In the ongoing phase I PROFILE 1001 study, crizotinib showed antitumor activity in patients with ROS1-rearranged advanced non-small-cell lung cancer (NSCLC). Here, we present updated antitumor ...activity, overall survival (OS) and safety data (additional 46.2months follow-up) for patients with ROS1-rearranged advanced NSCLC from PROFILE 1001.
ROS1 status was determined by FISH or reverse transcriptase–polymerase chain reaction. All patients received crizotinib at a starting dose of 250mg twice daily.
Fifty-three patients received crizotinib, with a median duration of treatment of 22.4months. At data cut-off, treatment was ongoing in 12 patients (23%). The objective response rate (ORR) was 72% 95% confidence interval (CI), 58% to 83%, including six confirmed complete responses and 32 confirmed partial responses; 10 patients had stable disease. Responses were durable (median duration of response 24.7months; 95% CI, 15.2–45.3). ORRs were consistent across different patient subgroups. Median progression-free survival was 19.3months (95% CI, 15.2–39.1). A total of 26 deaths (49%) occurred (median follow-up period of 62.6months), and of the remaining 27 patients (51%), 14 (26%) were in follow-up at data cut-off. Median OS was 51.4months (95% CI, 29.3 to not reached) and survival probabilities at 12, 24, 36, and 48months were 79%, 67%, 53%, and 51%, respectively. No correlation was observed between OS and specific ROS1 fusion partner. Treatment-related adverse events (TRAEs) were mainly grade 1 or 2, per CTCAE v3.0. There were no grade ≥4 TRAEs and no TRAEs associated with permanent discontinuation. No new safety signals were reported with long-term crizotinib treatment.
These findings serve as a new benchmark for OS in ROS1-rearranged advanced NSCLC, and continue to show the clinically meaningful benefit and safety of crizotinib in this molecular subgroup.
ClinicalTrials.gov identifier NCT00585195
There currently are no internationally recognised treatment guidelines for patients with advanced gastric cancer/gastro-oesophageal junction cancer (GC/GEJC) in whom two prior lines of therapy have ...failed. The randomised, phase III JAVELIN Gastric 300 trial compared avelumab versus physician’s choice of chemotherapy as third-line therapy in patients with advanced GC/GEJC.
Patients with unresectable, recurrent, locally advanced, or metastatic GC/GEJC were recruited at 147 sites globally. All patients were randomised to receive either avelumab 10mg/kg by intravenous infusion every 2weeks or physician’s choice of chemotherapy (paclitaxel 80mg/m2 on days 1, 8, and 15 or irinotecan 150mg/m2 on days 1 and 15, each of a 4-week treatment cycle); patients ineligible for chemotherapy received best supportive care. The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), objective response rate (ORR), and safety.
A total of 371 patients were randomised. The trial did not meet its primary end point of improving OS {median, 4.6 versus 5.0months; hazard ratio (HR)=1.1 95% confidence interval (CI) 0.9–1.4; P=0.81} or the secondary end points of PFS median, 1.4 versus 2.7months; HR=1.73 (95% CI 1.4–2.2); P>0.99 or ORR (2.2% versus 4.3%) in the avelumab versus chemotherapy arms, respectively. Treatment-related adverse events (TRAEs) of any grade occurred in 90 patients (48.9%) and 131 patients (74.0%) in the avelumab and chemotherapy arms, respectively. Grade ≥3 TRAEs occurred in 17 patients (9.2%) in the avelumab arm and in 56 patients (31.6%) in the chemotherapy arm.
Treatment of patients with GC/GEJC with single-agent avelumab in the third-line setting did not result in an improvement in OS or PFS compared with chemotherapy. Avelumab showed a more manageable safety profile than chemotherapy.
ClinicalTrials.gov: NCT02625623.
In a phase III trial in patients with advanced, well-differentiated, progressive pancreatic neuroendocrine tumors, sunitinib 37.5 mg/day improved investigator-assessed progression-free survival (PFS) ...versus placebo (11.4 versus 5.5 months; HR, 0.42; P < 0.001). Here, we present PFS using retrospective blinded independent central review (BICR) and final median overall survival (OS), including an assessment highlighting the impact of patient crossover from placebo to sunitinib.
In this randomized, double-blind, placebo-controlled study, cross-sectional imaging from patients was evaluated retrospectively by blinded third-party radiologists using a two-reader, two-time-point lock, followed by a sequential locked-read, batch-mode paradigm. OS was summarized using the Kaplan–Meier method and Cox proportional hazards model. Crossover-adjusted OS effect was derived using rank-preserving structural failure time (RPSFT) analyses.
Of 171 randomized patients (sunitinib, n = 86; placebo, n = 85), 160 (94%) had complete scan sets/time points. By BICR, median (95% confidence interval CI) PFS was 12.6 (11.1–20.6) months for sunitinib and 5.8 (3.8–7.2) months for placebo (HR, 0.32; 95% CI 0.18–0.55; P = 0.000015). Five years after study closure, median (95% CI) OS was 38.6 (25.6–56.4) months for sunitinib and 29.1 (16.4–36.8) months for placebo (HR, 0.73; 95% CI 0.50–1.06; P = 0.094), with 69% of placebo patients having crossed over to sunitinib. RPSFT analysis confirmed an OS benefit for sunitinib.
BICR confirmed the doubling of PFS with sunitinib compared with placebo. Although the observed median OS improved by nearly 10 months, the effect estimate did not reach statistical significance, potentially due to crossover from placebo to sunitinib.
NCT00428597.
In the past 4 years, many publications described a concentration-dependent deposition of gadolinium in the brain both in adults and children, seen as high signal intensities in the globus pallidus ...and dentate nucleus on unenhanced T1-weighted images. Postmortem human or animal studies have validated gadolinium deposition in these T1-hyperintensity areas, raising new concerns on the safety of gadolinium-based contrast agents (GBCAs). Residual gadolinium is deposited not only in brain, but also in extracranial tissues such as liver, skin, and bone. This review summarizes the current evidence on gadolinium deposition in the human and animal bodies, evaluates the effects of different types of GBCAs on the gadolinium deposition, introduces the possible entrance or clearance mechanism of the gadolinium and potential side effects that may be related to the gadolinium deposition on human or animals, and puts forward some suggestions for further research.
Dual blockade of PD-L1 and VEGF has enhanced anticancer immunity through multiple mechanisms and augmented antitumour activity in multiple malignancies. We aimed to assess the efficacy and safety of ...atezolizumab (anti-PD-L1) alone and combined with bevacizumab (anti-VEGF) in patients with unresectable hepatocellular carcinoma.
GO30140 is an open-label, multicentre, multiarm, phase 1b study that enrolled patients at 26 academic centres and community oncology practices in seven countries worldwide. The study included five cohorts, and the two hepatocellular carcinoma cohorts, groups A and F, are described here. Inclusion criteria for these two groups included age 18 years and older; histologically, cytologically, or clinically (per American Association for the Study of Liver Diseases criteria) confirmed unresectable hepatocellular carcinoma that was not amenable to curative treatment; no previous systemic treatment; and Eastern Cooperative Oncology Group performance status of 0 or 1. In group A, all patients received atezolizumab (1200 mg) and bevacizumab (15 mg/kg) intravenously every 3 weeks. In group F, patients were randomly assigned (1:1) to receive intravenous atezolizumab (1200 mg) plus intravenous bevacizumab (15 mg/kg) every 3 weeks or atezolizumab alone by interactive voice-web response system using permuted block randomisation (block size of two) and stratification factors of geographical region; macrovascular invasion, extrahepatic spread, or both; and baseline α-fetoprotein concentration. Primary endpoints were confirmed objective response rate in all patients who received the combination treatment for group A and progression-free survival in the intention-to-treat population in group F, both assessed by an independent review facility according to Response Evaluation Criteria in Solid Tumors version 1.1. In both groups, safety was assessed in all patients who received at least one dose of any study treatment. This study is registered with ClinicalTrials.gov, NCT02715531, and is closed to enrolment.
In group A, 104 patients were enrolled between July 20, 2016, and July 31, 2018, and received atezolizumab plus bevacizumab. With a median follow-up of 12·4 months (IQR 8·0–16·2), 37 (36%; 95% CI 26–46) of 104 patients had a confirmed objective response. The most common grade 3–4 treatment-related adverse events were hypertension (13 13%) and proteinuria (seven 7%). Treatment-related serious adverse events occurred in 25 (24%) patients and treatment-related deaths in three (3%) patients (abnormal hepatic function, hepatic cirrhosis, and pneumonitis). In group F, 119 patients were enrolled and randomly assigned (60 to atezolizumab plus bevacizumab; 59 to atezolizumab monotherapy) between May 18, 2018, and March 7, 2019. With a median follow-up of 6·6 months (IQR 5·5–8·5) for the atezolizumab plus bevacizumab group and 6·7 months (4·2–8·2) for the atezolizumab monotherapy group, median progression-free survival was 5·6 months (95% CI 3·6–7·4) versus 3·4 months (1·9–5·2; hazard ratio 0·55; 80% CI 0·40–0·74; p=0·011). The most common grade 3–4 treatment-related adverse events in group F were hypertension (in three 5% patients in the atezolizumab plus bevacizumab group; none in the atezolizumab monotherapy group) and proteinuria (in two 3% patients in the atezolizumab plus bevacizumab group; none in the atezolizumab monotherapy group). Treatment-related serious adverse events occurred in seven (12%) patients in the atezolizumab plus bevacizumab group and two (3%) patients in the atezolizumab monotherapy group. There were no treatment-related deaths.
Our study shows longer progression-free survival with a combination of atezolizumab plus bevacizumab than with atezolizumab alone in patients with unresectable hepatocellular carcinoma not previously treated with systemic therapy. Therefore, atezolizumab plus bevacizumab might become a promising treatment option for these patients. This combination is being compared with standard-of-care sorafenib in a phase 3 trial.
F Hoffmann-La Roche/Genentech.
Preclinical evidence suggests that MEK inhibition promotes accumulation and survival of intratumoral tumor-specific T cells and can synergize with immune checkpoint inhibition. We investigated the ...safety and clinical activity of combining a MEK inhibitor, cobimetinib, and a programmed cell death 1 ligand 1 (PD-L1) inhibitor, atezolizumab, in patients with solid tumors.
This phase I/Ib study treated PD-L1/PD-1-naive patients with solid tumors in a dose-escalation stage and then in multiple, indication-specific dose-expansion cohorts. In most patients, cobimetinib was dosed once daily orally for 21days on, 7days off. Atezolizumab was dosed at 800mg intravenously every 2weeks. The primary objectives were safety and tolerability. Secondary end points included objective response rate, progression-free survival, and overall survival.
Between 27 December 2013 and 9 May 2016, 152 patients were enrolled. As of 4 September 2017, 150 patients received ≥1 dose of atezolizumab, including 14 in the dose-escalation cohorts and 136 in the dose-expansion cohorts. Patients had metastatic colorectal cancer (mCRC; n=84), melanoma (n=22), non-small-cell lung cancer (NSCLC; n=28), and other solid tumors (n=16). The most common all-grade treatment-related adverse events (AEs) were diarrhea (67%), rash (48%), and fatigue (40%), similar to those with single-agent cobimetinib and atezolizumab. One (<1%) treatment-related grade 5 AE occurred (sepsis). Forty-five (30%) and 23 patients (15%) had AEs that led to discontinuation of cobimetinib and atezolizumab, respectively. Confirmed responses were observed in 7 of 84 patients (8%) with mCRC (6 responders were microsatellite low/stable, 1 was microsatellite instable), 9 of 22 patients (41%) with melanoma, and 5 of 28 patients (18%) with NSCLC. Clinical activity was independent of KRAS/BRAF status across diseases.
Atezolizumab plus cobimetinib had manageable safety and clinical activity irrespective of KRAS/BRAF status. Although potential synergistic activity was seen in mCRC, this was not confirmed in a subsequent phase III study.
NCT01988896 (the investigators in the NCT01988896 study are listed in the supplementary Appendix, available at Annals of Oncology online).
The fanning technique for endoscopic ultrasound-guided fine-needle aspiration (EUS - FNA) involves sampling multiple areas within a lesion with each pass. The aim of this study was to compare the ...fanning and standard techniques for EUS - FNA of solid pancreatic masses.
Consecutive patients with solid pancreatic mass lesions were randomized to undergo EUS - FNA using either the standard or the fanning technique. The main outcome measure was the median number of passes required to establish diagnosis. The secondary outcome measures were the diagnostic accuracy, technical failure, and complication rate of the two techniques.
Of 54 patients, 26 were randomized to the standard technique and 28 to the fanning technique. There was no difference in diagnostic accuracy (76.9 % vs. 96.4 %; P = 0.05), technical failure or complication rates (none in either cohort). There was a significant difference in both the number of passes required to establish diagnosis (median 1 interquartile range 1 - 3 vs. 1 1 - 1; P = 0.02) and the percentage of patients in whom a diagnosis was achieved on pass one (57.7 % vs. 85.7 %; P = 0.02) between the standard and fanning groups, respectively.
The fanning technique of FNA was superior to the standard approach because fewer passes were required to establish the diagnosis. If these promising data are confirmed by other investigators, consideration should be given to incorporating the fanning technique into routine practice of EUS - FNA. Registered at Clinical Trials.gov (NCT 01501903).
Approximately 5%–10% of gastric cancers have a fibroblast growth factor receptor-2 (FGFR2) gene amplification. AZD4547 is a selective FGFR-1, 2, 3 tyrosine kinase inhibitor with potent preclinical ...activity in FGFR2 amplified gastric adenocarcinoma SNU16 and SGC083 xenograft models. The randomized phase II SHINE study (NCT01457846) investigated whether AZD4547 improves clinical outcome versus paclitaxel as second-line treatment in patients with advanced gastric adenocarcinoma displaying FGFR2 polysomy or gene amplification detected by fluorescence in situ hybridization.
Patients were randomized 3:2 (FGFR2 gene amplification) or 1:1 (FGFR2 polysomy) to AZD4547 or paclitaxel. Patients received AZD4547 80 mg twice daily, orally, on a 2 weeks on/1 week off schedule of a 21-day cycle or intravenous paclitaxel 80 mg/m2 administered weekly on days 1, 8, and 15 of a 28-day cycle. The primary end point was progression-free survival (PFS). Safety outcomes were assessed and an exploratory biomarker analysis was undertaken.
Of 71 patients randomized (AZD4547n = 41, paclitaxel n = 30), 67 received study treatment (AZD4547n = 40, paclitaxel n = 27). Among all randomized patients, median PFS was 1.8 months with AZD4547 and 3.5 months with paclitaxel (one-sided P = 0.9581); median follow-up duration for PFS was 1.77 and 2.12 months, respectively. The incidence of adverse events was similar in both treatment arms. Exploratory biomarker analyses revealed marked intratumor heterogeneity of FGFR2 amplification and poor concordance between amplification/polysomy and FGFR2 mRNA expression.
AZD4547 did not significantly improve PFS versus paclitaxel in gastric cancer FGFR2 amplification/polysomy patients. Considerable intratumor heterogeneity for FGFR2 gene amplification and poor concordance between FGFR2 amplification/polysomy and FGFR2 expression indicates the need for alternative predictive biomarker testing. AZD4547 was generally well tolerated.
To demonstrate the noninferiority of capecitabine plus oxaliplatin (XELOX) versus 5-fluorouracil/folinic acid and oxaliplatin (FOLFOX-4) as second-line therapy in patients with metastatic colorectal ...cancer after prior irinotecan-based chemotherapy.
A total of 627 patients were randomly assigned to receive XELOX (n=313) or FOLFOX-4 (n=314) following disease progression/recurrence or intolerance to irinotecan-based chemotherapy. The primary end point was progression-free survival (PFS).
PFS for XELOX was noninferior to FOLFOX-4 hazard ratio (HR)=0.97; 95% confidence interval (CI) 0.83–1.14 in the intention-to-treat (ITT) population. Median PFS was 4.7 months with XELOX versus 4.8 months with FOLFOX-4. The robustness of the primary analysis was supported by multivariate and subgroup analyses. Median overall survival in the ITT population was 11.9 months with XELOX versus 12.5 months with FOLFOX-4 (HR=1.02; 95% CI 0.86–1.21). Treatment-related grade 3/4 adverse events occurred in 50% of XELOX- and 65% of FOLFOX-4-treated patients. Whereas grade 3/4 neutropenia (35% versus 5% with XELOX) and febrile neutropenia (4% versus < 1%) were more common with FOLFOX-4, grade 3/4 diarrhea (19% versus 5% with FOLFOX-4) and grade 3 hand–foot syndrome (4% versus < 1%) were more common with XELOX.
XELOX is noninferior to FOLFOX-4 when administered as second-line treatment in patients with metastatic colorectal cancer.
Although both Acute Kidney Injury Network (AKIN) and risk, injury, failure, loss, and end-stage (RIFLE) kidney disease criteria are frequently used to diagnose acute kidney injury (AKI), they have ...rarely been compared in the diagnosis of AKI in patients undergoing surgery for infrarenal abdominal aortic aneurysm (AAA). This study investigated the incidence of, and risk factors for, AKI, defined by AKIN and RIFLE criteria, and compared their ability to predict mortality after infrarenal AAA surgery.
This study examined 444 patients who underwent infrarenal AAA surgery between January 1999 and December 2011. Risk factors for AKI were assessed by multivariable analyses, and the impact of AKI on overall mortality was assessed by a Cox's proportional hazard model with inverse probability of treatment weighting (IPTW). Net reclassification improvement (NRI) was used to assess the performance of AKIN and RIFLE criteria in predicting overall mortality.
AKI based on AKIN and RIFLE criteria occurred in 82 (18.5%) and 55 (12.4%) patients, respectively. The independent risk factors for AKI were intraoperative red blood cell (RBC) transfusion and chronic kidney disease (CKD) by AKIN criteria, and age, intraoperative RBC transfusion, preoperative atrial fibrillation, and CKD by RIFLE criteria. After IPTW adjustment, AKI was related to 30 day mortality and overall mortality. NRI was 15.2% greater (P=0.04) for AKIN than for RIFLE criteria in assessing the risk of overall mortality.
Although AKI defined by either AKIN or RIFLE criteria was associated with overall mortality, AKIN criteria showed better prediction of mortality in patients undergoing infrarenal AAA surgery.
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