Guanghai Dai

Background: The efficacy of neoadjuvant chemotherapy (NAC) for locally advanced gastric cancer (LAGC) remains heterogeneous. The real‐world efficacy and comparison of triplet regimens against doublet regimens is unclear. Moreover, the immunological mechanisms underlying differential responses to NAC are poorly understood. This study aimed to compare the efficacy of doublet versus triplet NAC in a Chinese LAGC cohort, and characterize the post‐treatment tumor immune microenvironment (TIME) to identify immune correlates of response and survival. Methods: This retrospective study enrolled patients with locally advanced gastric cancer (GC) who received NAC followed by D2 gastrectomy. The clinical outcomes of patients treated with different NAC regimens were analyzed. The TIME was further characterized using fluorescent multiplex immunohistochemistry (mIHC) to analyze the density and spatial proximity of the immune cells the SOX regimen group. Results: A total of 141 GC patients with complete survival data were included in the final analysis. The overall efficacy of NAC was consistent with prior reports: 7.8% (11/141) achieved ypT0, 36.2% (51/141) achieved ypN0, and 6.4% (9/141) attained a pathological complete response (pCR). Triplet regimens did not provide a statistically significant survival and response advantage over doublet regimens. mIHC analysis showed longer DFS were consistently associated with higher densities of effector immune cells and lower densities of exhausted/immunosuppressive subsets. Favorable survival was also linked to a closer spatial proximity of CD68 ⁺ cells to tumor cells. In treatment response subgroups, responders exhibited distinct spatial patterns, including higher overall CD56 ⁺ cell density but fewer CD68 ⁺ cells near tumors, alongside a shorter CD56 ⁺ ‐to‐tumor distance. Conclusion: This study confirms the consistent anticancer efficacy of neoadjuvant chemotherapy in LAGC. To better inform individualized post‐NAC treatment strategies, analysis of the TIME using multiplex mIHC on surgical specimens is recommended.

Background Combination regimens of immunotherapy and chemotherapy have become the standard treatment for HER2-negative advanced gastric cancer (AGC). Here, we evaluate the therapeutic efficacy of first-line treatment regimens across different PD-L1 expression, circulating tumor DNA (ctDNA) and T-cell receptor (TCR). Methods This study retrospectively recruited 245 patients with AGC. 55 blood samples from 20 patients were prospectively collected before immunotherapy, after two cycles of treatment, and during disease progression. Results In the CPS < 5 cohort, chemotherapy + PD-1 inhibitor + anti-angiogenic treatment showed a higher progression-free survival (PFS). In the CPS ≥ 5 cohort, chemotherapy + PD-1 inhibitor improved median PFS (p = 0.04) and ORR (p = 0.014) over chemotherapy alone. ctDNA analysis revealed that at various time points, patients in the short-PFS group exhibited significantly elevated maxVAF and ctDNA levels. Post-treatment, ctDNA levels decreased in 50% of patients in the long-PFS group, whereas only 25% in the short-PFS group. The short-PFS group had a lower TCR clone count, while no significantly different in the diversity of the TCR repertoire compared with long-PFS groups. Conclusions These findings suggest the different efficacy of first-line treatment regimens across varying levels of PD-L1 expression, and the molecular characteristics of patients with long-term benefits from immunotherapy.

Background The survival benefit from later-line treatment for patients with metastatic colorectal cancer (mCRC) remains disappointing. Here, in a real-world study, we were aimed to evaluate which choice will affect the survival of mCRC patients after standard treatment in Chinese patients. Methods A total of 129 patients with refractory mCRC were involved in the study. They received targeted monotherapy or combined with chemo-agents or PD-1 inhibitor before death. Overall survival (OS) and progression-free survival (PFS) were reviewed and evaluated from clinical features and treatment options. Results Among the 129 patients, the median age was 56 years (25–81). The mOS from third-line was 12.5 months. OS of patients who treated with chemo plus targeted therapy group in third-line was shown to be superior to pd-1 inhibitor in combination with antiangiogenic agents or antiangiogenic monotherapy group (15.6 m vs. 10.5 m vs. 8.4 m, p < 0.05). Patients had received triplet-drugs (bevacizumab plus low-dose irinotecan and oxaliplatin) and had prolonged survival compared to those had not (21.3 m vs 10.3 m, p = 0.004). OS between patients who had immunotherapy history or not was not significantly different (p > 0.05). The mPFS was 3.5 months in patients who had administered with antiangiogenic targeted agents plus anti-pd-1 and 4.7 months in chemo plus targeted therapy group and 2.2 months in the other group. In the triplet drugs group, preliminary results showed that ORR was 13.3% and DCR was 80%. The median PFS was 5.1 m, and the median OS was 10.6 m. Conclusions Triplet drugs resulted in significantly longer overall survival, and immunotherapy may have limited benefit in MSS type CRC patients.

Summary: Background: Immune checkpoint inhibitors have been approved for first- and third-line treatment of advanced gastric cancer. However, pembrolizumab alone in the second line did not improve overall survival compared to chemotherapy in the KEYNOTE-061 study. In this study, we aimed to explore the efficacy and safety of a three-drug regimen of PD-1 inhibitor combined with albumin paclitaxel and apatinib (a VEGFR inhibitor) for the second-line treatment of patients with metastatic gastric cancer (mGC). Methods: This was a single-center, single-arm, phase II clinical study. Patients with mGC with stable microsatellite and negative HER-2 expression who failed first-line chemotherapy were enrolled. The enrolled patients were treated with PD-1 inhibitor (selected according to patients’ requirements) in combination with albumin paclitaxel (125 mg/m², intravenously, days 1 and 8, or 250 mg/m², intravenously, day 1) and apatinib (250 or 500 mg, orally, days 1–21) every 3 weeks. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were overall survival (OS), objective response rate (ORR), disease control rate (DCR), duration of response, and adverse events (AEs). Results: From July 11, 2019, to October 13, 2022, a total of 43 patients were enrolled, of whom 10 were PD-L1 negative, 11 were PD-L1 positive, and 22 had unknown PD-L1 expression. As of the data cutoff on April 1st, 2023, nine patients had partial response, 29 had stable disease, and five experienced progressive disease, with the ORR of 20.9% and DCR of 88.3%. The median PFS was 6.2 months (95% CI, 3.9–9.3), and the median OS was 10.1 months (95% CI, 7.5–14.1). All patients suffered from alopecia and neurotoxicity. The other main AEs of grade 1 or 2 were bone marrow suppression (N = 21, 48.8%), hand-foot reaction (N = 19, 44.2%), hypertension (N = 18, 41.9%), hypothyroidism (N = 11, 25.6%), gastrointestinal bleeding (N = 3, 7.0%), and liver function damage (N = 5, 11.6%). Two patients reported grade 3–4 immune-related liver damage. Conclusion: Second-line PD-1 inhibitor combined with albumin paclitaxel and apatinib showed certain efficacy and safety in patients with mGC. Trial registration: Clinical trials, NCT04182724. Registered 27 November 2019; retrospectively registered, https://clinicaltrials.gov/study/NCT04182724

Background: The aim of this study was to explore whether the Lung Immune Prognostic Index (LIPI) is associated with clinical outcomes in patients with metastatic gastric cancer (MGC) treated with a...

Background: Metastatic gastric cancer (MGC) patients with progression on first-line treatment still have poor outcomes on chemotherapy. The KEYNOTE-061 study demonstrated that pembrolizumab, a PD-1inhibitor, was not better than paclitaxel as second-line therapy for MGC. Herein, we explored the efficacy and safety of PD-1inhibitor based treatment for MGC patients in the second line.Methods: In this observational, retrospective study, we enrolled MGC patients treated with anti-PD-1 based therapy as second-line in our hospital. We primarily assessed the treatment’s efficacy and safety. We also evaluated the relationship between clinical features and outcomes using univariate and multivariate analyses.Results: We enrolled 129 patients with an objective response rate (ORR) of 16.3% and a disease control rate (DCR) of 79.1%. Patients treated with PD-1inhibitor combined with chemotherapy and anti-angiogenic agents had ORR of 19.6% and higher DCR of 94.1%. The median progression-free survival (PFS) was 4.10 months, and the median overall survival (OS) was 7.60 months. In univariate analysis, patients treated with PD-1inhibitor combined with chemotherapy and anti-angiogenic agents and with prior anti-PD-1 history were significantly associated with favorable PFS and OS. In the multivariate analysis, different combination therapy and prior anti-PD-1 history were independent prognosis biomarkers for PFS and OS. Grade 3 or 4 treatment-related adverse events (TRAEs) occurred in 28 (21.7%) patients. Common adverse events (AEs) included fatigue, hyper/hypothyroidism, neutrophil decrease, anemia, skin reactions, proteinuria, and hypertension. We did not observe treatment-related deaths.Conclusion: Our current results indicated that PD-1-inhibitor and chemo-anti-angiogenic agents combination therapy and prior PD-1 treatment history might improve clinical activity for GC immunotherapy as second-line treatment with acceptable safety profiles. Further studies are needed to verify those outcomes for MGC in other centers.

Background: Immunotherapy has shown promising results for metastatic gastric cancer (MGC) patients. Nevertheless, not all patients can benefit from anti-PD-1 treatment. Thus, this study aimed to develop and validate a prognostic nomogram for MGC patients that received immunotherapy.Methods: Herein, MGC patients treated with anti-PD-1 between 1 October 2016 and 1 June 2022 at two separate Chinese PLA General Hospital centers were enrolled and randomly divided into training and validation sets (186 and 80 patients, respectively). The nomogram was constructed based on a multivariable Cox model using baseline variables from the training cohort. Its predictive accuracy was validated by the validation set. The consistency index (C-index) and calibration plots were used to evaluate the discriminative ability and accuracy of the nomogram. The net benefit of the nomogram was evaluated using decision curve analysis (DCA). Finally, we stratified patients by median total nomogram scores and performed Kaplan–Meier survival analyses.Results: We developed the nomogram based on the multivariate analysis of the training cohort, including four parameters: surgery history, treatment line, lung immune prognostic index (LIPI), and platelet-to-lymphocyte ratio (PLR). The C-index of the nomogram was 0.745 in the training set. The calibration curve for 1- and 2-year survival showed good agreement between nomogram predictions and actual observations. In the validation group, the calibration curves demonstrated good performance of the nomogram, with a C-index for overall survival (OS) prediction of 0.713. The OS of patients with a score greater than the median nomogram score was significantly longer than patients with a score lower or equal to the median (p < 0.001).Conclusion: We constructed a nomogram to predict the outcomes of MGC patients that received immunotherapy. This nomogram might facilitate individualized survival predictions and be helpful during clinical decision-making for MGC patients under anti-PD-1 therapy.

Background: Fruquintinib, a vascular endothelial growth factor receptor inhibitor, is a new anticancer drug independently developed in China to treat refractory metastatic colorectal cancer (mCRC). In Japan, regorafenib combined with nivolumab has been demonstrated to be promising in patients with refractory mCRC. Here, in a real-world study, we were aimed to evaluate the efficacy of fruquintinib with various programmed death-1 (PD-1) inhibitors after standard treatment in Chinese non-microsatellite instability-high (MSI-H)/mismatch repair proficient mCRC patients.Methods: A total of 45 patients with refractory mCRC were involved in the study. They received fruquintinib (3 or 5 mg, orally administered once a day for 3 weeks followed by 1 week off in 4-week cycles) and a PD-1 inhibitor(200 mg pembrolizumab, 3 mg/kg nivolumab, 200 mg sintilimab or camrelizumab, intravenously administered on D1 once every 3 weeks). Progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and objective response rate (ORR) were reviewed and evaluated.Results: Among the 45 patients, the median age was 54 years (29-85). The ORR was 11.1% (5/45), DCR 62.2% (28/45), median PFS equal 3.8 months, and median OS was 14.9 months. The response duration was 3.4 months. PFS between left and right primary tumors and PFS with or without lung metastases were both not significantly different (p > 0.05), which was inconsistent with the result of REGONIVO study. The multivariate analysis indicated no association of OS benefit in the specified subgroups. No adverse-effect-related deaths were reported.Conclusions: Fruquintinib, in combination with anti-PD-1, was observed to have clinical activity in a small population of patients with heavily pretreated mCRC in our center. Further studies are needed to verify this outcome in a large population.