SummaryBackgroundPre-clinical and clinical evidence suggests that simultaneous blockade of VEGF receptor-2 (VEGFR-2) and PD-1 or PD-L1 enhances antigen-specific T-cell migration, antitumour activity, ...and has favourable toxicity. In this study, we aimed to assess the safety and preliminary antitumour activity of ramucirumab (an IgG1 VEGFR-2 antagonist) combined with pembrolizumab (an IgG4 PD-1 antagonist) in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma, non-small-cell lung cancer, or urothelial carcinoma. MethodsWe did a multicohort, non-randomised, open-label, phase 1a/b trial at 16 academic medical centres, hospitals, and clinics in the USA, France, Germany, Spain, and the UK. We enrolled adult patients aged 18 years or older with histologically confirmed gastric or gastro-oesophageal junction adenocarcinoma (cohorts A and B), non-small-cell lung cancer (cohort C), or urothelial carcinoma (cohort D), whose disease had progressed on one or two lines of previous therapy (for those with gastric or gastro-oesophageal junction adenocarcinoma) or one to three lines of previous therapy (for those with non-small-cell lung cancer and urothelial carcinoma) that included platinum (for all tumour types) or fluoropyrimidine or both (for gastric or gastro-oesophageal junction adenocarcinoma). Eligibility criteria included presence of measurable disease and an Eastern Cooperative Oncology Group performance status of 0–1. Patients with previously untreated gastric or gastro-oesophageal junction adenocarcinoma and non-small-cell lung cancer were also enrolled (in two additional separate cohorts); the results for these cohorts will be reported separately. The first 21-day treatment cycle was a dose-limiting toxicity observation period (phase 1a; safety run-in), followed by a phase 1b cohort expansion stage. Pembrolizumab 200 mg was administered intravenously on day 1, and intravenous ramucirumab was administered at 8 mg/kg on days 1 and 8 for cohort A or at 10 mg/kg on day 1 for cohorts B, C, and D, every 3 weeks, until disease progression or other discontinuation criteria were met. The primary endpoint was the safety and tolerability of ramucirumab in combination with pembrolizumab assessed by the incidence of adverse events in both phase 1a and 1b and as dose-limiting toxicities during phase 1a. The safety and activity analysis set included all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT02443324, and is no longer enrolling patients. FindingsBetween July 30, 2015 and June 24, 2016, we enrolled and treated 92 patients (41 with gastric or gastro-oesophageal junction adenocarcinoma, 27 with non-small-cell lung cancer, and 24 with urothelial carcinoma). Median follow-up was 32·8 months (IQR 28·1–33·6). During the first cycle of treatment (phase 1a safety run-in; n=11), one patient with gastro-oesophageal junction adenocarcinoma who received the 8 mg/kg dose of ramucirumab had grade 3 abdominal pain, colitis, hepatitis, interstitial lung disease, and jaundice, and grade 4 cholestasis, and died on treatment on day 40; the death was deemed related to progressive disease. No additional dose-limiting toxicities occurred and the decision was made to maintain the full planned doses of ramucirumab and pembrolizumab in phase 1b (n=81). Treatment-related adverse events occurred in 75 (82%) of 92 patients, the most common of which was fatigue (in 33 patients 36%), predominantly of grade 1 or 2 severity. 22 patients (24%) had one or more treatment-related adverse events of grade 3 or worse, most commonly hypertension (six patients; 7%) and colitis (five patients; 5%). Serious adverse events occurred in 53 (58%) of 92 patients, and were deemed related to treatment in 22 (24%) patients. The most common treatment-related serious adverse events were abdominal pain in patients with gastric or gastro-oesophageal junction adenocarcinoma (in three 7% of 41 patients); asthenia and myocardial infarction in patients with non-small-cell lung cancer (two 7% of 27 patients), and colitis in patients with urothelial carcinoma (two 8% of 24 patients). Six (7%) of 92 patients discontinued treatment because of treatment-related adverse events, and one death (from pulmonary sepsis in a patient with gastric or gastro-oesophageal junction adenocarcinoma) was deemed related to treatment. The number of patients achieving an objective response was three (7%; 95% CI 1·5–19·9) of 41 in the gastric or gastro-oesophageal junction adenocarcinoma cohort, eight (30%; 13·8–50·2) of 27 in the non-small-cell lung cancer cohort, and three (13%, 2·7–32·4) in the urothelial carcinoma cohort. InterpretationRamucirumab in combination with pembrolizumab showed a manageable safety profile with favourable antitumour activity in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma, non-small-cell lung cancer, and urothelial carcinoma. Our results contribute to the growing evidence that supports dual inhibition of the VEGF–VEGFR2 and PD-1–PD-L1 pathways. This combination could be further explored with or without chemotherapy, especially for patients with tumours for which single-agent checkpoint inhibitors have shown no additional benefit over chemotherapy. FundingEli Lilly and Company, and Merck and Co.
Treatment of solid tumors despite improved techniques in detection, surgery, radiation therapy, and chemotherapy remains difficult. Therefore, strategies to improve efficacy in accord with safety are ...needed. Many epithelial cancers have been found to overexpress the receptor to epidermal growth factor (EGFR), including head and neck, breast, colon, lung, prostate, kidney, ovary, brain, pancreas, and bladder. Because overexpression of EGFR has been associated with an overall poor prognosis in patients with cancer, a number of strategies to block or downregulate EGFR have been developed to inhibit tumor proliferation and improve overall clinical outcome. These include monoclonal antibodies to the EGFR, tyrosine kinase inhibitors, ligand-linked toxins, and antisense approaches. Antibodies such as IMC-C225 specifically target EGF receptors, whereas tyrosine kinase inhibition by many small molecules is less specific. Ultimately, IMC-C225 may prove to become a valuable contributor in the treatment of cancer. This report will focus on IMC-C225, a novel monoclonal antibody that targets the EGFR.
Summary Introduction The resolution rate of prenatal urinary tract dilation (UTD) has been documented in several retrospective studies. The present study analyzed prospective observational registry ...data, with the aim of determining time to resolution among patients prenatally identified with mild postnatal UTD. Materials and methods A total of 248 subjects, from four centers, were prospectively enrolled from 2008 to 2015. Exclusion criteria included other anomalies ( n = 69), fewer than two ultrasounds, and/or <3 months follow-up ( n = 26). Resolution was defined as Outcome A (SFU 0) and Outcome B (SFU 0/1). Fisher's exact test, Mann–Whitney U or Kruskal–Wallis test and Kaplan–Meier were used for analysis. Results/discussion The median follow-up for 179 ( n = 137 males) subjects was 15 months (IQR 7–24), range 0–56 months. VCUG was performed in 100 (57%) and VUR identified in 15 (15%). There was no association with reflux and resolution ( P = 0.72). For resolution assessment ( n = 153), lower grades were likely to resolve and demonstrated a higher rate in the Outcome B classification. Time to resolution also favored lower grades, with the majority resolving within 2 years (Figure). Surgical intervention was performed in 14 (8%). It is interesting to note that regardless of grade of UTD, there was no difference in frequency of US or the time that RUS was first performed. Practitioners performed the first RUS of life within a narrow window ranging from 0.27 RUS/month for Grade 1 UTD to 0.30 RUS/month for Grade 4 UTD. It was speculated that this practice pattern occurrence likely reflected the deficiency in knowledge by primary care providers, and identified a potential opportunity for education. The SFU registry substantiates that the vast majority of patients will demonstrate transient UTD and most cases that do not resolve will improve within 2 years of life. This data could be used to further an evidenced-based approach towards the evaluation and management of prenatal UTD, as outlined in the multidisciplinary consensus statement for prenatal urinary tract dilation. Conclusions This prospective registry confirms that the majority of prenatal UTD is transient, resolution occurs within the first 3 years of life, and most patients will not need intervention. Redefining SFU 1 as normal increased the resolution rate. A large proportion of patients were not evaluated with a VCUG, therefore impact of VUR could not be determined. Figure Kaplan–Meier curve depicting resolution for patients initially presenting with SFU Grade 1 (grey) or Grade 2 (black) hydronephrosis censored for follow-up and surgical intervention. At 6 months, the probability of resolution for both grades is 10%. At 2 years, the probability of resolution for Grade 1 is 71% and Grade 2 is 58%. At 2.5 years, the probability of resolution is 100% for Grade 1 and 72% for Grade 2. Figure
Axitinib, a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors, enhanced the efficacy of chemotherapy in human xenograft tumour models. This phase I ...study investigated the safety, tolerability, pharmacokinetics and antitumour activity of axitinib combined with chemotherapy.
A total of 42 patients with advanced solid tumours received a continuous axitinib starting dose of 5 mg twice daily (b.i.d.) plus paclitaxel (90 mg m(-2) weekly), docetaxel (100 mg m(-2) every 3 weeks) or capecitabine (1000 or 1250 mg m(-2) b.i.d., days 1-14).
Common treatment-related adverse events across all cohorts were nausea (45.2%), hypertension (45.2%), fatigue (42.9%), diarrhoea (38.1%), decreased appetite (33.3%) and hand-foot syndrome (31.0%). There was one complete response, nine partial responses and seven patients with stable disease. Ten patients (23.8%) remained on therapy for >8 months. Paclitaxel and capecitabine pharmacokinetics were similar in the absence or presence of axitinib, but docetaxel exposure was increased in the presence of axitinib. Axitinib pharmacokinetics were similar in the absence or presence of co-administered agents.
Axitinib combined with paclitaxel or capecitabine was well tolerated; no additive increase in toxicities was observed. Antitumour activity was observed for each treatment regimen and across multiple tumour types.
This phase I dose-finding trial evaluated safety, efficacy and pharmacokinetics of axitinib, a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors, ...combined with platinum doublets in patients with advanced non-small cell lung cancer (NSCLC) and other solid tumours.
In all, 49 patients received axitinib 5 mg twice daily (b.i.d.) with paclitaxel/carboplatin or gemcitabine/cisplatin in 3-week cycles. Following determination of the maximum tolerated dose, a squamous cell NSCLC expansion cohort was enroled and received axitinib 5 mg b.i.d. with paclitaxel/carboplatin.
Two patients experienced dose-limiting toxicities: febrile neutropenia (n=1) in the paclitaxel/carboplatin cohort and fatigue (n=1) in the gemcitabine/cisplatin cohort. Common nonhaematologic treatment-related adverse events were hypertension (36.7%), diarrhoea (34.7%) and fatigue (28.6%). No grade ≥3 haemoptysis occurred among 12 patients with squamous cell NSCLC. The objective response rate was 37.0% for patients receiving axitinib/paclitaxel/carboplatin (n=27) and 23.8% for patients receiving axitinib/gemcitabine/cisplatin (n=21). Pharmacokinetics of axitinib and chemotherapeutic agents were similar when administered alone or in combination.
Axitinib 5 mg b.i.d. may be combined with standard paclitaxel/carboplatin or gemcitabine/cisplatin regimens without evidence of overt drug-drug interactions. Both combinations demonstrated clinical efficacy and were well tolerated.
To determine the ability of amifostine to reduce the severity and/or incidence of the acute toxicities of concurrent chemotherapy and radiotherapy (RT) for non–small-cell lung cancer.
Patients with ...inoperable, nonmetastatic non–small-cell lung cancer receiving concurrent chemoradiotherapy were randomized to one of two treatment groups. Arm 1 patients received thoracic RT (total dose, 69.6 Gy in 58 fractions of 1.2 Gy b.i.d. 5 d/wk), plus oral etoposide (50 mg b.i.d. 30 min before thoracic RT for 10 days, repeated on Day 29) and cisplatin (50 mg/m
2 i.v. on Days 1, 8, 29, and 36). Arm 2 patients received the same treatment plus amifostine (500 mg i.v. 20–30 min before any treatment the first 2 days of each week). Acute effects were assessed using the National Cancer Institute Common Toxicity Criteria.
Sixty-two patients were enrolled between November 1998 and January 2001. The minimal follow-up was 24 months, and the median follow-up of living patients was 31 months. The patient and tumor characteristics were equally distributed between the patients in the two arms. The median survival time was 20 months in Arm 1 patients and 19 months in Arm 2 patients. The maximal esophageal toxicity was mild (Grade 1) in 23%, moderate (Grade 2) in 42%, and severe (Grade 3-4) in 35% of patients in Arm 1; the corresponding rates for the Arm 2 patients were 48%, 35%, and 16% (
p = 0.021). Severe pneumonitis occurred in 16% of the Arm 1 and none of the Arm 2 patients (
p = 0.020, chi-square test). Neutropenic fever occurred in 39% of Arm 1 and 16% of Arm 2 patients (
p = 0.046, chi-square test). Mild hypotension, dysgeusia, and sneezing were significantly more frequent among the patients in Arm 2.
Amifostine reduced the severity and incidence of acute esophageal, pulmonary, and hematologic toxicity resulting from concurrent cisplatin-based chemotherapy and RT. Amifostine had no apparent effect on survival in these patients with unresectable non–small-cell lung cancer, suggesting that it does not have a tumor-protective effect.
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