Xcovery (United States)

Simultaneous testing of one hypothesis at multiple alpha levels can be performed within a conventional Neyman-Pearson framework. This is achieved by treating the hypothesis as a family of hypotheses, each member of which explicitly concerns test level as well as effect size. Such testing encourages researchers to think about error rates and strength of evidence in both the statistical design and reporting stages of a study. Here, we show that these multi-alpha level tests can deliver acceptable expected total error costs. We first present formulas for expected error costs from single alpha and multiple alpha level tests, given prior probabilities of effect sizes that have either dichotomous or continuous distributions. Error costs are tied to decisions, with different decisions assumed for each of the potential outcomes in the multi-alpha level case. Expected total costs for tests at single and multiple alpha levels are then compared with optimal costs. This comparison highlights how sensitive optimization is to estimated error costs and to assumptions about prevalence. Testing at multiple default thresholds removes the need to formally identify decisions, or to model costs and prevalence as required in optimization approaches. Although total expected error costs with this approach will not be optimal, our results suggest they may be lower, on average, than when "optimal" test levels are based on mis-specified models.

BackgroundTargeted therapies have led to significant improvement in the management and prognosis of anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC). We performed a network meta-analysis of frontline treatment options of ALK-positive NSCLC to provide clinical guidance.MethodsPubMed, Embase, ClinicalTrials.gov, and international conference databases were searched to identify relevant trials from inception to June 30, 2021. Phase III randomized controlled trials (RCTs) comparing treatments for patients with ALK-positive advanced NSCLC in the first-line setting were included in a Bayesian network meta-analysis. Eligible studies reported at least one of the following clinical outcomes: progression-free survival (PFS), overall survival (OS), risk of the central nervous system (CNS) progression, adverse events (AEs) of grade (G) 3 or higher (G3 AEs), or serious AEs (SAEs). Hazard ratios (HRs) and CI for primary outcome of PFS and secondary outcome of OS and risk of CNS progression were obtained. A multivariate, consistency model, fixed-effects analysis was used in the network meta-analysis. Data on G3 AEs and SAEs were abstracted and meta-analyzed. Risk of bias (RoB) was assessed using the Cochrane Collaboration’s tool.ResultsNine RCTs comprising 2,484 patients were included with seven treatments: alectinib, brigatinib, ceritinib, crizotinib, ensartinib, lorlatinib, and chemotherapy. Compared with chemotherapy, ALK-tyrosine kinase inhibitors (TKIs) significantly prolong PFS and reduced risk of CNS progression except for ceritinib. Lorlatinib appears superior at reducing risk of CNS progression. None of the ALK-TKIs have a significantly prolonged OS as compared with chemotherapy. Lorlatinib increases the risk of G3 AEs as compared with alectinib (odds ratio 4.26 [95% CrI 1.22 to 15.53]), while alectinib caused the fewest G3 AEs.ConclusionsLorlatinib is associated with the highest PFS benefit and lowest risk of CNS progression benefits for patients with advanced ALK-positive NSCLC, compared with other first-line treatments, but with higher toxicity. The implementation of a newer generation of ALK-TKIs in the first-line treatment of ALK-positive NSCLC into current clinical practice is evolving rapidly.

e21019 Background: VEGF inhibition is suggested to enhance innate T cell function, activate dendritic cells, block recruitment of regulatory T cells, and decrease myeloid-derived suppressor cells. Vorolanib is a tyrosine kinase inhibitor that is structurally similar to sunitinib but designed to improve safety without compromising efficacy. Response to checkpoint inhibitors in patients with thoracic tumors is limited, thus we designed this multi-institutional, phase I/II study (NCT03583086) to explore safety and efficacy of combining vorolanib and nivolumab. Here we present updated results in the NSCLC, thymic, and SCLC cohorts, including patients previously treated with single agent IO. Methods: The Phase I maximum tolerated dose was 200 mg vorolanib and 240 mg nivolumab q2w. Phase II is ongoing and uses a two-stage MinMax design to assess the objective response rate (RR) in SCLC, thymic carcinoma, and three NSCLC cohorts: 1) IO naïve; 2) primary refractory, defined as radiographic progression < 12 weeks of starting IO; and 3) acquired resistance, defined as achieving at least stable disease ≥12 weeks to IO followed by progression. Results: As of December 2019, 37 patients had enrolled, 38% female, 11% never smokers, median age 66. The disease control rate (DCR) across all cohorts is 65% (20/31 evaluable patients) and the RR is 13% (4/31). In the NSCLC cohort, the overall RR is 14% (3/21); the RR is 33% (2/6) in IO naïve patients, including 2 on therapy > 17 months. RR in the NSCLC patients with acquired resistance is 14% (1/7) with an 86% (6/7) DCR. No responses in the primary refractory cohort but the DCR is 50% (4/8). DCR in the SCLC and thymic cohorts is 40% (2/5) and 50% (2/4), respectively; 1 thymic patient had a partial response with a complete response in target lesions. Exploratory correlatives, including mass cytometry analysis and single cell gene expression, are being performed in order to understand changes in macrophages and T cell activation markers to differentiate the underlying biology of the tumor and the microenvironment between responders and nonresponders. Conclusions: The addition of vorolanib nearly doubled the RR in the IO naïve NSCLC patients compared to historical data with single agent nivolumab. Additionally, 67% of NSCLC patients with prior IO achieved at least stable disease, 1 patient with acquired resistance had a response. Correlatives that may help define biomarkers of response to therapy will be presented among different cohorts of patients. Clinical trial information: NCT03583086 .

Purpose: Evaluate safety and determine the recommended phase II dose (RP2D) of ensartinib (X-396), a potent anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI), and evaluate preliminary pharmacokinetics and antitumor activity in a first-in-human, phase I/II clinical trial primarily in patients with non-small cell lung cancer (NSCLC).Patients and Methods: In dose escalation, ensartinib was administered at doses of 25 to 250 mg once daily in patients with advanced solid tumors; in dose expansion, patients with advanced ALK-positive NSCLC were administered 225 mg once daily. Patients who had received prior ALK TKI(s) and patients with brain metastases were eligible.Results: Thirty-seven patients enrolled in dose escalation, and 60 enrolled in dose expansion. The most common treatment-related toxicities were rash (56%), nausea (36%), pruritus (28%), vomiting (26%), and fatigue (22%); 23% of patients experienced a treatment-related grade 3 to 4 toxicity (primarily rash and pruritus). The maximum tolerated dose was not reached, but the RP2D was chosen as 225 mg based on the frequency of rash observed at 250 mg without improvement in activity. Among the ALK-positive efficacy evaluable patients treated at ≥200 mg, the response rate (RR) was 60%, and median progression-free survival (PFS) was 9.2 months. RR in ALK TKI-naïve patients was 80%, and median PFS was 26.2 months. In patients with prior crizotinib only, the RR was 69% and median PFS was 9.0 months. Responses were also observed in the central nervous system, with an intracranial RR of 64%.Conclusions: Ensartinib was active and generally well tolerated in patients with ALK-positive NSCLC. Clin Cancer Res; 24(12); 2771-9. ©2018 AACR.

A sequential approach, synchronizing cell-cycle specific chemotherapy during VEGFR-TKI treatment breaks, may improve the therapeutic index of this combination therapy. In this study we investigate the safety/tolerability and pharmacodynamic effects of docetaxel used in sequential combination with the novel VEGFR-TKI X-82. Patients with advanced solid malignancies underwent 21-day treatment cycles with X-82 administered daily on days 1-14, a treatment break on days 15-20, and docetaxel administered on day 21. Randomization was 1:1 to either a low-dose X-82 (200mg) or high-dose X-82 (400mg) arm. Patients were scheduled to undergo four 3'-deoxy-3'-18F-fluorothymidine (FLT) PET/CT scans to assess changes in tumor cell proliferation. PET standardized uptake values (SUV) were summarized for tumors and changes were assessed using mixed effects models. 14 patients were enrolled and treated with median 3.5 cycles (range 0-12). Three patients in the high-dose cohort (50%) and three patients in the low-dose cohort (38%) experienced at least one grade 3 adverse event during the study (infections, cytopenias, electrolyte abnormalities, and vascular complications). Four patients with 13 metastatic tumors underwent FLT PET/CT scanning. During the cycle 1 X-82 exposure period, tumor SUVmax decreased by - 11% (p = 0.04). After administration of docetaxel and the cycle 2 X-82 exposure period, tumor SUVmax decreased - 44% (p = 0.03). The sequential combination of X-82 and docetaxel was safe and led to diminished FLT uptake. Further, decrease in FLT uptake during cycle 2 (X-82 plus docetaxel) was greater than in cycle 1 (X-82 alone), suggesting sequential chemotherapy enhances the pharmacodynamic effect of therapy.