Shota Fukuoka

Preclinical efficacy of Sym004, novel anti-EGFR antibody mixture, in esophageal squamous cell carcinoma cell lines

Epidermal growth factor receptor (EGFR) is a well-validated oncological target molecule for monoclonal antibody therapies and Sym004 is a novel anti-EGFR antibody mixture comprising two recombinant chimeric IgG1 antibodies against non-overlapping epitopes of EGFR. Because EGFR is highly expressed in the majority of esophageal squamous cell carcinomas (ESCCs), we investigated the efficacy of Sym004 in human ESCC cell lines. Forty eight ESCC cell lines were treated with three kinds of anti-EGFR antibodies (Sym004, cetuximab, and panitumumab). Genetic background was investigated by next generation sequencing. The internalization of anti-EGFR antibodies into ESCC cells and inhibition of the EGFR signaling cascade by anti-EGFR antibodies were investigated in vitro. Furthermore, growth inhibition by anti-EGFR antibody treatment was investigated in vitro and in vivo. Sym004 treatments were more effective at inducing EGFR internalization and degradation than the two other anti-EGFR antibodies. Sym004 was more sensitive significantly to cell lines with EGFR gene amplification than those without amplification (P = 0.002). Growth inhibition of Sym004 was greater than in that of cetuximab or panitumumab in vitro and in vivo. These studies showed that Sym004 exhibited antitumor activity in some ESCC cell lines in preclinical settings and warrant a clinical evaluation in patients with ESCC. EGFR amplification is a potential biomarker of response to Sym004.

Prophylactic Use of Oral Dexamethasone to Alleviate Fatigue During Regorafenib Treatment for Patients With Metastatic Colorectal Cancer

Micro‐Abstract Fatigue is the most common toxicity of all grade‐associated toxicities associated with regorafenib for the treatment for colorectal cancer. A retrospective study was performed to clarify the safety and efficacy of prophylactic oral dexamethasone on fatigue. Our data suggest that the prophylactic use of dexamethasone reduced the incidence of fatigue during regorafenib therapy. Background: Fatigue is the most common toxicity of all grade toxicities with regorafenib, was the second most common toxicity in the CORRECT (regorafenib monotherapy for previously treated metastatic colorectal cancer) study, and is a major reason for early dose modification. The results from a recent randomized study suggested that dexamethasone (DEX) can improve cancer‐related fatigue. Patients and Methods: We retrospectively analyzed the effect of prophylactic use of an oral DEX on fatigue during regorafenib treatment in patients with metastatic colorectal cancer (mCRC). A total of 105 patients who had received regorafenib at our institution from May 2013 to August 2014 were divided into 2 groups according to oral DEX use (2 mg/day; at the physicians discretion). Results: Of the 105 patients, 31 received prophylactic DEX and 74 received regorafenib alone. The time to dose modification was significantly longer in the DEX group than in the no DEX group (15 days vs. 9 days; P = .009). The incidence of fatigue (grade ≥ 1) was significantly lower with DEX than without DEX (25.8% vs. 50.0%; P = .022). Fewer patients experienced a decreased appetite (grade ≥ 1; 3.2% vs. 35.1%; P < .001) and hand–foot skin reaction (HFSR; grade ≥ 3; 3.2% vs. 25.7%, P = .002) with DEX than without DEX. Conclusion: DEX was effective in reducing fatigue during regorafenib treatment, resulting in prolonging the time to dose modification for regorafenib. The decreased incidence of appetite loss and HFSR also suggest that concurrent DEX administration with regorafenib warrants further investigation.

Role of Predictive Value of the Modified Glasgow Prognostic Score for Later-line Chemotherapy in Patients With Metastatic Colorectal Cancer

Micro‐Abstract The survival and safety of patients with metastatic colorectal cancer treated with trifluridine/tipiracil or regorafenib as later‐line chemotherapy were retrospectively examined according to the modified Glasgow Prognostic Score (mGPS). Overall and progression‐free survival were strongly correlated with mGPS in all patients. The frequency of adverse events was generally similar in each mGPS group. Background Assessment of patient factors is essential for selecting later‐line chemotherapy in patients with metastatic colorectal cancer (mCRC). The efficacy, prognosis, and safety of each treatment regimen according to nutritional and inflammatory status still remain to be elucidated. Patients and Methods A total of 550 patients with mCRC who were registered in the REGOTAS study (Regorafenib versus TAS‐102 as Salvage‐line in patients with colorectal cancer refractory to standard chemotherapies: a multicenter observational study, UMIN 000020416) and treated with trifluridine/tipiracil (TFTD) or regorafenib as a later‐line therapy were retrospectively stratified according to the modified Glasgow Prognostic Score (mGPS), which divided patients into mGPS 0 to 2 by serum albumin and C‐reactive protein, and compared. Results The median overall survival (OS) of patients with mGPS 0, 1, and 2 was 10.0 months (95% confidence interval [CI], 9.2‐11.6 months), 6.5 months (95% CI, 5.3‐7.1 months), and 3.9 months (95% CI, 3.3‐4.9 months), respectively. The median progression‐free survival (PFS) with mGPS 0, 1, and 2 was 2.5 months (95% CI, 2.1‐3.0 months), 2.0 months (95% CI, 1.9‐2.3 months), and 1.7 months (95% CI, 1.4‐1.9 months), respectively. There were significant differences by mGPS in both OS and PFS (all P < .001). No significant differences in OS and PFS were observed between the patient groups treated with TFTD and regorafenib in each mGPS group. In patients aged ≥ 65 years with mGPS 2, the OS and PFS were worse with regorafenib than with TFTD (OS: hazard ratio, 1.45; 95% CI, 0.93‐2.25; P = .097; PFS: hazard ratio, 1.57, 95% CI, 1.01‐2.44; P = .047), but there were no consistent trends observed as mGPS increased. The frequency of grade 3 and more adverse events was generally similar in each mGPS group. The multivariate analyses showed that mGPS was the strongest predictive factor for OS. Conclusions The mGPS before later‐line chemotherapy is strongly correlated with survival in patients with mCRC.

A retrospective study of the safety and efficacy of paclitaxel plus ramucirumab in patients with advanced or recurrent gastric cancer with ascites

BackgroundRamucirumab has recently proved to be effective for advanced or recurrent gastric cancer (AGC). Ascites and peritoneal metastasis are among the most common complications of AGC. However, there are few data on the safety and efficacy of paclitaxel plus ramucirumab in patients with AGC with ascites. The purpose of this retrospective study was to evaluate the safety and efficacy of paclitaxel plus ramucirumab in patients with AGC with ascites.MethodsWe retrospectively evaluated the safety and efficacy of paclitaxel plus ramucirumab in patients with AGC with ascites in comparison with patients without ascites in a single institution from June 2015 to May 2016. The median progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method, and differences evaluated using the Log-lank test. The differences in baseline characteristics and response rates of each ascites group were calculated for homogeneity by chi-square tests and for trends by Fisher’s exact test.ResultsEighty-three patients were analyzed in this study. Ascites was detected in 40 patients, 26 patients (31%) had small to moderate ascites and 14 (17%) had massive ascites. The proportion of patients who started with a reduced dose of paclitaxel was higher for patients with massive ascites than others. The frequencies of any grade 3 or 4 hematological toxicity were 51% in patients without ascites, 77% in patients with small to moderate ascites, and 71% in patients with massive ascites. The frequencies of common ramucirumab-related adverse events were also not significantly different among ascites groups, however one patient had a tumor hemorrhage, and one patient had a gastrointestinal perforation. PFS and OS were shorter in patients with massive ascites than in patients with small or moderate ascites or patients without ascites.ConclusionsThe use of paclitaxel and ramucirumab in patients with AGC with large amounts of ascites was tolerable with adequate dose modification. However, we should pay attention to the risks of ramucirumab-related toxicity in patients with bleeding tumors or intestinal stenosis.

Gastrointestinal Perforation and Fistula Formation in 5 Patients With Colorectal Cancer During Treatment With Regorafenib

Regorafenib is an oral multikinase inhibitor that targets multiple pathways, including vascular endothelial growth factor receptor, and improves the survival of patients with metastatic colorectal cancer (mCRC). Gastrointestinal (GI) perforation and fistula are wellrecognized adverse events associated with agents that target the VEGF pathway, including bevacizumab. We report 5 cases of GI perforation or fistula formation during treatment with regorafenib. We identified 1 case of GI perforation (0.6%) and 4 cases of fistula formation (2.4%) among 170 patients with mCRC administered regorafenib in our hospital. In all 5 cases, GI perforation or fistula involved the residual tumor and were successfully treated with antibiotic therapy or surgery and recovered from these adverse events. It is important to recognize that GI perforation and fistula can occur in patients treated with regorafenib.

Abstract 139: M2698, a novel dual inhibitor of p70S6K and Akt: preclinical efficacy in gastric cancer

M2698 is a selective, ATP-competitive dual inhibitor of p70S6K and Akt1/3 that is being evaluated in a phase I clinical trial in cancer patients. The dual nature of M2698 may result in improved clinical efficacy by blocking the increased AKT activity in a compensatory feedback loop induced by PI3K/AKT/mTOR (PAM) pathway inhibition. In previous preclinical studies, M2698 was shown to have potent anti-proliferative activity in vitro, and inhibit tumor growth in some xenograft models in vivo. The current study examined the effects of M2698 on cell proliferation in a panel of 13 gastric cancer cell lines, as gastric cancers often harbor mutations in PAM pathway genes that deregulate this signalling pathway. Cells were treated with M2698 at a range of concentrations and proliferation was evaluated at least twice using the WST-8 cell proliferation assay kit (Dojindo Molecular Technologies, Inc. Japan). Two cell lines, HGC-27 and IM95m, were particularly sensitive to M2698 (50% growth inhibition concentration [GI50] 84 and 160 nM, respectively). The GI50 values for all other cell lines were >10-fold higher. Although HGC-27 and IM95m each carry a PIK3CA hotspot point mutation, the presence of an activating PI3K pathway mutation was not the sole determinant of sensitivity, as a third PIK3CA mutant cell line, MKN1, was far less sensitive to M2698 (GI50 9.0 uM). Western blot analysis of pharmacodynamic biomarkers showed that M2698 (1 uM) blocked the PAM pathway in both sensitive and resistant cell lines, inhibiting phospho[p]‐S6 and p‐PRAS40, despite increased p‐Akt. Some biomarkers from the PAM pathway and other signaling pathways appeared to be associated with sensitivity to M2698, but these candidate biomarkers need to be validated in a larger panel of cell lines. Treatment of HGC-27-tumor-bearing mice with M2698 (10, 20, 30 mg/kg/day) for 14 days resulted in significant tumor growth inhibition (80.2-98.6%) at Day 29 compared to treatment with vehicle (p Citation Format: Shota Fukuoka, Takashi Kojima, Yoshikatsu Koga, Mayumi Yamauchi, Masahiro Yasunaga, Yasuhiro Matsumura, Toshihiko Doi, Takayuki Yoshino, Toshio Kuronita, Anderson Clark, Brian Elenbaas, Atsuhi Ohtsu. M2698, a novel dual inhibitor of p70S6K and Akt: preclinical efficacy in gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 139. doi:10.1158/1538-7445.AM2017-139

Clinicopathological features of microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC) in Japanese patients.

629 Background: Recently, anti-programmed death 1 (PD-1) antibody has shown promising efficacy in a phase II trial for patients with microsatellite instability-high (MSI-H) tumors, especially in those with metastatic colorectal cancer (mCRC). Currently, several clinical trials of anti-PD-1 antibody for patients with MSI-H mCRC are ongoing. However, little is known about the frequencies and clinicopathological features of MSI-H mCRC in Japanese patients. Methods: Patients with histologically confirmed adenocarcinoma of mCRC were eligible for this observational study. MSI status was analyzed in tumors using the MSI Analysis System (Promega) composed of 5 mononucleotide markers. KRAS, NRAS, BRAF and PIK3CA mutations were also evaluated using the multiplex kit. Results: A total of 232 patients were enrolled until August 31, 2015, of which MSI-H was detected in 5 patients (2.1%). Among five patients with MSI-H mCRC, median age was 45 years (28-75), four had tumors on right-sided colon, five had moderately diff...

Prophylactic use of oral dexamethasone (DEX) to alleviate fatigue during regorafenib (REG) treatment for patients with advanced colorectal cancer (aCRC).

774 Background: Regorafenib (REG) is an oral multi-kinase inhibitor which demonstrated significant overall survival (OS) benefit for patient with advanced colorectal cancer (aCRC). Fatigue is the most common toxicity in all grade associated toxicity with REG, which is one of major reasons for early dose modification. On the other hand, recent study suggested that dexamethasone (DEX) improve the cancer associated fatigue. Methods: We retrospectively analyzed the effect of prophylactic use of oral DEX on fatigue during REG treatment for patients with aCRC. Ninety-three patients who received REG in our institution between May 2013 and June 2014 were divided into two groups according to use of oral DEX (2 mg per day; by investigator’s discretion). Outcomes measured in this study were a time to dose modification, incidences of toxicities, and anti-tumor effects. Results: Prophylactic DEX was administrated in 24 patients (DEX group) with regorafenib, and 69 patients received REG alone (no DEX). There were no si...

Clinical outcomes in 66 patients with advanced gastric cancer treated in phase I trials: The NCCHE experience.

213 Background: Patients with advanced gastric cancer (AGC) have a poor prognosis once standard therapies fail. Phase I trial of investigational drugs might be one of the treatment options for patients with sufficient general status. But, the clinical outcome of patients with AGC treated in phase I trials has not yet been reported in detail. Methods: We retrospectively reviewed the clinical outcomes in 66 consecutive patients with AGC who were treated in phase I trials after standard chemotherapies between March 2008 and July 2014. Results: Median age was 66 years (range, 28-78 years) and all had performance status ECOG 0 or 1. The median number of previous systemic chemotherapy was 3 (range, 1-6) with the median interval from beginning of first-line chemotherapy to enrollment for phase I trials of 18 months. Twenty-three patients were enrolled for two or more phase I trials. Objective response was observed in 5 patients (8%) and additional 8 patients (12%) achieved stable disease >3 months. Although the ...