PD-1 inhibition with retifanlimab and/or arginase inhibition with INCB001158 in Japanese patients with solid tumors: A phase I study.

BACKGROUND: Retifanlimab is a humanized monoclonal antibody targeting programmed death protein-1, and INCB001158 is an oral arginase inhibitor. This phase Ib study investigated retifanlimab, INCB001158, and their combination in Japanese patients with advanced solid tumors. METHODS: Patients received retifanlimab (500 mg every 4 weeks [Q4W] i.v.) or escalating doses of INCB001158 (75 or 100 mg twice daily [BID]) monotherapy in Part 1 and combination of retifanlimab (500 mg Q4W) and INCB001158 (100 mg BID) in Part 2. Primary endpoints were safety, tolerability, dose-limiting toxicities (DLTs), and determination of recommended phase II doses in Japanese patients. RESULTS: Eighteen patients (retifanlimab or INCB001158 monotherapy and combination; n = 6 each) were enrolled at 2 sites in Japan. There were no DLTs, fatal adverse events (AEs), or discontinuations due to AEs. Rash (all grade 1) was the most common treatment-emergent AE with retifanlimab (n = 6). Treatment-related AEs were reported with retifanlimab (n = 4) or INCB001158 (n = 2) monotherapy and with combination (n = 4); an immune-related AE (thyroid disorder, grade 2) was reported with combination. Two responses were observed with retifanlimab monotherapy (1 complete, 1 partial) and 1 stable disease (SD), for an overall response rate of 33.3% (95% confidence interval [CI], 4.3-77.7) and disease control rate (DCR) of 50% (95% CI, 11.8-88.2). Three patients had SD with INCB001158 monotherapy (DCR 50%; 95% CI, 11.8-88.2). No responses or SD were observed with combination therapy. CONCLUSION: Retifanlimab, INCB001158, and their combination had acceptable safety profiles. Promising retifanlimab antitumor activity warrants further investigation in Japanese patients.

Safety, efficacy and prognostic analyses of sunitinib in the post-marketing surveillance study of Japanese patients with gastrointestinal stromal tumor.

OBJECTIVE: This study was conducted to expand the sunitinib safety database in Japanese imatinib-resistant/-intolerant gastrointestinal stromal tumor patients. Retrospective analyses investigated common adverse events as potential prognostic markers. METHODS: Four hundred and seventy patients who received sunitinib between June 2008 and November 2009 were analyzed for safety, progression-free survival and overall survival; 386 for objective response rate; 88% received sunitinib on Schedule 4/2 starting at 50 mg/day. RESULTS: No unexpected safety issues occurred. Grade ≥ 3 adverse events occurred in 70%, most commonly thrombocytopenia (33%), neutropenia (22%) and leukopenia (15%). Objective response rate was 20% (95% confidence interval 16-24). Median progression-free survival was 22.4 weeks (95% confidence interval, 21.7-24.0). The overall survival rate at 24 weeks was 91% (95% confidence interval, 88-94). Higher relative dose intensity (≥70 vs. <70%) during the first 6 weeks and better Eastern Cooperative Oncology Group performance status (0 vs. ≥1) were associated with longer progression-free survival (24.0 vs. 20.1 weeks; P = 0.011; and 24.1 vs. 16.9 weeks; P < 0.001) and higher 24-week overall survival rate (94 vs. 83%; P < 0.001; and 96 vs. 83%; P < 0.001). Increased progression-free survival and overall survival rates were associated with specific adverse events. Cox proportional hazard modeling adjusted for relative dose intensity and performance status established hand-foot syndrome (hazard ratio = 0.636; 95% confidence interval, 0.456-0.888) and leukopenia (hazard ratio = 0.683; 95% confidence interval, 0.492-0.948) occurring within 12 weeks were significantly correlated with increased progression-free survival. CONCLUSION: Sunitinib showed good efficacy and tolerable safety. Factors associated with greater efficacy were relative dose intensity, performance status and specific early adverse events.

Phase I/II study of sunitinib malate in Japanese patients with gastrointestinal stromal tumor after failure of prior treatment with imatinib mesylate.

PURPOSE: To establish a recommended sunitinib dosing schedule in Japanese patients with imatinib-resistant/intolerant gastrointestinal stromal tumor (GIST) and to evaluate the efficacy, safety/tolerability, pharmacokinetics, and pharmacodynamics of sunitinib using this schedule. PATIENTS AND METHODS: In the phase I part of this open-label phase I/II trial, Japanese GIST patients received 25, 50, or 75 mg/day of sunitinib on Schedule 4/2 (4 weeks on treatment; 2 weeks off treatment) following imatinib failure. In phase II, patients received the recommended (maximum tolerated) dose on this schedule; the primary endpoint was clinical benefit rate (CBR; percent objective responses or stable disease [SD] ≥22 weeks). Additional efficacy, safety, pharmacokinetic, and biomarker analyses were performed. RESULTS: In phase I (12 patients), the recommended dose was determined to be 50 mg/day. Sunitinib pharmacokinetics were similar to those observed in studies with Western patients. In the phase II part (36 patients), the CBR was 39% (95% CI: 23­57%; 11% partial responses, 28% SD ≥22 weeks). The most common treatment-related non-hematologic adverse events (AEs) were hand­foot syndrome (86%) and fatigue (67%). A trend towards a correlation between decreases from baseline in plasma soluble KIT levels and improved CB was found. CONCLUSIONS: The pharmacokinetics observed and clinical outcomes achieved in Japanese GIST patients on sunitinib (50 mg/day, Schedule 4/2) after imatinib failure appeared similar to those of Western patients in previous sunitinib trials. Although some serious AEs were observed, AEs were generally manageable using dose interruption/modification and/or standard medical treatments.

Sporadic colorectal cancer in elderly people.

BACKGROUND/AIMS: The mechanism of the development of cancer in old age is not well understood in various cancers, especially colorectal cancer. Colorectal cancer in elderly patients often shows a high frequency of proximal colon cancer. Microsatellite instability cancers are often found in the proximal colon and show a lower incidence of p53 abnormality. While the aberrant expression of p53 is more frequent in the distal colon. To investigate the carcinogenesis of colorectal cancer in elderly patients, we studied the genetic background of these patients regarding microsatellite instability and the aberrant expression of p53. METHODOLOGY: In the present study, we examined the clinicopathological features and the frequency of p53 abnormality in elderly patients compared to younger patients, and the frequency of microsatellite instability in elderly patients. In microsatellite instability cancer, immunoreactivity of hMSH2 and hMLH1 were also examined. RESULTS: Colorectal cancer in elderly patients is associated with proximal location of the cancer (p = 0.008). Microsatellite instability was observed in only 1 case (2.8%). The immunoreactivity of hMLH1 showed negative staining in malignant glands. The frequency of aberrant expression of p53 showed no significant difference between two groups. CONCLUSIONS: We found colorectal cancer more frequently in proximal colon in elderly patients than in younger patients, and microsatellite instability frequency in elderly patients (2.8%) was lower than reported microsatellite instability frequency in sporadic colorectal cancer patients. Moreover, the frequency of aberrant expression of p53 did not differ between the two groups. In the present study, microsatellite instability appeared to be less important for the carcinogenesis of colorectal cancer in elderly patients as compared to younger patients.

Postoperative complications after local resection of the stomach.

PURPOSE: Local resection of the stomach for early gastric cancer is being performed more frequently, despite which no report focusing on the postoperative complications has been published. The purpose of this study was to investigate the incidence and factors affecting postoperative complications after local resection of the stomach. METHODS: Local resection of the stomach was performed in 37 patients with gastric cancers, submucosal tumors (SMT), or bleeding gastric ulcers, 24 of whom underwent gastroscopy at least once after their operation. We retrospectively examined the complications and background relating to the operations performed in those 24 patients. RESULTS: Postoperative hemorrhage occurred in 2 patients, an open ulcer developed on the suture line in 2 and leakage developed in 1. The hemorrhage and open ulcer were observed only when wide resection with regional lymph node dissection was performed for early gastric cancers in the middle third of the stomach. CONCLUSION: These findings show that the possibility of postoperative hemorrhage and open ulcers on the suture line should be borne in mind, especially when wide local resection with lymph node dissection is performed for cancers in the middle part of the stomach.