Youling Gong’s research while affiliated with Sichuan University and other places

e20547 Background: EGFR-TKIs is standard of care for treatment-naïve EGFR mutated ( EGFRm) advanced NSCLC (aNSCLC). The clinical outcome after 1L EGFR-TKI in clinical practice is not well studied prospectively. Herein, we reported the real-world clinical outcomes in Chinese EGFRm aNSCLC progressed from 1L EGFR-TKI. Methods: This prospective, observational study enrolled 300 Chinese patients (pts) from 16 sites between March, 2020 and August, 2021. At data cut-off date of August 27, 2023. 291 eligible pts were included into the full analysis set (FAS) and 225 pts in FAS received second-line EGFR-TKI or chemotherapy were included into outcome analysis set (OAS). The clinical outcome (PFS and OS, measured from 2 nd line treatment) were presented. Results: The median age of 291 pts in FAS was 62 years, 57.0% was females and 29.3% pts with brain metastasis. EGFR mutation included 19del (143 pts, 49.1%), L858R (126 pts, 43.3%) and others (22 pts, 7.6%). 273 (93.8%) and 18 (6.2%) pts progressed from 1L 1G/2G EGFR-TKIs and 3G EGFR-TKIs, respectively. In OAS, overall mPFS and mOS in T790M + patients (90 pts) who received 2L 3G EGFR-TKIs were 14.7 (10.40-18.0) and 32 (25.20-NE) months, respectively. The mPFS and mOS by type of sample and T790M test results were presented in table. 85 pts with T790M- who progressed from 1L 1/2G EGFR-TKIs, including 51, 9 and 25 pts received 3G EGFR-TKIs, prior EGFR-TKIs plus local therapy, and chemotherapy as 2L therapy, respectively. The corresponding mPFS were 7.60 (95% CI, 4.70-10.40), 10.20 (2.30-14.90), and 4.90 (2.50-6.90) months, respectively. The corresponding mOS were 21.20 (12.10-NE), 16.60 (6.00-28.60), and 15.00 (9.40-NE) months, respectively. For T790M- patients with 19del (21 pts) and L858R (26 pts) mutation who received 2L 3G EGFR-TKIs, the mPFS was 21.00 (2.60-NE), and 8.00 (5.00-10.40) months, respectively. mOS was NE (21.00-NE) and 16.60 (8.20-24.60) months, respectively. 12 pts progressed from 1L 3G EGFR-TKIs, 10 and 2 pts received chemotherapy-based regimen and prior EGFR-TKIs plus local therapy as 2L therapy, respectively. The corresponding overall mPFS were 8.40 (95% CI: 1.20-11.80) months. The overall mOS was 14.20 (2.80-NE) months. Conclusions: The real-world treatment pattern and corresponding prognosis of EGFR-mutated NSCLC progressed from first-line EGFR-TKI were diverse, and among them those who received 3G EGFR-TKI at progression showed a better clinical outcome. These results supplemented the clinical evidence for the use of 3G EGFR-TKIs in EGFRm aNSCLC pts who progressed from 1L 1/2G EGFR-TKIs in the real-world setting. Clinical trial information: NCT04207775 . [Table: see text]

Background: Despite a high response rate to cCRT, patients with limited-stage SCLC generally experience recurrence of disease after a few months and survival remains poor. Immunotherapy has shown benefit in many tumor types, including SCLC. In preclinical and clinical studies of solid tumors, co-inhibition of T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitor motif domains (TIGIT) and PD-1 enhanced antitumor activity of anti-PD-1. AdvanTIG-204 (NCT04952597) investigated the efficacy and safety of ociperlimab + tislelizumab + cCRT in patients with untreated limited-stage SCLC. Methods: Patients with limited-stage SCLC and no prior systemic therapy were randomized 1:1:1 to Arm A (ociperlimab [900 mg IV Q3W] + tislelizumab [200 mg IV Q3W] + cCRT for 4 cycles, then ociperlimab + tislelizumab), Arm B (tislelizumab + cCRT for 4 cycles, then tislelizumab), or Arm C (cCRT for 4 cycles). Study drugs (Arms A and B) were continued for up to 12 months or until progression, unacceptable toxicity, or withdrawal. Primary endpoint: investigator-assessed PFS per RECIST v1.1. Secondary analyses included additional efficacy and safety endpoints in the ITT population, and efficacy in patient subgroups by PD-L1 and TIGIT expression (both <1% vs ≥1%), using tumor area positivity (PD-L1) and immune cell scoring (TIGIT). No hypothesis testing was predefined (p-value for descriptive purposes only). Descriptive comparisons were conducted for Arm A vs C, B vs C, and A vs B. Results: As of July 26, 2023, 126 patients (median age, 61.5 years) were randomized to Arm A (n=41), Arm B (n=42), or Arm C (n=43). Median follow-up: ~18 months (all arms). There was a trend of improvement in median PFS in Arm A (12.6 months) and Arm B (13.2 months) vs Arm C (9.5 months); HR (95% CI): Arm A vs C, 0.84 (0.46-1.52; p=0.2793); Arm B vs C, 0.80 (0.45-1.44; p=0.2414). ORR was 85.4% (3 CR) in Arm A, 88.1% (4 CR) in Arm B, and 76.7% (1 CR) in Arm C. Median DoR was 10.1 months in Arm A, 11.5 months in Arm B, and 8.2 months in Arm C. Median OS was not reached in any arm. Analyses showed that PD-L1 or TIGIT expression did not correlate with efficacy, however, small subgroup size limits interpretability. All patients experienced ≥1 treatment-related adverse event (TRAE); rates of grade ≥3 TRAEs were 73.2%, 78.6% and, 65.1% in Arms A, B, and C, respectively. The most common TRAEs included anemia (80.5% in Arm A vs 83.3% in Arm B vs 81.4% in Arm C), nausea (80.5% vs 76.2% vs 65.1%), and WBC count decreased (78.0% vs 76.2% vs 62.8%). Rates of TRAEs leading to any treatment discontinuation were 26.8%, 21.4%, and 4.7% in Arms A, B, and C, respectively. One patient in each arm experienced a TRAE leading to death. Conclusion: In patients with untreated limited-stage SCLC, tislelizumab + cCRT yielded a trend of improvement in PFS and ORR vs cCRT; addition of ociperlimab did not show detectable improvement. The overall safety profile of the treatments was tolerable, manageable, and generally consistent with the known risks of ociperlimab, tislelizumab, and cCRT. Citation Format: Youling Gong, Qingsong Pang, Rong Yu, Zhengfei Zhu, Jiangqiong Huang, Yufeng Cheng, Diansheng Zhong, Hongbo Wu, Seung Soo Yoo, Tracy Dobbs, Zinan Bao, Yunxia Zuo, Boxian Wei, Pu Sun, You Lu. AdvanTIG-204: A phase 2, multicenter, randomized, 3-arm, open-label study investigating the preliminary efficacy and safety of ociperlimab (anti-TIGIT) + tislelizumab (anti-PD-1) + concurrent chemoradiotherapy (cCRT) in patients with untreated limited-stage small cell lung cancer (SCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT255.

Background The administration of immune checkpoint inhibitors (ICIs) in advanced non-small cell lung cancer (NSCLC) with oncogenic driver alterations other than epidermal growth factor receptor (EGFR) aroused a heated discussion. We thus aimed to evaluate ICI treatment in these patients in real-world routine clinical practice. Methods A multicenter, retrospective study was conducted for NSCLC patients with at least one gene alteration (KRAS, HER2, BRAF, MET, RET, ALK, ROS1) receiving ICI monotherapy or combination treatment. The data regarding clinicopathologic characteristics, clinical efficacy, and safety were investigated. Results A total of 216 patients were included, the median age was 60 years, 72.7% of patients were male, and 46.8% had a smoking history. The molecular alterations involved KRAS (n=95), HER2 (n=42), BRAF (n=22), MET (n=21), RET (n=14), ALK (n=14), and ROS1 (n=8); 56.5% of patients received immunotherapy in the first-line, and the rest 43.5% were treated as a second-line and above. For the entire cohort who received immunotherapy-based regimens in the first-line, the median progression-free survival (PFS) was 7.5 months and the median overall survival (OS) was 24.8 months. For the entire cohort who received immunotherapy-based regimens in the second-line and above, the median PFS was 4.7 months and median OS was 17.1 months. KRAS mutated NSCLC treated with immunotherapy-based regimens in the first-line setting had a median PFS and OS were 7.8 and 26.1 months, respectively. Moreover, the median PFS and OS of immunotherapy-based regimens for KRAS-mutant NSCLC that progressed after chemotherapy were 5.9 and 17.1 months. Programmed death ligand 1 (PD-L1) expression level was not consistently associated with response to immunotherapy across different gene alteration subsets. In the KRAS group, PD-L1 positivity [tumor proportion score (TPS) ≥1%] was associated with better PFS and OS according to the multivariate Cox analysis. No statistically significant association was found for smoking status, age, or gender with clinical efficacy in any gene group analyses. Conclusions KRAS-mutant NSCLC could obtain clinical benefits from ICIs either for treatment-naive patients or those who have experienced progression after chemotherapy, and PD-L1 positive expression (TPS >1%) may be a potential positive predictor. For NSCLC with ALK, RET and ROS1 rearrangement, MET exon 14 skipping mutation, or BRAF V600E mutation, effectiveness of single or combined ICI therapy remains limited, therefore, targeted therapies should be considered prior to immunotherapy regimens. Future studies should address the investigation of better predictive biomarkers for immunotherapy response in oncogene-driven NSCLC.

Background The initial phase II stuty (NCT03215693) demonstrated that ensartinib has shown clinical activity in patients with advanced crizotinib‐refractory, anaplastic lymphoma kinase ( ALK )‐positive non‐small cell lung cancer (NSCLC). Herein, we reported the updated data on overall survival (OS) and molecular profiling from the initial phase II study. Methods In this study, 180 patients received 225 mg of ensartinib orally once daily until disease progression, death or withdrawal. OS was estimated by Kaplan‒Meier methods with two‐sided 95% confidence intervals (CIs). Next‐generation sequencing was employed to explore prognostic biomarkers based on plasma samples collected at baseline and after initiating ensartinib. Circulating tumor DNA (ctDNA) was detected to dynamically monitor the genomic alternations during treatment and indicate the existence of molecular residual disease, facilitating improvement of clinical management. Results At the data cut‐off date (August 31, 2022), with a median follow‐up time of 53.2 months, 97 of 180 (53.9%) patients had died. The median OS was 42.8 months (95% CI: 29.3‐53.2 months). A total of 333 plasma samples from 168 patients were included for ctDNA analysis. An inferior OS correlated significantly with baseline ALK or tumor protein 53 ( TP53 ) mutation. In addition, patients with concurrent TP53 mutations had shorter OS than those without concurrent TP53 mutations. High ctDNA levels evaluated by variant allele frequency (VAF) and haploid genome equivalents per milliliter of plasma (hGE/mL) at baseline were associated with poor OS. Additionally, patients with ctDNA clearance at 6 weeks and slow ascent growth had dramatically longer OS than those with ctDNA residual and fast ascent growth, respectively. Furthermore, patients who had a lower tumor burden, as evaluated by the diameter of target lesions, had a longer OS. Multivariate Cox regression analysis further uncovered the independent prognostic values of bone metastases, higher hGE, and elevated ALK mutation abundance at 6 weeks. Conclusion Ensartinib led to a favorable OS in patients with advanced, crizotinib‐resistant, and ALK ‐positive NSCLC. Quantification of ctDNA levels also provided valuable prognostic information for risk stratification.

Patients with metastatic lung adenocarcinoma (MLA) and malignant pleural effusion (MPE) without driver gene mutations have a poor prognosis. None of the standard treatment strategies is recommended for such patients. We retrospectively analyzed the efficacy of the first-line treatment for this specific population: standard platinum-based doublet chemotherapy (CT), CT plus an immune checkpoint inhibitor (CT plus ICI), and CT plus bevacizumab (CT plus Bev). A total of 323 eligible patients were enrolled: CT alone (n = 166), CT plus Bev (n = 72), and CT plus ICI (n = 85). Treatment efficacy assessments were performed every two cycles according to the RECIST guidelines. The endpoints were overall survival (OS) and progression-free survival (PFS). Kaplan-Meier (K‒M) curves and the log-rank test were used to compare OS and PFS. p < 0.05 was the threshold of significance (statistical software: SPSS). The median follow-up was 11.4 months (range, 2.1–49.6 months). PFS and OS in the CT plus ICI/CT plus Bev cohort were significantly longer than those in the CT group (PFS: 7.8/6.4/3.9 months, p < 0.0001; OS: 16.4/15.6/9.6 months, p < 0.0001, respectively). CT plus Bev had better PFS and OS than CT plus ICI/CT in PD-L1 < 1% patients (PFS: 8.4/5.0/3.8 months, p < 0.0001; OS: 15.6/12.9/9.3 months, p < 0.0001). Among patients with PD-L1 1–49%, CT plus ICI led to a longer PFS and OS (PFS: 8.9/5.8/4.2 months, p = 0.009; OS: 24.2/18.8/11.5 months, p = 0.03). In the cohort with PD-L1 ≥ 50%, CT plus ICI was still the best first-line treatment (PFS: 19.7/13.8/9.6 months, p = 0.033; OS: 27.2/19.6/14.9 months, p = 0.047). In driver gene-negative MLA with MPE, CT plus Bev or ICI better controlled MPE and significantly prolonged survival compared to CT alone. PD-L1 expression (negative/positive) may be a key factor influencing the choice of CT plus Bev or ICI.

Background This study was designed to explore the optimal doses and timing of corticosteroids and the benefits of immunosuppressant administration when managing severe (grade 3+) cases of checkpoint inhibitor pneumonitis (sCIP). Methods A retrospective analysis of corticosteroid and immunosuppressant use among non-small cell lung cancer (NSCLC) patients diagnosed with sCIP at West China Hospital between 2019 and 2023 was conducted. The 90-day survival rates for these patients were analyzed using Kaplan-Meier curves. The X-tile procedure was used to assess the optimal timing of corticosteroid use, while patient treatment progress and associated outcomes were presented with Swimmer plots and Sankey diagrams. Results Approximately 2.2% (48/2,185) of analyzed NSCLC patients developed sCIP following immunotherapeutic treatment, and 39.6% (19/48) of these cases were steroid-refractory. Steroid-refractory sCIP patients exhibited a significantly worse 90-day survival rate than that of individuals with nonsteroid-refractory disease (40.4 vs. 63.5 days, p = 0.038). Relative to the other analyzed dose groups, significantly prolonged survival was observed for patients administered a 1–2 mg/kg corticosteroid dose (64.2 vs. 43.7 days, p=0.038). The addition of pirfenidone further improved 90-day survival outcomes in treated patients (71.8 vs. 45.7 days, p=0.021). The X-tile program calculated the optimal corticosteroid treatment duration to be 8–10 weeks, and survival curves confirmed that patients treated for 8–10 weeks exhibited the longest survival. Both Swimmer plots and Sankey diagrams underscored the importance of adding immunosuppressants at as early a time point as possible following sCIP patient failure to respond to corticosteroid treatment, and suggested that infliximab may be the best therapeutic option for these patients. ROC curves further demonstrated that a combination of three hematological indicators (PCT, lactic acid, and creatinine) at the time of new-onset sCIP diagnosis can effectively predict patient 90-day survival rates, with an area under the curve of 0.946. Conclusions These results suggest that the optimal corticosteroid dose and duration for use when treating patients with sCIP are 1–2 mg/kg and 8–10 weeks, respectively. In addition, immunosuppressive treatment should be initiated as quickly as possible following the onset of steroid-refractory CIP, and infliximab may be a promising therapeutic option for these patients.