Supplementary Figure 4. Comparison of immune dynamics between responders and non-responders.

Patients diagnosed with limited-stage small cell lung cancer (LS-SCLC) face dismal long-term outcomes, as relapse occurs frequently even after standard concurrent chemoradiotherapy. Integrating immune checkpoint blockade into chemoradiotherapy regimens may enhance sustained disease control, yet prospective evidence for this strategy in LS-SCLC remains sparse. In this single-arm phase II study, we investigated sintilimab in combination with concurrent chemoradiotherapy (CCRT) among LS-SCLC patients who had favorable functional status. Twenty-two histologically verified LS-SCLC patients were treated with four 3-weekly cycles of chemotherapy alongside sintilimab, with concurrent thoracic radiation (45 Gy delivered in 30 fractions). The primary endpoint was progression-free survival (PFS). After a median follow-up of 44.7 months, the median PFS reached 29.6 months, with 12- and 24-month PFS rates of 72.7% and 54.5%, respectively. Median overall survival (OS) stood at 40.6 months, and the corresponding 12- and 24-month OS rates were 95.5% and 72.7%, respectively. An objective response rate (ORR) of 95.5% was observed. Most grade 3-4 adverse events were hematologic in nature, particularly neutropenia and thrombocytopenia. Three patients developed pneumonitis, one of whom had grade 2 or higher. No deaths attributable to treatment occurred. Elevated human leukocyte antigen class I (HLA-I+) tumor cell expression correlated with longer PFS, suggesting potential value as a predictive biomarker. These findings suggest that concurrent administration of sintilimab with CCRT demonstrates encouraging antitumor efficacy and a manageable safety profile in LS-SCLC. (Trial registration number: ChiCTR2100043184).

BACKGROUND:This study evaluated biomarker profiles associated with therapeutic response and prognosis in resectable non-small cell lung cancer (NSCLC) receiving neoadjuvant camrelizumab plus chemotherapy. METHODS:In this single-arm phase II trial, patients with resectable stage IIIA-IIIB NSCLC received three cycles of camrelizumab plus chemotherapy, followed by surgery. Primary endpoints were pathological complete response (pCR). Secondary endpoints included major pathological response (MPR), disease-free survival (DFS), and safety. Exploratory analyses assessed immune subsets in the tumor microenvironment (TME) and peripheral blood, cytokine profiles, circulating tumor DNA (ctDNA) dynamics, and spatial immune-tumor interactions. RESULTS:Thirty patients were enrolled (22 squamous, 8 adenocarcinoma); 27 underwent radical resection. The pCR and MPR rates were 33.3% and 50.0%, respectively. At a median follow-up of 27.2 months, the 2-year DFS rate was 77.4%. Grade≥3 treatment-related adverse events occurred in 13.3%. Achieving pCR was associated with higher baseline levels of CD8+ T cells and naïve-like T cells in both blood and TME. Elevated baseline CD8+ naïve-like T cells in both peripheral blood and tumor nests and their closer proximity to tumor cells correlated with improved DFS. Higher circulating baseline chemokine (C-C motif) ligand 3 (CCL3) levels were associated with both pCR and prolonged DFS. Postneoadjuvant treatment ctDNA positivity predicted shorter DFS, while longitudinal ctDNA monitoring identified relapse as early as 17.6 months before radiographic progression. CONCLUSIONS:Baseline CD8+ naïve-like T-cell abundance and spatial proximity to tumor cells, circulating CCL3 levels, and ctDNA dynamics may serve as potential prognostic biomarkers in resectable NSCLC receiving neoadjuvant camrelizumab plus chemotherapy. TRIAL REGISTRATION NUMBER:NCT06241807.

Supplementary Figure 3. Longitudinal dynamics of peripheral blood lymphocytes.

BACKGROUND AND PURPOSE:Based on the assumption that radiation dose escalation to the primary tumor improves local control and therefore produces survival benefits under the condition of limiting the dose to the organ at risk (OAR), we launched a study to evaluate the effect of simultaneous integrated boost (SIB) radiotherapy implemented in stage III locally advanced non-small cell lung cancer (LA-NSCLC) patients. MATERIALS AND METHODS:A prospective, single-center, open-label, randomized phase II trial was performed in patients with stage III LA-NSCLC. Patients were randomized to receive SIB thoracic radiation: 50 Gy in 25 fractions of 2.0 Gy for planning target volume (PTV), 55 Gy in 25 fractions of 2.2 Gy for clinical target volume (CTV), 60-70 Gy in 25 fractions of 2.4-2.8 Gy for gross tumor volume (GTV), or control group: 30 fractions of 2.0 Gy for PTV. A platinum based concurrent chemotherapy was administered to patients in both groups. The primary endpoint was progression-free survival (PFS). The secondary endpoints were overall survival (OS), objective response rate (ORR), failure patterns, and treatment-related toxicities. Exploratory analyses of epidermal growth factor receptor (EGFR) and programmed death-ligand 1 (PD-L1) were performed for PFS and OS. RESULTS:From April 2015 to April 2018, 168 patients were included in the analysis, with 84 in the control group and 84 in the SIB group. The median PFS was 21.0 months in the SIB group and 11.0 months in the control group (P < 0.001, Hazard Ratio (HR) 0.48, 95% CI 0.34-0.68). The median OS was 42.0 months and 26.0 months(P = 0.002, HR 0.55, 95% CI 0.37-0.81) in the SIB group and the control group, respectively. The SIB group had a significantly lower risk of brain and other distant metastasis, with adjusted sub-distribution HR of 0.35 (95% CI, 0.14-0.87, P = 0.025) and 0.65 (95% CI, 0.45-0.94, P = 0.023), respectively. There was lower radiation-related pneumonitis (P = 0.015) in the SIB group because of the lower dose for the irradiated lung (irradiated-lung V5, 55.38±18.11 Gy vs. 61.95±15.45 Gy, P = 0.015). Most other OAR doses and incidences of grade ≥2 disease were similar between the two arms. Exploratory biomarker analysis reveals a trend toward superior survival benefit from SIB in patients with PD-L1 ≥1% or EGFR-mutant. CONCLUSIONS:We demonstrated that the routinely adaptive SIB strategy could significantly improve PFS and OS and reduce the dose to the irradiated lung without increasing the risk of tumor recurrence. Exploratory analyses of EGFR mutation status and PD-L1 expression suggested potential differences in treatment outcomes across biomarker-defined subgroups. This strategy represents a potentially feasible regimen to improve survival outcomes for patients with stage III LA-NSCLC eligible for definitive concurrent chemoradiotherapy and warrants further validation in larger prospective trials.

Supplementary Figure 1. Subgroup analysis of progression-free survival (PFS).

Abstract Patients with bulky, unresectable stage III non–small cell lung cancer (NSCLC) face poor outcomes with standard concurrent chemoradiotherapy (cCRT) due to large radiation fields and toxicity risks. We evaluated the feasibility and efficacy of induction immunochemotherapy to downstage tumors prior to cCRT. In this single-arm, phase II study, eligible patients received two cycles of induction serplulimab plus chemotherapy. Patients without progression underwent multidisciplinary restaging to receive either cCRT with serplulimab consolidation or surgery. The primary endpoints were objective response rate (ORR) after cCRT and changes in lung volume receiving ≥20 Gy (V20). Forty-nine patients were enrolled (75.5% stage IIIB/IIIC). Following induction, the V20 value was significantly reduced by 11.41% (P < 0.001). The ORR following cCRT was 77.14% (95% confidence interval, 59.86%–89.58%). The 12-month progression-free survival and overall survival rates were 76.15% and 90.54%, respectively. Notably, six patients successfully underwent R0 resection, with five achieving a pathologic complete response. Grade 3 adverse events occurred in 14.29% of patients, and toxicities were manageable. Induction serplulimab–chemotherapy prior to cCRT is a promising strategy for bulky, stage III NSCLC. This approach significantly reduced radiation volumes, achieved high response rates, and enabled curative surgery in selected patients with manageable toxicity.

Supplementary Figure 2. Sensitivity analysis of survival outcomes.

410 Background: Neoadjuvant chemotherapy or chemoradiotherapy followed by surgery is the standard of care for resectable locally advanced ESCC. SHR-1701, a new bifunctional fusion protein composed of a monoclonal antibody against PD-L1 fused with the extracellular domain of TGF-β receptor II, may enhance antitumor activity in combination with neoadjuvant standard therapies in ESCC patients (pts). The aim of this phase II trial is to determine the safety and efficacy of neoadjuvant chemoradiotherapy plus SHR-1701 followed by esophagectomy in pts with locally advanced resectable ESCC. Methods: Pts with resectable thoracic ESCC, diagnosed as clinical stage of cT1b-cT2N+M0 or cT3-cT4aNxM0 per AJCC 8th were eligible. Preoperative therapy included SHR-1701 (30 mg/kg every 3 weeks for 2 cycles), albumin paclitaxel (50 mg/m 2 , once a week for 5 weeks), carboplatin (AUC=2, once a week for 5 weeks) and radiotherapy (41.4Gy in 23 fractions). Following esophagectomy, pts received SHR-1701 up to 1 year. The primary endpoint was pathological complete response (pCR) rate in the per-protocol population. Secondary endpoints included R0 resection rate, major pathological response (MPR) rate, disease free survival (DFS) and safety. Results: Between Dec. 2021 and Feb. 2023, 43 pts were screened and 41 met the inclusion criteria, among whom the clinical stage I, II, III, and IVa at baseline were 1 (2.4%), 8 (19.5%), 31 (75.6%), and 1 (2.4%), respectively. All 41 pts received neoadjuvant SHR-1701 combined with chemoradiotherapy. As of Mar. 2024, 30 pts underwent surgery, and all achieved R0 resection. There was no in-hospital and postoperative 30-day mortality. 9 (30.0%) pts achieved pCR in both primary tumor and lymph nodes (ypT0N0), and 12 (40.0%) pts had complete pathological response of the primary tumor with residual disease in lymph nodes alone (ypT0N+). Treatment-related adverse events (TRAEs) occurred in all pts, and most of TRAEs were grade 1-2. Notable toxicity included pneumonitis (31.7%) and anastomotic leak (12.2%). Conclusions: The addition of SHR-1701 to neoadjuvant chemoradiotherapy in ESCC demonstrated promising efficacy with acceptable toxicity, and might be a promising approach for neoadjuvant treatment. Clinical trial information: ChiCTR2000041562.

Background:Extensive-stage small cell lung cancer (ES-SCLC) remains a challenging malignancy with a poor prognosis. The integration of immunochemotherapy and combined consolidative thoracic radiotherapy (cTRT) presents a potential paradigm shift in treatment. This study aims to evaluate the real-world efficacy and safety of this approach. Methods:In a single-center retrospective study conducted at Shandong Cancer Hospital, electronic medical records of 828 ES-SCLC patients treated between January 1, 2022, and December 31, 2023, were reviewed. Patients were divided into three cohorts based on treatment strategies: chemoradiotherapy (cohort A), immunochemotherapy without/with cTRT (cohort B/C). Propensity score matching was utilized to adjust for baseline differences. The primary outcomes were real-world progression-free survival (rwPFS) and overall survival (OS). Secondary outcomes included the incidence and severity of specific interested adverse events (AEs). Results:Of the 374 patients analyzed, cohort C showed significant improvements in rwPFS and OS compared to cohort A. The median rwPFS in cohort C (10.9 months) was longer than that of cohorts A (7.6 months) and B (8.0 months). The 12-month rwPFS rate was highest in cohort C (41%), compared to cohorts A (19%) and B (34%). The incidence of grade 3 or higher AEs was comparable across cohorts, with myelosuppression being the most common. However, the incidence of grade 3 or higher pneumonitis was notably higher in cohorts B and C, aligning with previous reports. Conclusions:The combination of cTRT with immunochemotherapy for ES-SCLC showed improved rwPFS and OS, indicating potential benefit in this population. The overall safety profile remained manageable. These findings highlight the need for further prospective studies to confirm the optimal integration of cTRT in ES-SCLC treatment strategies.

BACKGROUND:The optimal radiation dose for the treatment of small cell carcinoma of the esophagus (SCEC) has not been established. This study aimed to investigate the treatment outcomes and toxicities in patients with limited-stage SCEC (LS-SCEC) treated by radiotherapy. METHODS:Patients with LS-SCEC from 14 institutions were retrospectively identified between December 2000 and October 2021. The primary endpoints of the study included overall survival (OS), progression-free survival (PFS), and local regional control (LRC), and the secondary endpoints were treatment-related toxicity parameters. Patients were categorized into a high-dose (HD, ≥ 60 Gy) group and low-dose (LD, <60 Gy) group based on the radiation dose. Additionally, they were classified into two groups based on the treatment sequence: concurrent chemoradiotherapy (CCRT) and sequential chemoradiotherapy (SCRT). A 1:1 propensity score matching (PSM) approach was applied to balance the observable potential confounding factors between the groups. RESULTS:Of the 150 patients included in the study, 56 received LD, and 94 received HD radiotherapy. After 1:1 PSM, the OS, PFS, and LRC in the HD group were higher than those in the LD group; however, the difference was not statistically significant (P > 0.05). No significant differences in survival and the occurrence of treatment-related toxicity were observed between the CCRT and SCRT groups. CONCLUSIONS:Neither CCRT nor SCRT was significantly associated with longer survival in LS-SCEC when a higher radiation dose was selected. A lower radiation dose might be a preferable time-dose fraction scheme; however, additional studies are required to validate these findings.

BackgroundEpidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)-based combination therapy modalities for patients with EGFR-mutated stage IV non-small cell lung cancer (NSCLC) are being investigated. We evaluated the value and safety of third-generation EGFR-TKIs combined with thoracic radiotherapy (TRT) in patients with oligo-organ metastatic, along with the optimal TRT timing and dose.MethodsWe retrospectively enrolled patients with EGFR-mutated oligo-organ metastatic NSCLC who received first-line third-generation EGFR-TKIs from 2018 to 2023. Patients were divided into TKI-alone and TKI+TRT groups according to whether TRT was added. Propensity score matching (PSM) was implemented to decrease bias. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS) and safety.ResultsA total of 236 patients were included, the median follow-up was 28.4 months. After PSM, baseline characteristics were balanced between the TKI+TRT (n=69) and TKI-alone (n=108) groups. Compared with the TKI-alone group, the TKI+TRT group presented significantly better PFS (28.6 vs. 19.8 months, hazard ratio [HR]=0.48, P = 0.00024) and OS (42.2 vs. 35.1 months, HR = 0.54, P = 0.039). In patients who received TRT, the tumor shrinkage group demonstrated significantly improved PFS (HR = 0.36, P = 0.0035) and OS (HR = 0.13, P = 0.0012) compared to the tumor enlargement/Stabilization group. The high-dose group showed superior PFS (HR = 0.43, P = 0.011) and OS (HR = 0.36, P = 0.023) compared to the low-dose group. Only 5.8% of patients in the TKI+TRT group developed grade ≥3 pneumonitis.ConclusionIncorporating TRT provided significant survival benefits in patients with oligo-organ metastatic NSCLC who received first-line third-generation EGFR TKIs, with acceptable side effects. The administration of higher radiation doses during a phase of tumor shrinkage may be associated with optimal outcomes.

Background and objective:Several large-scale phase III clinical trials have confirmed the survival benefit of immunotherapy in patients with locally advanced or metastatic esophageal cancer (EC). The study aimed to investigate whether early use of immunotherapy can improve long-term survival. Methods:Patients with locally advanced or metastatic esophageal squamous cell cancer (ESCC) diagnosed from January 2018 to December 2021 were retrospectively analyzed. According to the time of immunotherapy, patients were divided into the early immunotherapy group (EIT group, first-line immunotherapy) and the late immunotherapy group (LIT group, second-line immunotherapy). A 1:1 propensity score matching (PSM) was applied to balance the observable potential confounding factors between the two groups. The primary outcome was overall survival (OS). Results:A total of 359 patients were enrolled; after propensity score matching, the clinical features were well balanced between the two groups, including 107 patients. The median OS was 15.7 months (95%CI: 12.81-18.59) in the EIT group and 17.7 months (95%CI: 14.89-20.57) in the LIT group, respectively (p = 0.185, HR = 1.25). The PFS1 of patients was 8.7 months (95%CI: 7.53-9.87) and 7.6 months (95%CI: 5.90-9.30), respectively, and the difference was statistically significant (p = 0.032, HR = 0.72). The PFS2 of patients was 12.97 months (95%CI: 11.37-14.58) and 12.93 months (95%CI: 11.65-14.21), respectively, and the difference was statistically significant (p = 0.045, HR = 0.73). Subgroup analysis showed that male patients with middle thoracic EC, younger than 65 years old, with only one site of metastasis, only lymph node progression, no combined radiotherapy after progression, and TP (paclitaxel + platinum) regimen chemotherapy may have greater benefits. The COX multivariate analysis showed that the EIT group and the differentiation degree of the tumor had an impact on OS (P: 0.03, 0.04; HR: 0.73, 0.70). Conclusion:Early immunotherapy can improve PFS without affecting OS for patients with locally advanced or metastatic ESCC.

Background:It is crucial for clinical decision-making to identify non-small cell lung cancer (NSCLC) patients who are likely to achieve major pathological response (MPR) following neoadjuvant immunotherapy and chemotherapy (NICT). This study conducted a thorough analysis of the regions surrounding and within resectable NSCLC tumors, creating an integrative tumor microenvironment model that encompasses features of both the peri-tumoral areas and habitat-based subregions, aiming at enhancing accurate predictions and supporting clinical decision-making processes. Methods:Our study involved an analysis of 243 NSCLC patients from three centers, treated with NICT and surgery and categorized into training, validation, and test cohorts. We conducted an extensive analysis of the tumor area, examining the intra-tumoral zone and the surrounding peri-tumoral regions at 2 mm, 4 mm and 6 mm, developing an algorithm for delineating tumor habitats. Features were standardized with Z-scores and de-duplicated by retaining one from each highly correlated pair. We finalized the feature set using least absolute shrinkage and selection operator (LASSO) regression and 10-fold cross-validation, forming a robust radiomics signature for machine learning models. Clinical features underwent univariable and multivariable analyses, combining with peri-tumoral and habitat signatures in a nomogram, of which its diagnostic accuracy and clinical utility were evaluated using receiver operating characteristic (ROC), calibration curves, and decision curve analysis (DCA). Results:The cohort showed a 68% MPR rate, with histology identified as a key predictor. An integrated nomogram including histology, Peri6mm and habitat signatures outperformed individual models with an area under the curve (AUC) of 0.894 in the training cohort, 0.831 in validation and 0.799 in testing. The nomogram demonstrated a clear advantage in predictive probabilities, as evidenced by DCA curve results. Conclusions:Our study's development of a predictive model using a nomogram integrating clinical and radiomics features significantly improved MPR prediction in NSCLC patients undergoing NICT, enhancing clinical decision-making.