Next‐generation sequencing (NGS) of tumor tissue (ie, clinical sequencing) can guide clinical management by providing information about actionable gene aberrations that have diagnostic and ...therapeutic significance. Here, we undertook a hospital‐based prospective study (TOP‐GEAR project, 2nd stage) to investigate the feasibility and utility of NGS‐based analysis of 114 cancer‐associated genes (the NCC Oncopanel test). We examined 230 cases (comprising more than 30 tumor types) of advanced solid tumors, all of which were matched with nontumor samples. Gene profiling data were obtained for 187 cases (81.3%), 111 (59.4%) of which harbored actionable gene aberrations according to the Clinical Practice Guidelines for Next Generation Sequencing in Cancer Diagnosis and Treatment (Edition 1.0) issued by 3 major Japanese cancer‐related societies. Twenty‐five (13.3%) cases have since received molecular‐targeted therapy according to their gene aberrations. These results indicate the utility of tumor‐profiling multiplex gene panel testing in a clinical setting in Japan. This study is registered with UMIN Clinical Trials Registry (UMIN 000011141).
The results of the TOP‐GEAR project (UMIN 000011141) indicate the utility of tumor‐profiling multiplex gene panel testing in a clinical setting in Japan.
Trastuzumab deruxtecan (DS-8201) is an antibody-drug conjugate consisting of an anti-HER2 (human epidermal growth factor receptor 2) antibody, a cleavable tetrapeptide-based linker, and a cytotoxic ...topoisomerase I inhibitor. The drug may have efficacy in patients with HER2-positive advanced gastric cancer.
In an open-label, randomized, phase 2 trial, we evaluated trastuzumab deruxtecan as compared with chemotherapy in patients with HER2-positive advanced gastric cancer. Patients with centrally confirmed HER2-positive gastric or gastroesophageal junction adenocarcinoma that had progressed while they were receiving at least two previous therapies, including trastuzumab, were randomly assigned in a 2:1 ratio to receive trastuzumab deruxtecan (6.4 mg per kilogram of body weight every 3 weeks) or physician's choice of chemotherapy. The primary end point was the objective response, according to independent central review. Secondary end points included overall survival, response duration, progression-free survival, confirmed response (response persisting ≥4 weeks), and safety.
Of 187 treated patients, 125 received trastuzumab deruxtecan and 62 chemotherapy (55 received irinotecan and 7 paclitaxel). An objective response was reported in 51% of the patients in the trastuzumab deruxtecan group, as compared with 14% of those in the physician's choice group (P<0.001). Overall survival was longer with trastuzumab deruxtecan than with chemotherapy (median, 12.5 vs. 8.4 months; hazard ratio for death, 0.59; 95% confidence interval, 0.39 to 0.88; P = 0.01, which crossed the prespecified O'Brien-Fleming boundary 0.0202 on the basis of number of deaths). The most common adverse events of grade 3 or higher were a decreased neutrophil count (in 51% of the trastuzumab deruxtecan group and 24% of the physician's choice group), anemia (38% and 23%, respectively), and decreased white-cell count (21% and 11%). A total of 12 patients had trastuzumab deruxtecan-related interstitial lung disease or pneumonitis (grade 1 or 2 in 9 patients and grade 3 or 4 in 3), as adjudicated by an independent committee. One drug-related death (due to pneumonia) was noted in the trastuzumab deruxtecan group; no drug-related deaths occurred in the physician's choice group.
Therapy with trastuzumab deruxtecan led to significant improvements in response and overall survival, as compared with standard therapies, among patients with HER2-positive gastric cancer. Myelosuppression and interstitial lung disease were the notable toxic effects. (Funded by Daiichi Sankyo; DESTINY-Gastric01 ClinicalTrials.gov number, NCT03329690.).
Summary Background Nivolumab is a human monoclonal IgG4 antibody that inhibits programmed cell death protein 1 (PD-1) expressed on activated T cells. We investigated the safety and activity of ...nivolumab in patients with treatment-refractory oesophageal cancer. Methods We did an open-label, single-arm, multicentre phase 2 study. Eligible patients had advanced squamous-cell carcinoma, adenosquamous-cell carcinoma, or adenocarcinoma of the oesophagus refractory or intolerant to fluoropyrimidine-based, platinum-based, and taxane-based chemotherapy. Patients were treated with 3 mg/kg nivolumab given intravenously once every 2 weeks in 6-week cycles. The primary endpoint was centrally assessed objective response (the proportion of patients whose best response was complete or partial response), according to the Response Evaluation Criteria In Solid Tumors, version 1.1. Adverse events and treatment-related adverse events (defined as events for which a causal relation to nivolumab could not be ruled out) were monitored throughout the study. The safety analysis was done in patients who received at least one dose of nivolumab, and drug activity was assessed in patients who received at least one dose of nivolumab and had at least one central assessment of tumour response. This study is registered with clinicaltrials.jp, number ONO-4538-07/JapicCTI-No.142422. Follow-up of patients is ongoing. Findings Between Feb 25 and Nov 14, 2014, 65 patients were enrolled, all with squamous-cell carcinoma. 64 patients were assessable for the primary endpoint as one patient was excluded due to having multiple primary cancers; all patients were assessable for safety. Median follow-up was 10·8 months (IQR 4·9–14·3). 11 (17%, 95% CI 10–28) of 64 patients had a centrally assessed objective response. Of the 65 patients assessed for adverse events, the most common grade 3 or 4 events were grade 4 dyspnoea and hyponatraemia (one 2%) patient each), grade 3 lung infection (five 8% patients), grade 3 decreased appetite (two 3% patients), grade 3 increased blood creatinine phosphokinase (two 3% patients), and grade 3 dehydration (two 3% patients). Serious adverse events that occurred during the study were lung infection (four 6% patients), dehydration (two 3%), interstitial lung disease (two 3%), and hyponatraemia, dyspnoea, fatigue, abnormal hepatic function, diarrhoea, bile duct stenosis, gastroenteritis, pneumonia, oedema, and back pain (one 2% patient each). There were no treatment-related deaths. Interpretation Nivolumab showed promising activity with a manageable safety profile. This drug could offer a potential new treatment approach for patients with treatment-refractory advanced squamous-cell carcinoma. Funding Ono Pharmaceutical, Bristol-Myers Squibb.
Recent studies have shown that immune-related adverse events (irAEs) caused by immune checkpoint inhibitors were associated with clinical benefit in patients with melanoma or lung cancer. In advanced ...gastric cancer (AGC) patients, there have been few reports about the correlation between irAEs and efficacy of immune checkpoint inhibitors. In this study, we retrospectively investigated the correlation between irAEs and efficacy in AGC patients treated with nivolumab.
The subjects of this study were AGC patients received nivolumab monotherapy between January 2015 and August 2018. IrAEs were defined as those AEs having a potential immunological basis that required close follow-up, or immunosuppressive therapy and/or endocrine therapy. We divided the patients who received nivolumab into two groups based on occurrence of irAEs; those with irAEs (irAE group) or those without (non-irAE group). We assessed the efficacy in both groups.
Of the 65 AGC patients that received nivolumab monotherapy, 14 developed irAEs. The median time to onset of irAEs was 30.5 days (range 3-407 days). Median follow-up period for survivors was 32 months (95% CI, 10.8 to 34.5). The median progression-free survival was 7.5 months (95% CI, 3.6 to 11.5) in the irAE group and 1.4 months (95% CI, 1.2 to 1.6) in the non-irAE group (HR = 0.11, p < 0.001). The median overall survival was 16.8 months (95% CI, 4.4 to not reached) in the irAE group and 3.2 months (95% CI, 2.2 to 4.1) in the non-irAE group (HR = 0.17, p < 0.001). Multivariate analysis demonstrated that number of metastatic sites ≥2 (HR = 2.15; 95% CI, 1.02 to 4.54), high ALP level (HR = 2.50; 95% CI, 1.27 to 4.54), and absence of irAEs (HR = 9.54, 95% CI, 3.34 to 27.30 for yes vs. no) were associated with a poor prognosis. The most frequent irAEs was diarrhea/colitis (n = 5). Grade 3 adverse events were observed in 6 patients; hyperglycemia (n = 2), diarrhea/colitis (n = 1), adrenal insufficiency (n = 1), aspartate aminotransferase increased (n = 1), peripheral motor neuropathy (n = 1). There were no grade 4 or 5 adverse events related to nivolumab.
Development of irAEs was associated with clinical benefit for AGC patients receiving nivolumab monotherapy.
After failure of first-line chemotherapy with fluoropyrimidines and platinum compounds for advanced gastric cancer, second-line chemotherapy with ramucirumab plus paclitaxel, which elicits a durable ...response, and third-line or later chemotherapy with nivolumab have been shown to lead to a more favorable prognosis in advanced gastric cancer patients. As new and more effective drugs are now available, sequential chemotherapy would contribute to prolonged survival. From this point of view, the patient’s disease course should be frequently monitored in order to adapt treatment regimens. This review summarizes the points to note in regard to radiological assessment, and discusses the integration of prognostic factors, tumor markers, and clinical symptoms that need to be taken into account to change treatment at an appropriate timing.
Trifluridine/tipiracil (TFTD), with or without bevacizumab (Bev), and regorafenib are salvage chemotherapy options for metastatic colorectal cancer (mCRC). Here, we examined the influence of ...precedent drug on the efficacy of subsequent drug.
The subjects were patients with mCRC who received salvage chemotherapy with TFTD (with/without Bev) followed by regorafenib (TFTD→Rego group/TFTD+Bev→Rego group), or reverse sequence (Rego→TFTD group) at the National Cancer Center Hospital between November 2013 and December 2020. The overall survival (OS), progression-free survival (PFS), disease control rate (DCR), tumor growth rate (TGR), and tumor growth kinetics (TGK) in the first evaluation were assessed in the three groups.
A total of 69 patients, including 27 in the TFTD→Rego group, 13 in the TFTD+Bev→Rego group, and 29 in the Rego→TFTD group, were identified. There were no significant differences in the OS among the three groups, and in the PFS and DCR between the precedent and subsequent therapies in any of the groups. The median TGR (%/month) and TGK (mm/month) in the precedent→subsequent therapy were 50.9→32.7 (p = 0.044) and 8.76→7.79 in the TFTD→Rego group, 25.4→36.1 and 7.49→9.92 in the TFTD+Bev→Rego group, and 40.8→24.4 (p = 0.027) and 8.02→7.20 in the Rego→TFTD group, respectively.
In crossover use of TFTD with/without Bev and regorafenib, both agents showed similar efficacy in terms of the conventional parameters, but the differences observed in the TGR and TGK might suggest some influence of prior regorafenib treatment on the efficacy of subsequent TFTD therapy, and vice versa.
This phase I study aimed to determine tolerability and preliminary efficacy of single‐agent alpelisib (BYL719) in Japanese patients with advanced solid malignancies. The primary objective of the ...study was to estimate the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) of oral alpelisib in patients with advanced solid tumors who had progressed despite standard therapy. The expansion part included patients with PIK3CA mutation/amplification; safety, preliminary efficacy, pharmacokinetic (PK)/pharmacodynamic profile, and food effect on the PK profile of alpelisib at the MTD/RP2D were determined. Oral alpelisib was given as a single agent on a continuous 28‐day treatment cycle once daily. Overall, 33 patients received alpelisib. Dose‐limiting toxicities were observed in 2 patients in the escalation part (at 400 mg/day) and 1 patient in the expansion part (at 350 mg/day). The RP2D of alpelisib was determined as 350 mg/day based on overall safety profile in the dose escalation part and previous data from a Western population; the MTD was not determined. The most common all‐grade treatment‐suspected adverse events were hyperglycemia and maculopapular rash (48.5% each) and diarrhea (45.5%). The PK of alpelisib in the Japanese population was similar to that reported in the Western population. The overall response rate, disease control rate, and median progression‐free survival at 350 mg/day were 3%, 57.6%, and 3.4 months, respectively. Alpelisib as single agent showed a favorable safety profile and encouraging preliminary efficacy in Japanese patients with advanced solid tumors.
This phase I study showed that alpelisib, an α‐specific PI3K inhibitor, as a single agent showed a favorable safety profile and encouraging preliminary efficacy in Japanese patients with advanced solid tumors.
EP4, a prostaglandin E2 receptor, has shown an immunosuppressive activity on cancer cells. This first‐in‐human study evaluated ONO‐4578, a highly selective EP4 antagonist, as monotherapy and in ...combination with nivolumab in patients with advanced or metastatic solid tumors. A daily dose ranging from 30 mg to 100 mg of ONO‐4578 monotherapy and that ranging from 2 mg to 60 mg of ONO‐4578 with biweekly nivolumab 240 mg were administered. A total of 31 patients were enrolled, 10 receiving monotherapy and 21 receiving combination therapy. Overall, 26 patients experienced treatment‐related adverse events. Dose‐limiting toxicities were observed in three patients; one of six patients receiving 100 mg monotherapy developed grade 3 duodenal ulcer and two of six patients receiving 60 mg combination therapy developed either grade 3 erythema multiforme or grade 3 increased amylase and grade 4 increased lipase. One patient with small‐cell lung cancer who received 40 mg combination therapy had a partial response, and three patients with monotherapy and six patients with combination therapy had stable disease. Pharmacodynamics analyses showed that ONO‐4578 had EP4 antagonistic activity at doses as low as 2 mg. In conclusion, the maximum tolerated dose of ONO‐4578 alone or in combination with nivolumab was not reached. ONO‐4578 was well tolerated at the tested doses and showed signs of antitumor activity. Considering safety, efficacy, and pharmacokinetics/pharmacodynamics results, ONO‐4578 40 mg daily with nivolumab 240 mg biweekly was selected as the recommended dose for future clinical trials. (Registration: JapicCTI‐173,496 and NCT03155061).
ONO‐4578 is a selective antagonist of the EP4 receptor for prostaglandin E2. ONO‐4578 alone or in combination with nivolumab was well tolerated and showed signs of anti‐tumor activity in patients with advanced or metastatic solid tumors. Considering safety, efficacy, and pharmacokinetics/pharmacodynamics results, ONO‐4578 40 mg daily with nivolumab 240 mg biweekly was selected as the recommended dose for future clinical trials.
to mg l, Plastics debris in the marine environment, including resin pellets, fragments and microscopic plastic fragments, contain organic
contaminants, including polychlorinated biphenyls (PCBs), ...polycyclic aromatic hydrocarbons, petroleum hydrocarbons, organochlorine
pesticides (2,2′-bis(, to µg g, and were correlated with the level of economic development., chlorophenyl)-1,1,1-trichloroethane, hexachlorinated hexanes), polybrominated diphenylethers, alkylphenols and bisphenol A,
at concentrations from sub ng g, . Some of these compounds are added during plastics manufacture, while others adsorb from the surrounding seawater. Concentrations
of hydrophobic contaminants adsorbed on plastics showed distinct spatial variations reflecting global pollution patterns.
Model calculations and experimental observations consistently show that polyethylene accumulates more organic contaminants
than other plastics such as polypropylene and polyvinyl chloride. Both a mathematical model using equilibrium partitioning
and experimental data have demonstrated the transfer of contaminants from plastic to organisms. A feeding experiment indicated
that PCBs could transfer from contaminated plastics to streaked shearwater chicks. Plasticizers, other plastics additives
and constitutional monomers also present potential threats in terrestrial environments because they can leach from waste disposal
sites into groundwater and/or surface waters. Leaching and degradation of plasticizers and polymers are complex phenomena
dependent on environmental conditions in the landfill and the chemical properties of each additive. Bisphenol A concentrations
in leachates from municipal waste disposal sites in tropical Asia ranged from sub µg l
Samples of polyethylene pellets were collected at 30 beaches from 17 countries and analyzed for organochlorine compounds. PCB concentrations in the pellets were highest on US coasts, followed by ...western Europe and Japan, and were lower in tropical Asia, southern Africa and Australia. This spatial pattern reflected regional differences in the usage of PCBs and was positively correlated with data from Mussel Watch, another monitoring approach. DDTs showed high concentrations on the US west coast and in Vietnam. In Vietnam, DDT was predominant over its metabolites (DDE and DDD), suggesting the principal source may be current usage of the pesticide for malaria control. High concentrations of pesticide HCHs were detected in the pellets from southern Africa, suggesting current usage of the pesticides in southern Africa. This study demonstrates the utility and feasibility of the International Pellet Watch approach to monitor POPs at a global scale.
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