Efficacy, safety and genomic analysis of SCT200, an anti-EGFR monoclonal antibody, in patients with fluorouracil, irinotecan and oxaliplatin refractory RAS and BRAF wild-type metastatic colorectal cancer: a phase â ¡ study.

BACKGROUND: Limited therapeutic options are available for metastatic colorectal cancer (mCRC) patients after failure of first- and second-line therapies, representing an unmet medical need for novel therapies. METHODS: This is an open-label, single arm, multicenter, phase Ⅱ study aiming to perform the efficacy, safety and genomic analysis of SCT200, a noval fully humanized IgG1 anti-epidermal growth factor receptor (EGFR) monoclonal antibody, in patients with fluorouracil, irinotecan and oxaliplatin refractory RAS and BRAF wild-type mCRC. SCT200 (6 mg/kg) was given weekly for the first six weeks, followed by a higher dose of 8 mg/kg every two weeks until disease progression or unacceptable toxicity. Primary endpoint was independent review committee (IRC)-assessed objective response rate (ORR) and secondary endpoints included ORR in patients with left-sided tumor, disease control rate (DCR), duration of response (DoR), time to response (TTR), progression-free survival (PFS), overall survival (OS) and safety. FINDINGS: From February 12, 2018 to December 1, 2019, a total of 110 patients aged between 26 and 77 years (median: 55; interquartile range [IQR]: 47-63) with fluorouracil, oxaliplatin, and irinotecan refractory RAS and BRAF wild-type mCRC were enrolled from 22 hospitals in China. As the data cut-off date on May 15, 2020, the IRC-assessed ORR and DCR was 31% (34/110, 95% confidence interval [CI] 22-40%) and 75% (82/110, 95% CI 65-82%), respectively. Thirty one percent (34/110) patients achieved confirmed partial response (PR). The median PFS and median OS were 5.1 months (95% CI 3.4-5.2) and 16.2 months (95% CI 11.1-not available [NA]), respectively. The most common ≥ grade 3 treatment-related adverse events (TRAEs) were hypomagnesemia (17%, 19/110) and acneiform dermatitis (11%, 12/110). No deaths occurred. Genomic analysis suggested positive association between MYC amplification and patients' response (P = 0.0058). RAS/RAF mutation and MET amplification were the most frequently detected resistance mechanisms. Patients with high circulating tumor DNA (ctDNA) at baseline or without ctDNA clearance at the 7th week after the first dose of SCT200 administration before receiving SCT200 had worse PFS and OS. INTERPRETATION: SCT200 exhibited promising clinical efficacy and manageable safety profiles in RAS and BRAF wild-type mCRC patients progressed on fluorouracil, irinotecan and oxaliplatin treatment. The baseline ctDNA and ctDNA clearance status at the 7th week after the first dose of SCT200 administration before receiving SCT200 could be a potential prognostic biomarker for RAS and BRAF wild-type mCRC patients with SCT200 therapy. FUNDING: This study was sponsored by Sinocelltech Ltd., Beijing, China and partly supported by the National Science and Technology Major Project for Key New Drug Development (2019ZX09732001-006, 2017ZX09304015).

Phase 2 randomized controlled trial of intravenous or intraperitoneal paclitaxel plus mFOLFOX6 vs. mFOLFOX6 as first-line treatment of advanced gastric cancer.

Objective: We conducted a phase 2 trial to compare the safety and efficacy of intravenous paclitaxel or intraperitoneal paclitaxel plus mFOLFOX6 vs. mFOLFOX6 in untreated advanced gastric cancer. Methods: Participants with untreated advanced gastric cancer were randomly assigned (1:1:1) to: intravenous paclitaxel 135 mg/m2 or intraperitoneal paclitaxel 80 mg/m2 plus mFOLFOX6 omitting bolus fluorouracil; or mFOLFOX6 (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, fluorouracil 400 mg/m2 bolus, fluorouracil 2,400 mg/m2 46-h continuous infusion). Treatment was every 14 days for up to 9 cycles followed by S-1 maintenance. The primary outcome was progression-free survival. Results: Of 90 enrolled participants, 30 in the intravenous paclitaxel group, 29 in the intraperitoneal paclitaxel group, and 30 in the mFOLFOX6 group were included in the analyses. The median progression-free survival was 6.52, 5.83, and 4.55 months, respectively, for the intravenous paclitaxel group, intraperitoneal paclitaxel group, and mFOLFOX6 group. The hazard ratios were 0.56 (95% CI: 0.33-0.94; p = 0.026) and 0.56 (95% CI: 0.33-0.96; p = 0.037), respectively, for the intravenous paclitaxel group and the intraperitoneal paclitaxel group vs. the mFOLFOX6 group. The most common grade 3/4 adverse events for the intravenous paclitaxel group, intraperitoneal paclitaxel group, and mFOLFOX6 group, respectively, were neutropenia (30.0%, 34.5%, 33.3%), diarrhea (13.3%, 20.7%, 13.3%), and leukopenia (10.0%, 13.8%, 10.0%). No treatment-related death occurred. Conclusion: The findings of this phase 2 trial suggest that adding intravenous paclitaxel or intraperitoneal paclitaxel to mFOLFOX6 for untreated advanced gastric cancer improved progression-free survival with manageable adverse events.

The Expression Pattern of Ferroptosis-Related Genes in Colon Adenocarcinoma: Highly Correlated to Tumor Microenvironment Characteristics.

In the latest literatures, ferroptosis caused by T cells in cancerous cells provided new insights of improving curative effect of the PD-1/PD-L1 antibody. The microenvironment on which tumor cells develop and survive was also emphasized as its crucial role in tumor occurrence, development, metastasis and immune escape. Thus, the interaction of ferroptosis related genes and tumor microenvironment (TME) was urgently be detected in a comprehensive perspective. We comprehensively evaluated the transcriptional feature of ferroptosis related genes in colon adenocarcinoma (COAD), and systematically associated these ferroptosis subtypes with DNA damage repair (DDR) and TME characteristics. We found two unique patterns of ferroptosis characterized by distinct biological pathways activation. We also demonstrated that FRG score constructed based on ferroptosis subtypes has a significant correlation with prognosis of colon cancer and could act as an independent prognostic biomarker for predicting patients' survival. The higher immune infiltrating level, immune functional pathways activation was observed in the high FRG score group. Furthermore, these results were verified by an independent external GEO cohort. This work revealed ferroptosis was highly associated with TME complexity and diversity. A novel ferroptosis subtypes related gene scoring system can be used for prognostic prediction in COAD. Targeting ferroptosis may be a therapeutic alternative for COAD.

Efficacy and safety of a novel anti-HER2 therapeutic antibody RC48 in patients with HER2-overexpressing, locally advanced or metastatic gastric or gastroesophageal junction cancer: a single-arm phase II study.

BACKGROUND: Current treatment options for human epidermal growth factor receptor 2 (HER2)-overexpressing gastric cancer at third-line have shown limited clinical benefit. Further, there is no specific treatment for HER2 immunohistochemistry (IHC) 2+ and fluorescence in-situ hybridization-negative patients. Here, we report the efficacy and safety of a novel anti-HER2 antibody RC48 for patients with HER2-overexpressing, advanced gastric or gastroesophageal junction cancer. METHODS: Patients with HER2-overexpressing (IHC 2+ or 3+), locally advanced or metastatic gastric or gastroesophageal junction cancer who were under at least second-line therapy were eligible and received RC48 2.5 mg/kg alone every 2 weeks. The primary endpoint was the objective response rate (ORR) assessed by an independent review committee. Secondary endpoints included progression-free survival (PFS), overall survival (OS), duration of response, time to progression, disease control rate, and safety. RESULTS: Of 179 patients screened, 125 were eligible and received RC48 treatment. The ORR was 24.8% (95% confidence interval [CI]: 17.5%-33.3%). The median PFS and OS were 4.1 months (95% CI: 3.7-4.9 months) and 7.9 months (95% CI: 6.7-9.9 months), respectively. The most frequently reported adverse events were decreased white blood cell count (53.6%), asthenia (53.6%), hair loss (53.6%), decreased neutrophil count (52.0%), anemia (49.6%), and increased aspartate aminotransferase level (43.2%). Serious adverse events (SAEs) occurred in 45 (36.0%) patients, and RC48-related SAEs were mainly decreased neutrophil count (3.2%). Seven patients had adverse events that led to death were not RC48-related. CONCLUSIONS: RC48 showed promising activity with manageable safety, suggesting potential application in patients with HER2-overexpressing, advanced gastric or gastroesophageal junction cancer who have previously received at least two lines of chemotherapy.

CPT2 downregulation triggers stemness and oxaliplatin resistance in colorectal cancer via activating the ROS/Wnt/ß-catenin-induced glycolytic metabolism.

Carnitine palmitoyltransferase 2 (CPT2) has been demonstrated to act as a tumor promotor or suppressor in different types of cancers. However, little is known about the effect of CPT2 on colorectal cancer (CRC). In the present study, we analyzed CPT2 expression in CRC tissues and cells. CPT2 was overexpressed in CRC cell lines (SW480 and RKO), and its effects and molecular mechanism on the proliferation, glycolysis, stemness, and oxaliplatin sensitivity were investigated. The xenograft experiment was used to confirm the influence of CPT2 on CRC tumorigenesis in vivo. We found that CPT2 expression was significantly downregulated in CRC patients, and its lower expression was associated with the poor prognosis, large tumor size, advanced TNM stage, and poor histological grade differentiation of patients. Upregulation of CPT2 significantly inhibited the proliferation, glycolytic metabolism, cancer stem cell properties, and oxaliplatin resistance in CRC cells. Also, the increase of CPT2 inhibited tumorigenesis, stemness and glycolysis, while enhanced oxaliplatin sensitivity in mouse models. Mechanistically, CPT2 functioned via suppressing the activation of Wnt/ß-catenin pathway through repressing ROS production. In conclusion, our results demonstrated that CPT2 was decreased in CRC, and CPT2 downregulation could trigger stemness and oxaliplatin resistance in CRC via activating the ROS/Wnt/ß-catenin-induced glycolytic metabolism. This study indicates that CPT2 is a potential therapeutic target for CRC.

Apatinib combined with paclitaxel-based chemotherapy in patients with taxane-resistant advanced gastric cancer: a single-arm exploratory study.

BACKGROUND: Apatinib combined with chemotherapy might be effective and safe for the management of advanced gastric cancer, but the available data are limited. To investigate the efficacy and safety of apatinib in combination with paclitaxel (PTX) alone or POF (PTX, oxaliplatin, and 5-fluorouracil) in patients with taxane-resistant advanced gastric cancer. METHODS: Patients with taxane-resistant advanced gastric cancer were enrolled in the single-center, open-labeled, single-arm, exploratory study (ClinicalTrials.gov #NCT02697838). Apatinib was administered at 850 mg po in combination with weekly PTX or the POF regimen. The primary endpoint was the objective response rate (ORR). The secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), the time to tumor progression (TTP), and safety. RESULTS: Twenty participants were recruited from 08/2016 to 01/2018. The duration of the study treatment was 2.07 (0.03-16.2) months. The median follow-up was 24.8 (0.3-26.0) months. The reasons for termination of treatment were disease progression (n=6), adverse events (AEs) (n=5), and patients' will (n=9). The ORR was 11.1% (95% CI: 1.4-34.7%) and the DCR was 77.8% (95% CI: 52.4-93.6%). The median PFS was 3.5 (95% CI: 1.9-5.1) months, the median OS was 4.7 (95% CI: 2.0-7.3) months, and the median TTP was 4.2 (95% CI: 0.562-7.838) months. All 20 (100%) patients had AEs, 17 (85%) had apatinib treatment-emergent AEs (TEAEs), and 18 (90%) had chemotherapy TEAEs. The main grade 3-4 TEAEs were neutropenia, leukopenia, hypertension, and anemia. CONCLUSIONS: This preliminary study suggests that apatinib combined with PTX or POF might be effective and tolerable in patients with chemotherapy-refractory gastric cancer. Studies are necessary to confirm the results. TRIAL REGISTRATION: ClinicalTrials.gov #NCT02697838.

Aflibercept plus FOLFIRI in Asian patients with pretreated metastatic colorectal cancer: a randomized Phase III study.

AIM: To investigate whether the benefit of combining aflibercept with 5-fluorouracil, folinic acid and irinotecan (FOLFIRI) chemotherapy could be confirmed in patients from the Asia-Pacific region (ClinicalTrials.gov: NCT01661270). Patients & methods: Asian patients with oxaliplatin-pretreated metastatic colorectal cancer were randomized to receive aflibercept or placebo, followed by FOLFIRI. The primary end point was progression-free survival. RESULTS: The intention-to-treat population comprised 332 patients. A clinical supply misallocation resulted in 198/332 (60%) patients receiving at least one cycle of misallocated treatment. Nevertheless, the addition of aflibercept to FOLFIRI was shown to improve progression-free survival (hazard ratio: 0.629; 95% CI: 0.488-0.812). Adverse events were in line with expectations. CONCLUSION: The beneficial treatment effect associated with the addition of aflibercept to FOLFIRI was confirmed in Asian patients with pretreated metastatic colorectal cancer.

Randomized multicenter phase III study of a modified docetaxel and cisplatin plus fluorouracil regimen compared with cisplatin and fluorouracil as first-line therapy for advanced or locally recurrent gastric cancer.

BACKGROUND: The V325 study showed that docetaxel, cisplatin, and fluorouracil (DCF) prolonged overall survival (OS) of patients with advanced gastric cancer, but with a high incidence of dose-limiting toxicities. We investigated the efficacy and safety of a modified DCF (mDCF) regimen for Chinese patients with advanced gastric cancer. METHODS: Untreated advanced gastric cancer patients randomly received docetaxel and cisplatin at 60 mg/m(2) (day 1) followed by fluorouracil at 600 mg/m(2)/day (days 1-5; mDCF regimen) or cisplatin at 75 mg/m(2) (day 1) followed by fluorouracil at 600 mg/m(2)/day (days 1-5; CF) every 3 weeks. The primary end point was progression-free survival (PFS). The secondary end points were OS, overall response rate (ORR), time-to-treatment failure (TTF), and safety. RESULTS: In total, 243 patients were randomized to treatment (mDCF regimen 121; CF 122). Compared with CF, the mDCF regimen significantly improved PFS and OS: the median PFS was 7.2 and 4.9 months, respectively [hazard ratio (HR) 0.58, log-rank P = 0.0008], and the median OS was 10.2 and 8.5 months, respectively (HR = 0.71, P = 0.0319). Additionally, the mDCF regimen improved the parameters used as secondary objectives: the ORR was 48.7% with the mDCF regimen versus 33.9% with CF (P = 0.0244); the median TTF was 3.4 months with the mDCF regimen and 2.4 months with CF (HR = 0.67, P = 0.0027). Grade 3 and grade 4 treatment-related adverse events occurred in 77.3 % of patients who received the mDCF regimen versus 46.1% of patients who received CF (P < 0.001). CONCLUSIONS: The mDCF regimen, compared with CF, significantly prolonged PFS and OS and enhanced ORR of Chinese patients with advanced gastric cancer. The mDCF regimen achieved efficacy comparable to that of DCF but with fewer toxicities, which is appropriate for the Chinese population.

Paclitaxel-based regimens as first-line treatment in advanced gastric cancer.

The aim of this study was to evaluate the efficacy and safety of paclitaxel-based regimens as first-line treatments in advanced gastric cancer. We reviewed 397 previously untreated patients with advanced gastric cancer, who non-randomly received one of three paclitaxel-based regimens: paclitaxel plus fluorouracil/leucovorin (PF), paclitaxel plus oxaliplatin (PO), and paclitaxel plus oxaliplatin plus fluorouracil/leucovorin (POF) between January 2003 and December 2010. The PF, PO, and POF response rates were 47.13, 52.08, and 63.78%, respectively. Overall survivals (OS) were 11.2, 11.7, and 11.7 months, respectively. Progression-free survivals (PFS) were 6.6, 7.2, and 7.1 months, respectively. Leucopenia was higher on the triplet regimen than the doublet regimens. The paclitaxel-based regimens appeared to be effective in patients with advanced gastric cancer. The triplet regimen produced a higher response rate than either doublet regimen with more side effects, while survivals were similar among all three treatments.

A phase 2 study of fluorouracil/leucovorin in combination with paclitaxel and oxaliplatin as a salvage treatment in patients with refractory or relapsed advanced gastric cancer.

The aim of this study was to evaluate the efficacy and safety of paclitaxel plus oxaliplatin plus fluorouracil/leucovorin (POF) as salvage chemotherapy in pretreated advanced gastric cancer. Fifty-two pretreated patients with the advanced gastric cancer were eligible for this study. The POF regimen consisted of a 3-hour infusion of paclitaxel (135 mg/m(2)) followed by oxaliplatin (85 mg/m(2)) and leucovorin (400 mg/m(2)), administered simultaneously over a 2-hour infusion period, followed by an infusion of fluorouracil (2400 mg/m(2)) over a 46-hour period, every 14 days. From an intention-to-treat analysis, overall response rate and stable disease rate were 28.8 and 38.5%, respectively. The median time to progression and overall survival were 4.1 and 7.9 months, respectively. Grade 3 or 4 neutropaenia, thrombocytopaenia, fatigue, and neuropathy were 38.5, 15.4, 17.3, and 15.4%, respectively. The POF regimen is active in pretreated advanced gastric cancer as salvage chemotherapy, with a favourable toxicity profile.

Retrospective analysis of adjuvant intraperitoneal chemotherapy effect prognosis of resectable gastric cancer.

OBJECTIVE: This study evaluated the efficacy and safety of adjuvant intraperitoneal perfusion chemotherapy (IPC) in resectable gastric cancer through retrospective analysis. METHODS: Three hundred and sixty T2-4bN0-3M0 resectable gastric cancer patients were included in this study. One hundred and eighty-four patients used systemic chemotherapy combined with IPC (IP+ group) and 176 systemic chemotherapy only (IP- group). RESULTS: With a median of 49.9 months of follow-up, the 5-year overall survival in IP+ patients was significantly better than in IP- patients (60.4 vs. 42.9%; p = 0.001), and the average progression-free survival in IP+ patients was significantly longer than in IP- patients (60.5 vs. 46.2 months; p = 0.001). Relapse rates of peritoneal carcinomatosis, celiac lymph node and hepatic metastasis in the IP+ patients were significantly lower than in the IP- patients. Patients with curative resection, a histological type other than mucinous adenocarcinoma and signet ring cell carcinoma, low and undifferentiated tumor grade, lymph node metastasis, and T3 and T4a benefited from adjuvant IPC. The toxicities were the same except for more patients with leukopenia in the IP+ group (p = 0.001). The number of cycles of IPC and the time of IPC start after surgery had an impact on overall and disease-free survival. CONCLUSION: Adjuvant IPC for resectable gastric cancer gave encouraging results and large multicenter prospective randomized controlled studies are warranted.

The combined administration of partially HLA-matched irradiated allogeneic lymphocytes and thalidomide in advanced renal-cell carcinoma: a case report.

Renal-cell carcinoma (RCC) is susceptible to immune therapy including the use of the nonmyeloablative allogeneic transplantation (NST). However, NST can produce severe toxicity, might not be appropriate for many patients with metastatic RCC. Other novel allogeneic immunotherapies are designed to induce an autologous immune response directed against the malignancy. In single-arm phase II trials, thalidomide has demonstrated a modest activity in the treatment of advanced RCC. Here we present a case report in which a patient with advanced RCC in the absence of transplant conditioning, that was receiving thalidomide, was infused with partially HLA-matched irradiated allogeneic lymphocytes. In this patient a complete response with weak acute graft-versus-host disease (GVHD) was observed. No evidence of the disease was present over the subsequent 36 months survival of the patient, suggesting that the infusions may have played a major role in the antineoplastic effect. A potential mechanism of this protocol may involve a host-versus-graft reactions-mediated antitumor effect against the malignancy. In addition, the present results suggest that a combination protocol with alternate treatment (e.g., chemotherapy) schedules merit further investigation in the management of various malignancies.

A phase II study of 5-fluorouracil/leucovorin in combination with paclitaxel and oxaliplatin as first-line treatment for patients with advanced gastric cancer.

The objective of this study was to evaluate the efficacy and safety of the POF regimen (biweekly 5-fluorouracil/leucovorin combined with paclitaxel and oxaliplatin) as first-line treatment for advanced gastric cancer (AGC). Twenty-seven previously untreated patients with advanced adenocarcinoma of the gastric or gastroesophageal junction were eligible for this study. The chemotherapy regimen consisted of a 3-hour infusion of paclitaxel (135 mg/m(2)) followed by oxaliplatin (85 mg/m(2)) and leucovorin (400 mg/m(2)), administered simultaneously over a 2-hour infusion period, followed by an infusion of 5-fluorouracil (2400 mg/m(2)) over a 46-hour period. Twenty-one patients had measurable lesions: four complete responses, eight partial responses and seven stable diseases. At a median follow-up of 610 days, median survival was 348 days. Frequent grade 3 to 4 toxicities were: neutropenia (29.6%), stomatitis (7.4%), nausea (7.4%), vomiting (7.4%), hepatic dysfunction (3.7%), and fatigue (18.5%). No treatment-related deaths occurred. The POF regimen appears to be efficacious and is well tolerated in patients with AGC.

[A randomized controlled trail of taxol-based combination regimens for advanced gastric cancer].

BACKGROUND & OBJECTIVE: Standard chemotherapy for advanced gastric cancer remains undefined. Phase II trials show that taxol is effective in treating advanced gastric cancer. This multi-center prospective open randomized controlled study was to compare the efficacy of Taxol plus calcium folinate (CF)/5-fluorouracil (5-FU), Taxol plus oxaliplatin (OXA), and CF/5-FU plus cisplatin (DDP) on advanced gastric cancer, and analyze their toxicities. METHODS: Patients with measurable unresectable and/or metastatic gastric carcinoma were randomized into CF/5-FU+DDP (control), CF/5-FU + Taxol, and Taxol + OXA groups, and received up to 8 cycles of chemotherapy. Treatment efficacy and adverse events were evaluated according to WHO criteria. RESULTS: A total of 180 patients were enrolled from May 2002 to May 2004, and randomized into the 3 groups; each group contained 60 patients. Of the 180 patients, 14 received 2 cycles of chemotherapy, 49 received 4 cycles, and 103 received 8 cycles. Treatment outcomes of 166 cases were evaluable. The response rate (RR) of naive patients or the patients with retroperitoneal lymph node metastasis was significantly higher in CF/5-FU+Taxol and Taxol+OXA groups than in control group (50.00% and 80.00% vs. 20.75%, P<0.05; 65.96% and 85.71% vs. 36.36%, P<0.05). But the RR of the patients with liver metastasis was similar among the 3 groups (28.57% and 39.13% vs. 34.62%, P>0.05). The occurrence rates of nausea/vomiting, anepithymia, stomatitis, and kidney damage were lower in study groups than in control group, but the occurrence rates of myelosuppression and peripheral nerve damage were higher in study groups than in control group. Allergic response occurred in 7 (5.88%) patients in study group, and 3 (2.52%) of them were serious. There was no treatment-related death. CONCLUSIONS: Despite its hematotoxicity, the treatment efficacy of Taxol-based combination regimens on advanced gastric cancer is better than that of CF/5-FU + DDP regimen with tolerable toxicities. We recommend Taxol-based combination regimens as first-line regimens for advanced gastric cancer.