e20726 Background: At present, third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are the standard first-line treatment for advanced EGFR-mutant non-small cell lung cancer (NSCLC). Nevertheless, the combination of first-/second-generation EGFR-TKIs and chemotherapy or anti-angiogenic agents remains commonly used in real-world practice in China. This study aimed to compare the real-world effectiveness of these two first-line strategies. Methods: In this retrospective study, data were collected from Shanghai Chest Hospital from January 2017 to December 2023. Previously-untreated patients with stage III/IV EGFR-mutant NSCLC were enrolled and classified into two groups: those receiving first-line first-/second-generation EGFR-TKI combination therapy, and those receiving third-generation EGFR-TKI monotherapy. Propensity-score matching (PSM) (1:2 ratio) was performed to balance baseline characteristics. The primary endpoint was progression-free survival (PFS). Overall survival (OS) was a secondary endpoint. Results: A total of 512 eligible patients were enrolled and the median follow-up was 40.4 months. After PSM, 364 patients were included. The median PFS was significantly longer in the third-generation TKI monotherapy group (n = 130, PFS: 20.5 months; 95% confidence interval [CI], 16.45-24.55) compared to the first-/second-generation TKI combination group (n = 234, median PFS: 16.0 months; 95% CI, 14.16-17.91; P < 0.001). Subgroup analysis of PFS consistently favored the third-generation EGFR-TKI across almost all variables. No significant difference in OS was observed between the two groups (46.1 months, 95%CI 39.64-52.49 vs. 41.6 months, 95%CI 38.51-45.14; P = 0.721). Besides, 165 (70.5%) patients in the combination group received third-generation EGFR-TKIs in later lines, and this subgroup demonstrated significantly longer OS than those who did not (45.4 vs 33.5 months, P = 0.017). Conclusions: This real-world study demonstrates that first-line third-generation EGFR-TKI monotherapy is associated with a significantly improved PFS compared to first-/second-generation EGFR-TKI combination therapy in EGFR-mutant NSCLC. The absence of OS difference may be attributed to the high proportion of patients in the combination group who subsequently received third-generation TKIs as a later-line therapy. These findings support the superior efficacy of third-generation EGFR-TKIs as the recommended first-line treatment and also indicate that the first-/second-generation EGFR-TKI combination therapy is a viable alternative in real-world practice.

e20146 Background: Extensive-stage small cell lung cancer (ES-SCLC) is a highly aggressive malignancy with limited treatment options. While immunochemotherapy constitutes standard first-line therapy, predictive biomarkers for treatment response remain undefined, impeding personalized therapeutic strategies. Methods: We investigated circulating small extracellular vesicle (sEV)-derived microRNAs (miRNAs) as non-invasive predictive biomarkers in treatment-naïve ES-SCLC patients receiving immunochemotherapy. Plasma samples from a training cohort (n = 33) and an independent prospective cohort (n = 5) were collected pre-treatment. sEVs were isolated, characterized, and subjected to small RNA sequencing to quantify miRNA expression. Results: Small RNA sequencing revealed 23 differentially expressed sEV miRNAs between responders (n = 19) and non-responders (n = 14). Machine learning refined these candidates into a predictive model. Recursive feature elimination (RFE) yielded an 11-sEV-miRNA signature. The top-performing model (Extra Trees Gini) incorporated 5 sEV miRNAs and 1 clinical feature, demonstrating high predictive accuracy in the training set (AUC = 0.855, sensitivity = 95%, specificity = 80%). Preliminary validation in the prospective cohort achieved 80% accuracy (4/5 correct classifications). Conclusions: We established a novel sEV-miRNA biomarker panel that robustly predicts immunochemotherapy response in ES-SCLC. High discriminatory performance and initial prospective validation underscore its clinical utility for guiding treatment decisions and optimizing outcomes by avoiding ineffective therapy in non-responders.

Subgroup analysis of (A) ORR, (B) DOR and (C) PFS confirmed by investigator

Serum cytokine concentrations before and during treatment

Detailed inclusion and exclusion criteria for the clinical trial (NCT04370405)

List of participating hospitals for the clinical trial NCT04370405

Number and frequency of TRAE that led to discontinuation from the trial

Background:Treatment of tyrosine kinase inhibitor (TKI)-resistant anaplastic lymphoma kinase (ALK) rearranged non-small cell lung cancer (NSCLC) remains an unmet need. Among these patients, the efficacy of immunotherapy has not been thoroughly investigated. The purpose of our study was to evaluate the efficacy of immunotherapy in patients with ALK-TKI-resistant NSCLC, stratified by programmed cell death ligand-1 (PD-L1) expression. Methods:We retrospectively collected the data of advanced NSCLC patients with ALK-rearrangement, who were treated with immunotherapy or chemotherapy after the development of ALK-TKI resistance at the Shanghai Chest Hospital. Progression-free survival (PFS) was used to evaluate the outcomes. Results:The final analysis included 89 patients between June 1, 2018, and December 31, 2022, who met the selection criteria. The entire cohort had a median follow-up time of 33.4 months. The patients who received immunotherapy had better PFS than those who received non-immunotherapy (median PFS: 5.3 vs. 2.5 months; P=0.009). The PD-L1-positive patients who received immunotherapy had a median PFS of 7.1 months, while those who received non-immunotherapy had a median PFS of 2.5 months (P=0.02). No such statistically significant difference was observed in the PD-L1-negative patients (median PFS for with immunotherapy vs. without immunotherapy: 1.5 vs. 2.9 months; P=0.68). The PD-L1-positive patients who underwent re-biopsy after the development of TKI resistance and who received immunotherapy had a PFS of 7.8 months, while those who received non-immunotherapy had a PFS of 2.7 months (P=0.002). Conclusions:This was the first real-world retrospective study to show that some patients with positive PD-L1 expression may benefit from immune-based therapy after the development of ALK-TKI resistance. However, we still recommend biopsy for patients who develop ALK-TKI resistance to provide further treatment guidance.

Comparison of PI3K inhibitor toxicities and their efficacies for relapsed and/or refractory indolent lymphoma treatments

Comparison of the concentrations of serum markers measured in patients with and without a response to linperlisib

Representativeness of Study Participants

Investigator-assessed response outcomes (FAS)

Background:As a rare tumor with poor prognosis, the first-line treatment strategy of advanced SMARCA4-deficient thoracic tumors is inconclusive. Although previous studies have shown immunotherapy to be effective, the efficacy and safety of different immune checkpoint inhibitors (ICIs) combination treatment strategies have not been explored in detail. This study aims to identify optimal immunotherapeutic combinations for this population. Methods:We collected the clinical and pathological information of 55 patients with SMARCA4-deficient non-small cell lung cancer (SMARCA4-deficient NSCLC) and SMARCA4-deficient undifferentiated tumor (SMARCA4-deficient UT), after which we evaluated and analyzed the survival status and clinicopathological characteristics of the patients. Results:Following statistical analysis, it was found that the patients were mainly male smokers with a mean age of 66 years (range, 46-81 years old). Histologically, NSCLC accounts for the majority (n=40, 72.7%). Survival analysis demonstrated that overall survival (OS) was significantly longer in patients who received first-line immunotherapy compared to those who did not receive immunotherapy for first line (21.67 vs. 8.80 months, P=0.003). A trend of prolonged OS was observed in patients who received immunotherapy in the first line compared with those who received immunotherapy in the latter line (21.67 vs. 15.30 months, P=0.14). Furthermore, the OS of patients who received anti-angiogenesis therapy plus immunotherapy was superior to that of patients who received three other first-line treatments [not reached vs. 21.67 months (chemotherapy plus immunotherapy) vs. 8.80 months (chemotherapy plus anti-angiogenesis therapy) vs. 7.83 months (chemotherapy), P=0.02]. Conclusions:The early use of ICI-based treatment may result in superior survival outcomes for these patients with SMARCA4-deficient thoracic tumors compared to other treatment modalities. Besides, ICIs combined with anti-angiogenesis therapy may be a potential first-line treatment.

Background Next-generation sequencing (NGS) is maturely applied for gene fusion detection. Although tumor fusion burden (TFB) has been identified as an immune marker for cancer, the relationship between these fusions and the immunogenicity and molecular characteristics of gastric cancer (GC) patients remains unclear. GCs have different clinical significance depending on their subtypes, and thus, this study aimed to investigate the characteristics and clinical relevance of TFB in non-Epstein–Barr-virus-positive (EBV+) GC with microsatellite stability (MSS). Methods A total of 319 GC patients from The Cancer Genome Atlas stomach adenocarcinoma (TCGA-STAD) and a cohort of 45-case from ENA (PRJEB25780) were included. The cohort characteristics and distribution of TFB among the patients were analyzed. Additionally, the correlations of TFB with mutation characteristics, pathway differences, relative abundance of immune cells, and prognosis were examined in the TCGA-STAD cohort of MSS and non-EBV (+) patients. Results We observed that in the MSS and non-EBV (+) cohort, the TFB-low group exhibited significantly lower gene mutation frequency, gene copy number, loss of heterozygosity score, and tumor mutation burden than in the TFB-high group. Additionally, the TFB-low group exhibited a higher abundance of immune cells. Furthermore, the immune gene signatures were significantly upregulated in the TFB-low group, 2-year disease-specific survival was markedly increased in the TFB-low group compared with to the TFB-high group. The rates of TFB-low cases were significantly higher TFB-than high cases in durable clinical benefit (DCB) and response groups with pembrolizumab treatment. Low TFB may serve as a predictor of GC prognosis, and the TFB-low group exhibits higher immunogenicity. Conclusion In conclusion, this study reveals that the TFB-based classification of GC patient may be instructive for individualized immunotherapy regimens.

Background In our previous phase 2 trial (NCT04370405), linperlisib, an oral phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor, demonstrated encouraging activity and manageable safety in adult patients with relapsed/refractory (R/R) follicular lymphoma (FL) who had received at least 2 prior systemic therapies. It's crucial to note that FL patients with bone marrow involvement (BMI) generally present more unfavorable prognosis. Here, we present a subgroup analysis from this phase 2 study, which is specifically focused on BMI at baseline. Methods Details of the trial design and study population have been previously reported. In brief, eligible patients (age > 18 years; histologically confirmed relapsed or refractory FL; disease progression post at least 2 prior systemic therapies) received 80 mg linperlisib tablets daily in a 28-day cycle, until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) assessed by independent review committee (IRC); secondary endpoints included the duration of response (DOR), disease control rate (DCR), progression free survival (PFS), overall survival (OS) and safety profile. For this subgroup analysis, patients were grouped based on the presence or absence of BMI at baseline. For those with baseline BMI, biopsies were evaluated to confirm complete responses. Evaluations of antitumor response were conducted every 2 treatment cycles, following the guidelines of the International Research Working Group. Results As previously reported, 84 patients included in the full analysis set (FAS). By subgroup, 25 had baseline BMI and 59 did not. Baseline characteristics by subgroup are shown in Table 1. In this subgroup analysis, a trend toward higher response rate was seen in R/R FL patients with BMI compared to those without such involvement: ORR based on IRC assessment was 88.0% vs 76.3%; best overall response (BOR) of CR was 24.0% vs 11.9%; BOR of PR was 64.0% vs 64.4%. Patients with BMI had DCR that was consistent with those without BMI (92.0% vs 93.2%). The median DOR and PFS were similar across this subgroup (DOR: 11.7 months vs 13.0 months; PFS: 13.3 months vs 13.7 months) (Table 2). Although the median OS was not reached, 12-month OS rates for patients with and without BMI was 91.7% and 91.5%, respectively (Table 2). Safety was evaluated in all R/R FL patients who had received ≥1 dose of linperlisib. Rates of any-grade treatment-related adverse events (TRAEs) were similar across this subgroup and comparable with the overall population (Table 2). When compared to the overall population, patients without BMI experienced fewer grade ≥3 TRAEs, while a marginally higher incidence of grade ≥3 TRAEs was observed in patients with BMI (Table 2). Conclusions This subgroup analysis indicated that linperlisib is an effective and well-tolerated treatment option for patients with R/R FL, irrespective of BMI. Although minor differences were observed in this subgroup, their significance is limited due to the small sample sizes and probably do not alter the overall clinical benefit of linperlisib. Nevertheless, these findings warrant further investigation.

Topic: 18. Indolent and mantle-cell non-Hodgkin lymphoma - Clinical Background: Elderly patients have limited therapy strategies due to physical condition and tolerability. Although PI3K inhibitors have been conditionally approved for some indications, the treatment-related toxicities compromise their long-term use. Linperlisib (YY-20394) is a novel highly selective PI3Kδ inhibitor. A multicenter phase 2 trial (NCT04370405) has shown the promising antitumor activity and manageable safety profile of linperlisib as third- or further-line treatment in patients with relapsed/refractory follicular lymphoma. Aims: This subgroup analysis aimed to explore the efficacy and safety of linperlisib in the elderly patients from this phase 2 trial. Methods: This phase 2 study was conducted at 25 sites in China, and 84 patients with relapsed/refractory follicular lymphoma who had failed at least two prior systemic therapies were enrolled between April 2019 and September 2020. Linperlisib 80 mg was given orally once daily until disease progression, unacceptable toxicity or withdrawal from the study. Response was assessed by an independent review committee according to the International Working Group consensus response evaluation criteria in lymphoma (RECIL 2017). Adverse events (AEs) were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. The primary endpoint was objective response rate (ORR). In this subgroup analysis, elderly patients were defined as those aged ≥60 years. Results: There were 16 elderly patients in this study, with a median age of 66 years (range, 60-78). Eleven (68.8%) patients had stage IV disease by Ann Arbor stage. Thirteen (81.3%) patients received at least three lines of prior therapies. The ORR was 75.0% (95% CI, 47.6-92.7), with a median response duration of 9.2 months (95% CI, 3.0-not reached). The median progression-free survival was 11.2 months (95% CI, 5.5-not reached). The 1-year overall survival rate was 100% (Table). The most common grade ≥3 treatment-related AEs were infectious pneumonia (31.3%), increased lipase (12.5%), and interstitial lung disease (6.3%) Summary/Conclusion: For elderly patients, linperlisib also showed promising efficacy, which was similar to the results in younger patients. Infectious pneumonia needs attention in elderly patients, but the overall safety profile is manageable.Keywords: Follicular lymphoma, Phase II, PI3K

Topic: 18. Indolent and mantle-cell non-Hodgkin lymphoma - Clinical Background: Linperlisib (YY-20394) is an oral PI3Kδ-selective inhibitor. In a multicenter phase 2 trial (NCT04370405), the efficacy and safety of linperlisib as third- or further-line treatment has been evaluated in patients with relapsed/refractory follicular lymphoma. The objective response rate (ORR) was 79.8% and the median progression-free survival (PFS) was 13.4 months. These compelling results have led to the conditional approval of linperlisib in China in 2022. Aims: This subgroup analysis aimed to separately analyze the efficacy and safety of linperlisib in patients with relapsed disease and those with refractory disease from this phase 2 trial. Methods: This phase 2 study enrolled 84 patients from 25 sites in China between April 2019 and September 2020, including 39 (46.4%) patients with relapsed-only disease and 45 (53.6%) patients with refractory disease. The refractory subgroup also included patients with both relapsed and refractory disease. All patients received oral linperlisib 80 mg once daily until disease progression, intolerable toxicity or withdrawal from the study. Response was assessed by an independent review committee according to the International Working Group consensus response evaluation criteria in lymphoma (RECIL 2017). Adverse events (AEs) were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. The primary endpoint was ORR. Results: The refractory subgroup had a shorter treatment time since diagnosis (median, 2.16 vs 4.03 years) and lower proportion of patients with at least three lines of prior therapies (73.3% vs 82.1%) compared with the relapsed-only group. All patients in both subgroups had received prior anti-CD20 antibody and alkylating agent. The ORR (73.3%, 33/45) in the refractory group was lower than that (87.2%, 34/39) in the relapsed-only group. The most common grade ≥3 treatment-related AEs were decreased neutrophil count (17.8%), infectious pneumonia (13.3%), and interstitial lung disease (6.7%) in the refractory group, and infectious pneumonia (25.6%) and decreased neutrophil count (12.8%) in the relapsed-only group (Table). Summary/Conclusion: The efficacy of linperlisib was numerically better in patients with relapsed follicular lymphoma than those with refractory follicular lymphoma. Grade ≥3 interstitial lung disease was relatively more common in patients with refractory follicular lymphoma.Keywords: PI3K, Follicular lymphoma, Phase II

Background: The oral PI3Kδ inhibitor linperlisib has proven to be a significant therapeutic option for patients with relapsed or refractory follicular lymphoma (FL) in a phase II study. As a result, linperlisib was approved in China for the management of adult patients with relapsed or refractory FL who had undergone at least two prior systemic treatments. In addition to linperlisib, several PI3K inhibitors were approved by Food and Drug Administration for relapsed or refractory FL. Despite their confirmed efficacy, these drugs encountered substantial tolerability issues, leading to the rescission from indications for FL. In response to these challenges, we undertook a post-hoc analysis of the phase II linperlisib study to evaluate its safety profile in treating FL, as well as assessing the impact of dose adjustments on prognosis of patients. Methods: In the single-arm, open-label, multicenter phase II study, eligible patients (adults with histologically confirmed relapsed or refractory FL showing disease progression post at least two prior systemic therapies) were administered daily doses of 80mg linperlisib until disease progression or the emergence of unacceptable toxicity. The primary endpoint was the objective response rate (ORR). For this post-hoc analysis, patients were stratified into three groups: the dose-adjusted group (patients who had dose adjusted or interrupted due to adverse events [AEs]); the treatment-terminated group (patients who ceased treatment for a variety of reasons, which included AEs, withdrawal of informed consent, and the investigator's judgment); and the dose-unadjusted group (patients who experienced neither dose adjustment nor interruption). Results: Of 84 patients in the study, dose adjustments or interruptions due to AEs were required for 26 patients, while 34 patients terminated their treatment (15 due to AEs, 6 as per the investigator's discretion, and 14 due to withdrawal of informed consent). A remaining subset of 24 patients experienced no dose modifications. Notably, the dose-adjusted and treatment-terminated groups contained more patients aged 60 and above (19.2% and 29.4% respectively), compared to only 4.2% in the dose-unadjusted group. Other baseline characteristics appeared comparable across all three groups. Among 26 patients in the dose-adjusted group, 25 had dose adjustments due to AEs, and 11 experienced dose interruptions. Infectious pneumonia and interstitial pneumonia were reported in 20.2% (17 cases) and 4.8% (4 cases) of patients, and represent the primary AEs causing treatment termination (9 cases and 4 cases, respectively). Thirteen patients experienced diarrhea during the study, with six requiring dose adjustments, and one patient ceasing treatment due to autoimmune colitis combined with a fungal infection. Rashes, which had an incidence of 11.9% (10 cases), necessitated dose interruptions in four patients but did not require any dose reductions. The ORR was comparable among the three groups (84.6% in dose-adjusted group, 79.4% in treatment-terminated group, and 75.0% in dose-unadjusted group). However, the dose-adjusted and dose-unadjusted groups demonstrated superior duration of response (median DOR, 15.9 months in dose-adjusted group, 9.7 months in treatment-terminated group, and 14.8 months in dose-unadjusted group) and progression-free survival (median PFS, 19.4 months in dose-adjusted group, 11.5 months in treatment-terminated group, and 16.6 months in dose-unadjusted group) than the treatment-terminated group (Figure 1). The median overall survival was not reached in three groups. Conclusion: Our post-hoc analysis reveals that elderly patients (≥60 years old) have reduced tolerance to linperlisib, necessitating more frequent dose adjustments due to AEs. Notably, treatment discontinuation results in inferior DOR and PFS, while dose adjustments or suspensions yield comparable DOR and PFS to full-dose treatment, suggesting that tolerability-guided dose modification effectively reduces AEs without sacrificing therapeutic efficacy.

Introduction Follicular lymphoma (FL) is the most common subtype of indolent non-Hodgkin lymphoma (NHL), originating in follicular central B cells, and accounts for approximately 22% of all newly diagnosed cases of NHL. Chemo-immunotherapy is the standard treatment option for FL. Unfortunately, the progression of the disease to relapsed or refractory FL (r/r FL) is still inevitable, which raised concern about subsequent effective treatments. Several δ isoform of phosphatidylinositol 3-kinase (PI3K-δ) inhibitors have ever been approved for r/r FL after ≥2 lines of prior therapies. However, most of their indications for r/r FL were withdrawal for increased risk of death and serious side effects. The latest data from the Chinese phase II clinical trial of linperlisib (Trial registration ID: NCT04370405), a novel oral PI3Kδ-selective inhibitor, in patients with r/r FL who had received at least two systemic therapies were presented. In this trial, linperlisib demonstrated compelling efficacy and was generally well-tolerated in the treatment of r/r FL patients after ≥2 prior systemic therapies. Linperlisib was approved by China National Medical Products Administration (NMPA) for adult r/r FL previously treated with at least two system therapies in November 2022. The ≥3 lines of treatment options are still unmet for the r/r FL. In this setting, this subgroup analysis of the linperlisib phase II trial aimed to evaluate outcomes of linperlisib in later-line treatment of r/r FL. Methods This study included all the patients with r/r FL who had received at least two systemic therapies previously enrolled in the open-label, single-arm, phase II trial (linperlisib, 80mg, po, q.d., in a 28-day cycle), with overall response rate (ORR) as the primary endpoint. In this subgroup analysis, the patients were divided into two groups according to the treatment lines they received: >3 prior lines of treatment and ≤3 prior lines of treatment. All of the statistical analyses were descriptive. Results A total of 84 r/r FL patients from 25 sites in China from April 2019 to September 2020 were enrolled in this trial, with a cutoff date of September 30, 2021. The ORR was 79.8%, with statistical significance in a heavily pretreated FL patient population with a median of 4 prior therapies, with a well-tolerated safety profile. A total of 43 patients received >3 prior lines of treatment, while 41 patients received ≤3 prior lines of treatment. The median age between the two groups was similar (range: 29.0 - 78.0, 52.0 years for >3 prior lines vs. 48.0 years for ≤3 prior lines). The majority of patients had Ann Arbor staging III-IV (40 for >3 prior lines vs. 34 for ≤3 prior lines). The median number of prior regimens was 4 for >3 prior lines and 3 for ≤3 prior lines. Overall, there were 67 patients achieved responses, with ORR of 83.7% (36, 95%CI:69.3, 93.2) for >3 prior lines vs. 75.6% (31, 95% CI: 59.7, 87.6) for ≤3 prior lines based on independent review committee assessment. Compared with patients who received ≤3 prior lines, patients received ≤3 prior lines achieved higher disease control rate (41[95.3] vs. 37 [90.2%]). The median DOR was 12 months (95% CI: 7.3, 15.9) for >3 prior lines vs. 13 months (95% CI: 9.2, NE). The median PFS was 11.9 months (95% CI: 9.1,19.4) for >3 prior lines vs. 13.3 months (95% CI: 8.2, NE) for ≤3 prior lines. The OS of both groups was not reached. The most common treatment-related adverse events (≥20%, TRAEs) were neutropenia (21 [48.8%] for >3 prior lines vs. 18 [43.9%] for ≤3 prior lines), leukocyte count decreased (15 [34.9%] vs. 15 [36.6%]), alanine aminotransferase increased (10 [23.3%] vs. 9 [22.0%]), lymphocyte count decreased (9 [20.9%] vs. 5 [12.2%]), hypertriglyceridemia (9 [20.9%] vs. 11 [26.8%]), and hypercholesteremia (6 [24.0%] vs. 7 [11.9%]). The most common grade ≥3 TRAEs (≥10%) were neutropenia (9 [20.9%] vs. 4 [9.8%]), pulmonary inflammation (3 [7.0%] vs. 6 [14.6%]), infectious pneumonia (2 [4.7%] vs. 5 [12.2%]). Conclusions This subgroup analysis revealed that linperlisib could achieve benefit in r/r FL patients who received at least 2 prior system therapies regardless of treatment lines. The AEs were well-tolerated. Further trials with large-scale samples were warranted.