Prognostic effect of TCF1+ CD8+ T cell and TOX+ CD8+ T cell infiltration in lung adenocarcinoma.

Recent studies have highlighted the pivotal roles of T cell transcription factors TCF-1 and TOX in modulating the immune response in cancer, with TCF-1 maintaining CD8+ T cell stemness and TOX promoting T cell exhaustion. The prognostic significance of these factors in lung adenocarcinoma (LUAD) remains a critical area of investigation. The retrospective study included 191 patients with LUAD who underwent surgery, of whom 83% were in stages II and III. These patients were divided into exploratory (n = 135) and validation (n = 56) groups based on the time of diagnosis. Multiplex fluorescence immunohistochemistry was used to examine the infiltration levels of CD8+ T cells, TCF1+ CD8+ T cells, and TOX+ CD8+ T cells. The percentage of CD8+ T cells in tumor was markedly lower than that in stroma (p < 0.05). In tumor-draining lymph nodes (TDLNs) invaded by tumor, the proportion of stem-like TCF1+ CD8+ T cells was significantly decreased (p < 0.01). Importantly, higher infiltration levels of CD8+ T cells and TCF1+ CD8+ T cells were associated with improved disease-free survival (DFS) (p = 0.009 and p = 0.006, respectively) and overall survival (OS) (p = 0.018 and p = 0.010, respectively). This study underscores the potential of TCF1+ CD8+ T cells as prognostic biomarkers in LUAD, providing insights into the tumor immune microenvironment and guiding future therapeutic strategies.

The later-line efficacy and safety of immune checkpoint inhibitors plus anlotinib in EGFR-mutant patients with EGFR-TKI-resistant NSCLC: a single-center retrospective study.

BACKGROUND: Effective treatment after EGFR-TKI resistance is of great clinical concern. We aimed to investigate the efficacy and safety of anlotinib in combination with an anti-PD-1/PD-L1 antibody in later-line therapy for EGFR-mutant NSCLC patients after TKI treatment failure and to explore the independent predictive factors of therapeutic efficacy. METHODS: A total of 71 patients with confirmed advanced EGFR-mutated NSCLC who progressed after previous standard EGFR-TKI therapy but still failed after multiline treatments were included retrospectively in this study. Most of the patients had previously received at least three lines of treatment. All were treated with anlotinib combined with anti-PD-1 or anti-PD-L1 therapy. The safety of this combined treatment was assessed by the incidence of adverse events. The efficacy of the regimens was evaluated by survival analysis (OS, PFS, ORR, DCR). RESULTS: The median follow-up period was 28.6 months (range: 2.3-54.0 months), and the median number of treatment lines was 4. The overall response rate (ORR) and disease control rate (DCR) were 19.7% and 77.5%, respectively. The median PFS was 5.8 months (95% CI 4.2-7.4 months), and the median OS was 17.1 months (95% CI 12.0-22.3 months). Patients who received immune checkpoint inhibitors plus anlotinib had an encouraging intracranial ORR of 38.5% and a DCR of 80.8%. ECOG performance status < 2 at baseline was independent protective factors of PFS. Metastatic organs and ECOG performance status were independent parameters in predicting OS. Treatment-related adverse events occurred in 66 (93.0%) patients; most of the adverse events were Grade 1-2, and no increase in adverse events was observed compared to monotherapy. CONCLUSION: Anlotinib combined with an anti-PD-1/PD-L1-based regimen exhibited promising efficacy and tolerance in NSCLC patients with EGFR mutations after previous TKI failure. The efficacy of this combined regimen in patients with EGFR mutations should be further evaluated.

Is there role of adjuvant radiotherapy after complete resection of locally advanced nonsmall cell lung cancer?

PURPOSE OF REVIEW: This review aims to provide a timely and relevant overview of the role of postoperative radiotherapy (PORT) in completely resected stage IIIA-N2 nonsmall cell lung cancer (NSCLC). Given the controversy surrounding the use of PORT and the emergence of advanced radiation techniques and therapies, this review provides valuable insight into current and potential treatment strategies. RECENT FINDINGS: The Lung ART and PORT-C trials have provided valuable insights into the efficacy of PORT in stage IIIA-N2 NSCLC. While the results have been mixed, studies have shown that advanced radiation techniques, such as intensity-modulated radiotherapy (IMRT) and proton therapy, can reduce cardiopulmonary toxicities associated with PORT. Molecular targeted therapies and immunotherapies have also shown potential in improving NSCLC treatment outcomes. SUMMARY: The role of radiotherapy becomes smaller and smaller in new era. However, it is too early to abolish radiotherapy for all the patients after complete resection of locally advanced NSCLC. Nowadays, it is recommended to adopt individualized treatment approaches guided by multidisciplinary team consultations. The integration of IMRT, proton therapy, and emerging therapies offers the potential to enhance treatment efficacy while minimizing toxicity. Further research is needed to optimize the use of PORT and explore the method to identify the patients who can really benefit from PORT.

Phase I/II clinical trial of efficacy and safety of EGCG oxygen nebulization inhalation in the treatment of COVID-19 pneumonia patients with cancer.

BACKGROUND: The antiviral drug Nirmatrelvir was found to be a key drug in controlling the progression of pneumonia during the infectious phase of COVID-19. However, there are very few options for effective treatment for cancer patients who have viral pneumonia. Glucocorticoids is one of the effective means to control pneumonia, but there are many adverse events. EGCG is a natural low toxic compound with anti-inflammatory function. Thus, this study was designed to investigate the safety and efficacy of epigallocatechin-3-gallate (EGCG) aerosol to control COVID-19 pneumonia in cancer populations. METHODS: The study was designed as a prospective, single-arm, open-label phase I/II trial at Shandong Cancer Hospital and Institute, between January 5, 2023 to March 31,2023 with viral pneumonia on radiographic signs after confirmed novel coronavirus infection. These patients were treated with EGCG nebulization 10 ml three times daily for at least seven days. EGCG concentrations were increased from 1760-8817umol/L to 4 levels with dose escalation following a standard Phase I design of 3-6 patients per level. Any grade adverse event caused by EGCG was considered a dose-limiting toxicity (DLT). The maximum tolerated dose (MTD) is defined as the highest dose with less than one-third of patients experiencing dose limiting toxicity (DLT) due to EGCG. The primary end points were the toxicity of EGCG and CT findings, and the former was graded by Common Terminology Criteria for Adverse Events (CTCAE) v. 5.0. The secondary end point was the laboratory parameters before and after treatment. RESULT: A total of 60 patients with high risk factors for severe COVID-19 pneumonia (factors such as old age, smoking and combined complications)were included in this phase I-II study. The 54 patients in the final analysis were pathologically confirmed to have tumor burden and completed the whole course of treatment. A patient with bucking at a level of 1760 umol/L and no acute toxicity associated with EGCG has been reported at the second or third dose gradients. At dose escalation to 8817umol/L, Grade 1 adverse events of nausea and stomach discomfort occurred in two patients, which resolved spontaneously within 1 hour. After one week of treatment, CT showed that the incidence of non-progression of pneumonia was 82% (32/39), and the improvement rate of pneumonia was 56.4% (22/39). There was no significant difference in inflammation-related laboratory parameters (white blood cell count, lymphocyte count, IL-6, ferritin, C-reactive protein and lactate dehydrogenase) before and after treatment. CONCLUSION: Aerosol inhalation of EGCG is well tolerated, and preliminary investigation in cancer population suggests that EGCG may be effective in COVID-19-induced pneumonia, which can promote the improvement of patients with moderate pneumonia or prevent them from developing into severe pneumonia. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05758571. Date of registration: 8 February 2023.

TIGIT blockade enhances tumor response to radiotherapy via a CD103 + dendritic cell-dependent mechanism.

Blockade of the T cell immunoreceptor with the immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) can enhance innate and adaptive tumor immunity and radiotherapy (RT) can enhance anti-tumor immunity. However, our data suggest that TIGIT-mediated immune suppression may be an impediment to such goals. Herein, we report on the synergistic effects of RT combined with anti-TIGIT therapy and the mechanism of their interaction. Treatment efficacy was assessed by measuring primary and secondary tumor growth, survival, and immune memory capacity. The function of CD103 + dendritic cells (DCs) under the combined treatment was assessed in wild-type and BATF3-deficient (BATF3-/-) mice. FMS-like tyrosine kinase 3 ligand (Flt3L) was used to confirm the role of CD103 + DCs in RT combined with anti-TIGIT therapy. TIGIT was upregulated in immune cells following RT in both esophageal squamous cell carcinoma patients and mouse models. Administration of the anti-TIGIT antibody enhanced the efficacy of RT through a CD8 + T cell-dependent mechanism. It was observed that RT and the anti-TIGIT antibody synergistically enhanced the accumulation of tumor-infiltrating DCs, which activated CD8 + T cells. The efficacy of the combination therapy was negated in the BATF3-/- mouse model. CD103 + DCs were required to promote the anti-tumor effects of combination therapy. Additionally, Flt3L therapy enhanced tumor response to RT combined with TIGIT blockade. Our study demonstrated TIGIT blockade can synergistically enhance anti-tumor T cell responses to RT via CD8 + T cells (dependent on CD103 + DCs), suggesting the clinical potential of targeting the TIGIT pathway and expanding CD103 + DCs in RT.

Prophylactic cranial irradiation (PCI) versus active surveillance in patients with limited-stage small cell lung cancer: a retrospective, multicentre study.

BACKGROUND: The recommendation of PCI for limited-stage small cell lung cancer (LS-SCLC) is primarily based on evidence from the pre-magnetic resonance imaging (MRI) era. However, as MRI accuracy improves and stereotactic radiosurgery advances, the role of PCI for LS-SCLC has become uncertain. This study aims to compare the contemporary survival outcomes of patients with LS-SCLC treated with PCI versus active surveillance. METHODS: We conducted a retrospective cohort study in which 1068 patients with LS-SCLC who achieved a good response to first-line chemoradiotherapy were consecutively enrolled from 5 tertiary medical centres between June 2009 and June 2019. Of these patients, 440 received PCI, while 628 received surveillance without PCI. Propensity score matching with a 1:1 ratio was performed to balance the baseline characteristics of the two cohorts. The endpoints were overall survival (OS) and the incidence of brain metastasis (BM). RESULTS: In total, 648 patients were matched. The baseline characteristics were generally well balanced. At a median follow-up of 64.5 months (range 2-190), patients who underwent PCI had a significantly lower risk for BM than those who underwent surveillance. The 3-year cumulative incidence rate of BM was 28.2% (95% CI 22.5-33.8%) in the PCI cohort and 38.5% (32.6-44.5%) in the surveillance cohort (Gray's p = 0.002). However, the lower incidence of BM in the PCI cohort did not translate into a significant extension of OS. The median OS was 35.8 months (95% CI 27.6-44.0 months) in the PCI cohort versus 32 months (26.4-37.6 months) in the surveillance cohort (HR 0.90, 95% CI 0.74-1.10, p = 0.29). Multivariable analysis showed that disease stage, chemoradiotherapy sequence, and response to chemoradiotherapy were independent prognostic factors for BM or OS. CONCLUSIONS: Overall, PCI reduces the risk for BM but does not substantially prolong OS compared with active surveillance. A phase 3, prospective clinical trial (NCT04829708) we initiated is currently underway, which is expected to corroborate our results.

Efficacy and safety of immune checkpoint inhibitors plus anlotinib in small cell lung cancer with brain metastases: a retrospective, multicentre study.

BACKGROUND: Previous studies showed that both immune checkpoint inhibitors (ICIs) and anlotinib have central nervous system (CNS) efficacy. This study aimed to evaluate the efficacy and safety of ICIs combined with anlotinib in small cell lung cancer (SCLC) patients with brain metastases (BMs). METHODS: We retrospectively reviewed SCLC patients with CNS metastases confirmed by brain magnetic resonance imaging (MRI). Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) and Response assessment in neuro-oncology brain metastases (RANO-BM) were used to evaluate treatment response to ICIs plus anlotinib. Kaplan-Meier analysis and Cox regression analysis were performed to determine patient's prognosis. RESULTS: Sixty-six patients with baseline BMs were included. For patients with measurable intracranial lesions, the intracranial objective response rate (ORR) was 29.2% based on RECIST 1.1 criteria and was 27.1% based on RANO-BM criteria. The median intracranial progression-free survival (PFS) was 9.0 months (95% confidence interval [CI], 6.5-11.5 months). The median overall survival (OS) was 13.4 months (95% CI, 10.7-20.5 months). Multivariate Cox regression analysis showed that high disease burden (hazard ratio [HR] = 4.83, P < 0.001), multiple BMs (HR = 2.71, P = 0.036), and more than or equal to 3 prior lines of therapy (HR = 2.56, P = 0.023) were independent negative predictors of OS. The overall incidence of treatment-related adverse events (TRAEs) was 75.8%, and grade 3-4 TRAEs were reported in 19.7% of patients. CONCLUSIONS: Our results suggested that ICIs plus anlotinib had potent CNS efficacy with tolerable toxicity and could be a promising treatment option for SCLC patients with BMs.

The prognostic value of TCF1+CD8+T in primary small cell carcinoma of the esophagus.

TCF1+CD8+T cells are reported to exhibit stem-like properties with the ability to self-renew and differentiate into terminal effector T cells (TCF1-CD8+T cells) to enhance antitumor response. Previous studies indicated that TCF1+CD8+ tumor-infiltrating lymphocytes (TILs) are related to response to immunotherapy. However, their role in predicting prognosis for patients with primary small cell carcinoma of the esophagus (PSCCE) remains unclear. In this study, the expression of TCF1+CD8+T was analyzed by multiplex fluorescence immunohistochemistry in tumor tissues of 79 patients with PSCCE. High infiltration of TCF1+CD8+T cells had longer overall survival (OS) than low infiltration (P = .009, hazard ratio [HR] = 0.506). High TCF1+CD8/CD8 ratio (>21%) showed superior OS compared with low ratio (≤21%) (P < .001, HR = 0.394). In the validation set (n = 20), the prognostic value of TCF1+CD8+T cells on OS was also verified. TCF1+CD8+T cells are strong prognostic predictors.

Epigallocatechin-3-gallate mouthwash protects mucosa from radiation-induced mucositis in head and neck cancer patients: a prospective, non-randomised, phase 1 trial.

Radiation-induced oral mucositis has a dismal outcome with limited treatment options. We conducted a phase I study to evaluate the safety and preliminary efficacy of epigallocatechin-3-gallate (EGCG) mouthwash when given along with radiation in head and neck cancer. Patients with pathologically confirmed head and neck cancer were eligible for this study. EGCG mouthwash was administered at the assigned dosage level (starting at 440 µmol/L, three times a day) in a standard 3 + 3 dose escalation design. Mucosal toxicity, patient satisfaction, and mucositis-related pain (MTP) were assessed weekly. The primary endpoint was safety of EGCG, and the secondary endpoint was to determine the relief of the mucositis symptom. The pre- and post-treatment parameters were compared using the paired t-test. 20 patients were enrolled. The maximum tolerated dose of the EGCG mouthwash was 2200 µmol/L. Burning (n = 1/20) and nausea (n = 3/20) were the most common toxicities. No patients experienced WHO Grade 3 or higher mucositis. MTP scores significantly decreased after EGCG administration over time (p < 0.05). Adding EGCG mouthwash to radiotherapy is feasible without increasing toxicities. The recommended dose for phase II study is determined to be 1760 µmol/L, and EGCG administration reduces radiation-induced oral mucosal injury in patients.

The Role of Radiation Oncology in Immuno-Oncology.

Despite the promising efficacy of immunotherapy in some patients, many other patients are resistant. The synergistic effect of radiotherapy (RT) in combination with immunotherapy reported in case reports and clinical trials has piqued the interest of radiologists in investigating the underlying mechanisms and efficacy of the combination in preclinical and clinical trials. To date, the reported data are limited to small-sized samples, trials lacking a comparison arm, and trials using diverse immunotherapies, various radiation doses, and fractionations. There are just a few studies comparing the efficacy of immunotherapy and radiotherapy to that of conventional therapies or different combinations. Radiologists should design and conduct clinical trials wisely to confirm the efficacy of the combination, particularly the abscopal effect, identify the best combination of various immunotherapeutic drugs and different radiation models for patients, identify the best sequence of the combination, determine the optimal timing of the combination, select the target site and volume, lower adverse effects, and explore predictive models to identify patients who may benefit from the combination therapy. We expect that these clinical trials performed by radiologists will offer definitive evidence for the wide use of the combination of RT and immunotherapy in clinical practice. IMPLICATIONS FOR PRACTICE: This review will provide an update on the use of a combination of radiotherapy and immunotherapy, a cautious interpretation of preliminary results, and future directions for radiologists to perform well-designed clinical trials.

Relationships between the changes of skin temperature and radiation skin injury.

Background: Radiation skin injury (RSI) causes changes in skin temperature, but detailed information on the thermographic responses is currently lacking. We investigated thermographic patterns after radiotherapy. We hypothesized that skin temperature may be used as a diagnostic and early predictor of RSI severity.Method: All breast cancer patients received radiotherapy after unilateral postmastectomy. The contralateral supraclavicular area served as control, and the frontal thermal image of torso was taken by a thermal infrared imager weekly. We defined areas of interest on bilateral symmetrical supraclavicular area, and analyzed the difference of average and maximum skin temperature (DSTaverage and DSTmax) between them. The extent of the weekly variation in DST (DSTW) was calculated using a mathematical formula to represent a trend of skin temperature change. RSI and symptoms related to RSI were scored from baseline to 2 weeks after the end of radiotherapy.Results: Forty-one patients were enrolled in this study. In comparison to the baseline, the DSTaverage and DSTmax increased significantly over time during radiotherapy (p < .05). The onset of DST increase was accompanied by the onset of radiation dermatitis, and the maximal DST also appeared at the peak of Radiation Therapy Oncology Group (RTOG) and symptom scores. Radiation dose, DSTaverage, burning-feeling and pulling were the independent variables affecting RTOG score according to multivariate analysis (p < .001, p < .034, p < .001, p < .001). Patients with DSTWaverage >1.223 or DSTWmax >1.114 in second week showed a late higher dermatitis score (RTOG score ≥2).Conclusion: This study confirmed that RSI was associated with thermographic response. Our results suggested that the follow-up observations of skin temperature during radiotherapy could provide the objective evaluation criteria and prediction methods for RSI.

MRI In rectal cancer: Correlations between MRI features and molecular markers Ki-67, HIF-1α, and VEGF.

PURPOSE: To investigate whether the apparent diffusion coefficient (ADC) values acquired from diffusion-weighted magnetic resonance imaging (DW-MRI) are correlated with molecular markers Ki-67, hypoxia-inducible factor 1α (HIF-1α), and vascular endothelial growth factor (VEGF) in rectal cancer (RC). MATERIALS AND METHODS: Ninety-one patients (64 males and 27 females) diagnosed with rectal cancer underwent 3.0T DW-MRI before any anticancer treatment. DW-MRI was performed using the single-shot echo-planar imaging technique (b = 0 and b = 800 s/mm(2) ). The patients underwent surgery within 1 week after MRI. Ki-67, HIF-1α, and VEGF expression were assessed by immunohistochemistry at both the resected margins and the center of the tumor. RESULTS: We noted that ADC values correlated positively with histology differentiations (r = 0.336, P = 0.001) and negatively with carcinoembryonic antigen level (r = -0.217, P = 0.039) in RC. Both the value and the level of Ki-67 expression were correlated inversely with the ADC values (r = -0.475, P < 0.001 and r = -0.555, P < 0.001). There was a weak negative correlation between HIF-1α expression and the ADC values (r = -0.304, P = 0.003). VEGF expression was correlated inversely with the ADC values of the RCs (r = -0.290, P = 0.005). However, no significant correlation was observed between VEGF expression and the ADC values in pT4 RCs (r = -0.166, P = 0.255). CONCLUSION: Our results suggest that the ADC values on DW-MRI may be used as a measurement of cell proliferation and hypoxia in RC. J. Magn. Reson. Imaging 2016;44:594-600.

Decreased Tumor Suppressor Candidate 3 Predicts Poor Prognosis of Patients with Esophageal Squamous Cell Carcinoma.

TUSC3 was recently identified as a potential tumor suppressor gene in a variety of human malignancies. However, no data are currently available regarding the expressions of TUSC3 in esophageal cancer (ESCC).The purposes of this study was to investigated the expressions of TUSC3 in ESCC tissues and assess the relationship between TUSC3 levels and clinico-pathological characteristics of ESCC patients. TUSC3 protein expressions were evaluated by immunohistochemistry (IHC) on tissue microarray slides in esophageal cancer, which included 95 esophageal squamous carcinoma specimens (ESCC), and 75 normal esophageal mucosa (NEM). We found that TUSC3 in ESCC was significant lower than that in NEM (P=0.000). According to multi-clinical classifications, TUSC3 level varied significantly with TNM stage, T stage, and N stage (p<0.001, p=0.0368, p<0.0001, respectively). Univariate analysis showed that gender, TNM stage, T stage, N stage, TUSC3 expression were prognostic factors for survival. Multivariate analysis showed that in our study, only TUSC3 expression was independent prognostic factors for ESCC. Our results indicated for the first time, a combined analysis of TUSC3 expressions as well as the clinical variables will help predict the prognosis of ESCC patients. Further large-sample validation and functional analysis should be performed to evaluate its potential prognostic and therapeutic values for ESCC patients.

Human epidermal growth factor receptor-2 expression in locally advanced rectal cancer: association with response to neoadjuvant therapy and prognosis.

The aim of this study was to determine whether pretreatment status of human epidermal growth factor receptor-2 (HER-2) could predict pathologic response to neoadjuvant chemoradiotherapy (nCRT) and outcomes for patients with locally advanced rectal cancer (LARC). A total of 119 patients diagnosed with LARC received standardized multimodal treatment. Their HER-2 status was determined in pretreatment biopsies by immunohistochemistry (IHC) and FISH. Tumor response was assessed in resected regimens using the tumor regression grade system and TNM staging system. Twenty-two cases in 119 patients assessed as IHC3+ or IHC2+ plus gene-amplified were determined as HER-2 positive. Positive HER-2 status was not associated with any pretreatment clinicopathologic parameters (P > 0.05). HER-2 status could not predict pathologic response to nCRT based on downstaging (P = 0.210) and tumor regression grade (P = 0.085) but it provides us with a trend that HER-2-positive tumors may be resistant to nCRT. Positive HER-2 status was significantly associated with poor 5-year disease-free survival (P = 0.015) and 5-year overall survival (P = 0.026). It can act as a worse prognostic factor for LARC patients.

Chemotherapy-free radiotherapy combined with immune checkpoint inhibitors: a new regimen for locally advanced non-small cell lung cancer?

Maintenance immunotherapy after concurrent chemoradiotherapy remains the standard therapeutic approach in patients with unresectable locally advanced non-small cell lung cancer (LA-NSCLC). The efficacy of pembrolizumab without chemotherapy in stage IV NSCLC has incited interest in similar approaches for LA-NSCLC. Several recent investigations involving the synergistic potential of immunotherapy combined with radiotherapy (iRT) have generated encouraging results. This review discusses the existing studies and prospective directions of chemotherapy-free iRT strategies in unresectable LA-NSCLC. Although the initial findings of chemotherapy-free iRT strategies have shown promising efficacy, we must consider the methodologic limitations of current studies and the myriad of challenges that accompany the implementation of chemotherapy-free iRT. These challenges include determining the optimal dose and fractionation, precise target volume delineation, and identification of additional suitable patient cohorts. Furthermore, the feasibility of chemotherapy-free iRT as a novel treatment modality for select patients with LA-NSCLC is contingent upon validation through randomized phase III trials.

Adebrelimab plus chemotherapy and sequential thoracic radiotherapy as first-line therapy for extensive-stage small-cell lung cancer (ES-SCLC): a phase II trial.

Background: This phase II prospective trial aimed to investigate the efficacy and safety of adebrelimab (PD-L1 antibody) plus first-line chemotherapy followed by sequential thoracic radiotherapy (TRT) combined with adebrelimab in extensive-stage small-cell lung cancer (ES-SCLC). Biomarkers associated with potential therapeutic effects were also explored. Methods: Patients with previously untreated ES-SCLC were enrolled at Shandong Cancer Hospital and Institute (Jinan, China). Patients received 4-6 cycles of adebrelimab (20 mg/kg, D1, Q3W) combined with EP/EC (etoposide, 100 mg/m2, D1-3, Q3W and cisplatin, 75 mg/m2, D1, Q3W or carboplatin, AUC = 5, D1, Q3W). Then patients with response sequentially underwent consolidative TRT (≥30 Gy in 10 fractions or ≥50 Gy in 25 fractions, involved-field irradiation), and maintenance adebrelimab until disease progression or intolerable adverse events (AEs). The primary endpoint was overall survival (OS). Genomic and circulating tumour DNA (ctDNA) profiling were also analyzed with tumour tissues and peripheral blood. This trial was registered with ClinicalTrials.gov, NCT04562337. Findings: From October 2020 to April 2023, 67 patients diagnosed with ES-SCLC were enrolled and received at least one dose of study treatment. All patients were included in the efficacy and safety analyses. 45 patients received sequential TRT as planned. The median OS and progression-free survival (PFS) was 21.4 months (95% CI: 17.2-not reached months) and 10.1 months (95% CI: 6.9-15.5 months), respectively. The confirmed objective response rate was 71.6% (48/67, 95% CI: 59.3-82.0%) and disease control rate was 89.6% (60/67, 95% CI: 79.7-95.7%). There were no treatment-related deaths. The most common grade 3 or higher treatment-related adverse events (TRAEs) were hematological toxicities. The incidence of any grade and G3+ pneumonitis was 25% (17/67) and 6% (4/67), respectively. No unexpected adverse events were observed. Patients without co-mutations of TP53/RB1 in both tissue and peripheral blood displayed longer PFS (tissue, P = 0.071; ctDNA, P = 0.060) and OS (tissue, P = 0.032; ctDNA, P = 0.031). Interpretation: Adebrelimab plus chemotherapy and sequential TRT as first-line therapy for ES-SCLC showed promising efficacy and acceptable safety. Funding: This study was funded by the National Natural Science Foundation of China (82172865), Jiangsu Hengrui Pharmaceuticals Co., Ltd. and Amoy Diagnostics Co., Ltd.

Ficonalkib (SY-3505) in Advanced ALK-Positive NSCLC: A Multicenter, Open-Label, Single-Arm, Phase 1/2 Study.

INTRODUCTION: Treatment options for second-generation (2nd-gen) ALK tyrosine kinase inhibitor (TKI)-resistant patients are limited. We evaluated the safety, pharmacokinetics, and efficacy of ficonalkib (SY-3505), a third-generation (3rd-gen) ALK TKI, in patients with advanced ALK-positive non-small cell lung cancer. METHODS: This first-in-human, phase 1/2 study (Chinese Clinical Trial Registry identifier: ChiCTR1900025619; ClinicalTrials.gov identifier: NCT05257512) had two parts. Phase 1 included a dose-escalation phase (25-800 mg quaque die [QD]) and a dose-expansion phase (500 mg QD or 600 mg QD). Phase 2 enrolled patients treated at recommended phase 2 dose. Primary end points were safety in phase 1 and objective response rate (ORR) in phase 2. RESULTS: Between April 21, 2020, and August 31, 2023, a total of 127 patients with advanced ALK-positive non-small cell lung cancer were enrolled, with 62 in phase 1. Ficonalkib was well absorbed and tolerated, with one dose-limited toxicity event occurring at 800 mg QD. Treatment-related adverse events occurred in 85.5% of patients, with 19.4% experienced greater than or equal to grade 3 events. The ORR was 38.3% (23 of 60, 95% confidence interval [CI]: 26.1%-51.8%) in phase 1, and 600 mg QD was established as recommended phase 2 dose. In phase 2, a total of 65 patients received ficonalkib at 600 mg QD. In total, 88 patients received ficonalkib at 600 mg QD in phase 1/2, and all had received prior 2nd-gen ALK TKI treatment. Furthermore, 90.9% of the patients experienced treatment-related adverse events and 14.8% experienced greater than or equal to grade 3 events. The ORR in efficacy-assessable patients who received ficonalkib at 600 mg QD was 47.5% (38 of 80, 95% CI: 36.2%-59.0%), with an intracranial ORR of 37.5% (12 of 32, 95% CI: 21.1%-56.3%) in these patients with measurable brain lesions at baseline. CONCLUSIONS: Ficonalkib (SY-3505) was well tolerated, with favorable safety profiles and promising efficacy in patients resistant to prior 2nd-gen ALK TKI.