction plus consolidation versus consolidation-only in patients with unresectable stage III non-small cell lung cancer (NSCLC).Methods This retrospective study enrolled 265 patients treated at two centers between March 2019 and August 2023. Patients were categorized into a consolidation-only group (n = 153) and an induction plus consolidation group (n = 112). Propensity score matching (PSM, 1:1 ratio) was used to balance baseline characteristics. Progression-free survival (PFS) and overall survival (OS) were assessed using Kaplan-Meier analysis and log-rank tests. Adverse events (AEs) were evaluated according to CTCAE v5.0.Results Before PSM, no significant survival differences were observed between groups (2-y PFS: 52.6% vs. 63.5%, p = 0.085; 2-y OS: 91.7% vs. 81.2%, p = 0.822). After PSM, outcomes remained comparable (2-y PFS: 56.8% vs. 62.2%, p = 0.179; 2-y OS: 94.9% vs. 87.9%, p = 0.514). Before PSM, the most common AE was pneumonitis (60.7% vs. 55.1%, p = 0.442). The induction plus consolidation group showed a lower incidence of anemia (p = 0.004) but a higher incidence of ALT/AST elevation (14.3% vs. 5.1%, p = 0.022). The incidence of all other AEs was comparable (p > 0.05). After PSM, only anemia was significantly higher in the consolidation-only group (52.8% vs. 27.8%, p = 0.004).Conclusion In treatment-tolerant patients, induction plus consolidation therapy demonstrated comparable efficacy and safety to consolidation-only therapy in unresectable stage III NSCLC.

This article discusses the emerging radiotherapy-free and chemo-free strategies in PD-L1-high, unresectable stage III NSCLC, reviewing the Evolution trial and comparing it with existing treatments. We highlight the need for further research to validate these approaches and ensure safe de-escalation without compromising curability.

e16119 Background: Based on the SANO trial establishing active surveillance non-inferiority after clinical complete response (cCR) in oesophageal cancer, and prior evidence of prognostic value of ctDNA (circulating tumor DNA) in locally advanced esophageal squamous cell carcinoma (ESCC), this phase II exploratory trial aims to evaluate the combined predictive value of ctDNA, PET-CT, and gastroscopy for treatment efficacy in cCR patients after neoadjuvant therapy. Methods: Patients (pts) with locally advanced or oligometastatic ESCC (cT1-4a N+ M0/M1 [limited to supraclavicular lymph node metastasis only]) were enrolled. Treatment comprised induction chemotherapy (albumin-bound paclitaxel/cisplatin/capecitabine, 3 cycles) followed by concurrent radiotherapy (50 Gy) with 2 cycles of anlotinib (10 mg, p.o., qd, d1-14, q3w) and camrelizumab (200 mg, iv, d1, q3w). Post-treatment response was assessed at 4-6 weeks. A post-radiotherapy surveillance regimen integrating ctDNA-based MRD (minimal residual disease) detection, PET-CT, and gastroscopy was implemented. Patients with no evidence of disease (negative for MRD [M], PET-CT [P], and gastroscopy [G]) were classified as MPGN. Any positive finding among these three modalities were classified as MPGP. Subsequent surgery considered residual disease and patient preference. The primary endpoint was the 2-year event-free survival (EFS) rate. Secondary endpoints included pathological complete response (pCR) rate, 2-year overall survival (OS) rate, and safety. Results: As of January 14, 2026, 40 pts were enrolled (median age 63 years). Stage distribution: 47.5% III, 25.0% IVA, 20.0% IVB. After a median follow-up of 17.5 months (IQR: 11.2, 33.5), the 2-year EFS rate was 55.6% (95% CI, 38.9-79.3), with a median EFS of 34.9 months (95% CI: 21.1-NA). Of the 16 patients (40.0%) undergoing radical surgery post-neoadjuvant therapy, pCR and R0 rates were 43.8% (95% CI: 19.8-70.1) and 93.8% (95% CI: 69.8-99.8), respectively. A primary tumor ΔSUVmax reduction of ≥65% post-radiotherapy correlated with improved EFS (p = 0.0052) and OS (p = 0.0050). Patients were classified as MPGN (n = 9) or MPGP (n = 28). The 2-year EFS rate was 85.7% (95% CI: 63.3-100.0) in MPGN vs. 47.1% (95% CI: 27.3-81.1) in MPGP; 2-year OS rate was 100.0% vs. 62.1% (95% CI: 42.3-91.3), respectively. Any-grade TEAEs occurred in 92.5% of patients, most commonly esophagitis (70.0%), odynophagia (60.0%), leukopenia (32.5%), and fatigue (22.5%). Conclusions: Integrated post-treatment assessment using ctDNA-based MRD, PET-CT, and endoscopy shows predictive potential for survival in locally advanced ESCC following induction chemotherapy and concurrent radiotherapy with anlotinib and camrelizumab. These results require prospective validation in larger cohorts with longer follow-up. Clinical trial information: ChiCTR2200056920.

Following the success of chemoradiotherapy (CRT) combined with consolidative immune checkpoint inhibitors (ICIs) in locally advanced tumors, over 30 ongoing randomized controlled trials (RCTs) are investigating the potential benefits of adding concurrent ICIs. To investigate the differences in efficacy and safety between adding and not adding concurrent ICIs to CRT followed by consolidative ICIs, a literature search was conducted in PubMed, Embase, and the Cochrane Library, incorporating RCTs comparing CRT combined with consolidative ICIs versus CRT alone, or CRT with both concurrent and consolidative ICIs versus CRT alone. The primary outcomes were overall survival (OS) and progression-free survival (PFS). To reduce potential bias, an additional mirror-design analysis was performed through network meta-analysis. A total of 13 RCTs comprising 6868 patients and 14 cohort studies comprising 4724 patients were included. While patients treated with CRT and consolidative ICIs demonstrated significantly superior OS and PFS to patients treated with CRT alone in RCTs (HR of OS, 0.743, 95% CI, 0.654-0.843; HR of PFS, 0.674, 95% CI, 0.577-0.786), CRT and concurrent-plus-consolidative ICIs did not improve OS and PFS compared with CRT alone (HR of OS, 0.942, 95% CI, 0.782-1.134; HR of PFS, 0.880, 95% CI, 0.752-1.030). Significant differences were detected in OS (p = 0.038) and PFS (p = 0.017) between CRT combined with consolidative ICIs treatment versus CRT combined with concurrent and consolidative ICIs treatment from RCTs. In conclusion, adding concurrent ICIs may dampen the survival benefits of CRT combined with consolidative ICIs. This evidence informs future RCT design strategies.

Despite the predictive impact of circulating tumor DNA (ctDNA) minimal residual disease (MRD), accurate prediction of failure risk after curative-intent treatments for early-stage or localized non-small cell lung cancer (NSCLC) patients to guide personalized therapy remains challenging. This study aimed to develop and validate an interpretable artificial intelligence-assisted model using global data resources. Liquid biopsy data, blood-based genomic alterations, clinicopathological features, and survival outcomes of stage I–III NSCLC patients who underwent surgery or definitive chemoradiotherapy were collected from 6 cohorts. PRIME (Progression Risk prediction by Interpretable Machine learning on ctDNA-MRD, Mutations, and clinical-therapeutic features) was trained by 6 machine learning algorithms across 4 cohorts and validated in 2 independent cohorts. Model performance was evaluated by the area under the curve (AUC) and interpreted by SHapley Additive exPlanations (SHAP). Whole-exome sequencing (WES) or whole-genome sequencing (WGS) of tumor tissue from 430 stage II–III NSCLC patients and RNA-sequencing (RNA-seq) data from 1149 subjects, sourced from The Cancer Genome Atlas, were used to validate the prognostic effect of mutations identified in peripheral blood and investigate the underlying mechanisms. A global dataset encompassing 781 blood samples from 493 patients was analyzed. Clinical stage, pre-treatment ctDNA, post-treatment MRD, blood-based Kelch-like ECH-associated protein 1 (KEAP1), serine/threonine kinase 11 (STK11), and cyclin-dependent kinase inhibitor 2A (CDKN2A) mutations, and treatment modality were significantly associated with the risk of disease progression and were thereby included in the model training. WES/WGS and RNA-seq confirmed the poor prognostic effect of KEAP1, STK11, and CDKN2A mutations, which were characterized by the suppressive tumor microenvironment and attenuated humoral immunity. The neural network (NN) model exhibited optimal prediction of treatment failure risk in the training (AUC = 0.85, 95

Non-small-cell lung cancer (NSCLC) exhibits pronounced molecular heterogeneity, and current predictive models rarely incorporate mitochondrial quality-control programs such as mitophagy. We hypothesize that an artificial intelligence model based on mitophagy-related genes (MRGs) at single-cell resolution could improve prediction of survival and immunotherapy benefit. We analyzed single-cell RNA sequencing data from treatment-naïve NSCLC tumors to evaluate the activity of MRGs and identify genes exhibiting differential expression between cells with high versus low mitophagy levels. These differentially expressed genes were then cross-referenced with mitophagy gene sets to pinpoint candidate prognostic markers. Using LASSO regression combined with multiple machine learning classifiers, we constructed a risk model, which was validated in both internal and external cohorts, including a clinical immunotherapy trial. We further examined the relationship between the risk model, immune cell infiltration, and drug sensitivity in silico. The key MRGs were then experimentally validated in A549 cells using qRT-PCR, Western blotting, immunofluorescence, and functional assays for cell migration and wound healing. We quantified the mitochondrial autophagy activity of 18,167 single cells. Differential expression yielded 1,668 genes; intersection with the MRG list produced 39 candidates. A six-gene panel (FOS, CANX, EIF4G1, CALCOCO2, HSP90AB1, and PRKAR1A) emerged from LASSO. Gradient boosting machine (GBM) achieved the optimal cross-validated performance (testing set: AUC = 0.80, validation set: AUC = 0.72). SHAP analysis ranked PRKAR1A and CALCOCO2 as the top risk contributors. Patients classified into the high-MRG-score group exhibited consistently shorter overall survival (OS) across all datasets (HR = 3.66, 95

IntroductionSmoking is the primary risk factor for lung cancer, and 37% - 42% of patients with non-small-cell lung cancer (NSCLC) harboring anaplastic lymphoma kinase (ALK) mutation being smokers. Nevertheless, the specific impact of smoking on prognosis in patients with unresectable stage III ALK-positive NSCLC remains to be elucidated.MethodThis two-centric, retrospective cohort study included 48 patients with unresectable stage III ALK-positive NSCLC. Gene ontology (GO) enrichment analysis was conducted on data from 25 patients who underwent NGS. We further performed Gene Set Enrichment Analysis (GSEA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis to validate these findings, using the GSE31852 dataset (n = 34) patients from the Gene Expression Omnibus (GEO) database.ResultsIn these 48 patients, the median age was 55.2 (range, 33-80) years; approximately half of the patients were men (50.0%) and smokers (45.8%); 62.5% patients had IIIB stage disease; 33.3% patients initially received chemoradiation therapy (CRT). After a median follow-up of 49.02 (interquartile range [IQR], 35.84 - 62.03) months, CRT significantly improved the locoregional-free survival (LRFS, P = 0.012). Univariate and multivariate Cox regression analysis suggested that smoking was independent prognostic factors for poorer OS (univariate HR = 3.01, P = 0.049; multivariate HR = 3.92, P = 0.023). Compared with never-smokers, smokers exhibited a significantly inferior 5-year OS (51.9% vs. 78.9%, Log-rank P = 0.038). GO analysis revealed distinct biological processes and cell components between never-smokers and smokers. Validation in the GSE31852 dataset subsequently confirmed these findings and further highlighted the significant differences in immune cell regulation, including immune cell infiltration, differentiation, and interactions between never-smokers and smokers.ConclusionsIn patients with unresectable stage III ALK-positive NSCLC, CRT improved the disease control. Smokers exhibited a significantly poorer OS and DMFS, and may require more risk-adapted treatment strategies, such as the combination of CRT with upfront ALK TKIs. These findings suggest that smoking may adversely affect survival by modulating the tumor immune microenvironment.

BACKGROUND:Checkpoint inhibitor pneumonitis (CIP) is the leading cause of treatment-related deaths for immune checkpoint inhibitor (ICI) combination therapies. CIP is problematic to diagnose and differentiate, particularly from radiation pneumonitis (RP), due to the lack of mechanistic distinctions between them. METHODS:Using single-cell RNA sequencing (scRNA-seq) and single-cell T cell receptor sequencing (scTCR-seq), we characterize the cellular landscape of bronchoalveolar lavage fluid (BALF) and peripheral blood from a discovery cohort (seven CIP, six RP, and six treatment-naive controls) and a validation cohort (five patients receiving combined ICI and radiotherapy who were diagnosed with RP). FINDINGS:We report a striking accumulation of alveolar CD8+ exhausted T cells (Texs) in CIP. The alveolar CD8+ Texs of CIP primarily differentiate from tissue-resident ZNF683hi CD8+ T cells, whereas those of RP predominantly originate from peripherally related GZMKhi CD8+ T cells. These findings were further validated in a prospectively enrolled validation cohort and ultimately guided successful clinical decisions regarding ICI rechallenge. CONCLUSIONS:These results highlight distinct cellular and molecular features in CIP and RP, thereby providing insights into clinical decision-making regarding ICI rechallenge in lung cancer patients. FUNDING:This study was supported by the National Natural Science Foundation of China.

PURPOSE:Preclinical studies showed that low-dose radiation therapy (LDRT) may act synergistically with immunotherapy in small cell lung cancer (SCLC); however, its role in the treatment of extensive-stage SCLC (ES-SCLC) remains unclear. METHODS AND MATERIALS:This single-arm, multicenter, Simon's 2-stage, phase 2 study enrolled treatment-naïve patients with ES-SCLC. Patients received 4 21-day cycles of intravenous cisplatin (75 mg/m2) or carboplatin (area under the curve value, 5 mg/mL/min), etoposide (100 mg/m2), and atezolizumab (1200 mg), with concurrent LDRT (15 Gy in 5 fractions [3 Gy/fraction]), followed by atezolizumab maintenance therapy until loss of clinical benefit, unacceptable toxicity, withdrawal of consent, or death. The primary endpoint was the confirmed objective response rate. The secondary endpoints were progression-free survival (PFS) and overall survival (OS). RESULTS:Fifty-six eligible patients were enrolled between December 16, 2020, and March 30, 2022. The median follow-up was 36.1 months (IQR, 30.9-38.7) at the cutoff date (June 30, 2024). The confirmed objective response rate was 87.5% (95% CI, 75.9-94.8). The median PFS and OS were 6.9 months (95% CI, 5.4-9.3) and 16.9 months (95% CI, 14.0-32.9), respectively. The PFS rates at 1 and 3 years were 27.3% and 20.7%, respectively, and the OS rates at 1 and 3 years were 69.6% and 35.1%. The median depth of tumor response among patients with confirmed objective response was 70.2%. The 3-year OS rates were 57.4% and 18.8% in patients above and below the median depth of tumor response, respectively (hazard ratio, 0.28; 95% CI, 0.13-0.60). The most common treatment-related grades 3 to 5 adverse events were decreased neutrophil count (60.7%) and decreased white blood cell count (58.9%). CONCLUSIONS:These findings suggest that upfront LDRT concurrent with atezolizumab plus chemotherapy was effective and tolerable as first-line treatment for ES-SCLC, warranting further verification in randomized controlled trials.