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PURPOSE: Clinical utility of comprehensive genomic profiling (CGP) for precision medicine has become evident. Although there are several reports on the genomic landscape of GI stromal tumors (GISTs), large-scale data specific to GIST are limited, especially in Asia. Additionally, the applicability of molecular-targeted agents identified using CGP has not been extensively examined. We investigated the status of genomic alterations in Japanese patients with advanced GISTs using the National Center for Cancer Genomics and Advanced Therapeutics (C-CAT) database to identify novel treatment strategies and drug development. MATERIALS AND METHODS: We retrospectively reviewed the clinical and CGP data of patients with advanced-stage GIST registered in the C-CAT database to assess the genomic landscape and potential actionable alterations. RESULTS: Data from 144 patients were reviewed. Oncogenic alterations were detected frequently in KIT (78%), CDKN2A (37%), CDKN2B (29%), RB1 (11%), STK11 (10%), TP53 (9%), PDGFRA (6%), and SDHB (6%). Loss of CDKN2A / CDKN2B was only observed in KIT/PDGFRA -mutated GISTs, while alterations in SDHA/SDHB were only detected in KIT/PDGFRA wild-type GISTs. Among 119 KIT/PDGFRA -mutated GISTs, 95 (80%) had oncogenic genomic alterations and 29 (24%) had actionable alterations, excluding KIT and PDGFRA. However, among 25 KIT/PDGFRA wild-type GISTs, 22 (88%) had oncogenic alterations and 11 (44%) had actionable alterations. Representative candidate drugs for genome-matched therapies in KIT/PDGFRA -mutated and wild-type GISTs were as follows: pembrolizumab for tumor mutation burden–high in one and two patients, respectively; poly-adenosine diphosphate ribose polymerase inhibitors for alterations related to homologous recombination deficiency in 12 and one patient, respectively; NTRK inhibitor for ETV6-NTRK3 fusion in one with KIT/PDGFRA wild-type GIST; and human epidermal growth factor receptor 2-antibody-drug conjugate in one with KIT/PDGFRA -mutated GIST. CONCLUSION: This study highlights the genomic landscape of advanced GISTs and the important role of CGP in identifying rational molecular-targeted therapeutic options. [ABSTRACT FROM AUTHOR]

Purpose: Tiragolumab is a monoclonal antibody that binds to the inhibitory immune checkpoint TIGIT (T-cell immunoreceptor with Ig and ITIM domains). In early phase clinical trials, tiragolumab in combination with the programmed death-ligand 1-inhibitor atezolizumab was well tolerated and has demonstrated preliminary anti-tumor activity in patients with advanced/metastatic solid tumors. We report the results of a phase I study of tiragolumab plus atezolizumab in Japanese patients (jRCT2080224926). Methods: Japanese patients ≥ 20 years old received tiragolumab (600 mg) and atezolizumab (1200 mg) intravenously every 21 days until unacceptable toxicity or disease progression. Primary endpoints were safety and pharmacokinetic (PK) parameters of tiragolumab plus atezolizumab. Secondary endpoints were anti-tumor activity. Results: Three patients were enrolled with diagnoses of non-small cell lung cancer, pancreatic cancer, and cholangiocarcinoma. No dose-limiting toxicities were observed. Two patients experienced treatment-related adverse events (AEs) of any grade. There were no grade ≥ 3 AEs, serious AEs, AEs leading to discontinuation, modification or withdrawal of any study drug, or AEs leading to death. At cycle 1, mean PK parameters of tiragolumab were as follows: Cmax 217 μg/mL; Cmin 54.9 μg/mL; area under the concentration–time curve from 0 to the last measurable concentration, 2000 μg·day/mL; t1/2, 17.6 days. Best overall response was stable disease in two patients. Conclusion: Tiragolumab plus atezolizumab was well tolerated in Japanese patients with advanced/metastatic solid tumors, and no differences in tiragolumab PK characteristics were noted between Japanese patients enrolled in this study, and non-Japanese patients enrolled in a global phase Ia/Ib study. These results may support the inclusion of Japanese patients in ongoing global phase III clinical trials. Trial registration number: jRCT2080224926. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Purpose: This two-part, open-label, non-randomized dose-escalation study aimed to define the maximum tolerated dose (MTD) of BI 836880 (humanized bispecific nanobody® targeting vascular endothelial growth factor and angiopoietin-2) as monotherapy and in combination with ezabenlimab (programmed death protein-1 inhibitor) in Japanese patients with advanced and/or metastatic solid tumors. Methods: In part 1, patients received an intravenous infusion of BI 836880 at 360 or 720 mg every 3 weeks (Q3W). In part 2, patients received BI 836880 at doses of 120, 360, or 720 mg in combination with ezabenlimab 240 mg Q3W. The primary endpoints were the MTD and the recommended phase II dose (RP2D) of BI 836880 as monotherapy and in combination with ezabenlimab, based on dose-limiting toxicities (DLTs) during the first cycle. Results: Twenty-one patients were treated; nine in part 1 and 12 in part 2. No DLTs were reported in either part and the MTD was not reached. The RP2Ds were BI 836880 720 mg Q3W as monotherapy and BI 836880 720 mg plus ezabenlimab 240 mg Q3W. The most common adverse events were hypertension and proteinuria (33.3%) with BI 836880 monotherapy and diarrhea (41.7%) with the combination. Four patients (44.4%) in part 1 had stable disease as best overall tumor response. In part 2, two patients (16.7%) had confirmed partial responses and five had stable disease (41.7%). Conclusion: MTD was not reached. BI 836880 alone and in combination with ezabenlimab had a manageable safety profile with preliminary clinical activity in Japanese patients with advanced solid tumors. Trial registration and date: NCT03972150, registered on June 3, 2019. [ABSTRACT FROM AUTHOR]

Background: Cluster of differentiation (CD) 73-targeted immunotherapy and CD73 inhibition may reduce adenosine production, which can augment the host and/or immunotherapy response to tumours. We aimed to assess the safety and tolerability, pharmacokinetics, and antitumour activity of oleclumab, an anti-CD73 monoclonal antibody, in adult Japanese patients with advanced solid malignancies resistant to standard therapy. Methods: In this phase I, single-centre, open-label study, patients received oleclumab 1500 mg (Cohort 1) or 3000 mg (Cohort 2) intravenously every 2 weeks. Results: In total, six patients were enrolled in the study (three in each cohort), and all six patients received the study treatment. The median patient age was 56.0 years and 4/6 were males. All patients (100%) reported adverse events (AEs) during the study; five (83.3%) patients reported AEs related to the study treatment. One (16.7%) patient reported a Grade 3 AE (neutrophil count decreased) that was not related to the study treatment. No AEs with an outcome of death were reported, and no patients reported AEs or serious AEs leading to oleclumab discontinuation/dose interruption. No dose-limiting toxicities were reported, and no patient discontinued due to an AE related to the study treatment. Oleclumab exposure increased dose proportionally. No patient achieved disease control at 8 weeks, and all six patients developed progressive disease. Conclusions: Oleclumab was well tolerated in adult Japanese patients with advanced solid malignancies and no unexpected safety concerns were raised; oleclumab exposure increased with dose. Future studies on combination therapy with other agents are warranted. [ABSTRACT FROM AUTHOR]

Purpose: Combination treatment using lenvatinib (a multikinase inhibitor) plus pembrolizumab (a programmed death-1 immune checkpoint inhibitor) has shown efficacy in the treatment of endometrial and renal cell cancers. This phase 1b study investigated the tolerability and safety of lenvatinib plus pembrolizumab in Japanese patients with metastatic selected solid tumors. Methods: Patients received a starting dose of 20 mg oral lenvatinib per day plus 200 mg intravenous pembrolizumab every 3 weeks in 21-day cycles. Dose-limiting toxicities were evaluated during the first cycle. Tumor assessments were performed by investigators based on modified RECIST v1.1. Pharmacokinetic parameters and serum biomarkers were assessed. Results: Among enrolled patients (N = 6), 3 had non-small cell lung cancer, and 3 had urothelial cancer. No patients experienced a dose-limiting toxicity. All patients experienced at least 1 treatment-related treatment-emergent adverse event. The objective response rate was 33.3% (95% confidence interval 4.3–77.7); both responses (1 complete, 1 partial) were observed in patients with urothelial cancer. Pharmacokinetics were consistent with previous studies. Serum angiopoietin-2 levels tended to decrease, and serum fibroblast growth factor-23 levels tended to increase from baseline to Cycle 2 Day 1. Conclusions: This study supports the tolerability of 20 mg lenvatinib/day plus 200 mg pembrolizumab every 3 weeks in Japanese patients, consistent with the results from a global study of lenvatinib plus pembrolizumab combination therapy in patients with selected solid tumors. Favorable antitumor activity was observed and there were no new safety signals identified. Trial registration : Clinical Trials.gov number: NCT03006887. [ABSTRACT FROM AUTHOR]

This phase 1, multi‐center, nonrandomized, open‐label, dose‐escalation study consisted of Part A wherein merestinib 80 or 120 mg (40‐mg tablets) was administered orally QD during a 28‐day cycle to patients diagnosed with solid tumors and Part B wherein merestinib 80 mg (40‐mg tablets) was administered orally QD, and cisplatin 25 mg/m2 + gemcitabine 1000 mg/m2 administered IV on Day 1 and Day 8 of a 21‐day cycle (for a maximum of eight cycles) to patients diagnosed with biliary tract carcinoma (BTC). Nineteen patients were screened and 18 patients were (Part A, n = 10; Part B, n = 8) enrolled in the trial and received treatment. All patients in Parts A and B were from Japan and were within an age range of 43–73 years, with an ECOG PS of 0.1. No dose‐limiting toxicity or deaths were experienced in the study. Dose‐limiting toxicity equivalent toxicity of Grade 4 platelet count decreased (n = 1) and was observed in Part B. In Part A, treatment‐related Grade ≥3 TEAEs were reported in one patient (PT: ALT increased and AST increased), while in Part B, five patients reported treatment‐related Grade ≥3 TEAEs with four of the five patients reporting an event of neutrophil count decreased. No complete response was reported in either Part. One patient in Part B reported partial response while four patients in each part reported stable disease. Merestinib monotherapy was concluded to be tolerable in Japanese patients, and its combination with cisplatin and gemcitabine is a tolerable regimen for Japanese patients with BTC. Trial registration: NCT03027284 (ClinicalTrials.gov) registered on 23 January 2017. [ABSTRACT FROM AUTHOR]

Purpose: Part 1 of this two-part, open-label, Phase 1 study (NCT03233139) assessed the safety, tolerability, pharmacokinetics, immunogenicity, and clinical activity of cemiplimab in Japanese patients with advanced malignancies.Methods: Patients received cemiplimab 250 mg (n = 6) or 350 mg (n = 7) every 3 weeks intravenously for up to 108 weeks in Part 1. Tumor responses were assessed by investigators every 9 weeks using the Response Evaluation Criteria in Solid Tumors version 1.1.Results: Of 13 patients enrolled, median age was 62 years (range 33-75) and eight patients were female. Median duration of cemiplimab exposure was 13.1 weeks (range 3.0‒113.6). At the time of data cut-off, 11 patients (84.6%) had discontinued treatment (majority due to disease progression: n = 8, 61.5%). The most common treatment-emergent adverse events (TEAEs) of any grade were contact dermatitis, rash, and viral upper respiratory tract infection (each n = 3, 23.1%). Five grade ≥ 3 TEAEs were reported in four patients: autoimmune colitis, dehydration, hyponatremia, hypophosphatemia, and muscular weakness. No dose-limiting toxicities were reported and no TEAEs led to death. Cemiplimab concentrations in serum were consistent with previously reported pharmacokinetic characteristics of cemiplimab. No anti-drug antibodies were detected in serum. Objective response rate [ORR; complete response + partial response (PR)] was 30.8% (four PR) and disease control rate [ORR + stable disease (SD)] was 46.2% (6/13; two SD).Conclusion: Cemiplimab exhibited antitumor activity in Japanese patients with advanced malignancies. The safety profile was comparable to those previously reported for cemiplimab and other PD-1 inhibitors.Trial Registration: NCT03233139 at ClinicalTrials.gov. [ABSTRACT FROM AUTHOR]

Niraparib is an oral, potent, highly selective poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) -1 and -2 inhibitor, and approved in US and Europe for the maintenance treatment of patients with recurrent ovarian cancer. Safety, tolerability and pharmacokinetics (PK) of niraparib were investigated in Japanese patients with advanced solid tumors. This Phase 1 study followed a standard 3 + 3 dose escalation design with two dose levels. Niraparib was administered orally once daily (QD) continuously for 21-days in a cycle until treatment discontinuation. Intensive PK was evaluated on day 1 and day 21 during cycle 1. Total of 9 subjects were enrolled, 3 in cohort 1 (200 mg) and 6 in cohort 2 (300 mg). No DLT was observed in cohort 1 whereas one DLT was observed in 1 of 6 subjects in cohort 2. The observed DLT was grade 4 thrombocytopenia. According to the preliminary data, the treatment-emergent adverse events reported in more than 1 subject were vomiting and thrombocytopenia/platelet count decreased (4 subjects each), nausea and anorexia (3 subjects each), and diarrhoea, alkaline phosphatase increased, creatinine increased, leukopenia/white blood cell count decreased, neutropenia-related events (including neutrophil count decreased and febrile neutropenia) and fatigue/malaise (2 subjects each). C max and AUC 24 of niraparib after a single and multiple dose (QD) administration were increased generally in dose-proportional manner between dose of 200 mg and 300 mg. The PK profiles were generally comparable across Western and Japanese patients. Three subjects stay on treatment at the timing of cutoff date (February 21, 2019) Niraparib was well tolerated and MTD was considered 300 mg or higher with recommended phase 2 dose as 300 mg in Japanese patients with advanced solid tumors. No unknown safety concerns were identified. No obvious PK difference was observed between Japanese and non-Japanese patients. [ABSTRACT FROM AUTHOR]