Risk factors for postgastric endoscopic submucosal dissection bleeding in direct oral anticoagulant users.

OBJECTIVES: Bleeding after endoscopic submucosal dissection (ESD) for gastric tumors in patients taking antithrombotic drugs, in particular direct oral anticoagulants (DOACs), remains unresolved; therefore, we evaluated the risk factors for post-ESD bleeding and drug differences in patients taking DOACs. METHODS: We included 278 patients taking antithrombotic drugs who underwent gastric ESD between January 2017 and March 2022. Antithrombotic drugs were withdrawn following the 2017 guidelines (Appendix on anticoagulants including DOACs). To further clarify differences in antithrombotic agents' effects, the peri-cancerous mucosa in the resected specimen was pathologically evaluated according to the Updated Sydney System. Multivariate analysis was performed to assess the risk of post-ESD bleeding. RESULTS: The incidence of post-ESD bleeding in patients taking DOACs was 19.6% (10/51). Among patients taking antithrombotic drugs, DOACs were identified as a possible factor involved in post-ESD bleeding (odds ratio [OR] 4.92). Among patients taking DOACs, possible factors included resection length diameter ≥30 mm (OR 3.72), presence of neutrophil infiltration (OR 2.71), lesions occurring in the lower third of stomach (OR 2.34), and preoperative antiplatelet use (OR 2.22). Post-ESD bleeding by DOAC type was 25.0% of patients (4/16) receiving apixaban, in 20.0% (3/15) receiving edoxaban, in 21.4% (3/14) receiving rivaroxaban, and in none of those receiving dabigatran. CONCLUSIONS: The administration of DOACs was shown to be a possible factor involved in post-ESD bleeding, and risk factors for patients taking DOACs included neutrophil infiltration. The pharmacological differences in the effects of DOACs contributing to bleeding in gastric ulcers suggest comparatively less bleeding with dabigatran after ESD.

Conversion surgery of Stage IV gastric cancer with peritoneal dissemination after nivolumab.

A 69-year-old man was clinically diagnosed as stage IV gastric cancer with peritoneal dissemination. We performed systemic chemotherapy consisting of S-1 plus oxaliplatin as a first line, and ramucirumab plus nab-paclitaxel as a second line. However, CT and EGD revealed growth of the primary tumor and the lymph nodes along the lesser curvature and adjacent to the cardia. In addition, CT revealed ascites in the rectovesical pouch. Therefore, treatment was switched to nivolumab. After 3 treatment courses, CT revealed shrinkage of lymph nodes and disappearance of ascites. After 12 courses of nivolumab, however, EGD revealed growth of the tumors in the stomach with minor hemorrhage, prompting the consideration of gastrectomy. At the time of laparotomy, the peritoneal dissemination had completely disappeared, and peritoneal cytology was negative. Therefore, total gastrectomy with D2 and paraaortic lymphadenectomy was performed, after 21 months following the initial diagnosis. To our knowledge, there are no previous reports that have demonstrated the disappearance of peritoneal dissemination and ascites in response to nivolumab, resulting in curative gastrectomy.

Efficacy and Safety of Ramucirumab/nab-paclitaxel for Previously Treated Advanced Gastric Cancer in Community Hospitals.

As the nanoparticle albumin-bound paclitaxel (nab-PTX) is free of ethanol and premedication, the duration of administration is shorter and patients can drive themselves to and from the hospital. In the 2018 Japanese gastric cancer treatment guidelines, ramucirumab (RAM) plus weekly nab-PTX is conditionally recommended for previously treated patients with advanced gastric cancer. Here, we retrospectively analysed the efficacy and safety of RAM+nab-PTX for such patients in community hospitals. From January 2018 to December 2019, 43 patients with metastatic and recurrent gastric cancer received RAM+nab-PTX treatment. Six patients (13.9%) were older than 80 years and 9 patients (20.9%) showed ECOG-PS 2. Progression-free survival (PFS), overall survival (OS), overall response rate (ORR), disease control rate (DCR), and adverse events (AEs) were reviewed retrospectively. Median PFS was 114 days (95% confidence interval [CI]: 84-190) and median OS was 297 days (95% CI: 180-398). ORR and DCR were 32.4% and 72.2%, respectively. The incidence rates of ≥grade 3 neutropenia and febrile neutropenia were 53.5% and 2.3%, respectively. No treatment-related deaths occurred. RAM plus nab-PTX combination therapy demonstrated manageable toxicity even patients who were elderly or had an ECOG-PS 2. This treatment is useful in community hospital settings.

Phase I safety and pharmacokinetic study of YM155, a potent selective survivin inhibitor, in combination with erlotinib in patients with EGFR TKI refractory advanced non-small cell lung cancer.

PURPOSE: This phase I study was conducted to evaluate the safety and pharmacokinetics of YM155, a potent, selective survivin inhibitor, in combination with erlotinib in patients with EGFR TKI refractory advanced non-small cell lung cancer (NSCLC). METHODS: The pimary objectives were to evaluate the safety and tolerability of YM155 at escalating doses (3.6, 4.8, 6.0, and 8.0 mg/m2/days) administered every 3 weeks as continuous intravenous infusion over 168 h in combination with erlotinib at a fixed dose (150 mg, once a day). Secondary objectives were to assess the pharmacokinetics of YM155, antitumor activity, and the relationship between biomarkers and efficacy. The changes in survivin expression in biopsied tumor pre- and post-YM155 administration and serum cytokine levels were also analyzed. RESULTS: Fifteen patients were treated. The most common YM155-related adverse event was the presence of urine microalbumin, whereas grades 3/4 toxicities were rare. One patient who received 4.8  mg/m2/days YM155 developed a dose-limiting grade 2 serum creatinine elevation. YM155 exposure in plasma showed dose proportionality across all dose ranges tested. No pharmacokinetic interaction occurred between YM155 and erlotinib. The serum cytokines IL-8, G-CSF, and MIP-1b showed decreasing trends in patients who achieved progression-free survival of ≥ 12 weeks. Durable stable disease for ≥ 24 weeks was observed in two patients. CONCLUSION: Up to 8.0 mg/m2/days YM155 administered every 3 weeks in combination with erlotinib exhibited a favorable safety profile and moderate clinical efficacy. These results suggest that inhibiting survivin is a potential therapeutic strategy for select patients with EGFR TKI refractory NSCLC. TRIAL REGISTRATION: UMIN000031912 at UMIN Clinical Trials Registry (UMIN-CTR).

Clinicopathological examination of ESD as salvage therapy for esophageal cancer after definitive chemo-radiation therapy.

BACKGROUND AND STUDY AIMS: Salvage therapy for esophageal cancer following chemo-radiation therapy (CRT) has not been established. We aimed to evaluate endoscopic submucosal dissection (ESD) as a salvage therapy based on histopathological features of lesions. PATIENTS AND METHODS: We compared 10 lesions in eight patients with local residual, recurrent, or metachronous esophageal squamous cell carcinoma treated by ESD after CRT (CRT group) and 59 lesions treated by ESD without CRT (non-CRT group) during the same period. RESULTS: The en bloc resection rate was 100 % while the complete resection rate was 80.0 % in the lesions after CRT, indicating no difference between the CRT and non-CRT groups. Pathological examination showed that fibrosis was more intense in the lamina propria mucosa, muscularis mucosa, and submucosa. The muscularis mucosa was thicker in both non-tumor and tumor sites in the CRT group compared to the non-CRT group. However, severe submucosal fibrosis was observed only in one lesion in the CRT group. The maximum diameter of the submucosal artery was significantly larger in the CRT group ( P  < 0.001). CONCLUSIONS: Compared to the non-CRT group, the lesions in the CRT group were accompanied by fibrosis while the muscularis mucosa were thicker; however, severe fibrosis of the submucosa was rare. It is important to dissect the muscularis mucosa appropriately during ESD, which makes successful dissection of the submucosa possible. Attention should be paid to bleeding from large arteries.

Gastrointestinal perforation related to lenvatinib, an anti-angiogenic inhibitor that targets multiple receptor tyrosine kinases, in a patient with metastatic thyroid cancer.

Lenvatinib, a novel potent multikinase inhibitor, was approved for the treatment of radioiodine-refractory differentiated thyroid cancer based on results from phase III trial (SELECT study). Thyroid cancer is a diverse disease that includes anaplastic thyroid cancer (ATC), which the most aggressive form of the disease, although it accounts for <2% of all thyroid cancers. Current treatments for ATC have limited efficacy. We report the case of a woman with recurrent well-differentiated papillary carcinoma of the thyroid that had transformed into ATC who developed a perforation of the small intestine secondary to a marked effect of lenvatinib. She received lenvatinib (24 mg once a day) at only two doses during two weeks due to pleurodesis with talc for malignant pleural effusion. Eventually, she developed peritonitis due to the perforation and died of sepsis. However, an autopsy revealed marked efficacy of lenvatinib for ATC at a metastatic site in the small intestine despite limited exposure to the drug. Here, we report on our experience with lenvatinib treatment and gastrointestinal perforation concerning anti-angiogenic therapy.

Retrospective study of unplanned hospital admission for metastatic cancer patients visiting the emergency department.

PURPOSE: The purpose of the study was to identify factors that predict unplanned admission for metastatic cancer patients visiting the emergency department (ED). METHODS: Patients visiting the ED of a general hospital from April 2012 to March 2013 were investigated retrospectively. Data including demographics, vital signs, and laboratory measurements were collected from a chart review for each patient. Factors related to emergency admission were identified by univariate and multivariate analyses. RESULTS: A total of 15,716 individuals visiting the ED during the study period included 1244 (7.9%) patients with cancer. Among the 491 cancer patients with metastasis, univariate analysis revealed that emergency admission was significantly associated with an age of ≥76 years; an altered mental status; fever (≥38 °C); a blood oxygen saturation of <90%; a white blood cell (WBC) count of ≤2000 or ≥10,000/µL; hypoalbuminemia (≤2.5 g/dL); and elevated levels of aspartate aminotransferase (≥100 IU/L), blood urea nitrogen (≥25 mg/dL), and C-reactive protein (CRP, ≥10 mg/dL). Multivariate analysis identified age, an altered mental status, hypoxemia, an abnormal WBC count, and elevated CRP as putative independent predictive factors for emergency admission. The number of these five factors present was also correlated with 30-day mortality (c-statistic = 0.72). CONCLUSIONS: Age, unconsciousness, hypoxemia, an abnormal WBC count, and elevated CRP were found to be associated with emergency admission and 30-day mortality for metastatic cancer patients. Prospective validation of a predictive scoring system based on these findings is warranted.

Progression-Free and Overall Survival of Patients With ALK Rearrangement-Positive Non-Small Cell Lung Cancer Treated Sequentially With Crizotinib and Alectinib.

INTRODUCTION: Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) show marked therapeutic efficacy in patients with non-small cell lung cancer (NSCLC) harboring the echinoderm microtubule-associated protein-like 4-ALK fusion gene. The effect on overall survival (OS) of sequential treatment with the first- and second-generation ALK-TKIs crizotinib and alectinib, respectively, has remained unknown. We have examined the clinical outcome of such sequential treatment in a retrospective analysis of patients with ALK-rearranged NSCLC. MATERIALS AND METHODS: Eleven patients with ALK-rearranged NSCLC treated with crizotinib followed by alectinib were identified. The progression-free survival (PFS) and OS for these patients were determined from a retrospective review of their medical records. RESULTS: The median PFS on crizotinib or alectinib was 6.1 months (range, 1.0-15.4 months) and 15.2 months (range, 1.0-28.3 months), respectively. The median combined PFS for both crizotinib and alectinib was 18.2 months (range, 10.4-43.7 months). Crizotinib was continued beyond radiographic evidence of progressive disease in 6 of the 11 patients, with a median duration of postprogression crizotinib treatment of 9.4 months (range, 0-20.5 months). The OS period from the diagnosis of metastatic disease or the initiation of crizotinib treatment was 51.1 months (range, 20.9-69.5 months) and 48.6 months (range, 19.8-50.1 months), respectively. CONCLUSION: Our retrospective study has revealed durable survival for alectinib treatment after crizotinib failure in patients with ALK-rearranged NSCLC.

Afatinib-refractory brain metastases from EGFR-mutant non-small-cell lung cancer successfully controlled with erlotinib: a case report.

Both afatinib and erlotinib are tyrosine kinase inhibitors that inhibit aberrant epidermal growth factor receptor (EGFR) signals in non-small-cell lung cancer (NSCLC). Afatinib is an irreversible inhibitor directed against EGFR, ErbB-2, and ErbB-4, whereas erlotinib is a reversible inhibitor directed against EGFR only. Although afatinib has been shown to be effective in the treatment for erlotinib-refractory and/or gefitinib-refractory central nervous system metastases from NSCLC, little is known about the efficacy of erlotinib for afatinib-refractory central nervous system metastases. In the present report we describe a case of EGFR mutation-positive NSCLC in which brain metastases developed during first-line afatinib treatment. Whole-brain radiation therapy and substitution of erlotinib for afatinib led to successful shrinkage of the brain metastases. Our report highlights the potential benefit of erlotinib for the management of brain metastases refractory over afatinib in patients with NSCLC.

Phase I study of weekly nab-paclitaxel combined with S-1 in patients with human epidermal growth factor receptor type 2-negative metastatic breast cancer.

We conducted a phase I study of a weekly nab-paclitaxel and S-1 combination therapy in patients with human epidermal growth factor receptor type 2-negative metastatic breast cancer. The primary objective was to estimate the maximum tolerated and recommended doses. Each treatment was repeated every 21 days. Levels 1, 2a, 2b, and 3 were set depending on the S-1 dose (65 or 80 mg/m(2) ) and nab-paclitaxel infusion schedule (days 1 and 8 or days 1, 8, and 15). Fifteen patients were enrolled. Dose-limiting toxicity was observed in one patient at Level 3 (100 mg/m(2) nab-paclitaxel on days 1, 8, and 15 with 80 mg/m(2) S-1 daily for 14 days, followed by 7 days of rest). Although the maximum tolerated dose was not reached, the recommended dose was determined to be Level 3. Neutropenia was the most frequent grade 3-4 treatment-related adverse event. For patients with measurable lesions, the response rate was 50.0% and the median time to treatment failure and median progression-free survival was 13.2 and 21.0 months, respectively. The present results show the feasibility and potential for long-term administration of this combination therapy.

Chronic nicotine exposure mediates resistance to EGFR-TKI in EGFR-mutated lung cancer via an EGFR signal.

BACKGROUND: Some of patients with non-small cell lung cancer (NSCLC) harboring somatic activating mutations of the epidermal growth factor receptor gene (EGFR mutations) show poor responses to EGFR-tyrosine kinase inhibitors (EGFR-TKIs) treatment. Cigarette smoking is the strongest documented risk factor for the development of lung cancer. Nicotine, while not carcinogenic by itself, has been shown to induce proliferation, angiogenesis, and the epithelial-mesenchymal transition; these effects might be associated with EGFR-TKI resistance. MATERIALS AND METHODS: PC-9 and 11_18 cell lines (EGFR-mutated NSCLC cell lines) were cultured with 1µM nicotine for 3 months and were designated as PC-9/N and 11_18/N cell lines, respectively. The sensitivities of these cell lines to EGFR-TKI were then tested in vitro. Moreover, the association between the smoking status and the progression-free survival (PFS) period was investigated in patients with EGFR-mutated NSCLC who were treated with gefitinib. RESULTS: The PC-9/N and 11_18/N cell lines were resistant to EGFR-TKI, compared with controls. The phosphorylation of EGFR in these cell lines was reduced by EGFR-TKI to a smaller extent than that observed in controls, and a higher concentration of EGFR-TKI was capable of further decreasing the phosphorylation. Clinically, smoking history was an independent predictor of a poor PFS period on gefitinib treatment. CONCLUSIONS: Chronic nicotine exposure because of cigarette smoking mediates resistance to EGFR-TKI via an EGFR signal. Smoking cessation is of great importance, while resistance may be overcome through the administration of high-dose EGFR-TKI.

Phase I study of amatuximab, a novel monoclonal antibody to mesothelin, in Japanese patients with advanced solid tumors.

Amatuximab is a chimeric monoclonal antibody that targets mesothelin, which is expressed in virtually all mesotheliomas and pancreatic adenocarcinomas. The objective of this study was to determine the dose-limiting toxicity and the maximum tolerated dose. Patients with mesothelioma, pancreatic adenocarcinoma or other mesothelin-positive solid tumors were eligible for this study. Amatuximab was administered weekly as an intravenous infusion in 4-week cycles at progressively increasing doses ranging from 50 to 200 mg/m(2). Seventeen patients received amatuximab. Two dose-limiting toxicities were observed: one at 50 mg/m(2) and one at 200 mg/m(2); the maximum tolerated dose of this study was determined to be 200 mg/m(2). Of the 17 patients, 13 patients (76.5%) experienced treatment-related adverse events. The most common adverse events were grade 1 fatigue (29.4%) and pyrexia (23.5%). The maximum serum concentration and area under the concentration curve values increased in an almost dose-proportional manner. Three patients had stable disease. Amatuximab was generally well tolerated at doses up to 200 mg/m(2). The pharmacokinetic profile of amatuximab in the Japanese population was similar to that seen in the United States population (Clinical Trials.gov Identifier: NCT01018784).

The anti-HER3 antibody patritumab abrogates cetuximab resistance mediated by heregulin in colorectal cancer cells.

We previously showed that tumor-derived heregulin, a ligand for HER3, is associated with both de novo and acquired resistance to cetuximab. We have now examined whether patritumab, a novel neutralizing monoclonal antibody to HER3, is able to overcome such resistance. Human colorectal cancer (DiFi) cells that are highly sensitive to cetuximab were engineered to stably express heregulin by retroviral infection, and the effects of cetuximab and patritumab on the resulting DiFi-HRG cells were examined. DiFi-HRG cells released substantial amounts of heregulin and showed resistance to cetuximab. Cetuximab alone inhibited EGFR and ERK phosphorylation in DiFi-HRG cells, but it had no effect on the phosphorylation of HER2, HER3, or AKT, suggesting that sustained AKT activation by HER2 and HER3 underlies cetuximab resistance in these cells. In contrast, patritumab in combination with cetuximab markedly inhibited the phosphorylation of EGFR, HER2, HER3, ERK, and AKT. The combination therapy also inhibited the growth of DiFi-HRG tumor xenografts in nude mice to a greater extent than did treatment with either drug alone. Activation of HER2-HER3 signaling associated with the operation of a heregulin autocrine loop confers resistance to cetuximab, and patritumab is able to restore cetuximab sensitivity through inhibition of heregulin-induced HER3 activation.

Risk factors for cisplatin-induced nephrotoxicity and potential of magnesium supplementation for renal protection.

BACKGROUND: Nephrotoxicity remains a problem for patients who receive cisplatin chemotherapy. We retrospectively evaluated potential risk factors for cisplatin-induced nephrotoxicity as well as the potential impact of intravenous magnesium supplementation on such toxicity. PATIENTS AND METHODS: We reviewed clinical data for 401 patients who underwent chemotherapy including a high dose (≥60 mg/m2) of cisplatin in the first-line setting. Nephrotoxicity was defined as an increase in the serum creatinine concentration of at least grade 2 during the first course of cisplatin chemotherapy, as assessed on the basis of National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. The severity of nephrotoxicity was evaluated on the basis of the mean change in the serum creatinine level. Magnesium was administered intravenously to 67 patients (17%). RESULTS: Cisplatin-induced nephrotoxicity was observed in 127 patients (32%). Multivariable analysis revealed that an Eastern Cooperative Oncology Group performance status of 2 (risk ratio, 1.876; P = 0.004) and the regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) (risk ratio, 1.357; P = 0.047) were significantly associated with an increased risk for cisplatin nephrotoxicity, whereas intravenous magnesium supplementation was associated with a significantly reduced risk for such toxicity (risk ratio, 0.175; P = 0.0004). The development of hypomagnesemia during cisplatin treatment was significantly associated with a greater increase in serum creatinine level (P = 0.0025). Magnesium supplementation therapy was also associated with a significantly reduced severity of renal toxicity (P = 0.012). CONCLUSIONS: A relatively poor performance status and the regular use of NSAIDs were significantly associated with cisplatin-induced nephrotoxicity, although the latter association was marginal. Our findings also suggest that the ability of magnesium supplementation to protect against the renal toxicity of cisplatin warrants further investigation in a prospective trial.

A phase I study of split-dose cisplatin and etoposide with concurrent accelerated hyperfractionated thoracic radiotherapy in elderly patients with limited-disease small cell lung cancer.

OBJECTIVE: The optimal treatment for elderly patients with limited-disease small cell lung cancer has not been defined. We therefore performed a Phase I study for split-dose cisplatin plus etoposide combined with early concurrent accelerated hyperfractionated thoracic radiotherapy in elderly (70 years of age or older) patients with limited-disease small cell lung cancer. METHODS: Chemotherapy consisted of cisplatin at 20 or 25 mg/m(2) and etoposide at 80 mg/m(2), both administered on Days 1-3 of a 28-day cycle. Radiotherapy was initiated at the onset of chemotherapy and administered at a dose of 1.5 Gy twice daily over 3 weeks up to a total dose of 45 Gy. RESULTS: Twelve patients with a median age of 76 years (range, 70-85) were enrolled. Dose-limiting toxicities occurred in two (hyponatremia of Grade 4 or cardiac ischemia of Grade 3) of the six patients treated at dose Level 1 as well as in three (perforation of the sigmoid colon of Grade 3, febrile neutropenia of Grade 3, or hyponatremia of Grade 3) of the six patients treated at dose Level 2. The most frequent non-hematologic adverse events included anorexia, fatigue, esophagitis and pneumonitis, but most of these events were of Grade 1 or 2. CONCLUSIONS: The recommended dose for cisplatin and etoposide chemotherapy administered on Days 1-3 was determined to be 20 and 80 mg/m(2), respectively. Our results indicate that split-dose cisplatin plus etoposide chemotherapy combined with early concurrent accelerated hyperfractionated thoracic radiotherapy is well tolerated by elderly patients with limited-disease small cell lung cancer. CLINICAL TRIALS REGISTRATION NO: UMIN Clinical Trials Registry (UMIN-CTR) C000000143.

Phase I pharmacokinetic study of S-1 granules and nedaplatin for advanced head and neck cancer.

AIM: We performed a pharmacokinetic phase I trial of the combination of S-1 granules and nedaplatin for head and neck squamous cell carcinoma (HNSCC). PATIENTS AND METHODS: Patients were treated with both nedaplatin on day 1 at a dose starting at 80 mg/m(2) (level 1) escalating up to 90 mg/m(2) (level 2), and S-1 granules at a daily dose of 80 mg/m(2) on days 1 to 14 every three weeks. The primary end-point was determination of the recommended dose. RESULTS: Twenty patients were enrolled. Dose-limiting toxicities occurred in one out of six patients at dose level 1 (neutropenia) and in all three patients at level 2 (neutropenia and thrombocytopenia). The recommended dose was determined as level 1. Pharmacokinetic parameters of S-1 granule did not differ from the capsula formulation. The response rate was 42.1%. CONCLUSION: This combination was well-tolerated and manifested a promising activity against HNSCC.

Bronchoscopic findings for bevacizumab-related pulmonary hemorrhage in advanced non-small cell lung cancer.

We report contemporaneous bronchoscopic findings for a case of bevacizumab-related pulmonary hemorrhage in a patient with advanced non-small cell lung cancer (NSCLC). Flexible bronchoscopy at diagnosis revealed abnormal capillary dilation that was suggestive of endobronchial involvement at the primary tumor location. The patient developed massive hemoptysis despite of marked tumor shrinkage achieved by bevacizumab-containing chemotherapy. Emergency flexible bronchoscopy for hemoptysis suggested that the location of the primary tumor was the source of bleeding. Subsequent follow-up flexible bronchoscopy revealed an ulcerative mucosal-like lesion associated with a white necrotic substance as well as attenuation of the dilation of submucosal vessels compared with that apparent at diagnosis. Our case report highlights the potential mechanistic insights into bevacizumab-related bleeding and importance of performing bronchoscopy at diagnosis in NSCLC patients, given that abnormal bronchoscopic findings may be a risk factor for bleeding.

Clinical phase I study of elpamotide, a peptide vaccine for vascular endothelial growth factor receptor 2, in patients with advanced solid tumors.

Targeting of tumor angiogenesis with vaccines is a potentially valuable approach to cancer treatment. Elpamotide is an immunogenic peptide derived from vascular endothelial growth factor receptor 2, which is expressed at a high level in vascular endothelial cells. We have now carried out a phase I study to evaluate safety, the maximum tolerated dose, and potential pharmacodynamic biomarkers for this vaccine. Ten HLA-A*24:02-positive patients with advanced refractory solid tumors received elpamotide s.c. at dose levels of 0.5, 1.0, or 2.0 mg once a week on a 28-day cycle. Five patients experienced an injection site reaction of grade 1 and 2, which was the most frequent adverse event. In the 1.0 mg cohort, one patient experienced proteinuria of grade 1 and another patient developed both hypertension and proteinuria of grade 1. No adverse events of grade 3 or higher were observed, and the maximum tolerated dose was therefore not achieved. The serum concentration of soluble vascular endothelial growth factor receptor 2 decreased significantly after elpamotide vaccination. Microarray analysis of gene expression in PBMCs indicated that several pathways related to T cell function and angiogenesis were affected by elpamotide vaccination, supporting the notion that this peptide induces an immune response that targets angiogenesis in the clinical setting. In conclusion, elpamotide is well tolerated and our biomarker analysis indicates that this anti-angiogenic vaccine is biologically active. Clinical trial registration no. UMIN000008336.

Overcoming erlotinib resistance in EGFR mutation-positive non-small cell lung cancer cells by targeting survivin.

Loss of PTEN was recently shown to contribute to resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) in EGFR mutation-positive non-small cell lung cancer (NSCLC) through activation of the protein kinase AKT. We previously showed that downregulation of the expression of the antiapoptotic protein survivin by EGFR-TKIs contributes to EGFR-TKI-induced apoptosis in EGFR mutation-positive NSCLC cells. We have now investigated the role of survivin expression in EGFR-TKI resistance induced by PTEN loss. The EGFR-TKI erlotinib did not affect survivin expression or induce apoptosis in EGFR mutation-positive NSCLC cells with PTEN loss. Downregulation of survivin either by transfection with a specific short interfering RNA or by exposure to the small-molecule survivin suppressor YM155 reversed erlotinib resistance in such cells in vitro. Furthermore, combination therapy with YM155 and erlotinib inhibited the growth of tumors formed by EGFR mutation-positive, PTEN-deficient NSCLC cells in nude mice to a greater extent than did treatment with either drug alone. These results thus indicate that persistent activation of signaling by the AKT-survivin pathway induced by PTEN loss underlies a mechanism of resistance to erlotinib-induced apoptosis in EGFR mutation-positive NSCLC. They further suggest that the targeting of survivin has the potential to overcome EGFR-TKI resistance in EGFR mutation-positive NSCLC.

MET tyrosine kinase inhibitor crizotinib (PF-02341066) shows differential antitumor effects in non-small cell lung cancer according to MET alterations.

INTRODUCTION: Tyrosine kinase inhibitors (TKIs) targeted to MET are undergoing clinical trials in patients with solid tumors, but the precise mechanism of the antitumor activity of these drugs remains unclear. We examined the antitumor action of the MET-TKI crizotinib (PF-02341066) in lung cancer cells that are positive or negative for MET amplification or mutation. METHODS: The antitumor action of crizotinib was evaluated on the basis of signal transduction, cell proliferation, apoptosis, and progression of tumor xenografts. RESULTS: Inhibition of MET signaling by crizotinib or by RNA interference-mediated MET depletion resulted in the induction of apoptosis accompanied by inhibition of AKT and extracellular signal-regulated kinase phosphorylation in lung cancer cells with MET amplification but not in cells with a MET mutation or in those without amplification or mutation of MET. These results suggest that MET signaling is essential for the survival of cells with MET amplification but not for that of cells without this genetic change, including those with a MET mutation. Crizotinib up-regulated the expression of BIM, a proapoptotic member of the Bcl-2 family, and down-regulated that of survivin, a member of the inhibitor of apoptosis protein family, in cells with MET amplification. Forced depletion of BIM and expression of survivin each inhibited crizotinib-induced apoptosis, suggesting that both up-regulation of BIM and down-regulation of survivin contribute to the proapoptotic effect of crizotinib. CONCLUSIONS: Crizotinib shows a marked antitumor action in MET amplification-positive lung cancer cells but not in cells without MET amplification, including those with a MET mutation.