Safety, antitumor activity and biomarkers of sugemalimab in Chinese patients with advanced solid tumors or lymphomas: results from the first-in-human phase 1 trial.

BACKGROUND: This first-in-human phase 1 trial is to evaluate the safety, pharmacokinetics, preliminary efficacy, and biomarkers of sugemalimab, a full-length, fully human anti-PD-L1 monoclonal antibody, in Chinese patients with advanced malignancies. METHODS: Eligible patients with unresectable advanced or metastatic solid tumors or lymphomas were enrolled in phase 1a to receive sugemalimab following a modified 3 + 3 design. The primary endpoints included safety, tolerability, and the recommended Phase 2 dose (RP2D). In phase 1b, patients with 7 selected types of tumor received sugemalimab at the RP2D alone (monotherapy cohorts) or in combination with standard-of-care (SOC) chemotherapy (combination cohorts). The primary endpoint of phase 1b was investigator-assessed objective response rate (ORR). RESULTS: As of 19 February 2020, 29 and 178 patients were treated in phase 1a and 1b, respectively. No dose-limiting toxicities were observed in phase 1a, and the RP2D of sugemalimab was determined as 1200 mg fixed dose once every 3 weeks. Sugemalimab-related adverse events (AEs) were mostly (75.9%) grade 1-2 in phase 1a. Antitumor activity was observed across dose levels with an ORR of 24.1%. In phase 1b, 15.9% and 40.4% of patients in the monotherapy and combination cohorts, respectively, reported grade 3-5 sugemalimab-related AEs. Promising efficacy was observed in all combination cohorts, with ORRs ranging from 47.6 to 75.0%. Exploratory biomarker analysis did not indicate significant differences in responses at different PD-L1 expression/tumor mutation burden levels. CONCLUSIONS: Sugemalimab was well-tolerated and showed promising antitumor activity as monotherapy or in combination with SOC chemotherapy in advanced malignancies. This trial was registered with ClinicalTrials.gov on Oct 18, 2017, number NCT03312842.

Camrelizumab versus investigator's choice of chemotherapy as second-line therapy for advanced or metastatic oesophageal squamous cell carcinoma (ESCORT): a multicentre, randomised, open-label, phase 3 study.

BACKGROUND: Patients with advanced or metastatic oesophageal squamous cell carcinoma have poor prognosis and few treatment options after first-line therapy. We aimed to assess efficacy and safety of the anti-PD-1 antibody camrelizumab versus investigator's choice of chemotherapy in previously treated patients. METHODS: ESCORT is a randomised, open-label, phase 3 study of patients aged 18 to 75 years with a histological or cytological diagnosis of advanced or metastatic oesophageal squamous cell carcinoma done at 43 hospitals in China. Eligible patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and had progressed on, or were intolerant to, first-line standard therapy. Patients were randomly assigned (1:1) to camrelizumab (200 mg every 2 weeks) or chemotherapy with docetaxel (75 mg/m2 every 3 weeks) or irinotecan (180 mg/m2 every 2 weeks), all given intravenously. Central randomisation was done using the Randomization and Trial Supply Management system with block size randomly generated as four or six and stratified by disease and ECOG performance status. The primary endpoint was overall survival, assessed in randomised patients who had received at least one dose of treatment. Safety was assessed in all treated patients. The trial is registered with ClinicalTrials.gov, NCT03099382, and is closed to new participants. FINDINGS: From May 10, 2017, to July 24, 2018, 457 (75%) of 607 screened patients were randomly assigned to treatment, of whom 228 received camrelizumab treatment and 220 received chemotherapy. As of data cutoff on May 6, 2019, with a median follow-up time of 8·3 months (IQR 4·1-12·8) in the camrelizumab group and 6·2 months (3·6-10·1) in the chemotherapy group, median overall survival was 8·3 months (95% CI 6·8-9·7) in the camrelizumab group and 6·2 months (5·7-6·9) in the chemotherapy group (hazard ratio 0·71 [95% CI 0·57-0·87]; two-sided p=0·0010). The most common treatment-related adverse events of grade 3 or worse were anaemia (camrelizumab vs chemotherapy: six [3%] vs 11 [5%]), abnormal hepatic function (four [2%] vs one [<1%]), and diarrhoea (three [1%] vs nine [4%]). Serious treatment-related adverse events occurred in 37 (16%) of 228 patients in the camrelizumab group, and in 32 (15%) of 220 patients in the chemotherapy group. Ten treatment-related deaths occurred, seven (3%) in the camrelizumab group (three deaths from unknown causes, one enterocolitis, one hepatic function abnormal, one pneumonitis, and one myocarditis) and three (1%) in the chemotherapy group (two deaths from unknown causes, and one gastrointestinal haemorrhage). INTERPRETATION: Second-line camrelizumab significantly improved overall survival in patients with advanced or metastatic oesophageal squamous cell carcinoma compared with chemotherapy, with a manageable safety profile. It might represent a potential option of standard second-line treatment for patients with oesophageal squamous cell carcinoma in China. FUNDING: Jiangsu Hengrui Medicine.

Degradation of MCL-1 by bufalin reverses acquired resistance to osimertinib in EGFR-mutant lung cancer.

Although osimertinib, an EGFR tyrosine kinase inhibitor, has become the standard therapy for treating non-small cell lung cancer (NSCLC) patients with EGFR-activating mutation, upregulation of MCL-1 induces acquired resistance to osimertinib. Bufalin, a natural digoxin-like ingredient isolated from a traditional Chinese medicine Chan Su, has been shown to downregulate MCL-1 in NSCLC cells. However, whether bufalin reverses this acquired resistance to osimertinib in NSCLC cells remains unclear. In this study, bufalin reduced cell viability and promoted apoptosis in osimertinib-resistant cells. Moreover, co-treatment with bufalin and osimertinib restored the sensitivity of osimertinib-resistant cells to osimertinib-induced growth regression and apoptosis in vitro and in vivo. Mechanistically, MEK/ERK-dependent MCL-1 phosphorylation and Ku70-mediated MCL-1 overexpression confer osimertinib resistance in EGFR-mutant NSCLC cells. In osimertinib-resistant cells, bufalin modulates Ku70-mediated MCL-1 degradation, but not MEK/ERK/MCL-1 signaling. In conclusion, our study suggests that bufalin eliminates resistance to osimertinib by inhibiting Ku70-mediated MCL-1 overexpression, indicating that a combination of osimertinib and bufalin could be an effective additional treatment to overcome acquired resistance to osimertinib in NSCLC cells.

Degradation of Mcl-1 through GSK-3ß Activation Regulates Apoptosis Induced by Bufalin in Non-Small Cell Lung Cancer H1975 Cells.

BACKGROUND/AIMS: Mcl-1, an anti-apoptotic Bcl-2 family member, is often overexpressed in non-small cell lung cancer (NSCLC). Bufalin has been reported to induce apoptosis in various tumor cells. However, there is no report showing that bufalin could downregulate Mcl-1 expression in NSCLC. METHODS: Cell proliferation was analyzed by cell counting kit-8 (CCK-8) assay in H1975 cells. Cell apoptosis was detected by flow cytometry. Mcl-1 mRNA was detected by RT-PCR. The expression of apoptosis-associated proteins in H1975 cells was detected by western blotting. The levels of Mcl-1 ubiquitination and NOXA were analyzed by Immunoprecipitation assay. RESULTS: Cell growth was inhibited by bufalin in a time and dose-dependent manner. Bufalin induced apoptosis in NSCLC cells by activating caspase cascades and downregulating Mcl-1 expression. However, overexpression of Mcl-1 diminished bufalin-induced apoptosis. Furthermore, bufalin did not reduce Mcl-1 mRNA expression in H1975 cells, but strongly promoted Mcl-1 protein degradation. Proteasome inhibitor MG132 markedly prevented the degradation of Mcl-1 and blocked bufalin-induced Mcl-1 reduction. Bufalin did not significantly affect NOXA protein levels, but downregulated the expression of p-GSK-3ß. GSK-3 inhibitor and GSK-3ß siRNA resulted in increased levels of Mcl-1 and reversed the bufalin-induced Mcl-1 degradation. CONCLUSION: Bufalin induced cell apoptosis in H1975 cells may be through downregulation of Mcl-1. Proteasomal degradation of Mcl-1 via GSK-3ß activation was involved in bufalin-induced apoptosis.

RNF125 is a ubiquitin-protein ligase that promotes p53 degradation.

BACKGROUND/AIMS: Although early studies show that Mdm2 is the primary E3 ubiquitin ligase for the p53 tumor suppressor, an increasing amount of data suggests that p53 ubiquitination and degradation are more complex than once thought. Here, we investigated the role of RNF125, a non-Mdm2 ubiquitin-protein ligase, in the regulation of p53. METHODS AND RESULTS: RNF125 physically interacted with p53 in exogenous/endogenous co-immunoprecipitation (IP) and GST-pull down assay, and a C72/75A mutation of RNF125 did not interfere with this interaction. Expression of RNF125 decreased the level of p53 in a dose-dependent manner, whereas knockdown of RNF125 by RNA interference increased the level of p53. As shown by Western blotting and ubiquitin assay, RNF125 ubiquitinated p53 and targeted it for proteasome degradation. Furthermore, RNF125 repressed p53 functions including p53-dependent transactivation and growth inhibition. CONCLUSION: Our data suggest that RNF125 negatively regulates p53 function through physical interaction and ubiquitin-mediated proteasome degradation.

PSMA7 directly interacts with NOD1 and regulates its function.

BACKGROUND/AIMS: Recent reports showed that proteasome subunit alpha type-7 (PSMA7) was overexpressed in colorectal cancer. To investigate the mechanism of PSMA7 in promotion of colorectal cancer, we screened for its interaction partners. METHODS AND RESULTS: This study found that PSMA7 associated with nucleotide-binding oligomerization domain-containing protein 1 (NOD1) by yeast two-hybrid screening, co-immunoprecipitation (IP), and GST-pull down assay. As shown by Western blotting and ubiquitin assay, PSMA7 downregulated the expression of NOD1 in a proteasome-dependent manner. Overexpression of PSMA7 in HCT116 cells resulted in an inhibition of NOD1-mediated apoptosis and NF-κB activation, whereas knockdown of PSMA7 by RNA interference enhanced NOD1 activity. CONCLUSION: Our data suggest that PSMA7 is a negative regulator of the NOD1, and may promote tumor growth by its inhibitory role on NOD1.

Safety and efficacy of anti-EGFR monoclonal antibody (SCT200) as second-line therapy in advanced esophageal squamous cell carcinoma.

OBJECTIVE: The mainstay treatment of esophageal squamous cell carcinoma (ESCC) involves chemotherapy and immunotherapy. However, alternative therapies are required for patients who are refractory or intolerant to existing therapies. METHODS: In this single-arm, multicenter, open-label phase Ib study, 30 patients received an intravenous infusion of SCT200, an antiepidermal growth factor receptor (EGFR) monoclonal antibody, 6.0 mg/kg once a week for 6 weeks, followed by 8.0 mg/kg once every 2 weeks until disease progression or intolerable toxicity. The primary endpoint was the objective response rate (ORR). The secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Thirty patients were enrolled between July 2018 and May 2019. The ORR was 16.7% (95% CI: 5.6%-34.7%). The median PFS and OS were 3.1 months (95% CI: 1.5-4.3) and 6.8 months (95% CI: 4.7-10.1), respectively. A numerical difference without any statistical significance in ORR was observed in patients with different EGFR expressions (≥ 50%: 25.0% vs. < 50%: 0%, P = 0.140) or TP53 mutation abundance (< 10%: 23.8% vs. ≥ 10%: 0%, P = 0.286). Improved median PFS (3.4 vs. 1.4 months, P = 0.006) and OS (8.0 vs. 4.2 months, P = 0.027) were associated with TP53 mutation abundance of < 10%. The most common treatment-related adverse events of grade 3 or 4 (occurring in ≥ 2 patients) were hypomagnesemia [7 (23.3%)] and rash [2 (6.7%)]. No treatment-related death occurred. CONCLUSIONS: SCT200 monotherapy as the second- or further-line treatment for advanced ESCC showed favorable efficacy, with an acceptable safety profile. TP53 mutation abundance might serve as a potential predictive biomarker.

Toripalimab plus chemotherapy in treatment-naïve, advanced esophageal squamous cell carcinoma (JUPITER-06): A multi-center phase 3 trial.

Platinum-based chemotherapy is the standard first-line treatment for advanced esophageal squamous cell carcinoma (ESCC). In this phase 3 study (ClinicalTrial.gov: NCT03829969), 514 patients with treatment-naïve advanced ESCC were randomized (1:1) to receive toripalimab or placebo in combination with paclitaxel plus cisplatin (TP) every 3 weeks for up to 6 cycles, followed by toripalimab or placebo maintenance. At the prespecified final analysis of progression-free survival (PFS), a significant improvement in PFS is observed for the toripalimab arm over the placebo arm (hazard ratio [HR] = 0.58; 95% CI, 0.46-0.74; p < 0.0001). The prespecified interim analysis of overall survival (OS) also reveals a significant OS improvement for patients treated with toripalimab plus TP over placebo plus TP (HR = 0.58; 95% CI, 0.43-0.78; p = 0.0004). The incidences of grade ≥3 treatment-emergent adverse events are similar between the two arms. Toripalimab plus TP significantly improves PFS and OS in patients with treatment-naïve, advanced ESCC, with a manageable safety profile.

Blocking C-Raf alleviated high-dose small-volume radiation-induced epithelial mesenchymal transition in mice lung.

The goal of this study was to develop a potential druggable target for lung injury after SABR through the small animal model. Utilising the model, a radiation dose of 70 Gy or 90 Gy was focally (small volume) delivered to the left lung of mice. The highly expressed phosphorylation form of C-Raf was discovered through a protein array experiment, with the protein being extracted from the area of radiated mouse lung tissue, and was confirmed by IHC and western blot. C-Raf activation, along with morphological change and EMT (Epithelial to Mesenchymal Transition) marker expression, was observed after radiation to the mouse type II alveolar cell line MLE-12. C-Raf inhibitor GW5074 was able to reverse the EMT in cells effectively, and was found to be dependent on Twist1 expression. In the animal experiment, pretreatment of GW5074 alleviated EMT and lung injury after 70 Gy radiation was focally delivered to the lung of mice. Conclusively, these results demonstrate that C-Raf inhibitor GW5074 inhibits high-dose small-volume radiation-induced EMT via the C-Raf/Twist1 signalling pathway in mice. Therefore, pharmacological C-Raf inhibitors may be used effectively as inhibitors of SABR-induced lung fibrosis.

Erratum to efficacy and safety of mecapegfilgrastim for prophylaxis of chemotherapy-induced neutropenia in patients with breast cancer: a randomized, multicenter, active-controlled phase III trial.

[This corrects the article DOI: 10.21037/atm.2019.07.95.].

Efficacy and safety of mecapegfilgrastim for prophylaxis of chemotherapy-induced neutropenia in patients with breast cancer: a randomized, multicenter, active-controlled phase III trial.

BACKGROUND: Neutropenia is a common complication from chemotherapy. Mecapegfilgramtim (code name HHPG-19K), a long-acting recombinant human granulocyte colony-stimulating factor (rhG-CSF), has been developed. This study was to evaluate the efficacy and safety of mecapegfilgrastim for reducing neutropenia compared with filgrastim. METHODS: This was a randomized, controlled non-inferiority study. A total of 339 breast cancer patients who were eligible for (neo) adjuvant chemotherapy were randomized assigned into three groups to receive mecapegfilgrastim 100 µg/kg, mecapegfilgrastim fixed dose of 6 mg or filgrastim 5 µg/kg/day in the first cycle of chemotherapy. The primary endpoint was the duration of grade ≥3 neutropenia in cycle 1. The secondary endpoints included the duration of grade ≥3 neutropenia in cycles 2-4, incidence of grade ≥3 neutropenia, and febrile neutropenia (FN). The safety profile was also evaluated. RESULTS: The mean duration of grade ≥3 neutropenia was 1.06 [95% confidence interval (CI): 0.65, 1.26] days in mecapegfilgrastim 100 µg/kg group, 1.23 (95% CI: 0.84, 1.88) days in mecapegfilgrastim 6 mg group, and 2.06 (95% CI: 1.66, 2.46) days in the filgrastim group. The mean difference between mecapegfilgrastim 100 µg/kg and filgrastim was -1.00 (95% CI: -1.52, -0.48), the mean difference between mecapegfilgrastim 6 mg and filgrastim was -0.83 (95% CI: -1.36, -0.30). The upper bounds of 95% CI for the difference between mecapegfilgrastim and filgrastim were all <1 day (the predefined non-inferiority margin). For the incidence of grade ≥3 and grade 4 neutropenia, the mean duration of grade 4 neutropenia, mecapegfilgrastim showed better performance compared with filgrastim. For the incidence of FN, there was no difference between patients treated with mecapegfilgrastim and filgrastim. For safety profile, mecapegfilgrastim of two doses groups were all well-tolerated. Fixed 6 mg dose of mecapegfilgrastim exhibited comparable efficacy and safety in comparison with 100 µg/kg during 4 cycles. CONCLUSIONS: Long-acting mecapegfilgrastim (100 µg/kg and fixed 6 mg) is very effective and well tolerated when administered in the primary prophylaxis of chemotherapy induced neutropenia and in consecutive-cycle treatment. In some clinical parameters, mecafilgrastim is non-inferior and even superior to filgrastim. The fixed 6 mg-dose regimen showed similar efficacy and safety profile compared with 100 µg/kg regimen, and would be the preference in clinical practice, due to the convenient once-per-cycle administration and high-degree treatment compliance for the patients. This study provided new evidence for the novel long-acting rhG-CSF, mecapegfilgrastim, which would be a new alternative for clinical practice for prophylaxis of chemotherapy induced neutropenia.

Effect and mechanism of ginsenoside Rg3 on postoperative life span of patients with non-small cell lung cancer.

OBJECTIVE: To explore the effect and mechanism of ginsenoside Rg3 (Shenyi Capsule) on the postoperative life span of patients with non-small cell lung cancer (NSCLC). METHODS: The prospective, randomized, controlled method was adopted. One hundred and thirty-three patients with NSCLC were randomly assigned to 3 groups: Shenyi Capsule group (43 cases), combined therapy group (Shenyi Capsule plus chemotherapy, 46 cases), and chemotherapy group (44 cases). The survival rates, immune function and the correlation between vascular endothelial growth factor (VEGF) expression and clinical effect were analyzed in the three groups. RESULTS: (1) The 1-year survival rate in the Shenyi group, the combined group and the chemotherapy group was 76.7% (33/43), 82.6% (38/46), and 79.5% (35/44), respectively; the 2-year survival rate was 67.4% (29/43), 71.7% (33/46), and 70.5% (31/44), respectively; and the 3-year survival rate was 46.5% (20/43), 54.3% (25/46), and 47.7% (21/44), respectively. There was no significant difference among the 3 groups (P>0.05). (2) NK cells were increased to different degrees and the ratio of CD4/CD8 was normal in the Shenyi Capsule group and the combined group, while the ratio of CD4/CD8 was disproportional in the chemotherapy group. (3) In the chemotherapy group, the 3-year survival rate was lower in patients with positive expression of VEGF than in patients with negative expression (37.0% vs 64.7%, chi2=17.9, P<0.01), but no signifi cant statistical difference was shown in the other two groups (53.6% vs 55.6%, P>0.05; 44.4% vs 50.0%, P>0.05). CONCLUSION: Shenyi Capsule, especially in combination with chemotherapy, can improve the life span of patients with NSCLC after operation. The mechanism might be correlated with improving the immune function and anti-tumor angiogenesis

Radiosensitivity enhancement by arsenic trioxide in conjunction with hyperthermia in the EC-1 esophageal carcinoma cell line.

OBJECTIVE: To explore the effect on radiosensitivity of arsenic trioxide (As203) in conjunction with hyperthermia on the esophageal carcinoma EC-1 cell line. METHOD: Inhibition of EC-1 cell proliferation at different concentrations of As203 was assessed using the methyl thiazolyl blue colorimetric method (MTT method), with calculation of IC50 value and choice of 20% of the IC50 as the experimental drug concentration. Blank control, As203, hyperthermia, radiotherapy group, As203 + hyperthermia, As203 + radiotherapy, hyperthermia + radiotherapy and As203 + hyperthermia + radiotherapy groups were established, and the cell survival fraction (SF) was calculated from flat panel colony forming analysis, and fitted by the 'multitarget click mathematical model'. Flow cytometry (FCM) was used to detect changes in cell apoptosis and the cell cycle. RESULTS: As203 exerted inhibitory effects on proliferation of esophageal carcinoma EC-1 cells, with an IC50 of 18.7 µmol/L. After joint therapy of As203 + hyperthermia + radiotherapy, the results of FCM showed that cells could be arrested in the G2/M phase, and as the ratio of cells in G0/G1 and S phases decreased, cell death became more pronounced. CONCLUSION: As203 and hyperthermia exert radiosensitivity effects on esophageal carcinoma EC-1 cells, with synergy in combination. Mechanistically, As203 and hyperthermia mainly influence the cell cycle distribution of EC-1 esophageal carcinoma cells, decreasing the repair of sublethal damage and inducing apoptosis, thereby enhancing the killing effects of radioactive rays.

Antitumor activity of a combination of rAd2p53 adenoviral gene therapy and radiotherapy in esophageal carcinoma.

The objective of this study was to determine if a combination of recombinant adenovirus 2 p53 (rAd2p53) gene therapy and radiotherapy would have significantly improved outcome from esophageal carcinoma when compared to radiotherapy (RT) alone. Forty-five patients diagnosed with esophageal carcinoma (confirmed squamous cell carcinoma) were randomly assigned to one of two study arms: treatment group: rAd2p53 gene therapy + RT (n = 22); and control group: radiotherapy (n = 23). For the treatment group, rAd2p53 was injected into multiple areas of the lesion once a week for 6 weeks avoiding deep ulcers points. RT was administered after 3 days of injection of rAd2p53. Patients in the control group only received radiotherapy. The overall response rate was significantly higher in the treatment group than in control group (P < 0.05). Furthermore, the complete response rate was 3 times higher in the treatment group than in the control group (P < 0.05). Transient fever and pain at injection site were the only side effects mentioned in the treatment group. In conclusion, this recombinant virus-RT combination is significantly more beneficial in palliation than RT alone, with minor side affects. However, its role as neoadjuvant therapy prior to surgical resection needs to be further investigated.