Qian Xu's research while affiliated with University of Jinan (Jinan, China) and other places

4009 Background: Integrating immunotherapy with trastuzumab and chemotherapy has shown a significant improvement in overall response rate (ORR) and progression-free survival (PFS) in HER2-overexpression gastric or gastroesophageal junction cancer (GC/GEJC). However, the overall survival (OS) did not achievestatistical significance, and there was no benefit in patients with a PD-L1 combined positive score (CPS) <1. RC48, an antibody-drug conjugate drug, has proven its effect in advanced HER2-positive (HER2 3+ or 2+ by IHC, regardless of FISH positivity) GC/GEJC in later-line treatment setting. This trial was to assess the efficacy and safety of combining RC48, immunotherapy (Tislelizumab), and S-1 as a first-line treatment for HER2-overexpressing GC/GEJC. Methods: This was a single-arm, multi-center, phase II trial conducted in patients with HER2-overexpressing metastatic or unresectable GC/GEJC for first-line treatments. Participants received RC48 (2.5 mg/kg), Tislelizumab (200 mg), and S-1 (40-60 mg BID for 14 days) every 3 weeks until disease progression or intolerable toxicities. The primary endpoint was ORR, while the secondary endpoints included disease control rate (DCR), PFS, OS, and safety. Results: A total of 47 patients were enrolled from 8 centers, median 65 (39 ~ 81) years old, 37 male, 37 GC and 8 GEJC, and all adenocarcinoma. Of them, 30 (63.8%) were HER2 IHC 3+, 11 (23.4%) HER2 IHC 2+/FISH+, and 6 (12.8%) IHC 2+/FISH-. Patients with PD-L1 CPS≥5, ≥1 accounted for 14.9%, 36.2% respectively. With a median follow-up duration of 116.5 days, patients received a median of 5.0 treatment cycles. As of January 20, 2024, 40 patients were included for efficacy analysis, and 44 patients for safety. The ORR reached 95.0% (38/40, 95% CI: 83.1-99.4%), clinical Complete Response rate was 20.0% (5/40, 95% CI: 4.2-26.8%), and the DCR was 100.0% (95% CI: 91.2-100.0%). The median PFS and OS were not reached, while the 6-month and 9-month PFS rates were 100.0% and 80.8%, the 6-month and 9-month OS rates were 100.0% and 83.8%. ORR among the HER2 IHC 3+, IHC 2+/FISH+, and IHC 2+/FISH- groups showed no significant difference (93.3%, 100.0%, 100.0%). ORR for patients with CPS≥1 or < 1 were 100.0%, 92.9%, respectively. One stage IVA GC patient (cT4bN3M0, HER2 3+, CPS 0) and another stage IVB GEJC one (cT3N2M1, HER2 2+/FISH+, CPS≥5) received radical surgery and both achieved pathological complete response. Grade 3/4 treatment-related adverse events occurred in 40.9% of patients, notably neutropenia, fatigue, and diarrhea. Conclusions: The combination of RC48, Tislelizumab, and S-1 showed notable efficacy with manageable safety in the first-line treatment of advanced HER2-overexpressing GC/GEJC patients. These findings support further exploration in this context. Clinical trial information: NCT05586061 .

Background: Immune checkpoint inhibitors (ICIs) have shown great promise in treating late-stage gastric cancer, but their efficacy in the neoadjuvant setting has not been studied in large cohorts. Here, we explored the efficacy and safety of neoadjuvant ICI-based therapy in locally advanced gastric cancer. Patients and methods: We included studies containing patients with locally advanced gastric/gastroesophageal cancer who received ICI-based neoadjuvant therapy. We searched PubMed, Embase, Cochrane library, and abstracts from major international oncology conferences. We performed this meta-analysis using the META package in R.3.6.1. Results: Twenty-one prospective phase I/II studies comprising 687 patients were identified. The pathological complete response (pCR) rate was 0.21 (95% CI 0.18-0.24), major pathological response (MPR) rate was 0.41 (95% CI 0.31-0.52), and R0 resection rate was 0.94 (95% CI 0.92-0.96). The efficacy was highest with ICI plus radiochemotherapy, lowest with ICI alone, and in the middle with ICI and chemotherapy ± anti-angiogenesis. dMMR/MSI-H and PD-L1-high patients benefited more than pMMR/MSS and PD-L1-low patients. Grade 3 or higher toxicity rate was 0.23 (95% CI 0.13-0.38). These results exceeded those in trials of neoadjuvant chemotherapy, where the rate of pCR was 0.08 (95% CI 0.06-0.11), MPR was 0.22 (95% CI 0.19-0.26), R0 section was 0.84 (95% CI 0.80-0.87), and overall grade 3 or higher toxicity was 0.28 (95% CI 0.13-0.47) in 4800 patients across 21 studies. Conclusions: In summary, the integrated results show promising efficacy and safety of ICI-based neoadjuvant therapy for locally advanced gastric cancer and support further investigation in large multicenter randomized trials.

Despite neoadjuvant/conversion chemotherapy, the prognosis of cT4a/bN+ gastric cancer is poor. Immune checkpoint inhibitors (ICIs) and antiangiogenic agents have shown activity in late-stage gastric cancer, but their efficacy in the neoadjuvant/conversion setting is unclear. In this single-armed, phase II, exploratory trial (NCT03878472), we evaluate the efficacy of a combination of ICI (camrelizumab), antiangiogenesis (apatinib), and chemotherapy (S-1 ± oxaliplatin) for neoadjuvant/conversion treatment of cT4a/bN+ gastric cancer. The primary endpoints are pathological responses and their potential biomarkers. Secondary endpoints include safety, objective response, progression-free survival, and overall survival. Complete and major pathological response rates are 15.8% and 26.3%. Pathological responses correlate significantly with microsatellite instability status, PD-L1 expression, and tumor mutational burden. In addition, multi-omics examination reveals several putative biomarkers for pathological responses, including RREB1 and SSPO mutation, immune-related signatures, and a peripheral T cell expansion score. Multi-omics also demonstrates dynamic changes in dominant tumor subclones, immune microenvironments, and T cell receptor repertoires during neoadjuvant immunotherapy. The toxicity and post-surgery complications are limited. These data support further validation of ICI- and antiangiogenesis-based neoadjuvant/conversion therapy in large randomized trials and provide candidate biomarkers. Immune checkpoint inhibitors and antiangiogenic agents have shown some activity in patients with late-stage gastric cancer. Here the authors report the results of a phase II trial of neoadjuvant anti-PD1 (camrelizumab), antiangiogenic agent (apatinib), and chemotherapy (S-1 ± Oxaliplatin) in stage T4a/bN + M0 gastric cancer patients.

Pyroptosis is a programmed cell death characterized by inflammation and may coordinate with cancer immunotherapy, but assessments of pyroptosis in patients with immunotherapy are lacking. We evaluated the pyroptosis potentials in 71 cohorts with 24,388 cancer patients. They were elevated in tumors compared to normal tissues but had a weak relationship with prognosis. High pyroptosis potentials indicated "hot tumors" characteristics and high objective response rates to PD1/PDL1 inhibitors derived from clinical trials. In 15 cohorts with patients treated with immunotherapy, a pyroptosis score showed predictive values in objective response rate, progression-free survival, and overall survival. Systematic treatments, such as chemotherapy or endocrine therapy, enhanced pyroptosis in drug-resistant tumors. These results were further validated in three independent clinical cohorts and our two institutional cohorts by immunohistochemistry. Our findings uncover a value of pyroptosis potentials to predict immunotherapy responses and a theoretical rationale for combining pyroptosis inducers and immunotherapy in cancer treatment.

Background Immune checkpoint inhibitors (ICIs) have significantly improved survival for advanced wild-type non-small cell lung cancer, but there is no direct comparison to confirm which first-line treatment may lead to the longest overall survival. What qualifies as long-term survival (LS) is even unclear. Methods By searching PubMed, Embase, and the Cochrane Central Register of Controlled Trials from January 2005 to December 2020, we included randomized controlled trials (RCTs) of first-line ICI-containing treatments to perform an integrated analysis (IA) to determine the criterion of LS and then screened regimens with LS for network meta-analysis (NMA). The main outcomes for NMA were median overall survival (mOS), 1-year survival rate (1ySR), and 2-year survival rate (2ySR); those for IA were the pooled mOS (POS), 1ySR (P1SR), and 2ySR (P2SR). Results By IA of 16 first-line ICIs from 20 RCTs, the POS was 16.20 (95% CI 14.79–17.60) months, with P1SR of 63% (95% CI 59–66%) and P2SR of 37% (33–41%). Thus, we defined LS as mOS ≥ POS (16.20 m) for regimens and screened for RCTs with outcomes meeting this criterion. Eleven ICI-based regimens can bring LS for the overall population, among which ICI with bevacizumab and chemotherapy achieved the longest POS of 19.50 m (16.90–22.10 m) and the highest P1SR (74%, 61%–87%) and P2SR (49%, 38%–61%). Pembrolizumab with chemotherapy ranked first in mOS and 1ySR, while atezolizumab plus bevacizumab and chemotherapy ranked first in 2ySR. Conclusions Through the IA of first-line treatment regimens, a POS of 16.20 m can be determined as the LS standard. Further considering 1ySR and 2ySR, atezolizumab combined with bevacizumab and chemotherapy or pembrolizumab plus chemotherapy are likely to bring the longest LS in the overall population, while single ICI may be adequate for patients with a high PD-L1 expression. ICIs with bevacizumab and chemotherapy may be the best combination for LS for its further advantage over time.

291 Background: Immune checkpoint inhibitors (ICI) have made significant breakthroughs in late-stage gastric cancer. It is an attractive issue whether ICIs also function in the neoadjuvant setting. Methods: A systematic review was performed using combined terms related to “stomach cancer”, “gastric cancer”, “gastroesophageal cancer”, “immune checkpoint inhibitor”, “PD-1”, “PD-L1” and “neoadjuvant” in PubMed and annual meeting of ASCO, ASCO GI, ESMO, and ESMO GI from 2019 to 2021. Complete pathological response (CPR) rates, major pathological response (MPR) rates, R0 resection rates, and side effects were pooled and analyzed. MPR was defined as ≤10% viable tumor cells and included CPR. Study outcomes were pooled using the function METAPHOR in the META package in R.3.6.1. The I ² and P statistics were used to evaluate heterogeneity among studies. Funnel plots were used for publication bias assessment. Results: A total of 13 phase I/II clinical trials, including 332 resectable gastric cancer (T2-4 or N+) patients with neoadjuvant ICI-containing treatments, were collected. The pooled rates of CPR, MPR, and R0 resection were 0.16 (95% credible intervals (CI), 0.12-0.22), 0.36 (95% CI, 0.24-0.51), and 0.97 (95% CI, 0.94-0.99), respectively. As a comparison, outcomes from 25 studies on neoadjuvant chemotherapy were also pooled, with rates of CPR 0.08 (95% CI, 0.06-0.11), MPR 0.22 (95% CI, 0.19-0.26), and R0 resection 0.84 (95% CI, 0.80-0.87). Besides, the overall grade 3 or higher toxicity rates were 0.24 (95% CI 0.03-0.54) vs. 0.28 (95% CI 0.13-0.47) in ICI-based treatment and chemotherapy groups. Stratified by treatment strategies, ICI alone showed the lowest efficacy (CPR 0.07, 95% CI 0.02-0.19 and MPR 0.16, 95% CI 0.03-0.29). Addition of chemotherapy to ICI promoted the CPR (0.15, 95% CI 0.10-0.22) and MPR (0.36, 95% CI 0.22-0.50). Further addition of radiotherapy displayed the highest CPR (0.35, 95% CI 0.21-0.52) and MPR (0.74, 95% CI 0.54-0.93). Only four trials reported the outcomes of dMMR/MSI-H patients, with superior CPR (0.39, 95% CI 0.20-0.62) and MPR (0.82, 95% CI 0.82-1.00), while those of pMMR/MSS patients were 0.05 (95% CI 0.00-0.13) and 0.20 (95% CI 0.20-0.31) respectively, among which 2 trials used ICI only. Conclusions: Neoadjuvant ICI plus chemotherapy/radiotherapy, instead of ICI alone, has better pathological responses and R0 resection rates than chemotherapy. dMMR/MSI-H is a superior biomarker for neoadjuvant ICI therapy for resectable gastric cancer. The value or biomarker of immunotherapy in pMMR/MSS patients remains exploring.[Table: see text]

Background Although various third-line treatments of advanced gastric cancer (AGC) significantly improved the overall survival, the optimal regimen has not been determined by now. This study aims to evaluate the efficacy and safety of multiple third-line treatments of AGC via integrated analysis and network meta-analysis (NMA) to provide valuable evidence for the optimal third-line systemic therapy for AGC. Methods By searching the databases of PubMed, Embase and the Cochrane Central Register of Controlled Trials from Jan 01, 2005 to Dec 31, 2020, we included phase II/III randomized clinical trials (RCTs) of the third-line treatments for AGC to perform NMA. The main outcomes for NMA were median overall survival (mOS), median progression-free survival (mPFS), disease control rate (DCR) and adverse events (AEs). We also included phase IB/II non-RCTs and II/III RCTs of the third-line immune checkpoint inhibitors (ICIs) for integrated analysis for pooled mOS (POS), pooled mPFS (PPFS) and other outcomes. Results Eight phase II/III RCTs and 2 ICIs-related phase IB/II non-RCTs were included for analysis, involving 9 treatment regimens and 3012 AGC patients. In terms of mOS, apatinib (hazard ratio [HR] 0.61, 95% credible interval [CrI] 0.48-0.78) and nivolumab (HR 0.62, 95% CrI 0.51-0.76) were the most effective treatments compared with placebo. Apatinib also significantly improved mPFS versus placebo (HR 0.38, 95% CrI 0.29-0.49). Nivolumab ranked first among all regimens for 1-year OS rate and achieved the best OS in patients with HER-2 positive tumor, patients with gastroesophageal junction (GEJ) cancer and patients without gastrectomy history. TAS-102 (OR 7.46, 95% CrI 4.61-12.51) was the most toxic treatment in terms of AEs of grade 3 and higher (≥3 AEs). Pembrolizumab was more likely to cause immune related adverse event. Finally, the POS, pooled 1-year OS rate, pooled ORR and PPFS of AGC patients treated with third-line ICIs were 5.1 months, 25%, 10% and 1.71 months respectively. Conclusions Apatinib and nivolumab are the most effective treatments for the third-line treatment of AGC in contrast to the third-line chemotherapy. For AGC patients with HER-2 positive tumor, patients with GEJ cancer and patients without gastrectomy history, ICIs could be the optimal third-line treatment choice.

Background Immune checkpoint inhibitors (ICIs) have improved survival for advanced wild-type non-small cell lung cancer (NSCLC) significantly, but few studies compared single ICI (SICI)-based treatments and double ICIs (DICI)-based treatments. We summarized the general efficacy of ICI-related treatments, compared the efficacy and safety of SICI-based [programmed death 1 (PD-1)/programmed death-ligand 1 (PD-L1) or cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) inhibitors ± chemotherapy (CT)] and DICI-based (PD-1/PD-L1 inhibitors+CTLA-4 inhibitors ± chemotherapy) treatments vs. CT in the first-line treatment. Methods We included phase II/III randomized controlled trials (RCTs), including patients with histologically confirmed stage IIIB–IV driver-gene wild-type NSCLC who received first-line ICI-related therapy in at least one arm. PubMed, Embase, and Cochrane Library were searched from January 1, 2005, to December 31, 2020. This network meta-analysis was performed in a Bayesian framework using GEMTC and JAGS package in R.3.6.1. The research was registered with PROSPERO (CRD42020184534). Results Twenty RCTs were involved, including 13,032 patients and 17 treatment regimens. The results showed that ICI-based therapies could provide a pooled median overall survival (mOS) (POS) of 15.79 (95% CI: 14.85–16.73) months, and there were no significant differences in OS, progression-free survival (PFS), objective response rate (ORR), and grade 3 or higher adverse events (≥3AEs) between DICI-based treatments (POS: 14.81, 12.11–17.52 months) and SICI-based treatments (POS: 16.17, 14.59–17.74 months) in overall patients. However, DICI-based treatments had significantly prolonged the OS over SICI-based treatments in squamous and PD-L1 <1% subgroups. The ranking of OS benefit by Bayesian surface under the cumulative ranking curve (SUCRA) spectrum showed that DICI+chemotherapy ranked first for overall population and subgroups including squamous, non-squamous, any level of PD-L1 expression, smoking, male, Eastern Cooperative Oncology Group performance status (ECOG PS) = 0/1, age < 65/≥65 while SICI+CT for low tumor mutation burden (TMB), non-smoking, and female subgroups, and DICI for high TMB subgroups. Conclusions In the first-line therapy for advanced wild-type NSCLC, both SICI- and DICI-based treatments could bring significant overall advantages over chemotherapy, with comparable outcomes of efficacy and ≥3AEs. DICI-based treatments were more effective than SICI-based treatments in squamous and PD-L1 <1% subgroups. For most populations, DICI+chemotherapy could be the best choice with a survival benefit, while SICI+chemotherapy has established its position actually. Systematic Review Registration [PROSPERO], identifier [CRD42020184534].

Gastric cancer is a leading cause of cancer-related deaths with considerable heterogeneity among patients. Appropriate classifications are essential for prognosis prediction and individualized treatment. Although immunotherapy showed potential efficacy in a portion of patients with gastric cancer, few studies have tried to classify gastric cancer specifically based on immune signatures. In this study, we established a 3-subtype cluster with low (CLIM), medium (CMIM), and high (CHIM) enrichment of immune signatures based on immunogenomic profiling. We validated the classification in multiple independent datasets. The CHIM subtype exhibited a relatively better prognosis and showed features of “hot tumors”, including low tumor purity, high stromal components, overexpression of immune checkpoint molecules, and enriched tumor-infiltrated immune cells (activated T cells and macrophages). In addition, CHIM tumors were also characterized by frequent ARID1A mutation, rare TP53 mutation, hypermethylation status, and altered protein expression (HER2, β-catenin, Cyclin E1, PREX1, LCK, PD-L1, Transglutaminase, and cleaved Caspase 7). By Gene Set Variation Analysis, “TGFβ signaling pathway” and “GAP junction” were enriched in CLIM tumors and inversely correlated with CD8⁺ and CD4⁺ T cell infiltration. Of note, the CHIM patients showed a higher response rate to immunotherapy (44.4% vs. 11.1% and 16.7%) and a more prolonged progression-free survival (4.83 vs. 1.86 and 2.75 months) than CMIM and CLIM patients in a microsatellite-independent manner. In conclusion, the new immune signature-based subtypes have potential therapeutic and prognostic implications for gastric cancer management, especially immunotherapy.