In era of immunotherapy: the value of trastuzumab beyond progression in patients with trastuzumab-resistant HER2-positive advanced or metastatic gastric cancer.

Background: For patients with human epidermal growth factor receptor-2 (HER2)-positive advanced or metastatic gastric cancer who have progressed on first-line trastuzumab therapy, the clinical value of the continuous use of trastuzumab beyond progression (TBP) is controversial. Objectives: The present study was conducted to evaluate the efficacy and explore new treatment strategies of TBP for patients with trastuzumab-resistant HER2-positive advanced or metastatic gastric cancer in the era of cancer immunotherapy. Design: Retrospective analysis. Methods: Patients with HER2-positive advanced or metastatic gastric cancer who have failed first-line treatment based on trastuzumab-targeted therapy from June 2019 to December 2020 were retrospectively analyzed. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety. Survival curves of patients were estimated by the Kaplan-Meier method and compared using the log-rank test. Results: In all, 30 patients received TBP with chemotherapy, immunotherapy, or anti-angiogenic therapy, and the other 26 patients received treatment of physician's choice without trastuzumab. The median PFS in the TBP and non-TBP population was 6.0 [95% confidence interval (CI) = 3.8-8.2] and 3.5 (95% CI = 2.2-4.8) months, respectively (p = 0.038), and the median OS was 12.3 (95% CI = 10.4-14.2) and 9.0 (95% CI = 6.6-11.4) months (p = 0.008). The patients who received TBP treatment had more favorable PFS and OS than the non-TBP population. In the TBP group, patients who received trastuzumab plus chemotherapy and immunotherapy had higher ORR (40.0% versus 16.7%), DCR (90.0% versus 50.0%), and showed a significant improvement in PFS (7.0 versus 1.9 m) compared to TBP with chemotherapy alone. Subgroup analysis suggested that patients with male, HER2 positive with immunohistochemistry score 3+ and PFS of first-line treatment less than 6 months had a greater benefit from TBP. The incidence of Grade 3-4 adverse events in the TBP and non-TBP groups was 43.3% and 38.5%. Conclusion: The continuous use of TBP improves PFS and OS in patients with trastuzumab-resistant HER2-positive advanced or metastatic gastric cancer with well-tolerated toxicity. In the era of immunotherapy, TBP combined with chemotherapy and immunotherapy may further enhance the clinical benefit and provide a new treatment strategy. Trial registration: This study is a retrospective study, which does not require clinical registration.

The value of TBP in trastuzumab-resistant HER2-positive advanced or metastatic gastric cancer Patients with human epidermal growth factor receptor-2 (HER2) positive advanced or metastatic gastric cancer who have failed from first-line treatment based on trastuzumab targeted therapy from June 2019 to December 2020 were retrospectively analyzed. 30 patients received TBP with chemotherapy, immunotherapy or anti-angiogenic therapy, and the other 26 patients received treatment of physician's choice without trastuzumab. The median PFS in the TBP and non-TBP population was 6.0(95% CI = 3.8-8.2) and 3.5 (95% CI = 2.2-4.8) months, respectively (P = 0.038), and the median OS was 12.3 (95% CI = 10.4-14.2) and 9.0 (95% CI = 6.6-11.4) months (P = 0.008). In TBP group, patients who received trastuzumab plus chemotherapy and immunotherapy had higher ORR, DCR and showed a significant improvement in PFS compared to TBP with chemotherapy-alone (p = 0.024). Subgroup analysis suggested that patients with male, HER2-positive with IHC score 3+ and PFS of first-line treatment less than 6 months had a greater benefit from TBP. The continuous use of TBP does not increase the incidence of adverse events (AEs). The continuous use of TBP improve PFS and OS in patients with trastuzumab-resistant HER2-positive advanced or metastatic gastric cancer with well tolerated toxicity. In the era of immunotherapy, TBP combined with chemotherapy and immunotherapy further enhanced the clinical benefit and provide new treatment strategy.

Novel GSH-responsive prodrugs derived from indole-chalcone and camptothecin trigger apoptosis and autophagy in colon cancer.

Antineoplastic agents that target tubulin have shown efficacy as chemotherapeutic drugs, yet they are often constrained by multidrug resistance (MDR) and unwanted side effects. A multi-targeted strategy demonstrates great potency in reducing toxicity and enhancing efficacy and provides an alternative way for attenuating MDR. In this study, a series of dual-targeted anti-cancer agents based on indole-chalcone derivatives and the camptothecin (CPT) scaffold were synthesized. Among them, 14-1 demonstrated superior anti-proliferative activity than its precursor 13-1, CPT or their physical mixtures against tested cancer cells, including multidrug-resistant variants, while exhibited moderate cytotoxicity toward human normal cells. Mechanistic studies revealed that 14-1 acted as a glutathione-responsive prodrug, inducing apoptosis by substantially enhancing intracellular uptake of CPT, inhibiting tubulin polymerization, increasing the accumulation of intracellular reactive oxygen species, and initiating a mitochondrion-dependent apoptotic pathway. Moreover, 14-1 notably induced autophagy and suppressed topoisomerase I activity to further promote apoptosis. Importantly, 14-1 displayed potent inhibitory effect on tumor growth in paclitaxel (PTX)-resistant colorectal cancer (HCT-116/PTX) xenograft models without inducing obvious toxicity compared with CPT- or combo-treated group. These results suggest that 14-1 holds promise as a novel candidate for anti-cancer therapy, particularly in PTX-resistant cancers.

Revealing the role of CCoAOMT1: fine-tuning bHLH transcription factors for optimal anther development.

The tapetum, a crucial innermost layer encompassing male reproductive cells within the anther wall, plays a pivotal role in normal pollen development. The transcription factors (TFs) bHLH010/089/091 redundantly facilitate the rapid nuclear accumulation of DYSFUNCTIONAL TAPETUM 1, a gatekeeper TF in the tapetum. Nevertheless, the regulatory mechanisms governing the activity of bHLH010/089/091 remain unknown. In this study, we reveal that caffeoyl coenzyme A O-methyltransferase 1 (CCoAOMT1) is a negative regulator affecting the nuclear localization and function of bHLH010 and bHLH089, probably through their K259 site. Our findings underscore that CCoAOMT1 promotes the nuclear export and degradation of bHLH010 and bHLH089. Intriguingly, elevated CCoAOMT1 expression resulted in defective pollen development, mirroring the phenotype observed in bhlh010 bhlh089 mutants. Moreover, our investigation revealed that the K259A mutation in the bHLH089 protein disrupted its translocation from the nucleus to the cytosol and impeded its degradation induced by CCoAOMT1. Importantly, transgenic plants with the probHLH089::bHLH089K259A construct failed to rescue proper pollen development or gene expression in bhlh010 bhlh089 mutants. Collectively, these findings emphasize the need to maintain balanced TF homeostasis for male fertility. They firmly establish CCoAOMT1 as a pivotal regulator that is instrumental in achieving equilibrium between the induction of the tapetum transcriptional network and ensuring appropriate anther development.

Comprehensive genomic profiling of small bowel adenocarcinoma by tissue and plasma biopsy.

Small bowel adenocarcinoma (SBA) is a rare and aggressive malignancy with limited treatment options and poor prognosis. The molecular landscape and immunological characteristics of SBA are poorly understood. Here, we performed comprehensive mutation profiling of tissue and plasma biopsies from 143 and 42 patients with SBA. Analysis showed that SBA had a distinct mutation spectrum from left- and right-sided colorectal carcinoma. Plasma biopsy had high concordance with tissue biopsy for single nucleotide variants and structural variants, but low concordance for copy number variations, which showed that plasma biopsy can be an alternative to tissue biopsy. Moreover, we analyzed the association of TMB with clinical and molecular features, and found that TMB was significantly higher in tumors with DNA damage response alterations. Our findings provide valuable insights into the molecular and immunological features of SBA and demonstrate the potential of plasma biopsy as a non-invasive method for SBA diagnosis and treatment.

Immune checkpoint inhibitors enhanced the antitumor efficacy of disitamab vedotin for patients with HER2-positive or HER2-low advanced or metastatic gastric cancer: a multicenter real-world study.

BACKGROUND: Novel ADC drugs provide a new therapeutic strategy for gastric cancer.The present study aimed to analyze the clinical efficacy and drug toxicities of disitamab vedotin (RC48) plus immune checkpoint inhibitors(ICIs) and RC48 as third-line therapies and beyond for advanced and metastatic gastric cancer patients. METHODS: This was an observational multicenter real-world study.From August 2021 to January 2022,patients with HER2-positive or HER2-low advanced and metastatic gastric cancer and failed from two or more lines of prior therapy were enrolled and treated with RC48 plus ICIs or RC48. In this study, progression free survival(PFS) was the primary end point. Other evaluation indicators were objective response rate(ORR),disease control rate(DCR),overall survival(OS) and drug toxicities. RESULTS: 45 patients were enrolled,of which 25 patients received RC48 plus ICIs,20 patients received RC48.Patients who received RC48 plus ICIs obtained better ORR (36.0% vs. 10.0%, P = 0.044) and DCR (80.0% vs. 50.0%, P = 0.034) compared with RC48,and simultaneously,the median PFS in RC48 plus ICIs group were superior to RC48 group(6.2 m vs. 3.9 m).The median OS was not reached.No statistically differences were found between HER2-positive and HER2-low group with respect to ORR (27.3% vs. 16.7%, P = 0.464),DCR (66.7% vs. 66.7%, P = 1.000),median PFS(5.7 m vs. 4.3 m, P = 0.299).The most common adverse events (AEs) were decreased white blood count,decreased neutrophil count,fatigue,hypoaesthesia and alopecia.Grade 3-4 AEs occurred in 7(35.0%) patients of RC48 group and 10(40.0%) patients of RC48 plus ICIs group,respectively. CONCLUSION: Compared with RC48 monotherapy, ICIs plus RC48 demonstrated superior third-line and beyond therapeutic efficacy for HER2-positive or HER2-low advanced and metastatic gastric cancer patients with manageable safety.

ARF3-Mediated Regulation of SPL in Early Anther Morphogenesis: Maintaining Precise Spatial Distribution and Expression Level.

Early anther morphogenesis is a crucial process for male fertility in plants, governed by the transcription factor SPL. While the involvement of AGAMOUS (AG) in SPL activation and microsporogenesis initiation is well established, our understanding of the mechanisms governing the spatial distribution and precise expression of SPL during anther cell fate determination remains limited. Here, we present novel findings on the abnormal phenotypes of two previously unreported SPL mutants, spl-4 and spl-5, during anther morphogenesis. Through comprehensive analysis, we identified ARF3 as a key upstream regulator of SPL. Our cytological experiments demonstrated that ARF3 plays a critical role in restricting SPL expression specifically in microsporocytes. Moreover, we revealed that ARF3 directly binds to two specific auxin response elements on the SPL promoter, effectively suppressing AG-mediated activation of SPL. Notably, the arf3 loss-of-function mutant exhibits phenotypic similarities to the SPL overexpression mutant (spl-5), characterized by defective adaxial anther lobes. Transcriptomic analysis revealed differential expression of the genes involved in the morphogenesis pathway in both arf3 and spl mutants, with ARF3 and SPL exhibited opposing regulatory effects on this pathway. Taken together, our study unveils the precise role of ARF3 in restricting the spatial expression and preventing aberrant SPL levels during early anther morphogenesis, thereby ensuring the fidelity of the critical developmental process in plants.

PXL1 and SERKs act as receptor-coreceptor complexes for the CLE19 peptide to regulate pollen development.

Gametophyte development in angiosperms occurs within diploid sporophytic structures and requires coordinated development; e.g., development of the male gametophyte pollen depends on the surrounding sporophytic tissue, the tapetum. The mechanisms underlying this interaction remain poorly characterized. The peptide CLAVATA3/EMBRYO SURROUNDING REGION-RELATED 19 (CLE19) plays a "braking" role in preventing the harmful overexpression of tapetum transcriptional regulators to ensure normal pollen development in Arabidopsis. However, the CLE19 receptor is unknown. Here, we show that CLE19 interacts directly with the PXY-LIKE1 (PXL1) ectodomain and induces PXL1 phosphorylation. PXL1 is also required for the function of CLE19 in maintaining the tapetal transcriptional regulation of pollen exine genes. Additionally, CLE19 induces the interactions of PXL1 with SOMATIC EMBRYOGENESIS RECEPTOR-LIKE KINASE (SERK) coreceptors required for pollen development. We propose that PXL1 and SERKs act as receptor and coreceptor, respectively, of the extracellular CLE19 signal, thereby regulating tapetum gene expression and pollen development.

High DCR and Better Survival in Patients with Advanced or Metastatic Gastric Cancer Receiving Anti-Angiogenic TKI plus Chemotherapy: A Real-World Study.

Objectives: This study was carried out to assess the efficacy and drug toxicity of anti-angiogenic tyrosine kinase inhibitor (TKI) plus chemotherapy as second-line or above therapeutic regime in advanced or metastatic gastric cancer patients. Methods: From November 2017 to April 2020, advanced or metastatic gastric cancer patients who have failed from prior treatment and received apatinib combined with irinotecan or irinotecan treatment were analyzed. The primary observed indicator was progression-free survival (PFS). Objective: response rate (ORR), disease control rate (DCR), overall survival (OS), and drug toxicity were also evaluated. Results: 26 patients received apatinib combined with irinotecan and 29 patients received irinotecan. The ORR in the combination therapy and monotherapy population was 26.9% and 17.2%, respectively. The DCR in the apatinib combined with irinotecan group was higher than in irinotecan monotherapy population (80.8% vs 55.2%, P = .043). Median PFS was 4.2 months in the combination group and 3.3 months in the monotherapy group (P = .020). Median OS was 8.0 months in the combination group and 5.9 months in the monotherapy group (P = .048). Except for ECOG PS 2, PFS and OS were generally consistent across subgroups by sex, age, number of metastatic sites and primary tumor site. The incidence of Grade 3-4 adverse events in combination and monotherapy group was 23.1% and 20.7%, respectively. In apatinib combined with irinotecan group, adverse events that were attributed to apatinib were secondary hypertension (in seven patients, 26.9%), hand-foot syndrome (5,19.2%), and proteinuria (5, 19.2%). Univariate analysis demonstrated that secondary hypertension was considered to be a favorable factor (P = .040) for longer OS in combination therapy group. Conclusions: Compared with chemotherapy alone, anti-angiogenic TKI plus chemotherapy showed better PFS, OS and DCR in advanced or metastatic gastric cancer as second-line or above therapy, with a tolerable and manageable safety profile.

An Exploration of Trifluridine/Tipiracil Monotherapy and in Combination With Bevacizumab or Immune Checkpoint Inhibitors for Patients With Metastatic Colorectal Cancer: A Real-World Study.

BACKGROUND: Trifluridine/tipiracil (TAS-102) has achieved modest efficacy in the late-line treatment of metastatic colorectal cancer. The present study aimed to explore the clinical efficacy and drug toxicities of TAS-102 for patients with metastatic colorectal cancer in real-world clinical setting. METHODS: From October 2020 to February 2022, patients with metastatic colorectal cancer who failed from 2 or more lines of prior therapy and treated with TAS-102 monotherapy, in combination with bevacizumab or immune checkpoint inhibitors (ICIs) were analyzed. The evaluation indicators were progression free survival (PFS), objective response rate , disease control rate (DCR), overall survival (OS) and drug toxicities. RESULTS: A total of 70 patients were enrolled. The objective response rate and DCR were 1.4% and 68.6%. The median PFS and OS were 6.0 (95% CI: 4.1-7.9) and 10.0 (95% CI: 8.3-11.7) months. Compared with TAS-102 monotherapy and TAS-102 plus ICIs, TAS-102 plus bevacizumab obtained superior DCR (75.9% vs. 50% vs. 40%, P = .047), PFS (6.3m vs. 3.0 m vs. 3.0 m, P = .041) and OS (12.0 m vs. 6.5 m vs. 6.0m, P = .013). Patients without prior regorafenib or fruquintinib therapy obtained better median PFS (6.3 vs. 4.3 m, P = .031) and OS (NR vs. 9.0 m, P = .036). Other indicators, including age, tumor site, KRAS status and use of fluoropyrimidine as last regimen before TAS-102, did not affect the clinical efficacy of TAS-102. The most frequent adverse events were leukopenia, neutropenia, anemia, fatigue, nausea, and vomiting. CONCLUSION: In real-world clinical setting, TAS-102 showed consistent clinical efficacy and manageable safety with previous prospective clinical studies. Compared with monotherapy and TAS-102 plus ICIs, TAS-102 plus bevacizumab demonstrated better clinical efficacy for metastatic colorectal cancer.

Tailoring second-line or above therapy for patients with advanced or metastatic gastric cancer: A multicenter real-world study.

Background: There is currently still a lack of effective therapeutic manner after the failure of first-line therapy for patients with advanced or metastatic gastric cancer. The present study aimed to evaluate the clinical efficacy and safety of different treatment strategies as second-line or above therapy for patients with advanced or metastatic gastric cancer. Methods: This was an observational multicenter real-world study. From January 2018 to December 2020, advanced or metastatic gastric cancer patients who have failed prior therapy were enrolled and treated with chemotherapy, anti-angiogenic TKIs (tyrosine kinase inhibitors) + chemotherapy or TKIs + ICIs (immune checkpoint inhibitors). In this study, progression free survival (PFS) was the primary end-point. Other evaluation indicators were objective response rate (ORR), disease control rate (DCR), overall survival (OS) and drug toxicities. Results: 162 patients were enrolled, of which 61 patients received chemotherapy, 47 patients received TKIs plus chemotherapy, and 54 patients received TKIs + ICIs. No statistically significant difference existed in ORR among groups (16.4% vs. 19.1% vs. 18.5%, p = 0.924). Patients who received TKIs plus chemotherapy obtained better DCR compared with the chemotherapy group (78.7% vs. 54.1%, p = 0.008), and simultaneously, the median PFS (3.3 m vs. 2.8 m, p = 0.001) and OS (8.0 m vs. 5.8 m, p = 0.005) in TKIs plus chemotherapy group were superior to chemotherapy group. Consistent results were observed in subgroup analysis, including sex, age, ECOG, number of metastatic sites and treatment line. No statistically differences were found between TKIs + ICIs and the chemotherapy group concerning DCR (63.0% vs. 54.1%, p = 0.336), median PFS (3.0 m vs. 2.8 m, p = 0.051) and OS (5.2 m vs. 5.8 m, p = 0.260). Different treatment manner present a special spectrum of adverse events (AEs), and the incidence of Grade 3-4 AEs were 31.1%, 38.3% and 18.5%, respectively. Conclusion: Compared with chemotherapy, anti-angiogenic TKIs plus chemotherapy demonstrated superior second-line or above therapeutic efficacy for advanced or metastatic gastric cancer with well tolerated toxicity. However, TKIs + ICIs failed to demonstrate a clinical advantage over chemotherapy.

Efficacy of regorafenib combined with PD-1 inhibitors in elderly patients with advanced metastatic colorectal cancer.

OBJECTIVE: This is the first clinical study that wants to investigate the treatment patterns, clinical outcomes, and prognostic factors of regorafenib plus PD-1 inhibitors therapy in Chinese elderly patients with advanced colorectal cancer. METHODS: A cohort of metastatic colorectal cancer patients 60 years or older who received treatment with regorafenib combined with PD-1 inhibitors was included in our analysis. The endpoints included overall survival (OS), progression-free survival (PFS), and prognostic factors. RESULTS: In total, 24 patients were enrolled with the median age of 68 years, and 62.5% were female. The median OS and PFS were 15.03 months (95% CI 7.0-23.0) and 4.0 months (95% CI 1.8-6.2), respectively. The objective response rate was 8.3%, and the disease control rate was 70.8%. Patients previously treated with regorafenib had a longer median PFS than those without (6.3 versus 2.8 months). In terms of final daily doses, it showed a trend toward better PFS (median PFS was 10.0 months) in high-dose group (daily dose above 80 mg of regorafenib) compared to low-dose group (daily dose no more than 80 mg of regorafenib) (median PFS was 3.5 months). CONCLUSIONS: This real-world evidence confirms that Chinese elderly patients with advanced colorectal cancer may benefit from the treatment of regorafenib combined with PD-1 inhibitors, similarly with this combination therapy strategies in all age patients.

Microsatellite stable metastatic colorectal cancer without liver metastasis may be preferred population for regorafenib or fruquintinib plus sintilimab as third-line or above therapy:A real-world study.

Objectives: The antitumor activity of nivolumab plus regorafenib in colorectal cancer from a phase Ib REGONIVO study is encouraging. The present study was conducted to evaluate the efficacy and safety of regorafenib or fruquintinib plus sintilimab as third-line or above therapy in patients with microsatellite stable (MSS) metastatic colorectal cancer. Methods: Patients with MSS metastatic colorectal cancer who have failed from prior treatment and received regorafenib or fruquintinib plus sintilimab as third-line or above therapy from January 2019 to December 2020 were prospectively analyzed based on real-world clinical practice. The primary end point was progression free survival (PFS). Secondary end points included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. Results: 42 patients received regorafenib plus sintilimab(RS), and the other 30 patients received fruquintinib plus sintilimab(FS). In the general population, the ORR and DCR were 13.9% and 70.8%, and the median PFS and OS was 4.2(95% CI=2.9-5.5) and 10.5 (95% CI=8.6-12.4) months, respectively. There were no statistically significant differences between RS and FS group in PFS (3.5(2.2-4.8) vs. 5.5(3.5-7.5) months, P=0.434) and OS (11.0(7.0-15.0) vs. 10.5(3.8-17.2) months, P=0.486). Subgroup analysis suggested that patients without liver metastasis responded well to this combination regimen (ORR: 21.4% vs. 9.1%) and obtained better OS (26(8.8-43.2) vs. 10.0(7.4-12.6) months, P=0.016). The incidence of Grade 3-4 adverse events (AEs) was 15.3% and the toxicities were generally tolerable and manageable. Conclusions: Regorafenib or fruquintinib plus sintilimab as third-line or above therapy provide a feasible treatment regimen for MSS metastatic colorectal cancer with tolerated toxicity. Patients without liver metastasis may be the preferred population for this combination regimen.

bHLH010/089 Transcription Factors Control Pollen Wall Development via Specific Transcriptional and Metabolic Networks in Arabidopsis thaliana.

The pollen wall is a specialized extracellular cell wall that protects male gametophytes from various environmental stresses and facilitates pollination. Here, we reported that bHLH010 and bHLH089 together are required for the development of the pollen wall by regulating their specific downstream transcriptional and metabolic networks. Both the exine and intine structures of bhlh010 bhlh089 pollen grains were severely defective. Further untargeted metabolomic and transcriptomic analyses revealed that the accumulation of pollen wall morphogenesis-related metabolites, including polysaccharides, glyceryl derivatives, and flavonols, were significantly changed, and the expression of such metabolic enzyme-encoding genes and transporter-encoding genes related to pollen wall morphogenesis was downregulated in bhlh010 bhlh089 mutants. Among these downstream target genes, CSLB03 is a novel target with no biological function being reported yet. We found that bHLH010 interacted with the two E-box sequences at the promoter of CSLB03 and directly activated the expression of CSLB03. The cslb03 mutant alleles showed bhlh010 bhlh089-like pollen developmental defects, with most of the pollen grains exhibiting defective pollen wall structures.

Molecular subtypes based on Wnt-signaling gene expression predict prognosis and tumor microenvironment in hepatocellular carcinoma.

Based on increasing research evidence, hepatocellular carcinoma (HCC) is heterogeneous, and genetic profiling has led to the identification of multiple subtypes of this disease. To advance our knowledge and the ability to use individualized medicine in the treatment of HCC, it is essential to perform a complete and methodical characterization of various molecular subtypes. The canonical Wnt/ß-catenin pathway is an evolutionarily conserved complicated signaling mechanism that plays a role in carcinogenesis and progression of HCC. In this study, we acquired RNA sequencing, somatic mutation, and clinical data from 701 patients from The Cancer Genome Atlas and Gene Expression Omnibus databases and stratified patients into two subgroups: WNT-high and WNT-low. In general, the WNT-high subtype is associated with an immunosuppressive microenvironment, poor prognosis, cancer-related pathways, and a low response to immune checkpoint therapy. We also found that WNT3 is negatively linked to CD8+ T-cell infiltration using multiple immunofluorescence assays. Finally, we developed a WNT-related prognostic model to predict the survival time of patients with HCC. In summary, we developed a new classification scheme for HCC based on Wnt signaling signatures. This classification produced substantial clinical effects, both in terms of assessing patient prognosis and immunotherapy administered to patients with HCC.

Successes and failures of immunotherapy for gastric cancer.

Many exploratory clinical studies have been conducted on immune checkpoint inhibitors (ICIs) as new therapeutic approaches for the first-line treatment of patients with advanced gastric cancer. Despite varying interpretations of the successes and failures of this clinical research, most analyses have focused on the results from the perspective of exploring the superiority of immunotherapy. Consequently, the role of chemotherapy as an important partner of immunotherapy in first-line combination therapy regimens for gastric cancer has attracted less attention. Here, we explore and analyze first-line immunotherapies for gastric cancer from the perspective of chemotherapy, to understand reasons for the failure of studies and to indicate directions for future clinical research.

Preclinical studies of the triazolo[1,5-a]pyrimidine derivative WS-716 as a highly potent, specific and orally active P-glycoprotein (P-gp) inhibitor.

Multidrug resistance (MDR) is the main cause of clinical treatment failure and poor prognosis in cancer. Targeting P-glycoprotein (P-gp) has been regarded as an effective strategy to overcome MDR. In this work, we reported our preclinical studies of the triazolo[1,5-a]pyrimidine-based compound WS-716 as a highly potent, specific, and orally active P-gp inhibitor. Through direct binding to P-gp, WS-716 inhibited efflux function of P-gp and specifically reversed P-gp-mediated MDR to paclitaxel (PTX) in multiple resistant cell lines, without changing its expression or subcellular localization. WS-716 and PTX synergistically inhibited formation of colony and 3D spheroid, induced apoptosis and cell cycle arrest at G2/M phase in resistant SW620/Ad300 cells. In addition, WS-716 displayed minimal effect on the drug-metabolizing enzyme cytochrome P4503A4 (CYP3A4). Importantly, WS-716 increased sensitivity of both pre-clinically and clinically derived MDR tumors to PTX in vivo with the T/C value of 29.7% in patient-derived xenograft (PDX) models. Relative to PTX treatment alone, combination of WS-716 and PTX caused no obvious adverse reactions. Taken together, our preclinical studies revealed therapeutic promise of WS-716 against MDR cancer, the promising data warrant its further development for cancer therapy.

Clinical Study of Anlotinib as Third-Line or Above Therapy in Patients With Advanced or Metastatic Gastric Cancer: A Multicenter Retrospective Study.

Background: The present study was conducted to evaluate the efficacy and safety of anlotinib as third-line or above therapy for patients with advanced or metastatic gastric cancer. Methods: Patients with advanced or metastatic gastric cancer who have failed from second-line treatment and treated with anlotinib monotherapy or combined with chemotherapy or immunotherapy from June 2019 to January 2021 in 3 institutions across China were retrospectively analyzed. The primary end point was progression free survival (PFS). Secondary end points included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety. Results: 43 patients with advanced or metastatic gastric cancer who have failed prior treatment received anlotinib monotherapy or combination therapy as third-line or above therapy. In the general population, 4 patients achieved PR, 21 patients had SD and 18 patients had PD. The overall ORR and DCR were 9.3% (4/43) and 58.1% (25/43), respectively. Median PFS and OS were 3.0 months (95% CI=2.5-3.5) and 6.0 months (95% CI=4.4-7.6), respectively. The incidence of Grade 3-4 adverse events(AEs) was 34.9%. Subgroup analysis suggested that the ORR of anlotinib combination therapy was superior than anlotinib monotherapy, but with similar PFS and OS. The clinical benefit of anlotinib was not associated with previously anti-angiogenesis therapy with apatinib. Conclusions: Anlotinib monotherapy or combination therapy provide a feasible third-line or above therapeutic strategy in patients with advanced or metastatic gastric cancer a median PFS of 3.0 months and median OS of 6.0 months was obtained with well tolerated toxicity.

The Efficacy and Safety of Sintilimab Combined With Nab-Paclitaxel as a Second-Line Treatment for Advanced or Metastatic Gastric Cancer and Gastroesophageal Junction Cancer.

Background: Unresectable advanced or recurrent gastric cancer patients have a poor prognosis. PD-1 monotherapy regimen and PD-1 combined chemotherapy regimen have become the standard third- and first-line treatment for advanced gastric cancer, respectively. However, the status of immune checkpoint inhibitors in the second-line treatment for advanced gastric cancer has not been established. The combination of chemotherapy and anti-PD-1 antibody has been demonstrated to have a synergistic effect. In this study, we aimed to evaluate the efficacy and safety of sintilimab combined with nab-paclitaxel in the second-line treatment for advanced gastric cancer (GC)/gastroesophageal junction (GEJ) cancer patients. Patients and Methods: We retrospectively analyzed patients with advanced GC/GEJ cancer that progressed after first-line systemic therapies with sintilimab combined with nab-paclitaxel from April 1, 2019 to December 31, 2021. The primary endpoint was progression-free survival (PFS). The secondary endpoints included objective response rate (ORR), disease control rate (DCR), and safety. Results: Thirty-nine patients were enrolled and eligible for response assessment. Complete response (CR) was not observed, 15 patients achieved partial response (PR), 16 patients had stable disease (SD) and 9 patients had progressive disease (PD). The ORR and DCR were 15 (38.5%) and 31 (79.5%), respectively. Median PFS was 5.4 months (95%CI: 3.072-7.728). PFSs between different subgroups were analyzed. The results showed that gender, age, Human epidermal growth factor receptors 2 (HER2) status, PD-L1 expression, primary tumor site and chemotherapy cycles had no significant effect on PFS. Most of the adverse events (AEs) were of grade 1-2 and manageable. The common treatment-related adverse events of grade 3 or 4 included anemia (12.8%), neutropenia (12.8%), leukopenia (10.3%), hand-foot syndrome (7.7%), thrombocytopenia (7.7%). The potential immune-related adverse events (irAEs) were grade 1 pneumonia (1 pts [2.6%]) and grade 4 hepatitis (1 pts [2.6%]). There were no treatment-related deaths. Conclusion: These results indicate that sintilimab combined with nab-paclitaxel exhibits good anti-tumor activity and an acceptable safety profile as a second-line treatment for advanced or metastatic gastric cancer. These results warrant further investigation and evaluation to identify patients who can benefit more from the combined treatment strategy.

Retrospective Study on the Efficacy and Safety of Pyrotinib-Based Therapy for HER2-Positive Nonbreast Advanced Solid Tumors.

Background: Human epidermal growth factor receptor 2 (HER2) is a member of the large ErbB family and an important oncogene in many solid tumors. Pyrotinib has been approved for the treatment of HER2-positive, recurrent, or metastatic breast cancer. However, there are very few clinical studies on pyrotinib in other HER2-positive solid tumors. Therefore, more evidence of clinical research is impendently needed to shepherd pyrotinib-based therapy in HER2-positive nonbreast advanced solid tumors. Patients and Methods. We performed a retrospective analysis of HER2-positive nonbreast advanced solid tumors patients with HER2 amplification or mutations who were administered with pyrotinib-based therapy in Henan Cancer Hospital between July 1, 2019, and December 2, 2021. In our research, 25 eligible patients were included with 16 patients with lung cancer, 6 patients with gastric cancer, 2 patients with colorectal cancer, and 1 patient with cholangiocarcinoma. Progression-free survival (PFS) is our main research end point. Results: The median PFS was 188 days (95% CI: 83-not reached (NR)), and overall survival (OS) was 250 days (95% CI: 188-NR), respectively. 16 patients with lung cancer had a median PFS of 204 days (95% CI: 55-NR) and 6 patients with gastric cancer had PFS of 142 days (95% CI: 83-NR), respectively. The median OS was 366 days (95% CI: 248-NR) in patients with lung cancer and 179 days (95% CI: 90-NR) in patients with gastric cancer. The median PFS and OS of patients receiving >3 line treatment were lower than those receiving ≤3 line treatment (PFS: 188 days vs 204 days, p = 0.92; OS: 188 days vs 366 days, p = 0.43). All 25 patients can be evaluated. The objective response rate (ORR) was 24%, and the disease control rate (DCR) was 68%. Lung cancer ORR was 25%, and gastric cancer ORR was 16.7%. In addition, the DCR of lung cancer was 62.5% and that of gastric cancer was 66.7%. In addition, the ORR and DCR of patients receiving treatment ≤3 lines were higher than those receiving treatment >3 lines (ORR: 35.7% vs 9.1%, p = 0.18; DCR: 71.4% vs 63.6%, p > 0.99). The most common treatment-related adverse events (TRAEs) were diarrhea (84%), but only 3 patients (12%) reported grade 3 diarrhea with good control. Conclusion: These results show that in HER2-positive nonbreast advanced solid tumors, the treatment based on pyrotinib regimen has good antitumor activity and acceptable safety. This retrospective study aims to promote larger clinical studies to further clarify the efficacy and safety of pyrotinib in the treatment of nonbreast solid tumors.

Fruquintinib Enhances the Antitumor Immune Responses of Anti-Programmed Death Receptor-1 in Colorectal Cancer.

Background: Programmed death receptor-1 (PD-1) blockade shows little benefit in patients with microsatellite-stable colorectal cancer (MSS-CRC). Fruquintinib is a China-made anti-angiogenic drug which is approved for the third line therapy in mCRC. This study investigates the effect of the combination of fruquintinib and PD-1 blockade on MSS-CRC and its relative mechanisms. Methods: The mouse allograft tumor models that represent MSS and microsatellite instability (MSI) CRC were established using murine CT26 and MC38 colon cancer cells, respectively, to assess the treatment efficacy. The percentages of immune cells were detected in the peripheral blood, spleen and tumor tissues in the tumor-bearing mice by flow cytometry analysis. Angiogenesis in tumor tissues was detected by immunofluorescence. The safety of drug treatment was evaluated by histopathology analysis in murine main organs. The efficacy of the combination of fruquintinib and sintilimab were verified in the treatment of MSS-CRC patients. Results: Our results showed that the combination of fruquintinib and sintilimab exhibited the strongest inhibition of tumor growth and achieved the longest survival time in mice bearing MC38 or CT26 xenograft tumors, compared to fruquintinib and sintilimab alone. Mechanistically, the combination of fruquintinib and sintilimab reduced angiogenesis, reprogramed the vascular structure, enhanced the infiltration of CD8+T cells (p<0.05), CD8+TNFα+ (p<0.05) T cells and CD8+IFNγ+ (p<0.05) T cells and reduced the ratios of MDSCs and macrophages in mice. There was no obvious toxicity observed in the main organs of the tumor-bearing mice with the combined treatment. Moreover, the treatment using the combination of fruquintinib and sintilimab achieved effective response in five patients with refractory advanced MSS CRC. Conclusion: Our results show that the combination of fruquintinib and sintilimab greatly inhibits CRC growth by altering tumor immune microenvironment. This study provides the rational for using the combination of fruquintinib and anti-PD-1 antibody for the treatment of advanced CRC.