Phase Ib study of anlotinib combined with TQB2450 in pretreated advanced biliary tract cancer and biomarker analysis.

BACKGROUND AND AIMS: We evaluated the efficacy and safety of the antiangiogenic tyrosine kinase inhibitor anlotinib plus TQB2450, a programmed death-ligand 1 inhibitor in pretreated advanced biliary tract cancers (BTCs). APPROACH AND RESULTS: In this pooled analysis of two single-center, phase Ib clinical trials (TQB2450-Ib-05 and TQB2450-Ib-08 trials), 66 patients with advanced BTCs who had progressed or declined or were ineligible for first-line chemotherapy were included. With the treatment of anlotinib plus TQB2450, two patients achieved complete response, and 12 had a partial response assessed by Response Evaluation Criteria in Solid Tumors 1.1, yielding an objective response rate of 21.21%, a disease control rate (DCR) of 72.73%, and a clinical benefit rate (CBR) of 42.42%. With a median follow-up of 19.68 months, median progression-free survival (PFS) and overall survival (OS) were 6.24 (95% confidence interval [CI], 4.11-8.25) and 15.77 (95% CI, 10.74-19.71) months, respectively. Adverse events (AEs) were reported in 64 (96.97%) patients, and the most common grade 3 or worse treatment-related AEs included elevated levels of aspartate aminotransferase (7.58%), alanine aminotransferase (6.06%), and hypertension (6.06%). Patients with high tumor mutational burden (TMB; ≥5 mutations/Mbp) had a better CBR (70.8% vs. 22.2%), longer OS (14.32 vs. 9.64 months), and a trend toward longer PFS (7.03 vs. 4.06 months). Patients with kirsten rat sarcoma viral oncogene homolog ( KRAS ) mutations showed a lower CBR (12.5% vs. 58.8%) and shorter PFS (2.02 vs. 6.80 months) and OS (10.53 vs. 13.13 months). CONCLUSIONS: Anlotinib combined with TQB2450 showed promising efficacy and was well tolerated in advanced BTCs. KRAS mutation and high TMB might serve as predictors of treatment efficacy.

Gremlin1: a BMP antagonist with therapeutic potential in Oncology.

Gremlins, originating from early 20th-century Western folklore, are mythical creatures known for causing mechanical malfunctions and electronic failures, aptly dubbed "little devils". Analogously, GREM1 acts like a horde of these mischievous entities by antagonizing the bone morphogenetic protein (BMP signaling) pathway or through other non-BMP dependent mechanisms (such as binding to Fibroblast Growth Factor Receptor 1and Epidermal Growth Factor Receptor) contributing to the malignant progression of various cancers. The overexpression of GREM1 promotes tumor cell growth and survival, enhances angiogenesis within the tumor microenvironment, and creates favorable conditions for tumor development and dissemination. Consequently, inhibiting the activity of GREM1 or blocking its interaction with BMP presents a promising strategy for suppressing tumor growth and metastasis. However, the role of GREM1 in cancer remains a subject of debate, with evidence suggesting both oncogenic and tumor-suppressive functions. Currently, several pharmaceutical companies are researching the GREM1 target, with some advancing to Phase I/II clinical trials. This article will provide a detailed overview of the GREM1 target and explore its potential role in cancer therapy.

Serum Biomarker Status with a Distinctive Pattern in Prognosis of Gastroenteropancreatic Neuroendocrine Carcinoma.

OBJECTIVE: Gastroenteropancreatic neuroendocrine carcinoma (GEPNEC) is a major research focus, but the application of biomarkers to guide its prognostication and management is unsatisfying. Clinical values of conventional serum biomarkers, neuron-specific enolase (NSE), carcinoembryonic antigen (CEA), and carbohydrate antigen 19-9 (CA199) warrant scrutiny. METHODS: Patients diagnosed with GEPNEC with baseline NSE, CEA, and CA199 levels provided in Peking University Cancer Hospital were retrospectively studied. Relationships between biomarkers and prognosis were investigated by the χ2 test, Kaplan-Meier analysis, and univariate and multivariate Cox regression analyses. RESULTS: A total of 640 GEPNEC patients were enrolled. NSE, CEA, and CA199 were elevated in 59.5%, 28.5%, and 21.3% of the population, respectively. Higher NSE had worse median overall survival (OS) (17.0 months vs. not reached, hazard ratio = 2.77 [2.06, 3.73], p < 0.001), and so did patients with higher CEA and CA199. Multivariable analysis confirmed that NSE and CA199 correlated with OS independently. Baseline NSE level and NSE remission predicted OS and the response of patients with first-line etoposide plus cisplatin (EP) treatment. Furthermore, we combined NSE/CEA/CA199 to segregate GEPNEC into novel subgroups, namely, adenocarcinoma-like NEC (ALN), neuroendocrine-like NEC (NLN), and triple-normal NEC (TNN). The groups shared distinctive clinicopathologic features and prognosis (21.0 months vs. 17.1 months vs. not reached, p < 0.001). The EP regimen remained the priority treatment option in NLN/TNN, while ALN was predisposed to "adenocarcinoma-like chemotherapy." CONCLUSIONS: Elevation of NSE, CEA, or CA199 was common and independently indicates poor prognosis in GEPNEC patients. Serum biomarker-based subtypes suggest meaningful clinical implications and appropriate therapeutic approaches, illuminating promising ways to characterize the prognosis of GEPNEC.

Phase I study of the recombinant humanized anti-HER2 monoclonal antibody-MMAE conjugate RC48-ADC in patients with HER2-positive advanced solid tumors.

PURPOSE: RC48 contains the novel humanized anti-HER2 antibody hertuzumab conjugated to MMAE via a cleavable linker. A phase I study was initiated to evaluate the toxicity, MTD, PK, and antitumor activity of RC48 in patients with HER2-overexpressing locally advanced or metastatic solid carcinomas, particularly gastric cancer. PATIENTS AND METHODS: This was a 2-part phase I study. Successive cohorts of patients received escalating doses of RC48 (0.1 mg/kg, 0.5 mg/kg, 1.0 mg/kg, 2.0 mg/kg, 2.5 mg/kg, and 3.0 mg/kg). Dose expansion proceeded at the dose of 2.0 mg/kg Q2W. The efficacy and safety set included all patients who received at least one dose of RC48. RESULTS: Fifty-seven patients were enrolled, the MTD was unavailable due to termination of 3.0 mg/kg cohort; 2.5 mg/kg Q2W was declared the RP2D. RC48 was well tolerated, the most frequent grade 3 or worse TRAEs included neutropenia (19.3%), leukopenia (17.5%), hypoesthesia (14.0%), and increased conjugated blood bilirubin (8.8%). Four deaths occurred during the whole study, three of which were believed to be related to RC48. Overall, ORR and DCR were 21.0% (12/57) and 49.1% (28/57). Notably, patients who were HER2 IHC2+/FISH- responded similarly to those who were IHC2+/FISH+ and IHC3+, with ORRs of 35.7% (5/14), 20% (2/10), and 13.6% (3/22), respectively. In patients who were pretreated with HER2-targeted drugs, RC48 also showed promising efficacy, with ORR of 15.0% (3/20) and DCR of 45.0% (9/20). CONCLUSION: RC48 was well tolerated and showed promising antitumor activity in HER2-positive solid tumors, including gastric cancer with HER2 IHC 2+/FISH- status. CLINICAL TRIAL INFORMATION: NCT02881190.

Dynamic monitoring of circulating tumour cells to evaluate therapeutic efficacy in advanced gastric cancer.

BACKGROUND: This study was intended to determine the clinical significance of circulating tumour cells (CTCs) in patients with advanced gastric cancer (AGC), particularly the potential role of CTCs for dynamic monitoring of the therapeutic response. METHODS: A single-centre, prospective study was undertaken in 136 patients with newly diagnosed AGC. The patients' CTCs were enumerated using CellSearch at baseline and at the first response evaluation. In 15 patients whose clinical condition permitted longitudinal study, CTCs were longitudinally enumerated during treatment. RESULTS: Following 6 weeks of chemotherapy, an unfavourable post-therapy CTC level (⩾3 CTCs per 7.5 ml) was closely correlated with the objective response rate (P=0.016) and the disease control rate (P=0.013), and it also independently predicted a shorter progression-free survival and overall survival. Particularly, conversion to a favourable CTC level following therapy improved the prognosis, but patients who changed to an unfavourable CTC level fared significantly worse. Elevated CTCs during therapy may be associated with a poor prognosis. CONCLUSIONS: Post-therapy CTC level may help in evaluating therapeutic response in patients with AGC and predicting their prognosis. In addition, changes in CTCs following therapy may be useful in rapidly identifying ineffective treatments and poor prognosis.

Aneuploidy of chromosome 8 in circulating tumor cells correlates with prognosis in patients with advanced gastric cancer.

OBJECTIVE: Previous work indicated that aneuploidy of chromosome 8 in circulating tumor cells (CTCs) correlated with therapeutic efficacy for advanced gastric cancer (AGC) patients. In this follow-up study performed on the same population of AGC patients, we investigated whether and how aneuploidy of chromosome 8 in CTCs correlates with patients' clinical prognosis. METHODS: The prospective study was performed on 31 patients with newly diagnosed AGC. Previously established integrated subtraction enrichment (SE) and immunostaining-fluorescence in situ hybridization (iFISH) platform was applied to identify, enumerate and characterize CTCs. Quantification of CTCs and analysis of their aneuploidy of chromosome 8 were performed on patients before and after therapy. RESULTS: CTCs were measured in 93.5% of AGC patients, and two CTC subtypes with diverse threshold values were identified, multiploid CTCs with the threshold of ≥2 per 7.5 mL and multiploid plus triploid CTCs with the threshold of ≥4, which were found to significantly correlate with poor progression-free survival (PFS) and overall survival (OS). In particular, patients with ≥10% increased multiploid CTCs after an initial 6 weeks of therapy had poor PFS and OS, whereas improved PFS and OS were observed on those who had ≥10% decreased multiploid CTCs. After adjusting for clinically significant factors, ≥10% increased post-therapy multiploid CTCs was the only independent predictor of PFS and OS. CONCLUSIONS: Aneuploidy of CTCs correlates with prognosis of AGC patients. Quantitative comparison monitoring multiploid CTCs before and after therapy may help predict improved or inferior prognosis and chemoresistance.

[Trastuzumab combined with chemotherapy in patients with HER2-positive chemo-refractory advanced gastric or gastro-esophageal junction adenocarcinoma].

OBJECTIVE: To evaluate the efficacy and safety of trastuzumab combined with chemotherapy in the treatment for HER-2-positive chemo-refractory advanced gastric or gastro-esophageal junction adenocarcinoma. METHODS: Twenty consecutive cases of chemo-refractory advanced gastric or gastro-esophageal junction adenocarcinoma treated in Peking University Cancer Hospital between 2009 June and 2013 August were included in this study. The patients with adenocarcinoma were previously confirmed and were eligible if their tumor showed overexpression of HER-2+++ by immunohistochemistry or HER-2 gene amplification-positive by FISH, and if they failed to at least one previous chemotherapy. Response and toxicities were evaluated with RECIST 1.0 and CTC AE 3.0 criteria. RESULTS: The twenty patients received trastuzumab plus second- or later-line chemotherapy, consisting of nine platinum with fluoropyrimidines, five paclitaxel with fluoropyrimidines, three fluoropyrimidines monotherapy, two irinotecan monotherapy, and one docetaxel monotherapy. In these 20 cases, 3 PR (15.0%) and 10 SD (50.0%) were achieved, with a disease control rate of 65.0%. The median PFS was 6.1 months (95%CI 3.0-9.2) and median OS was 11.1 months (95%CI 8.4-13.7). The median cycle number of Trastuzumab administration was 6.5. The patients treated with Trastuzumab ≥ 6 times had a median OS of 13.8 months, significantly longer than that of 9.5 months in the patients treated <6 times (P < 0.001). The patients treated with Trastuzumab ≥ 6 times had a median PFS of 7.8 months, significantly longer than that of 3.7 months in patients treated <6 times (P = 0.029). Among the 20 cases, loss of appetite (13 cases of grade 1-2), neutropenia (12 cases of grade 1-2 and 3 cases of grade 3-4) and fatigue (9 cases of grade 1-2 and 3 cases of grade 3-4) were the most frequent adverse events. No cardiac events including asymptomatic decreases in LVEF ≥ 10% and no treatment-related death were recorded. CONCLUSIONS: Combination of trastuzumab with chemotherapy is effective and safe in patients with HER2-positive advanced chemo-refractory gastric or gastro-esophageal junction adenocarninoma. However, prospective studies are warranted to further confirm its efficacy and safety.

Rechallenge with immune checkpoint inhibitors for advanced esophageal squamous cell carcinoma.

BACKGROUND: Despite the widespread use of immune checkpoint inhibitors (ICIs) in cancer treatment, disease progression remains common in the majority of patients and subsequent therapeutic options for this population are limited. ICI rechallenge has been validated favorably in terms of efficacy and safety in many cancer types, while data in esophageal squamous cell carcinoma (ESCC) are still lacking. METHODS: Clinical and pathological characteristics of advanced ESCC patients who received ICI rechallenge were collected retrospectively. The primary outcomes of interest were the disease control rate (DCR) and progression-free survival (PFS). Treatment-related adverse events were also recorded. We categorized patients into primary resistance and secondary resistance based on a 6-month disease control duration following the initial immunotherapy and further conducted exploratory analyses. RESULTS: A retrospective cohort study spanning January 2018 and October 2023, at Peking University Cancer Hospital, scrutinized 45 advanced ESCC patients undergoing two lines of ICI-based therapies (ICI-1 and ICI-2). The initial therapeutic approach involved combining ICIs with chemotherapy, and the ICI rechallenge primarily comprised ICIs and angiogenesis inhibitors. The median PFS for ICI-1 was 6.7 months with a disease control rate of 88.9 %. Following the ICI rechallenge, the median PFS and disease control rate remained at 3.2 months and 73.3 %, respectively. It is noteworthy that patients with secondary resistance to ICI-1 exhibited a higher 6-month PFS rate (29.6 % v.s. 11.1 %) in the ICI-2 stage. Any grade of treatment-related adverse events was observed in 29 (64.4 %) and 18 (40.0 %) patients at ICI-1 and ICI-2. The incidence of treatment-related adverse events in grades 3-4 was 9.1 % at ICI-1 and 9.1 % at ICI-2. CONCLUSION: ICI rechallenge may offer a potential survival benefit and a favorable safety profile for patients with ESCC who have progressed after initial immunotherapy. Patients exhibiting acquired resistance during initial immunotherapy are more likely to achieve prolonged disease control after undergoing rechallenge therapy. Prospective studies are required to further explore the optimal combined therapy and select targeted population.

Recent developments in immunotherapy for gastrointestinal tract cancers.

The past few decades have witnessed the rise of immunotherapy for Gastrointestinal (GI) tract cancers. The role of immune checkpoint inhibitors (ICIs), particularly programmed death protein 1 (PD-1) and PD ligand-1 antibodies, has become increasingly pivotal in the treatment of advanced and perioperative GI tract cancers. Currently, anti-PD-1 plus chemotherapy is considered as first-line regimen for unselected advanced gastric/gastroesophageal junction adenocarcinoma (G/GEJC), mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) colorectal cancer (CRC), and advanced esophageal cancer (EC). In addition, the encouraging performance of claudin18.2-redirected chimeric antigen receptor T-cell (CAR-T) therapy in later-line GI tract cancers brings new hope for cell therapy in solid tumour treatment. Nevertheless, immunotherapy for GI tumour remains yet precise, and researchers are dedicated to further maximising and optimising the efficacy. This review summarises the important research, latest progress, and future directions of immunotherapy for GI tract cancers including EC, G/GEJC, and CRC.

Prognostic and predictive value of angiogenesis-associated serum proteins for immunotherapy in esophageal cancer.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have significantly improved patient survival in multiple cancers. However, therapy response in esophageal cancer is limited to subgroups of patients and clinically useful predictive biomarkers are lacking. METHODS: We collected a series of plasma samples from 91 patients with esophageal cancer before and after ICI treatment. The Olink Immuno-Oncology panel (92 proteins) with proximity extension assays was used to detect the dynamic changes in plasma and potential biomarkers associated with treatment outcomes. We screened all survival-related proteins and established a risk score model to better predict the prognosis and treatment response in patients with esophageal cancer immunotherapy. RESULTS: We found that 47 out of 92 quantified proteins had significant changes in plasma levels during ICI treatment (p<0.050), and these changed proteins were involved in immune-related reactions, such as intercellular adhesion and T-cell activation. Notably, the baseline levels of three angiogenesis-related proteins (IL-8, TIE2, and HGF) were significantly associated with the survival outcomes of patients treated with ICIs (p<0.050). According to these prognostic proteins, we established an angiogenesis-related risk score, which could be a superior biomarker for ICI response prediction. In addition, antiangiogenic therapy combined with ICIs significantly improved overall survival compared with ICI monotherapy (p=0.044). CONCLUSIONS: An angiogenesis-related risk score based on three proteins (IL-8, TIE2, and HGF) could predict ICI response and prognosis in patients with esophageal cancer, which warrants verification in the future. Our study highlights the potential application of combining ICIs and antiangiogenic therapy and supports Olink plasma protein sequencing as a liquid biopsy method for biomarker exploration.

Disitamab vedotin (RC48) plus toripalimab for HER2-expressing advanced gastric or gastroesophageal junction and other solid tumours: a multicentre, open label, dose escalation and expansion phase 1 trial.

Background: Although the antibody-drug conjugates (ADCs) have significantly improved the survival outcomes of patients with human epidermal receptor 2 (HER2)-expressing gastric or gastroesophageal junction (G/GEJ) cancer, the efficacy of ADC used as a single agent is limited. Therefore, it is necessary to investigate effective and safe combination regimens. Preclinical data indicated a synergetic antitumour effect of RC48 and programmed cell death protein 1 (PD-1) inhibitors. We aimed to evaluate the safety and efficacy of RC48 plus toripalimab in patients with HER2-expressing G/GEJ cancer and other solid tumours. Methods: This was a open-label, multicentre, phase 1 trial performed at three hospitals in China. Eligible patients had advanced G/GEJ cancer or other solid tumours with HER2 IHC≥1 or ISH positivity and were refractory to at least one line of treatment, or standard treatment was intolerable or unavailable for these patients. This study followed a "3 + 3" design with predefined RC48 dosages of 2.0 mg/kg and 2.5 mg/kg plus toripalimab 3 mg/kg, once every 2 weeks (q2w). The primary objectives were to evaluate the safety and determine the recommended phase II dose (RP2D), and the secondary objectives included assessing the pharmacokinetics (PK) and preliminary efficacy. This study was registered with ClinicalTrials.gov, NCT04280341. Findings: Between July 13, 2020 and August 30, 2022, 56 patients, including 30 patients with G/GEJ cancer and 26 patients with other solid tumours, were enrolled and received RC48 plus toripalimab (n = 7 for RC48 2.0 mg/kg, toripalimab 3 mg/kg, q2w; n = 49 for RC48 2.5 mg/kg, toripalimab 3 mg/kg, q2w). No dose-limiting toxic effects occurred. The RP2D was declared as RC48 2.5 mg/kg plus toripalimab 3 mg/kg, q2w. The most common grade 3 adverse events were a decreased neutrophil count (n = 13), and a decreased white blood cell count (n = 7). The efficacy assessment was completed for 52 patients. Among patients with G/GEJ cancer (n = 30), the confirmed objective response rate (ORR) was 43% (12/28, 95% CI 25, 63), median progression-free survival (PFS) was 6.2 months (95% CI 4.0, 6.9), median overall survival (OS) was 16.8 months (95% CI 7.2, NE). The ORR of patients with G/GEJ cancer receiving RP2D (n = 24) reached 50% (11/22, 95% CI 28, 72), with median PFS of 5.1 months (95% CI 1.4, 7.3) and median OS of 14.0 months (95% CI 6.3, NE). Among patients with G/GEJ cancer who received RP2D, a clinical benefit was observed in both HER2-positive and low HER2 expressing populations, with an ORR of 56% (5/9, 95% CI 21, 86) vs. 46% (6/13, 95% CI 19, 75), median PFS of 7.8 months (95% CI 0.9, NE) vs. 5.1 months (95% CI 1.2, 6.9), median OS of NE months (95% CI 4.3, NE) vs. 14.0 months (95% CI 5.1, NE), respectively. Antitumour activity was also observed for other solid tumours, including breast cancer (5/13) and endometrial carcinoma (1/1). Interpretation: Our findings suggested that RC48 plus toripalimab had a manageable safety profile and showed encouraging efficacy in pretreated patients with HER2-positive and low HER2-expressing G/GEJ cancer. The findings of our phase 1 clinical trial support further investigation of HER2-targeted ADC plus immunotherapy in HER2-expressing G/GEJ cancer and pancancer treatment in the future. Funding: Beijing Municipal Medical Research Institutes, Beijing Medical Research Institute (Z200015).

Helicobacter pylori and immunotherapy for gastrointestinal cancer.

Helicobacter pylori infection is associated with the risk of gastrointestinal (GI) cancers; however, its impact on immunotherapy for GI cancers remains uncertain. In this study, we included 10,122 patients who underwent 13C-urea breath tests. Among 636 patients with Epstein-Barr virus-negative microsatellite-stable gastric cancer (GC) who were treated with anti-PD-1/PD-L1 therapy, H. pylori-positive patients exhibited significantly longer immune-related progression-free survival (irPFS) compared with H. pylori-negative patients (6.97 months versus 5.03 months, p < 0.001, hazard ratio [HR] 0.76, 95% confidence interval [CI] 0.62-0.95, p = 0.015). Moreover, the H. pylori-positive group demonstrated a trend of 4 months longer median immune-related overall survival (irOS) than the H. pylori-negative group. H. pylori-positive GC displayed higher densities of PD-L1+ cells and nonexhausted CD8+ T cells, indicative of a "hot" tumor microenvironment. Transcriptomic analysis revealed that H. pylori-positive GC shared molecular characteristics similar to those of immunotherapy-sensitive GC. However, H. pylori-positive patients with DNA mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) colorectal adenocarcinoma and esophageal squamous cell carcinoma (ESCC) had shorter irPFS compared with H. pylori-negative patients (16.13 months versus not reached, p = 0.042, HR 2.26, 95% CI 1.13-4.50, p = 0.021 and 5.57 months versus 6.97 months, p = 0.029, HR 1.59, 95% CI 1.14-2.23, p = 0.006, respectively). The difference in irOS between H. pylori-positive and -negative patients had the same trend as that between dMMR/MSI-H colorectal adenocarcinoma and ESCC patients. We also identified a trend of shorter irPFS and irOS in H. pylori-positive liver cancer and pancreatic cancer patients. In summary, our findings supported that H. pylori infection is a beneficial factor for GC immunotherapy by shaping hot tumor microenvironments. However, in dMMR/MSI-H colorectal adenocarcinoma and ESCC patients, H. pylori adversely affects the efficacy of immunotherapy.

Clinical efficacy and identification of factors confer resistance to afatinib (tyrosine kinase inhibitor) in EGFR-overexpressing esophageal squamous cell carcinoma.

Epidermal growth factor receptor (EGFR) is reportedly overexpressed in most esophageal squamous cell carcinoma (ESCC) patients, but anti-EGFR treatments offer limited survival benefits. Our preclinical data showed the promising antitumor activity of afatinib in EGFR-overexpressing ESCC. This proof-of-concept, phase II trial assessed the efficacy and safety of afatinib in pretreated metastatic ESCC patients (n = 41) with EGFR overexpression (NCT03940976). The study met its primary endpoint, with a confirmed objective response rate (ORR) of 39% in 38 efficacy-evaluable patients and a median overall survival of 7.8 months, with a manageable toxicity profile. Transcriptome analysis of pretreatment tumors revealed that neurotrophic receptor tyrosine kinase 2 (NTRK2) was negatively associated with afatinib sensitivity and might serve as a predictive biomarker, irrespective of EGFR expression. Notably, knocking down or inhibiting NTRK2 sensitized ESCC cells to afatinib treatment. Our study provides novel findings on the molecular factors underlying afatinib resistance and indicates that afatinib has the potential to become an important treatment for metastatic ESCC patients.

Claudin18.2-specific CAR T cells in gastrointestinal cancers: phase 1 trial final results.

Claudin18.2 (CLDN18.2) is highly expressed with the development of various malignant tumors, especially gastrointestinal cancers, and is emerging as a new target for cancer treatment. Satricabtagene autoleucel (satri-cel)/CT041 is an autologous chimeric antigen receptor (CAR) T cell targeting CLDN18.2, and the interim results of the CT041-CG4006 trial were reported in June 2022. Here we present the final results of this single-arm, open-label, phase 1 trial, which evaluated the safety and efficacy of satri-cel in patients with CLDN18.2-positive advanced gastrointestinal cancers. This trial included a dose-escalation stage (n = 15) and a dose-expansion stage in four different cohorts (total n = 83): cohort 1, satri-cel monotherapy in 61 patients with standard chemotherapy-refractory gastrointestinal cancers; cohort 2, satri-cel plus anti-PD-1 therapy in 15 patients with standard chemotherapy-refractory gastrointestinal cancers; cohort 3, satri-cel as sequential treatment after first-line therapy in five patients with gastrointestinal cancers; and cohort 4, satri-cel monotherapy in two patients with anti-CLDN18.2 monoclonal antibody-refractory gastric cancer. The primary endpoint was safety; secondary endpoints included efficacy, pharmacokinetics and immunogenicity. A total of 98 patients received satri-cel infusion, among whom 89 were dosed with 2.5 × 108, six with 3.75 × 108 and three with 5.0 × 108 CAR T cells. Median follow-up was 32.4 months (95% confidence interval (CI): 27.3, 36.5) since apheresis. No dose-limiting toxicities, treatment-related deaths or immune effector cell-associated neurotoxicity syndrome were reported. Cytokine release syndrome occurred in 96.9% of patients, all classified as grade 1-2. Gastric mucosal injuries were identified in eight (8.2%) patients. The overall response rate and disease control rate in all 98 patients were 38.8% and 91.8%, respectively, and the median progression-free survival and overall survival were 4.4 months (95% CI: 3.7, 6.6) and 8.8 months (95% CI: 7.1, 10.2), respectively. Satri-cel demonstrates therapeutic potential with a manageable safety profile in patients with CLDN18.2-positive advanced gastrointestinal cancer. ClinicalTrials.gov identifier: NCT03874897 .

Immune checkpoint inhibitor-induced colitis with endoscopic evaluation in Chinese cancer patients: a single-centre retrospective study.

Background: We investigated the clinical and endoscopic features, management strategies, and outcomes of Chinese cancer patients with immune checkpoint inhibitor (ICI)-induced colitis. Method: This single-centre retrospective study included patients who developed ICI-induced colitis and underwent endoscopic evaluation from June 1, 2019 to October 1, 2023. We analysed clinical features, ICI-induced colitis-related information, management strategies, and outcomes. Results: A total of 25 patients were included; most were male (88%) with a median age of 59 years. Eleven (44%) patients had grade 2 colitis, and 14 (56%) had grade 3 colitis. The median time from ICI initiation to colitis onset was 105 days. The median duration from symptom onset to endoscopic evaluation was 11 days. Regarding endoscopic evaluation, colitis involved the entire colon in 13 (52%) patients, and 15 (60%) had ulcers. Twenty-three (92%) patients received steroids, and 3 (12%) added infliximab (IFX). Most patients (n=19, 76%) achieved remission with complete tapering of the steroid taken for the first colitis episode. Among the 6 (24%) patients who did not taper initial, 5 patients increased their steroid dosage with 2 added IFX, leading to symptom remission and successful steroid tapering, while one patient experienced continuous non-remission despite increasing the steroid and receiving two infusions of IFX. Of the 8 (32%) ICI rechallenge patients, 4 achieved long-lasting benefit without colitis recurrence. The other 4 experienced recurrent colitis after ICI rechallenge and permanently discontinued ICIs. The median duration from ICI rechallenge to colitis recurrence was shorter than the time to colitis onset. One patient developed steroid-refractory colitis and recovered with one infusion of IFX. Conclusion: Endoscopy has value in the evaluation and optimal management of ICI-induced colitis in Chinese cancer patients. IFX is necessary for treating colitis, especially in steroid-refractory/resistant patients. ICI rechallenge can achieve benefit, but permanently discontinuing ICIs is needed if colitis recurs. Future large-scale prospective studies are required for more accurate assessments and validation.

Surufatinib plus toripalimab in patients with advanced solid tumors: a single-arm, open-label, phase 1 trial.

PURPOSE: This phase 1 trial evaluated the safety, preliminary efficacy, and pharmacokinetics of surufatinib, a small molecular tyrosine kinase inhibitor, combined with toripalimab, a programmed cell death protein-1 antibody, in patients with advanced solid tumors. METHODS: This is an open-label, dose-escalation and expansion study in patients with solid tumors who had failed standard therapies or had no effective treatment. In the dose-escalation stage, patients were treated with surufatinib, at dose levels of 200, 250, or 300 mg once daily (QD) in combination with toripalimab 240 mg, every 3 weeks (Q3W), to estimate maximum tolerated dose. Additional patients were enrolled in the dose expansion stage to further assess the efficacy, safety, and pharmacokinetics profile. Recommended phase 2 dose (RP2D) was determined based on the safety, tolerability, and preliminary efficacy from dose-escalation and expansion stages. RESULTS: From Feb 14, 2019 to Dec 20, 2020, 33 patients were screened, of which 30 patients were enrolled. One patient in the 300 mg cohort experienced dose limited toxicity, a grade 3 hyperthyroidism. The most frequent treatment-related adverse events of grade ≥ 3 were hypertension (20.0%), transaminases increased (13.3%), and blood bilirubin increased (13.3%). No treatment-related death or treatment discontinuation was identified. The RP2D was determined to be surufatinib 250 mg QD plus toripalimab 240 mg Q3W. Objective response rate was 24.1% (95% confidence interval 10.3‒43.5%) in this study. CONCLUSIONS: Surufatinib plus toripalimab was well tolerated, with no unexpected safety signals, and showed preliminary anti-tumor activity in patients with advanced solid tumors. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT03879057; registration date: March 18, 2019.

Pyrotinib alone or in combination with docetaxel in refractory HER2-positive gastric cancer: A dose-escalation phase I study.

AIM: Pyrotinib (an irreversible pan-ErbB small-molecular tyrosine kinase inhibitor) was approved in human epidermal growth factor receptor 2 (HER2)-positive breast cancer and showed great antitumor activity in preclinical studies of gastric cancer (GC). This study was first designed to prospectively assess pyrotinib in pretreated HER2-positive GC. METHODS: This multicenter, phase I study followed a standard "3 + 3" design and included two parts. In the pyrotinib part, pyrotinib was administered orally, once per day at dose levels of 240, 320, 400, and 480 mg. In the pyrotinib plus docetaxel part, patients received pyrotinib (qd, d1-21, q3W) combined with docetaxel (60 mg/m2 , d1, q3W) at dose levels of 240, 320, and 400 mg. Primary endpoints were to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of pyrotinib as monotherapy or coadministered with docetaxel. RESULTS: A total of 25 patients were enrolled and received pyrotinib (n = 15) or pyrotinib plus docetaxel (n = 10). One DLT was observed in pyrotinib monotherapy part (Grade 3 uncontrolled diarrhea after supportive care) and pyrotinib plus docetaxel part (Grade 4 neutropenia and leukopenia). In the pyrotinib monotherapy part, MTD was not reached. Diarrhea, anemia, neutropenia, and leukopenia were the most common treatment-related adverse events (TRAEs). The RP2D for pyrotinib monotherapy was recommended as 400 mg. After combining with docetaxel, the risk of leukopenia and neutropenia was increased. Grade ≥3 TRAEs were reported for four patients in the monotherapy part and for eight patients in the combination part. Mean t1/2 was approximately 20 h. Pyrotinib exposure was dose-dependent with a nonlinear relationship versus dose. There were five patients who had confirmed partial response (monotherapy: one each at 240, 400, and 480 mg dose cohort; combination therapy: two at 240 mg dose cohort), resulting in an objective response rate of 21% and 20%, respectively. CONCLUSIONS: Pyrotinib alone and combined with docetaxel showed acceptable toxicities in patients with pretreated HER2-positive GC. TRIAL REGISTRATION: This study was registered with ClinicalTrials.gov, NCT02378389.

Psychological distress and resilience in patients with gastroenteropancreatic neuroendocrine tumor.

An increased incidence of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) has been reported in many countries. However, the prevalence and impact factors of psychological distress and resilience in patients with GEP-NETs are unclear. We recruited 200 patients with GEP-NETs to assess psychological distress and resilience. Measures comprised the Distress Thermometer, the Hospital Anxiety and Depression Scale, Connor-Davidson Resilience scale and Medical Coping Modes Questionnaire. Our results found that the prevalence of distress, anxiety, depression and low resilience were 31.5%, 31%, 17.8%, and 25.9%, respectively. Female patients were more likely to be distressed, as were those with NET Grade 1, were partly aware of diagnosis, and had known the diagnosis less than 3 months. Distress positively correlated with acceptance-resignation, and resilience positively correlated with confrontation and avoidance. Resilience negatively correlated with psychological distress. Patients coping disease with acceptance-resignation had higher odds of anxiety, depression, and low resilience. Our findings indicate that psychological distress and low resilience were common in patients with GEP-NETs. This suggests a need to integrate psychosocial domain into GEP-NETs clinical practice.

Efficacy and Safety Comparison of Regorafenib and Fruquintinib in Metastatic Colorectal Cancer-An Observational Cohort Study in the Real World.

BACKGROUND: Regorafenib and fruquintinib are tyrosine kinase inhibitors that are recommended for refractory colorectal cancer (CRC) in China. However, to date, no head-to-head trials have been conducted to guide clinical practice. METHODS AND PATIENTS: An ambispective observational cohort study was conducted in Beijing Cancer Hospital. Patients with metastatic CRC who received regorafenib or fruquintinib were retrospectively collected between January 2018 and April 2020, and prospectively enrolled between May 2020 and February 2021. The primary outcome was time-to-treatment failure (TTF), and secondary outcomes were overall survival (OS) and adverse events. An additional goal of the study was to explore the appropriate sequence of regorafenib and fruquintinib treatment. RESULTS: A total of 366 patients with metastatic CRC were enrolled to receive regorafenib (n = 260) or fruquintinib (n = 106) between January 2018 and February 2021. No difference was observed for median TTF (regorafenib 2.7 months vs. fruquintinib 3.1 months, P = .200) or median OS (regorafenib 13.8 months vs. fruquintinib 11.3 months, P = .527). The propensity score analysis showed similar results for median TTF and median OS between the 2 groups, as did the results of subgroup analysis for prospective set (n = 146). For sequence analysis, patients with regorafenib followed by fruquintinib (n = 84) showed longer OS than that with the reverse (n = 29) (28.1 months vs. 18.4 months, P = .024). Most patients tolerated regorafenib at a reduced dose (93.1%), and most patients tolerated fruquintinib at a standard dose (68.9%). The incidences of most adverse events were similar between the two groups, while any grade of hand-foot skin reaction and hyperbilirubinemia were more frequently observed in the regorafenib group and ≥grade 3 hypertension was more common in the fruquintinib group. CONCLUSION: Regorafenib and fruquintinib had similar efficacy and toxicity profiles with various frequency. Regorafenib followed by fruquintinib showed longer OS than the reverse, but the sequence needs to be further confirmed.

A Phase Ib Study of the Simmitecan Single Agent and in Combination With 5-Fluorouracil/Leucovorin or Thalidomide in Patients With Advanced Solid Tumor.

Background: Simmitecan is a potent inhibitor of topoisomerase I with anti-tumor activity. This phase Ib trial was conducted to investigate the safety and anti-tumor effect of simmitecan alone or in combination with other drugs. Methods: Eligible patients with advanced solid tumor had no further standard treatment options. Patients were allocated to receive simmitecan alone, simmitecan in combination with 5-fluorouracil (5-FU)/leucovorin (LV), or simmitecan in combination with thalidomide, 14 days a cycle, until disease progression or unacceptable toxicity occurred. Results: A total of 41 patients were enrolled, with a median age of 55 (range 29-69) years. Among them, 13 patients received simmitecan monotherapy, 10 received simmitecan + 5-FU/LV, and 18 received simmitecan + thalidomide. No dose-limiting toxicity occurred. Overall, the most common grade 3/4 adverse event (AE) was neutropenia (46.2, 70.0, and 88.9%, respectively, in simmitecan, simmitecan + 5-FU/LV, and simmitecan + thalidomide cohorts), and treatment-related severe AEs included anemia and febrile neutropenia (7.7% each in simmitecan cohort), diarrhea (10% in simmitecan +5-FU/LV cohort), and febrile neutropenia (5.6% in simmitecan + thalidomide cohort). The majority of patients (24/41, 58.3%) had progressed on prior irinotecan; nevertheless, partial response was achieved in one colorectal cancer patients treated with simmitecan + thalidomide. The disease control rates of simmitecan, simmitecan + 5-FU/LV, and simmitecan + thalidomide cohorts were 46.2, 80.0, and 61.1%, respectively. Conclusion: This study demonstrated a manageable safety profile of simmitecan as a single agent or as part of a combination therapy. There have not been any safety concerns with simmitecan in combination when compared to simmitecan alone. Simmitecan + 5-FU/LV regimen seemed to have a better efficacy. Nonetheless, the efficacy of this regimen needs to be further explored in the subsequent study.