To establish recommended phase II dose (RP2D) in phase I and evaluate safety and efficacy of abivertinib in patients with EGFR Thr790Met point mutation (T790M)-positive(+) non-small cell lung cancer (NSCLC) with disease progression from prior EGFR inhibitors in phase II.
Abstract The importance of uncommon/rare oncogenic drivers in non‐small cell lung cancer (NSCLC) was underscored during the 20th China Lung Cancer Summit. These drivers, while present in a significant proportion of NSCLC patients, remain a challenge for diagnosis and therapeutic targeting. In the never‐smokers/low smokers category with mutations such as EGFR and HER2, the efficacy of immune checkpoint inhibitors (ICIs) remains suboptimal, attributed to lower PD‐L1 expression and tumor mutation burden (TMB). However, heavy smokers, often with mutations like KRAS, may derive benefits from ICIs, as supported by trials like CheckMate‐057. With the complex landscape of these drivers and their clinical implications, the summit culminated in six pivotal consensus points, aiming to guide future research and clinical decisions. Despite the advancements, the detection, interpretation, and therapeutic strategies involving these drivers necessitate further exploration and standardization.
Introduction It has been proven that ALK‐rearranged non‐small cell lung cancer (NSCLC) is sensitive to ALK inhibitors while the chemotherapy resistance is unavoidable. In this study, safety and antitumor activity of the novel ALK inhibitor (ALKi) CT‐707 were evaluated in Chinese patients with advanced ALK‐rearranged NSCLC. Methods This single‐center, open‐label phase I study recruited adult patients with ALK‐rearrangement (confirmed by fluorescence in situ hybridization and/or immunohistochemistry) of locally advanced/metastatic malignancies including NSCLC. This study consisted of two parts: dose escalation and dose expansion. CT‐707 was administered orally once a day for 21 days. Results A total of 13 patients who were treated with CT‐707 from 450 to 600 mg (in the dose increasing phase) were enrolled in this trial (two patients were previously treated with crizotinib). There were 12 patients diagnosed with lung adenocarcinoma and one patient with malignant pleural mesothelioma. After treatment, grade 3 diarrhea (600 mg once a day) was found as dose‐limiting toxicity (DLT).The most common adverse events included diarrhea (92%), elevated aspartate aminotransferase (61%), elevated alanine aminotransferase (54%), hair loss (38%), and vomiting (31%). The overall response rate was 77% (10/13). Among all patients, four of the five patients who did not receive any treatment, one of the two patients who had received treatments with crizotinib, and five of the six patients who received standard chemotherapy achieved partial response (PR). One patient reached a complete remission (CR). Conclusions This study indicated that CT‐707 is clinically effective as a new antitumor drug for Chinese lung adenocarcinoma patients with ALK rearrangement. It is safe and reliable and the dose‐expansion phase recruitment has started.
BRAF V600 mutations and MET exon 14 skipping (METex14) mutations are both recognized as actionable oncogenic drivers in NSCLC, respectively accounting for 1-2% of newly diagnosed cases. Metastatic NSCLC with BRAF V600 or METex14 mutations could be effectively treated with dabrafenib plus trametinib or capmatinib. For patients with non-metastatic, resectable diseases, surgery with neoadjuvant or adjuvant chemotherapy is the standard of care. Nevertheless, a significant proportion of patients still undergo disease recurrence after complete resection and (neo)adjuvant chemotherapy. In NSCLC with oncogenic EGFR or ALK alterations, targeted therapies in the adjuvant and neoadjuvant setting have demonstrated promising efficacy. While whether patients with BRAF V600 or METex14 mutations could benefit from neoadjuvant, and adjuvant targeted therapies remains unknown. This is a multi-center, phase II, two cohort study to evaluate the safety and efficacy of neoadjuvant and adjuvant targeted therapies in patients with BRAF V600- or METex14-positive NSCLC. Eligible patients are ≥ 18 years, diagnosed with stage IB-IIIA and selected IIIB (AJCC V8) NSCLC, have BRAF V600 or METex14 mutations, eligible for surgical resection and scheduled for surgery within 6 weeks after the last does of neoadjuvant treatment. Patients will receive neoadjuvant targeted therapy with dabrafenib plus trametinib or capmatinib for 8 weeks before surgery, followed by a two-year adjuvant targeted treatment. Other pre-surgical anticancer treatments are not allowed. The application of adjuvant chemotherapy for a maximal of 4 cycles is at the discretion of the treating physician. The two molecularly defined cohorts will be enrolled in parallel, with an estimated target enrollment of 20 patients for each. Primary endpoint is the complete pathologic response (pCR) rate based on local review. Secondary endpoints include major pathological response (MPR) rate, event-free survival (EFS), disease-free survival (DFS), overall survival (OS) and safety. NCT06054191. The authors. Novartis.
Background Evidence of the association between serum lipid profiles and intraplaque neovascularization (IPN) is still limited. We aimed to study the value of a novel Doppler method, superb microvascular imaging, in correlating serum lipid profiles and evidence of IPN in a population with a high risk of stroke. Methods and Results A community-based cross-sectional study was conducted in Beijing, China. Residents (aged ≥40 years) underwent questionnaire interviews, physical examinations, and laboratory testing in 2018 and 2019. Subjects with a high risk of stroke were then selected. Standard carotid ultrasound and carotid plaque superb microvascular imaging examinations were then performed on the high-stroke-risk participants. Logistic regression was used to evaluate the relationship between serum lipid profiles and carotid plaque IPN. Overall, a total of 250 individuals (mean age, 67.20±8.12 years; 66.4% men) met the study inclusion criteria. Superb microvascular imaging revealed carotid plaque IPN in 96 subjects (38.4%). Subjects with IPN were more likely to be current smokers (34.0% versus 46.9%, P=0.046), and their identified carotid plaques were much thicker (2.35±0.63 mm versus 2.75±0.80 mm, P=0.001). Serum lipids, including total cholesterol, non-high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol were positively associated with the presence of IPN (4.33±1.00 mmol/L versus 4.79±1.12 mmol/L, P=0.001; 2.96±0.92 mmol/L versus 3.40±1.01 mmol/L, P=0.001; 2.18±0.76 mmol/L versus 2.46±0.80 mmol/L, P=0.005, respectively), and after adjustment for other confounders, the positive relationship remained significant. Furthermore, non-high-density lipoprotein cholesterol (odds ratio, 2.62 [95% CI, 1.35-5.06]) was significantly associated with the presence of carotid plaque IPN even after adjusting for low-density lipoprotein cholesterol. Conclusions Total cholesterol, non-high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol were positively associated with the presence of carotid IPN in a Chinese high-stroke-risk population. Further prospective studies should be conducted to better understand how much finding IPN adds to current stroke prediction tools.
Abstract Background Immune checkpoint inhibitors (ICIs) have greatly improved the prognosis and overall management of non‐small cell lung cancer (NSCLC) patients, but in the long term less than 20% of patients benefit from treatment with ICIs. Therefore, it is necessary to guide the choice of immunotherapy population through biomarkers in order to maximize the benefit for NSCLC patients. This article mainly explores the relationship between the efficacy of immunotherapy and specific tumor mutation gene characteristics in an NSCLC population. Methods This was a prospective analysis of patients with advanced NSCLC who visited the Department of Respiratory Medicine of Peking Union Medical College Hospital from March 2018 to June 2019 and were instructed to use PD‐1 inhibitors. The follow‐up deadline was 31 December 2019. The tumor pathological tissues were tested for tumor mutation genes, and the patients were evaluated for efficacy according to RECIST 1.1. The patients were divided into the durable benefit group (DCB) and the nonsustainable benefit group (NDB). DCB/NDB was used as the outcome variable. Various statistics methods were used to explore the independent predictors of long‐term benefits associated with immunotherapy and to draw a progression‐free survival curve for the relevant predictors. Results A total of 44 patients were examined for tumor mutation genes in pathological tissues; 20 in the DCB group and 24 in the NDB group. Specific gene mutations occurred in TP53 38.64%, KRAS 31.82%, EGFR 20.45%, BRCA 20.45%, ERBB (excluding EGFR ) 18.18%, PTEN 15.91%, CDK4/6 13.64%, POLE 11.36%, MET 11.36%, PIK3CA 9.10%, FGFR 9.10%, BRAF 9.10%, JAK 9.10%, ALK 6.82%, POLD1 4.55%, BLM 4.55%. Chi‐square test results showed that there were statistically significant differences between DCB and NDB groups with eight mutations such as KRAS . Logistic regression showed that the KRAS mutation was statistically significant ( P < 0.001). Two accuracy indicators, Random Forest Classification of Mean Decrease Gini and Mean Decrease Accuracy, evaluated the importance of the impact of different gene mutations on the outcome. Under two different measures, the variables were all KRAS mutations. It is suggested that the mutation of the KRAS gene is an independent predictor of the long‐term benefit of immunotherapy. Conclusions The mutation of KRAS gene in tumor tissues is an independent predictor of the long‐term benefit of immunotherapy, and the predictive ability is better.
We aimed to describe the clinical characteristics and outcomes of patients with transverse myelitis (TM) as a rare manifestation in systemic lupus erythematosus (SLE) and explore the risk factors and prognosis of SLE-related TM (SLE-TM). We conducted a retrospective case-control and cohort analysis. All patients with SLE-TM (58 patients) and 232 with SLE without TM, as a control group, were admitted to Peking Union Medical College Hospital between January 1993 and May 2021. Factors associated with the presence of SLE-TM and its prognosis were assessed using logistic regression and Cox proportional hazard models. Multivariate analysis revealed that positive anti-Ro/Sjogren's syndrome A (anti-Ro/ SSA) (<0.01) and increased erythrocyte sedimentation rate (ESR) (p < 0.01) were associated with SLE-TM. Regarding prognosis, methylprednisolone (MP) pulse therapy within 2 weeks of onset (adjusted hazard ratio (AHR), 2.12; 95% confidence interval (CI), 1.06-4.23; p = 0.03) was associated with short-term neurological improvement. An American Spinal Injury Association Impairment Scale (AIS) grades of A, B, or C at onset (AHR, 0.12; 95% CI 0.05-0.28; p < 0.001) and hypoglycorrhachia (AHR, 0.29; 95% CI, 0.13-0.65; p < 0.01) were associated with a short-term non-improved outcome. The positive anti-Ro/SSA antibodies and increased ESR may be associated with the presence of SLE-TM. An initial presentation with severe myelitis and hypoglycorrhachia appear to be predictors of a poor neurological outcome. Early steroid pulse therapy may improve the prognosis.
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