First-in-human phase 1 study of the anti-TIGIT antibody vibostolimab as monotherapy or with pembrolizumab for advanced solid tumors, including non-small-cell lung cancer☆.

BACKGROUND: In this first-in-human phase 1 study (NCT02964013; MK-7684-001), we investigated the safety and efficacy of the anti-TIGIT (T cell immunoglobulin and ITIM domain) antibody vibostolimab as monotherapy or in combination with pembrolizumab. PATIENTS AND METHODS: Part A enrolled patients with advanced solid tumors, and part B enrolled patients with non-small-cell lung cancer (NSCLC). Patients received vibostolimab 2.1-700 mg alone or with pembrolizumab 200 mg in part A and vibostolimab 200 mg alone or with pembrolizumab 200 mg in part B. Primary endpoints were safety and tolerability. Secondary endpoints included pharmacokinetics and objective response rate (ORR) per RECIST v1.1. RESULTS: Part A enrolled 76 patients (monotherapy, 34; combination therapy, 42). No dose-limiting toxicities were reported. Across doses, 56% of patients receiving monotherapy and 62% receiving combination therapy had treatment-related adverse events (TRAEs); grade 3-4 TRAEs occurred in 9% and 17% of patients, respectively. The most common TRAEs were fatigue (15%) and pruritus (15%) with monotherapy and pruritus (17%) and rash (14%) with combination therapy. Confirmed ORR was 0% with monotherapy and 7% with combination therapy. In part B, 39 patients had anti-PD-1 (programmed cell death protein 1)/PD-L1 (programmed death-ligand 1)-naive NSCLC (all received combination therapy), and 67 had anti-PD-1/PD-L1-refractory NSCLC (monotherapy, 34; combination therapy, 33). In patients with anti-PD-1/PD-L1-naive NSCLC: 85% had TRAEs-the most common were pruritus (38%) and hypoalbuminemia (31%); confirmed ORR was 26%, with responses occurring in both PD-L1-positive and PD-L1-negative tumors. In patients with anti-PD-1/PD-L1-refractory NSCLC: 56% receiving monotherapy and 70% receiving combination therapy had TRAEs-the most common were rash and fatigue (21% each) with monotherapy and pruritus (36%) and fatigue (24%) with combination therapy; confirmed ORR was 3% with monotherapy and 3% with combination therapy. CONCLUSIONS: Vibostolimab plus pembrolizumab was well tolerated and demonstrated antitumor activity in patients with advanced solid tumors, including patients with advanced NSCLC.

Intracranial and extracranial efficacy of lorlatinib in patients with ALK-positive non-small-cell lung cancer previously treated with second-generation ALK TKIs.

BACKGROUND: Lorlatinib, a potent, brain-penetrant, third-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI), has substantial activity against ALK-positive non-small-cell lung cancer (NSCLC). This study assessed the overall, intracranial, and extracranial efficacy of lorlatinib in ALK-positive NSCLC that progressed on second-generation ALK TKIs. PATIENTS AND METHODS: In the ongoing phase II study (NCT01970865), patients with ALK-positive advanced NSCLC treated with ≥1 prior second-generation ALK TKI ± chemotherapy were enrolled in expansion cohorts (EXP) based on treatment history. Overall, intracranial and extracranial antitumor activity were assessed independently per modified Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. RESULTS: Of the 139 patients with ≥1 prior second-generation ALK TKI (EXP3B-5), 28 received one prior second-generation ALK TKI (EXP3B), 65 two prior ALK TKIs (EXP4), and 46 three prior ALK TKIs (EXP5). In EXP3B-5, the objective response rate (ORR) [95% confidence intervals] was 39.6% (31.4-48.2), intracranial ORR (IC-ORR) was 56.1% (42.4-69.3), extracranial ORR (EC-ORR) was 36.7% (28.7-45.3), median duration of response (DOR) was 9.6 months [5.6-16.7; IC-DOR, 12.4 (6.0-37.1); EC-DOR, 9.7 (6.1-33.3)], median progression-free survival was 6.6 (5.4-7.4) months, and median overall survival was 20.7 months (16.1-30.3). In EXP3B, the ORR was 42.9% (24.5-62.8), the IC-ORR was 66.7% (29.9-92.5), and the EC-ORR was 32.1% (15.9-52.4). In EXP4 and EXP5, the ORR was 38.7% (29.6-48.5), the IC-ORR was 54.2% (39.2-68.6), and the EC-ORR was 37.8% (28.8-47.5). CONCLUSIONS: Lorlatinib had clinically meaningful intracranial and extracranial antitumor activity in the post-second-generation ALK TKI setting, with elevated intracranial versus extracranial ORR, particularly in patients with fewer lines of therapy.

Molecular correlates of response to capmatinib in advanced non-small-cell lung cancer: clinical and biomarker results from a phase I trial.

BACKGROUND: Dysregulation of receptor tyrosine kinase MET by various mechanisms occurs in 3%-4% of non-small-cell lung cancer (NSCLC) and is associated with unfavorable prognosis. While MET is a validated drug target in lung cancer, the best biomarker strategy for the enrichment of a susceptible patient population still remains to be defined. Towards this end we analyze here primary data from a phase I dose expansion study of the MET inhibitor capmatinib in patients with advanced MET-dysregulated NSCLC. PATIENTS AND METHODS: Eligible patients [≥18 years; Eastern Cooperative Oncology Group (ECOG) performance status ≤2] with MET-dysregulated advanced NSCLC, defined as either (i) MET status by immunohistochemistry (MET IHC) 2+ or 3+ or H-score ≥150, or MET/centromere ratio ≥2.0 or gene copy number (GCN) ≥5, or (ii) epidermal growth factor receptor wild-type (EGFRwt) and centrally assessed MET IHC 3+, received capmatinib at the recommended dose of 400 mg (tablets) or 600 mg (capsules) b.i.d. The primary objective was to determine safety and tolerability; the key secondary objective was to explore antitumor activity. The exploratory end point was the correlation of clinical activity with different biomarker formats. RESULTS: Of 55 patients with advanced MET-dysregulated NSCLC, 40/55 (73%) had received two or more prior systemic therapies. All patients discontinued treatment, primarily due to disease progression (69.1%). The median treatment duration was 10.4 weeks. The overall response rate per RECIST was 20% (95% confidence interval, 10.4-33.0). In patients with MET GCN ≥6 (n = 15), the overall response rate by both the investigator and central assessments was 47%. The median progression-free survival per investigator for patients with MET GCN ≥6 was 9.3 months (95% confidence interval, 3.8-11.9). Tumor responses were observed in all four patients with METex14. The most common toxicities were nausea (42%), peripheral edema (33%), and vomiting (31%). CONCLUSIONS: MET GCN ≥6 and/or METex14 are suited to predict clinical activity of capmatinib in patients with NSCLC (NCT01324479).

Larotrectinib in adult patients with solid tumours: a multi-centre, open-label, phase I dose-escalation study.

BACKGROUND: NTRK1, NTRK2 and NTRK3 gene fusions (NTRK gene fusions) occur in a range of adult cancers. Larotrectinib is a potent and highly selective ATP-competitive inhibitor of TRK kinases and has demonstrated activity in patients with tumours harbouring NTRK gene fusions. PATIENTS AND METHODS: This multi-centre, phase I dose escalation study enrolled adults with metastatic solid tumours, regardless of NTRK gene fusion status. Key inclusion criteria included evaluable and/or measurable disease, Eastern Cooperative Oncology Group performance status 0-2, and adequate organ function. Larotrectinib was administered orally once or twice daily, on a continuous 28-day schedule, in increasing dose levels according to a standard 3 + 3 dose escalation scheme. The primary end point was the safety of larotrectinib, including dose-limiting toxicity. RESULTS: Seventy patients (8 with tumours with NTRK gene fusions; 62 with tumours without a documented NTRK gene fusion) were enrolled to 6 dose cohorts. There were four dose-limiting toxicities; none led to study drug discontinuation. The maximum tolerated dose was not reached. Larotrectinib-related adverse events were predominantly grade 1; none were grade 4 or 5. The most common grade 3 larotrectinib-related adverse event was anaemia [4 (6%) of 70 patients]. A dose of 100 mg twice daily was recommended for phase II studies based on tolerability and antitumour activity. In patients with evaluable TRK fusion cancer, the objective response rate by independent review was 100% (eight of the eight patients). Eight (12%) of the 67 assessable patients overall had an objective response by investigator assessment. Median duration of response was not reached. Larotrectinib had limited activity in tumours with NTRK mutations or amplifications. Pharmacokinetic analysis showed exposure was generally proportional to administered dose. CONCLUSIONS: Larotrectinib was well tolerated, demonstrated activity in all patients with tumours harbouring NTRK gene fusions, and represents a new treatment option for such patients. CLINCALTRIALS.GOV NUMBER: NCT02122913.

First-in-human phase 1 study of margetuximab (MGAH22), an Fc-modified chimeric monoclonal antibody, in patients with HER2-positive advanced solid tumors.

Background: Margetuximab is an anti-HER2 antibody that binds with elevated affinity to both the lower and higher affinity forms of CD16A, an Fc-receptor important for antibody dependent cell-mediated cytotoxicity (ADCC) against tumor cells. A Phase 1 study was initiated to evaluate the toxicity profile, maximum tolerated dose (MTD), pharmacokinetics, and antitumor activity of margetuximab in patients with HER2-overexpressing carcinomas. Patients and methods: Patients with HER2-positive breast or gastric cancer, or other carcinomas that overexpress HER2, for whom no standard therapy was available, were treated with margetuximab by intravenous infusion at doses of 0.1-6.0 mg/kg for 3 of every 4 weeks (Regimen A) or once every 3 weeks (10-18 mg/kg) (Regimen B). Results: Sixty-six patients received margetuximab (34 patients for Regimen A and 32 patients for Regimen B). The MTD was not reached for either regimen. Treatment was well-tolerated, with mostly Grade 1 and 2 toxicities consisting of constitutional symptoms such as pyrexia, nausea, anemia, diarrhea, and fatigue. Among 60 response-evaluable patients, confirmed partial responses and stable disease were observed in 7 (12%) and 30 (50%) patients, respectively; 26 (70%) of these patients had received prior HER2-targeted therapy. Tumor reductions were observed in over half (18/23, 78%) of response-evaluable patients with breast cancer including durable (>30 weeks) responders. Ex vivo analyses of patient peripheral blood mononuclear cell samples confirmed the ability of margetuximab to support enhanced ADCC compared with trastuzumab. Conclusions: Margetuximab was well-tolerated and has promising single-agent activity. Further development efforts of margetuximab as single agent and in combination with other therapeutic agents are ongoing. Trial Registration ID: NCT01148849.

Hepatitis C virus infection in intravenous drug users.

Intravenous drug use (IVDU) remains a major means of hepatitis C virus (HCV) transmission. In this study, 101 drug users were studied prospectively after cessation of IVDU. Of these, 75.8% were anti-HCV positive, and 71.4% had elevated levels of alanine aminotransferase. These levels decreased significantly within 1 month of IVDU cessation (p 0.02). Liver biopsies showed minimal or mild fibrosis in 32 (71%) of 45 subjects, and severe fibrosis in two (4.4%) subjects. Anti-HCV-positive intravenous drug users in this study presented with mild liver disease and variable stages of disease progression. Biochemical disease activity might be affected by IVDU.

Small intestinal bacterial overgrowth in patients with cirrhosis: prevalence and relation with spontaneous bacterial peritonitis.

OBJECTIVES: The significance of small intestinal bacterial overgrowth in patients with cirrhosis is not fully understood and its diagnostic criteria are not uniform. We examined the association of small intestinal bacterial overgrowth with spontaneous bacterial peritonitis and compared various microbiological criteria. METHODS: Jejunal secretions from 70 patients with cirrhosis were cultivated quantitatively and classified according to various definitions. Clinical characteristics of patients were evaluated and the incidence of spontaneous bacterial peritonitis was monitored during a 1-yr follow-up. RESULTS: Small intestinal bacterial overgrowth, defined as > or = 10(5) total colony-forming units/ml jejunal secretions, was present in 61% of patients. Small intestinal bacterial overgrowth was associated with acid-suppressive therapy (p = 0.01) and hypochlorhydria (p < 0.001). Twenty-nine patients with persistent ascites were observed. Six episodes of spontaneous bacterial peritonitis occurred after an average 12.8 wk. Occurence of spontaneous bacterial peritonitis correlated with ascitic fluid protein concentration (p = 0.01) and serum bilirubin (p = 0.04) but not with small intestinal bacterial overgrowth (p = 0.39). Its association with acid-suppressive therapy was of borderline significance (hazard ratio = 7.0, p = 0.08). CONCLUSIONS: Small intestinal bacterial overgrowth in cirrhotic patients is associated with acid-suppressive therapy and hypochlorhydria, but not with spontaneous bacterial peritonitis. The potential role of acid-suppressive therapy in the pathogenesis of spontaneous bacterial peritonitis merits further studies.

Bacterial translocation of enteric organisms in patients with cirrhosis.

BACKGROUND/AIMS: The aim of the study was to investigate the prevalence and associated risk factors for bacterial translocation in patients with cirrhosis, a mechanism involved in the pathogenesis of bacterial infections in experimental cirrhosis. METHODS: Mesenteric lymph nodes were obtained for microbiological culture from 101 patients with cirrhosis and from 35 non-cirrhotic patients. RESULTS: Enteric organisms were grown from mesenteric lymph nodes in 8.6% of non-cirrhotic patients. In the 79 cirrhotic patients without selective intestinal decontamination, the prevalence of bacterial translocation significantly increased according to the Child-Pugh classification: 3.4% in Child A, 8.1% in Child B and 30.8% in Child C patients (chi2 = 6.106, P < 0.05). However, translocation by Enterobacteriaceae, the organisms commonly responsible for spontaneous bacteremia and peritonitis in cirrhosis, was only observed in 25% of the cases. The prevalence of bacterial translocation in the 22 cirrhotic patients undergoing selective intestinal decontamination, all Child-Pugh class B and C, was 4.5%. The Child-Pugh score was the only independent predictive factor for bacterial translocation (odds ratio 2.22, P = 0.02). CONCLUSIONS: Translocation of enteric organisms to mesenteric lymph nodes is increased in patients with advanced cirrhosis and is reduced to the level found in non-cirrhotic patients by selective intestinal decontamination.

Derivation and validation of guidelines for stool cultures for enteropathogenic bacteria other than Clostridium difficile in hospitalized adults.

CONTEXT: The yield of in-hospital stool cultures performed more than 72 hours after admission is low, and a commonly used policy dictates that laboratories reject these cultures to save costs. However, enteropathogenic bacteria other than Clostridium difficile (EPB) may cause nosocomial illness that would be missed by use of such a "3-day rule." OBJECTIVE: To develop guidelines for hospital use of stool cultures that are sensitive to clinically relevant cases of sporadic and epidemic nosocomial diarrhea. DESIGN: Five-part study that incorporated a derivation sample based on retrospective chart review and a prospective cohort study (including cost savings analysis), and a validation sample based on retrospective chart review. SETTING: Four European academic health care centers. PATIENTS: Derivation sample: 1735 adult inpatients from whom 3416 stool cultures were obtained during a 19-month period (1995-1997) and 68 adult inpatients for whom EPB were grown from stool cultures during a 10-year period (1988-1998); validation sample: 65 patients with sporadic isolation of EPB (1993-1998), 56 patients involved in 2 nosocomial Salmonella outbreaks (1992 and 1997), and 330 patients who had stool cultures performed (1998). MAIN OUTCOME MEASURE: Performance of derived criteria in detecting pathogenic bacteria and outbreaks and reducing total number of stool cultures performed. RESULTS: Stool cultures grew EPB in 3.3% of samples obtained 72 hours after admission was not associated with clinical symptoms or signs but was associated with community-acquired diarrhea (24%), age 65 years or older with preexisting comorbid disease (25%), neutropenia (13%), HIV infection (10%), and nondiarrheal manifestations of enteric infections (16%). Twelve percent were asymptomatic carriers. These characteristics were used to create criteria for selecting patients for whom stool cultures would be indicated. These criteria were applied post hoc to a series of 1025 stool cultures; the number of stool cultures would have been reduced by 52% and no clinically significant cases would have been missed. Annual savings to a 355-bed institution would be approximately $7800 for reagent costs and 75 hours of technician time. In the validation samples, only 2 patients of 65 who had EPB would not have been identified, and neither required treatment. If the 3-day rule had been applied, 52 cases would not have been identified, 28 of which required antibiotic treatment. CONCLUSION: Our modified 3-day rule for use in selecting cases for stool culture is sensitive to sporadic and epidemic cases of nosocomial diarrhea in hospitalized adults.

[Chronic diarrhea: therapy with antibiotics]. / Chronische Diarrhöe: Therapie mit Antibiotika.

Chronic diarrhoea in developed countries is most frequently caused by organic or functional disorders. Infectious agents are infrequently involved, and antibiotic chemotherapy should therefore generally rest on a microbiological diagnosis. However, there may be a role for empirical antibiotic treatment in well defined circumstances such as persistent traveller's diarrhoea or suspected small intestinal bacterial overgrowth.

Diagnosis of small intestinal bacterial overgrowth in patients with cirrhosis of the liver: poor performance of the glucose breath hydrogen test.

BACKGROUND/AIMS: Small intestinal bacterial overgrowth is known to occur in association with cirrhosis of the liver and studies are needed to assess its pathophysiological role. The glucose breath hydrogen test as an indirect test for small intestinal bacterial overgrowth has been applied to patients with cirrhosis but has not yet been validated against quantitative culture of jejunal secretion in this particular patient population. METHODS: Forty patients with cirrhosis underwent glucose breath hydrogen test and jejunoscopy. Jejunal secretions were cultivated quantitatively for aerobe and anaerobe microorganisms. RESULTS: Small intestinal bacterial overgrowth was detected by culture of jejunal aspirates in 73% of patients, being associated with age and the administration of acid-suppressive therapy. The glucose breath hydrogen test correlated poorly with culture results, sensitivity and specificity ranging from 27%-52% and 36%-80%, respectively. CONCLUSIONS: In patients with cirrhosis, the glucose breath hydrogen test correlates poorly with the diagnostic gold standard for small intestinal bacterial overgrowth. Until other non-invasive tests have been validated, studies addressing the role of small intestinal bacterial overgrowth in patients with cirrhosis should resort to microbiological culture of jejunal secretions.

Diagnosis, treatment and prevention of spontaneous bacterial peritonitis.

Spontaneous bacterial peritonitis (SBP) is a frequent complication in cirrhotic patients with ascites. Diagnosis of SBP is established by a polymorphonuclear cell count in ascitic fluid > or =250 cells/mm(3). The organism responsible for the infection is isolated in 60-70% of the cases. The remaining cases are considered to have a variant of SBP (culture-negative SBP) and are treated in the same way as those with a positive culture. The SBP resolution rate ranges between 70 and 90%, and hospital survival between 50 and 70%. An early diagnosis and the use of a more adequate antibiotic therapy are the most probable reasons for the improvement in prognosis for SBP in recent decades. Despite the resolution of the infection, SBP may trigger severe complications such as renal impairment, gastrointestinal bleeding and accentuation of hepatic insufficiency which are responsible for the associated mortality. Patients recovering from an episode of SBP should be considered as potential candidates for liver transplantation.

Vertebral osteomyelitis caused by group B streptococci (Streptococcus agalactiae) secondary to urinary tract infection.

Infections due to group B streptococci usually occur in the peri- and neonatal setting or in adults with chronic underlying diseases. A case of pyogenic vertebral osteomyelitis caused by Streptococcus agalactiae in a 54-year-old man suffering from phimosis with urinary retention and urinary tract infection is reported. This case adds to the few existing reports of vertebral osteomyelitis caused by group B streptococci.

Drug-induced hepatocellular liver injury due to benzylpenicillin with evidence of lymphocyte sensitization.

BACKGROUND/AIMS: Reports on drug-induced liver injury due to benzylpenicillin are scarce and predominantly describe cases of intrahepatic cholestasis. To our knowledge, no immunologically documented case of hepatocellular liver injury due to benzylpenicillin has been reported so far. CASE REPORT: A previously healthy man required long-term therapy with benzylpenicillin because of vertebral spondylitis. After 4 weeks of treatment, liver tests showed a marked increase in transaminases associated with high peripheral eosinophil counts. Discontinuation of benzylpenicillin resulted in gradual recovery. INVESTIGATIONS: Levels of eosinophil cationic protein were elevated, indicating eosinophil activation and the presence of an immunoallergic reaction. Skin tests and assays for specific Ig E-antibodies to benzylpenicillin were negative, but lymphocyte transformation tests demonstrated T-cell sensitization to benzylpenicillin. CONCLUSIONS: According to current causality assessment schemes, our report constitutes a probable case of drug-induced hepatocellular liver injury due to benzylpenicillin.

Invasive candidiasis complicating spontaneous esophageal perforation (Boerhaave syndrome).

Spontaneous esophageal perforation is a rare condition that frequently results in infectious complications. Empirical broad-spectrum antibacterial therapy is therefore part of the standard management. We describe two patients suffering from spontaneous esophageal perforation who developed invasive candidiasis with hematogenous dissemination. One patient died of multiple organ failure due to Candida sepsis. Preexistent Candida colonization, incomplete mediastinal drainage, broad-spectrum antibacterial therapy, and prolonged intensive care therapy place patients with esophageal perforation at high risk for secondary fungal infection. Intense microbiological searching is mandatory, but the distinction between colonization and infection may be impossible. Empirical antifungal treatment with imidazole derivatives, particularly in patients with potential risk factors, should be considered.

Prolonged sedation due to accumulation of conjugated metabolites of midazolam.

Midazolam is a short-acting benzodiazepine routinely used in intensive-care medicine. Conjugates of its main metabolite, alpha-hydroxymidazolam, have been shown to accumulate in renal failure but have not previously been related to the prolonged sedative effects commonly observed in critically ill patients. We report five patients with severe renal failure who had prolonged sedation after administration of midazolam. In all five patients, the comatose state was immediately reversed by the benzodiazepine-receptor antagonist flumazenil. Serum concentration monitoring showed high concentrations of conjugated alpha-hydroxymidazolam when concentrations of the unconjugated metabolite and the parent drug were below the therapeutic range. In-vitro binding studies showed that the affinity of binding to the cerebral benzodiazepine receptor of glucuronidated alpha-hydroxymidazolam was only about ten times weaker (affinity constant 16 nmol/L) than that of midazolam (1.4 nmol/L) or unconjugated alpha-hydroxymidazolam (2.2 nmol/L). Conjugated metabolites of midazolam have substantial pharmacological activity. Physicians should be aware that these metabolites can accumulate in patients with renal failure.

[Neurocysticercosis]. / Neurozystizerkose.

A 49-year-old woman from Croatia, resident in Switzerland for 22 years, had a history of headaches and arterial hypertension for 8 years. While in hospital for assessment and treatment she developed focal seizures. She had an eosinophilia (10%) and computed tomography of the skull demonstrated cysts and multiple calcified foci in the left cerebral hemisphere. Antibodies against Taenia solium antigen were found in both serum and cerebrospinal fluid. Anthelminthic treatment with albendazole (15 mg/kg daily for 25 days) and anticonvulsive treatment with phenytoin (serum levels between 10 and 20 mg/l) markedly improved the symptoms and the cysts regressed. Neurocysticercosis, caused by the larvae of the pork tapeworm, is occurring even more frequently because of the migration of people from countries where the disease is endemic.