OBJECTIVE: The safety profile of programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors when associated with chemotherapy for the treatment of patients with extensive-stage small-cell lung cancer is still not fully unraveled.
METHODS: We performed a comprehensive searrch of the PubMed, Embase, and Cochrane databases for randomized controlled trials that investigated the addition of PD-1 or PD-L1 inhibitors to standard investigator choice chemotherapy. We used risk -ratios (RRs) with 95% confidence intervals (CIs) for all endpoints.
RESULTS: Six studies and 2,995 patients were included. At the baseline, the median age of the patients varied from 62 to 65 years, 311 (10.4%) had brain metastases, and 1,060 (35.4%) had liver metastases. PD-1/PD-L1 inhibitors were found to reduce fatal toxicities-related mortality (RR: 0.85; 95% CI: 0.80-0.91; p < 0.001; I2 = 49%). The intervention group had a higher incidence of decreased appetite (RR: 1.19; 95% CI: 1.02-1.40; p = 0.03; I2 = 0%), hyponatremia (RR: 1.51; 95% CI: 1.08-2.12; p = 0.02; I2 = 0%), and hypothyroidism (RR: 3.14; 95% CI: 1.10-8.95; p = 0.03; I2 = 81%) of any grade. Regarding adverse events of grade 3-4, there was no association of the addition of PD-1/PD-L1 inhibitors with an increased occurrence of any of the evaluated outcomes.
CONCLUSIONS: In this systematic review and meta-analysis, the incorporation of PD-1/PD-L1 inhibitors to chemotherapy demonstrated an excellent safety profile and to be a promising prospect for reshaping the established treatment paradigms for patients with extensive-stage small cell lung cancer.

UNASSIGNED: This retrospective study evaluates the efficacy of camrelizumab combined with anlotinib versus chemotherapy in patients with extensive-stage small-cell lung cancer (ES-SCLC) undergoing second-line treatment.
UNASSIGNED: Data were sourced from medical records at a Chinese medical facility, involving 34 patients diagnosed with ES-SCLC after failing first-line treatment. Patients were divided into two groups: one received camrelizumab (200 mg every 3 weeks) with anlotinib (12 mg daily for 14 days followed by a 7-day rest), while the other group received physician-chosen chemotherapy administered every 3 weeks. The primary endpoint was progression-free survival (PFS), with secondary endpoints including overall survival (OS), objective response rate (ORR), and disease control rate (DCR).
UNASSIGNED: The combination therapy group showed a significant improvement in PFS compared to the chemotherapy group (median PFS: 7 months vs. 3 months; hazard ratio (HR): 0.34; 95% confidence interval (CI): 0.15-0.77; p<0.001). However, there was no statistically significant difference in OS between the groups (16.3 months vs. 17.3 months; p=0.82). The ORR was 52.9% in the combination therapy group versus 23.5% in the chemotherapy group (p=0.08), and the DCR was 82.4% compared to 58.8% (p=0.26). Grade 3 or higher adverse events were observed in 17.6% of the combination therapy group and 29.4% of the chemotherapy group.
UNASSIGNED: The findings suggest that the combination of camrelizumab and anlotinib offers a superior anti-tumor response with a manageable safety profile in a second-line setting for ES-SCLC patients. This combination regimen may be a viable option for second-line ES-SCLC treatment.

BACKGROUND: We explored potential predictive biomarkers of immunotherapy response in patients with extensive-stage small-cell lung cancer (ES-SCLC) treated with durvalumab (D) + tremelimumab (T) + etoposide-platinum (EP), D + EP, or EP in the randomized phase 3 CASPIAN trial.
METHODS: 805 treatment-naïve patients with ES-SCLC were randomized (1:1:1) to receive D + T + EP, D + EP, or EP. The primary endpoint was overall survival (OS). Patients were required to provide an archived tumor tissue block (or ≥ 15 newly cut unstained slides) at screening, if these samples existed. After assessment for programmed cell death ligand-1 expression and tissue tumor mutational burden, residual tissue was used for additional molecular profiling including by RNA sequencing and immunohistochemistry.
RESULTS: In 182 patients with transcriptional molecular subtyping, OS with D ± T + EP was numerically highest in the SCLC-inflamed subtype (n = 10, median 24.0 months). Patients derived benefit from immunotherapy across subtypes; thus, additional biomarkers were investigated. OS benefit with D ± T + EP versus EP was greater with high versus low CD8A expression/CD8 cell density by immunohistochemistry, but with no additional benefit with D + T + EP versus D + EP. OS benefit with D + T + EP versus D + EP was associated with high expression of CD4 (median 25.9 vs. 11.4 months) and antigen-presenting and processing machinery (25.9 vs. 14.6 months) and MHC I and II (23.6 vs. 17.3 months) gene signatures, and with higher MHC I expression by immunohistochemistry.
CONCLUSIONS: These findings demonstrate the tumor microenvironment is important in mediating better outcomes with D ± T + EP in ES-SCLC, with canonical immune markers associated with hypothesized immunotherapy mechanisms of action defining patient subsets that respond to D ± T.
BACKGROUND: ClinicalTrials.gov, NCT03043872.

BACKGROUND: This study aimed to explore the incidence of occult lymph node metastasis (OLM) in clinical T1 - 2N0M0 (cT1 - 2N0M0) small cell lung cancer (SCLC) patients and develop machine learning prediction models using preoperative intratumoral and peritumoral contrast-enhanced CT-based radiomic data.
METHODS: By conducting a retrospective analysis involving 242 eligible patients from 4 centeres, we determined the incidence of OLM in cT1 - 2N0M0 SCLC patients. For each lesion, two ROIs were defined using the gross tumour volume (GTV) and peritumoral volume 15 mm around the tumour (PTV). By extracting a comprehensive set of 1595 enhanced CT-based radiomic features individually from the GTV and PTV, five models were constucted and we rigorously evaluated the model performance using various metrics, including the area under the curve (AUC), accuracy, sensitivity, specificity, calibration curve, and decision curve analysis (DCA). For enhanced clinical applicability, we formulated a nomogram that integrates clinical parameters and the rad_score (GTV and PTV).
RESULTS: The initial investigation revealed a 33.9% OLM positivity rate in cT1 - 2N0M0 SCLC patients. Our combined model, which incorporates three radiomic features from the GTV and PTV, along with two clinical parameters (smoking status and shape), exhibited robust predictive capabilities. With a peak AUC value of 0.772 in the external validation cohort, the model outperformed the alternative models. The nomogram significantly enhanced diagnostic precision for radiologists and added substantial value to the clinical decision-making process for cT1 - 2N0M0 SCLC patients.
CONCLUSIONS: The incidence of OLM in SCLC patients surpassed that in non-small cell lung cancer patients. The combined model demonstrated a notable generalization effect, effectively distinguishing between positive and negative OLMs in a noninvasive manner, thereby guiding individualized clinical decisions for patients with cT1 - 2N0M0 SCLC.

OBJECTIVE: There is limited clinical data for recommendations on how to deliver thoracic radiation therapy (TRT) concurrently with chemotherapy in limited-stage small cell lung cancer. We reviewed radiation therapy treatment plans in a randomized phase 2 trial comparing high-dose with standard-dose twice-daily TRT to assess treatment planning techniques, dose-volume data for target volumes and organs at risk (OARs), evaluate compliance with the protocol, associations with radiation-induced toxicity, and whether an imbalance in treatment planning parameters might be a reason for the large survival benefit of the higher dose (median overall survival 43.6 vs 22.6 months).
METHODS: In the study, 170 patients were to receive 4 courses of platinum/etoposide and were randomized to receive twice-daily TRT of 60 Gy/40 fractions (fx) or 45 Gy/30 fx. TRT treatment plans for those who received 1 or more fx of TRT (n = 166) were analyzed.
RESULTS: The most common treatment planning technique was 3-dimensional conformal radiation therapy (67%). The 75th percentile of the reported dose-volume parameters for the OARs were within the protocol-recommended limits for both groups. Mean doses to the esophagus of 25.5 Gy (IQR, 20.2-31.3; 60 Gy/40 fx) and 24.3 Gy (IQR, 20.3-27.5; 45 Gy/30 fx) were associated with 21% and 18% ≥ grade 3 acute esophagitis, respectively. In the 60 Gy/40 fx group, a mean dose to the lungs of 16.5 Gy (IQR, 15.8-16.9), V20 Gy of 29.5% (IQR, 28.8-30.4), and V5 Gy of 65.6% (IQR, 61.5-68.7) led to ≥ grade 3 pneumonitis in 4% of the patients. There was no ≥ grade 3 pneumonitis in the 45 Gy/30 fx group. The treatment planning techniques, the percentage change in volumes between original and redelineated OARs, planning target volumes, relative doses, and laterality were well balanced between the randomly assigned groups.
CONCLUSIONS: Considering the incidences of severe radiation-induced toxicities were within the range of other recent trials, the reported doses to the OARs appear to be safe. Treatment planning parameters were well balanced between the randomly assigned groups, supporting that the survival benefit of the twice-daily 60 Gy/40 fx TRT schedule was due to the higher dose.

OBJECTIVE: To develop a computed tomography (CT)-based deep learning model to predict overall survival (OS) among small-cell lung cancer (SCLC) patients and identify patients who could benefit from prophylactic cranial irradiation (PCI) based on OS signature risk stratification.
METHODS: This study retrospectively included 556 SCLC patients from three medical centers. The training, internal validation, and external validation cohorts comprised 309, 133, and 114 patients, respectively. The OS signature was built using a unified fully connected neural network. A deep learning model was developed based on the OS signature. Clinical and combined models were developed and compared with a deep learning model. Additionally, the benefits of PCI were evaluated after stratification using an OS signature.
RESULTS: Within the internal and external validation cohorts, the deep learning model (concordance index [C-index] 0.745, 0.733) was far superior to the clinical model (C-index: 0.635, 0.630) in predicting OS, but slightly worse than the combined model (C-index: 0.771, 0.770). Additionally, the deep learning model had excellent calibration, clinical usefulness, and improved accuracy in classifying survival outcomes. Remarkably, patients at high risk had a survival benefit from PCI in both the limited and extensive stages (all P < 0.05), whereas no significant association was observed in patients at low risk.
CONCLUSIONS: The CT-based deep learning model exhibited promising performance in predicting the OS of SCLC patients. The OS signature may aid in individualized treatment planning to select patients who may benefit from PCI.

BACKGROUND: Part E of the KEYNOTE-011 (NCT01840579) study assessed the safety and antitumor activity of pembrolizumab plus platinum-etoposide chemotherapy in Japanese patients with previously untreated extensive-stage small-cell lung cancer (ES-SCLC).
METHODS: Patients received 4 cycles of pembrolizumab (200 mg) every 3 weeks in combination with cisplatin (75 mg/m2) and etoposide (100 mg/m2; days 1, 2, 3) in cohort 1; with carboplatin (AUC 5 mg/mL/min) and etoposide (100 mg/m2; days 1, 2, 3) in cohort 2; or with cisplatin/etoposide and pegfilgrastim (3.6 mg; cycle 1, day 4) in cohort 3. Combination therapy was followed by pembrolizumab monotherapy (31 cycles). The primary endpoint was safety and tolerability (including dose-limiting toxicities; DLTs).
RESULTS: Fifteen patients were included in the study (cohort 1, n = 6; cohort 2, n = 6; cohort 3, n = 3). Median time from treatment allocation to data cutoff was 22.1 months (range, 4.1‒32.4 months). DLTs occurred in 3 patients in cohort 1 (one patient with grade 4 laryngeal stenosis and grade 3 febrile neutropenia; two patients with grade 3 febrile neutropenia); no patients in cohorts 2 or 3 experienced DLTs. Grade ≥ 3 treatment-related adverse events included leukopenia (67%) and neutropenia (87%). Among all patients, ORR was 67% (95% CI, 38%‒88%) and median DOR was 4.5 months (range, 2.8‒28.8 months). Median PFS was 4.2 months (95% CI, 3.0‒7.8 months) and median OS was 22.1 months (95% CI, 7.4‒25.9 months).
CONCLUSIONS: Pembrolizumab in combination with platinum-etoposide therapy had manageable toxicity with no new safety signals and was associated with antitumor activity in Japanese patients with ES-SCLC.
BACKGROUND: ClinicalTrials.gov , NCT01840579.

UNASSIGNED: Although pretreatment autoantibodies have been associated with immune-related adverse events (irAEs) and immune checkpoint inhibitor treatment efficacy in some types of cancer, their importance has not been evaluated in patients with SCLC.
UNASSIGNED: A multicenter prospective observational study was conducted on a total of 52 patients with extensive-disease SCLC who received immune checkpoint inhibitors in combination with chemotherapy as the first-line treatment at either of the six participating centers in Japan. Pretreatment serum samples were collected and analyzed for autoantibodies (rheumatoid factor, antinuclear antibodies, and antithyroid). Moreover, 12 antineuronal antibodies (AMPH, CV2, PNMA2, Ri, Yo, Hu, Recoverin, SOX1, Titin, Zic4, GAD65, and Tr) were analyzed using immunoblot assays. The primary end point was the incidence of irAEs with or without autoantibodies. The secondary end points were progression-free survival (PFS) and overall survival (OS) on the basis of the presence or absence of autoantibodies.
UNASSIGNED: PFS and OS were 4.4 and 25.3 months, respectively. Autoantibodies (rheumatoid factor, antinuclear antibodies, and antithyroid antibodies) were detected in 29 patients (56%). In total, irAEs were observed in 18 patients (35%); irAE incidence was 48% in the autoantibody-positive group and 17% in the autoantibody-negative group (p = 0.039). There was no difference in PFS or OS between patients with and without autoantibodies (4.4 mo versus 4.6 mo, p = 0.36; 15.3 mo versus 18.2 mo, p = 0.36). Antineuronal antibodies were detected in 16 patients (31%). However, the development of neurologic irAEs was not observed in both groups.
UNASSIGNED: Vigilance is required against the development of irAEs in pretreatment antibody-positive patients.

Background: SYHA1807 is a novel lysine specific demethylase 1 inhibitor being developed for the treatment of small-cell lung cancer. Aim: This study aimed to establish a ultra-performance liquid chromatography-mass spectrometry (UPLC-MS)/MS method for measuring SYHA1807 in human plasma, supporting its application in a first-in-human study. Methods: SYHA1807 was separated on an ACQUITY UPLC BEH® C18 Column (2.1 × 50 mm, 1.7 μm) after protein precipitation of plasma samples. Mass spectrometry analysis was performed with a Xevo TQS triple quadrupole mass spectrometer utilizing a positive electronic spray ionization source. The established method was fully validated according to bioanalytical guidelines. Results & conclusion: A rapid, specific and robust UPLC-MS/MS method was first established for quantifying SYHA1807 and successfully applied in a first-in-human study.

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