Dana Ghiorghiu

Selumetinib Plus Docetaxel Compared With Docetaxel Alone and Progression-Free Survival in Patients With KRAS-Mutant Advanced Non-Small Cell Lung Cancer: The SELECT-1 Randomized Clinical Trial.

Importance There are no specifically approved targeted therapies for the most common genomically defined subset of non–small cell lung cancer (NSCLC), KRAS-mutant lung cancer. Objective To compare efficacy of the mitogen-activated protein kinase kinase (MEK) inhibitor selumetinib + docetaxel with docetaxel alone as a second-line therapy for advanced KRAS-mutant NSCLC. Design, Setting, and Participants Multinational, randomized clinical trial conducted at 202 sites across 25 countries from October 2013 through January 2016. Of 3323 patients with advanced NSCLC and disease progression following first-line anticancer therapy tested for a KRAS mutation, 866 were enrolled and 510 randomized. Primary reason for exclusion was ineligibility. The data cutoff date for analysis was June 7, 2016. Interventions Patients were randomized 1:1; 254 to receive selumetinib + docetaxel and 256 to receive placebo + docetaxel. Main Outcomes and Measures Primary end point was investigator assessed progression-free survival. Secondary end points included overall survival, objective response rate, duration of response, effects on disease-related symptoms, safety, and tolerability. Results Of 510 randomized patients (mean age, 61.4 years [SD, 8.3]; women, 207 [41%]), 505 patients (99%) received treatment and completed the study (251 received selumetinib + docetaxel; 254 received placebo + docetaxel). At the time of data cutoff, 447 patients (88%) had experienced a progression event and 346 deaths (68%) had occurred. Median progression-free survival was 3.9 months (interquartile range [IQR], 1.5-5.9) with selumetinib + docetaxel and 2.8 months (IQR, 1.4-5.5) with placebo + docetaxel (difference, 1.1 months; hazard ratio [HR], 0.93 [95% CI, 0.77-1.12]; P = .44). Median overall survival was 8.7 months (IQR, 3.6-16.8) with selumetinib + docetaxel and 7.9 months (IQR, 3.8-20.1) with placebo + docetaxel (difference, 0.9 months; HR, 1.05 [95% CI, 0.85-1.30]; P = .64). Objective response rate was 20.1% with selumetinib + docetaxel and 13.7% with placebo + docetaxel (difference, 6.4%; odds ratio, 1.61 [95% CI, 1.00-2.62]; P = .05). Median duration of response was 2.9 months (IQR, 1.7-4.8; 95% CI, 2.7-4.1) with selumetinib + docetaxel and 4.5 months (IQR, 2.3-7.3; 95% CI, 2.8-5.6) with placebo + docetaxel. Adverse events of grade 3 or higher were more frequent with selumetinib + docetaxel (169 adverse events [67%] for selumetinib + docetaxel vs 115 adverse events [45%] for placebo + docetaxel; difference, 22%). Conclusions and Relevance Among patients with previously treated advanced KRAS-mutant non–small cell lung cancer, addition of selumetinib to docetaxel did not improve progression-free survival compared with docetaxel alone. Trial Registration clinicaltrials.gov: NCT01933932

Advanced Solid Tumors Treated with Cediranib: Comparison of Dynamic Contrast-enhanced MR Imaging and CT as Markers of Vascular Activity

PURPOSE To assess baseline reproducibility and compare performance of dynamic contrast material-enhanced (DCE) magnetic resonance (MR) imaging versus DCE computed tomographic (CT) measures of early vascular response in the same patients treated with cediranib (30 or 45 mg daily). MATERIALS AND METHODS After institutional review board approval, written informed consent was obtained from 29 patients with advanced solid tumors who had lesions 3 cm or larger and in whom simultaneous imaging of an adjacent artery was possible. Two baseline DCE MR acquisitions and two baseline DCE CT acquisitions 7 days or fewer apart (within 14 days of starting treatment) and two posttreatment acquisitions with each modality at day 7 and 28 (±3 days) were obtained. Nonmodeled and modeled parameters were derived (measured arterial input function [AIF] for CT, population-based AIF for MR imaging; temporal sampling rate of 0.5 second for CT, 3-6 seconds for MR imaging). Baseline variability was assessed by using intra- and intersubject analysis of variance and Bland-Altman analysis; a paired t test assessed change from baseline to after treatment. RESULTS The most reproducible parameters were DCE MR imaging enhancement fraction (baseline intrapatient coefficient of variation [CV]=8.6%), volume transfer constant (CV=13.9%), and integrated area under the contrast agent uptake curve at 60 seconds (CV=15.5%) and DCE CT positive enhancement integral (CV=16.0%). Blood plasma volume was highly variable and the only parameter with CV greater than 30%. Average reductions (percentage change) from baseline were consistently observed for all DCE MR imaging and DCE CT parameters at day 7 and 28 for both starting-dose groups (45 and 30 mg), except for DCE CT mean transit time. Percentage change from baseline for parameters reflecting blood flow and permeability were comparable, and reductions from baseline at day 7 were maintained at day 28. CONCLUSION DCE MR imaging and DCE CT can depict vascular response to antiangiogenic agents with response evident at day 7. Improved reproducibility with MR imaging favors its use in trials with small patient numbers.

Exploring intra- and inter-reader variability in uni-dimensional, bi-dimensional, and volumetric measurements of solid tumors on CT scans reconstructed at different slice intervals

OBJECTIVE Understanding magnitudes of variability when measuring tumor size may be valuable in improving detection of tumor change and thus evaluating tumor response to therapy in clinical trials and care. Our study explored intra- and inter-reader variability of tumor uni-dimensional (1D), bi-dimensional (2D), and volumetric (VOL) measurements using manual and computer-aided methods (CAM) on CT scans reconstructed at different slice intervals. MATERIALS AND METHODS Raw CT data from 30 patients enrolled in oncology clinical trials was reconstructed at 5, 2.5, and 1.25 mm slice intervals. 118 lesions in the lungs, liver, and lymph nodes were analyzed. For each lesion, two independent radiologists manually and, separately, using computer software, measured the maximum diameter (1D), maximum perpendicular diameter, and volume (CAM only). One of them blindly repeated the measurements. Intra- and inter-reader variability for the manual method and CAM were analyzed using linear mixed-effects models and Bland-Altman method. RESULTS For the three slice intervals, the maximum coefficients of variation for manual intra-/inter-reader variability were 6.9%/9.0% (1D) and 12.3%/18.0% (2D), and for CAM were 5.4%/9.3% (1D), 11.3%/18.8% (2D) and 9.3%/18.0% (VOL). Maximal 95% reference ranges for the percentage difference in intra-reader measurements for manual 1D and 2D, and CAM VOL were (-15.5%, 25.8%), (-27.1%, 51.6%), and (-22.3%, 33.6%), respectively. CONCLUSIONS Variability in measuring the diameter and volume of solid tumors, manually and by CAM, is affected by CT slice interval. The 2.5mm slice interval provides the least measurement variability. Among the three techniques, 2D has the greatest measurement variability compared to 1D and 3D.

Abstract LB-145: Results of a phase I study of AZD4547, an inhibitor of fibroblast growth factor receptor (FGFR), in patients with advanced solid tumors .

Background: AZD4547 is an orally bioavailable, selective inhibitor of FGFR 1, 2, and 3, with activity in a wide range of cell lines and xenografts dependent upon FGFR signalling, including patient-derived explant models with FGFR gene amplification. Methods: A 3-part study of AZD4547 was initiated in patients with advanced solid tumors (NCT00979134): Part A to determine the maximum tolerated dose (MTD) and/or continuous tolerable dose (RD); Part B to characterize the pharmacokinetic and safety profile (Parts A and B unselected for FGFR amplification); Part C1 to assess safety and clinical activity of AZD4547 (80 mg bid continuous dosing) in patients with advanced solid tumors prospectively selected for amplification of FGFR 1 and 2. FGFR gene amplification status was determined using fluorescent in situ hybridization (FISH) analysis of archival or fresh tumor tissue. Pharmacodynamic biomarkers including phosphate and FGF23 were assessed in plasma samples. Results: At data cut-off (15 January 2013), 43 patients had been treated (dose range 20-200 mg bid) in the dose-escalation phase (Part A) of this study, and the RD was determined as 80 mg bid continuous dosing. Dose-limiting toxicities included increased liver enzymes, stomatitis, renal failure, hyperphosphataemia, and mucositis. In the dose-expansion phase of the study (Part B), a total of 6 patients were treated to confirm the tolerability of the RD. In Part C1, 21 patients with FGFR 1 or 2 amplified tumors received AZD4547 80 mg bid; these patients had diverse tumor types and a range of gene copy number gain (mostly low gene copy number Conclusions: AZD4547 80 mg bid continuous dosing was generally tolerated. Encouraging evidence of anti-tumor activity was seen in some patients, most notably a partial response in a patient with squamous NSCLC who had a high level FGFR gene amplification. Pharmacodynamic plasma biomarker data will be presented. Studies remain ongoing in patients with tumors selected for high levels of FGFR amplification. Citation Format: Fabrice Andre, Malcolm Ranson, Emma Dean, Andrea Varga, Ruud van der Noll, Paul K. Stockman, Dana Ghiorghiu, Elaine Kilgour, Paul D. Smith, Merran Macpherson, Peter Lawrence, Andrew Hastie, Jan HM Schellens. Results of a phase I study of AZD4547, an inhibitor of fibroblast growth factor receptor (FGFR), in patients with advanced solid tumors . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-145. doi:10.1158/1538-7445.AM2013-LB-145

Study Design and Rationale for a Randomized, Placebo-Controlled, Double-Blind Study to Assess the Efficacy and Safety of Selumetinib in Combination With Docetaxel as Second-Line Treatment in Patients With KRAS-Mutant Advanced Non-Small Cell Lung Cancer (SELECT-1)

BACKGROUND Oncogenic KRAS mutations represent the largest genomically defined subset of lung cancer, and are associated with activation of the RAS/RAF/MEK/ERK pathway. There are currently no therapies specifically approved for patients with KRAS-mutant (KRASm) non-small-cell lung cancer (NSCLC), and these patients derive less clinical benefit from chemotherapy than the overall NSCLC population. In a recent phase II study, selumetinib (AZD6244, ARRY-142886), an oral, potent and selective, allosteric MEK1/2 inhibitor with a short half-life, combined with docetaxel, improved clinical outcome as second-line treatment for patients with KRASm NSCLC. This combination will be further evaluated in the phase III SELECT-1 study. PATIENTS AND METHODS SELECT-1 (NCT01933932) is a randomized, double-blind, placebo-controlled phase III study assessing the efficacy and safety of selumetinib plus docetaxel in patients with KRASm locally advanced or metastatic NSCLC, eligible for second-line treatment. The primary endpoint is progression-free survival (PFS); secondary endpoints include overall survival, objective response rate, duration of response, and safety and tolerability. Approximately 634 patients will be randomized 1:1 to receive selumetinib (75 mg twice daily on a continuous oral administration schedule) in combination with docetaxel (75 mg/m(2), intravenously on day 1 of every 21-day cycle) or placebo in combination with docetaxel (same schedule), until objective disease progression. Patients may continue to receive treatment after objective disease progression if deemed appropriate by the investigator. CONCLUSIONS If the primary endpoint of PFS is met, selumetinib plus docetaxel would be the first targeted treatment for patients with KRASm advanced NSCLC who are eligible for second-line treatment.

Assessing the effect of CT slice interval on unidimensional, bidimensional and volumetric measurements of solid tumours

Abstract Objectives: To study the magnitude of differences in tumour unidimensional (1D), bidimensional (2D) and volumetric (VOL) measurements determined from computed tomography (CT) images reconstructed at 5, 2.5 and 1.25 mm slice intervals. Materials and Methods: A total of 118 lesions in lung, liver and lymph nodes were selected from 30 patients enrolled in early phase clinical trials. Each CT scan was reconstructed at 5, 2.5 and 1.25 mm slice intervals during the image acquisition. Lesions were semi-automatically segmented on each interval image series and supervised by a radiologist. 1D, 2D and VOL were computed based on the final segmentation results. Average measurement differences across different slice intervals were obtained using linear mixed-effects analysis of variance models. Results: Lesion diameters ranged from 6.1 to 80.1 mm (median 18.4 mm). The largest difference was seen between 1.25 and 5 mm (mean difference of 7.6% for 1D [P < 0.0001], 13.1% for 2D [P < 0.0001], −5.7% for VOL [P = 0.0001]). Mean differences between 1.25 and 2.5 mm were all within ±3.5% (within ±6% confidence interval). For VOL, there was a larger average difference between measurements on different slice intervals for the smaller lesions (<10 mm) compared with the larger lesions. Conclusions: Different slice intervals may give different 1D, 2D and VOL measurements. In clinical practice, it would be prudent to use the same slice interval for consecutive measurements.

Selumetinib in Combination With Dacarbazine in Patients With Metastatic Uveal Melanoma: A Phase III, Multicenter, Randomized Trial (SUMIT).

Purpose Uveal melanoma is the most common primary intraocular malignancy in adults with no effective systemic treatment option in the metastatic setting. Selumetinib (AZD6244, ARRY-142886) is an oral, potent, and selective MEK1/2 inhibitor with a short half-life, which demonstrated single-agent activity in patients with metastatic uveal melanoma in a randomized phase II trial. Methods The Selumetinib (AZD6244: ARRY-142886) (Hyd-Sulfate) in Metastatic Uveal Melanoma (SUMIT) study was a phase III, double-blind trial ( ClinicalTrial.gov identifier: NCT01974752) in which patients with metastatic uveal melanoma and no prior systemic therapy were randomly assigned (3:1) to selumetinib (75 mg twice daily) plus dacarbazine (1,000 mg/m2 intravenously on day 1 of every 21-day cycle) or placebo plus dacarbazine. The primary end point was progression-free survival (PFS) by blinded independent central radiologic review. Secondary end points included overall survival and objective response rate. Results A total of 129 patients were randomly assigned to receive selumetinib plus dacarbazine (n = 97) or placebo plus dacarbazine (n = 32). In the selumetinib plus dacarbazine group, 82 patients (85%) experienced a PFS event, compared with 24 (75%) in the placebo plus dacarbazine group (median, 2.8 v 1.8 months); the hazard ratio for PFS was 0.78 (95% CI, 0.48 to 1.27; two-sided P = .32). The objective response rate was 3% with selumetinib plus dacarbazine and 0% with placebo plus dacarbazine (two-sided P = .36). At 37% maturity (n = 48 deaths), analysis of overall survival gave a hazard ratio of 0.75 (95% CI, 0.39 to 1.46; two-sided P = .40). The most frequently reported adverse events (selumetinib plus dacarbazine v placebo plus dacarbazine) were nausea (62% v 19%), rash (57% v 6%), fatigue (44% v 47%), diarrhea (44% v 22%), and peripheral edema (43% v 6%). Conclusion In patients with metastatic uveal melanoma, the combination of selumetinib plus dacarbazine had a tolerable safety profile but did not significantly improve PFS compared with placebo plus dacarbazine.

CNS Efficacy of Osimertinib in Patients With T790M-Positive Advanced Non–Small-Cell Lung Cancer: Data From a Randomized Phase III Trial (AURA3)

Purpose In patients with epidermal growth factor receptor ( EGFR) mutation-positive advanced non-small-cell lung cancer (NSCLC), there is an unmet need for EGFR-tyrosine kinase inhibitors with improved CNS penetration and activity against CNS metastases, either at initial diagnosis or time of progression. We report the first comparative evidence of osimertinib CNS efficacy versus platinum-pemetrexed from a phase III study (AURA3; ClinicalTrials.gov identifier: NCT02151981) in patients with EGFR T790M-positive advanced NSCLC who experience disease progression with prior EGFR-tyrosine kinase inhibitor treatment. Methods Patients with asymptomatic, stable CNS metastases were eligible for enrollment and were randomly assigned 2:1 to osimertinib 80 mg once daily or platinum-pemetrexed. A preplanned subgroup analysis was conducted in patients with measurable and/or nonmeasurable CNS lesions on baseline brain scan by blinded independent central neuroradiological review. The CNS evaluable for response set included only patients with one or more measurable CNS lesions. The primary objective for this analysis was CNS objective response rate (ORR). Results Of 419 patients randomly assigned to treatment, 116 had measurable and/or nonmeasurable CNS lesions, including 46 patients with measurable CNS lesions. At data cutoff (April 15, 2016), CNS ORR in patients with one or more measurable CNS lesions was 70% (21 of 30; 95% CI, 51% to 85%) with osimertinib and 31% (5 of 16; 95% CI, 11% to 59%) with platinum-pemetrexed (odds ratio, 5.13; 95% CI, 1.44 to 20.64; P = .015); the ORR was 40% (30 of 75; 95% CI, 29% to 52%) and 17% (7 of 41; 95% CI, 7% to 32%), respectively, in patients with measurable and/or nonmeasurable CNS lesions (odds ratio, 3.24; 95% CI, 1.33 to 8.81; P = .014). Median CNS duration of response in patients with measurable and/or nonmeasurable CNS lesions was 8.9 months (95% CI, 4.3 months to not calculable) for osimertinib and 5.7 months (95% CI, 4.4 to 5.7 months) for platinum-pemetrexed; median CNS progression-free survival was 11.7 months and 5.6 months, respectively (hazard ratio, 0.32; 95% CI, 0.15 to 0.69; P = .004). Conclusion Osimertinib demonstrated superior CNS efficacy versus platinum-pemetrexed in T790M-positive advanced NSCLC.

SELECT-3: a phase I study of selumetinib in combination with platinum-doublet chemotherapy for advanced NSCLC in the first-line setting.

Background:We investigated selumetinib (AZD6244, ARRY-142886), an oral, potent, and highly selective, allosteric MEK1/2 inhibitor, plus platinum-doublet chemotherapy for patients with advanced/metastatic non-small cell lung cancer.Methods:In this Phase I, open-label study (NCT01809210), treatment-naïve patients received selumetinib (50, 75, 100 mg BID PO) plus standard doses of gemcitabine or pemetrexed plus cisplatin or carboplatin. Primary objectives were safety, tolerability, and determination of recommended Phase II doses.Results:Fifty-five patients received treatment: selumetinib 50 or 75 mg plus gemcitabine/cisplatin (n=10); selumetinib 50 mg plus gemcitabine/carboplatin (n=9); selumetinib 50, 75 or 100 mg plus pemetrexed/carboplatin (n=21); selumetinib 75 mg plus pemetrexed/cisplatin (n=15). Most frequent adverse events (AEs) were fatigue, nausea, diarrhoea and vomiting. Grade ⩾3 selumetinib-related AEs were reported in 30 (55%) patients. Dose-limiting toxicities (all n=1) were Grade 4 anaemia (selumetinib 75 mg plus gemcitabine/cisplatin), Grade 4 thrombocytopenia/epistaxis and Grade 4 thrombocytopenia (selumetinib 50 mg plus gemcitabine/carboplatin), Grade 4 febrile neutropenia (selumetinib 100 mg plus pemetrexed/carboplatin), and Grade 3 lethargy (selumetinib 75 mg plus pemetrexed/cisplatin). Partial responses were confirmed in 11 (20%) and unconfirmed in 9 (16%) patients.Conclusions:Standard doses of pemetrexed/carboplatin or pemetrexed/cisplatin were tolerated with selumetinib 75 mg BID. The selumetinib plus gemcitabine-containing regimens were not tolerated.

1242PA PHASE I STUDY OF THE MEK1/2 INHIBITOR SELUMETINIB IN COMBINATION WITH FIRST-LINE CHEMOTHERAPY REGIMENS FOR NSCLC

ABSTRACT Aim: Selumetinib (AZD6244, ARRY-142886) is an orally available MEK1/2 inhibitor with activity in combination with docetaxel in the second-line setting for KRAS mutation-positive advanced NSCLC. This Phase I study assessed the safety, tolerability, recommended Phase II combination dose (RP2D), pharmacokinetics (PK) and preliminary efficacy of selumetinib in combination with first-line chemotherapy regimens in unselected patients (pts) with advanced/metastatic NSCLC. Methods: This open-label, multicentre study (NCT01809210) enrolled pts into dose-finding cohorts of orally administered selumetinib (50 mg bid [sel50] to 75 mg bid [sel75]) in combination with standard doses of gemcitabine (gem) or pemetrexed (pem) plus cisplatin (cis) or carboplatin (carb). Each dose cohort consisted of at least 3 and up to 6 evaluable pts. On completion of chemotherapy, pts had the option of maintenance selumetinib. Results: As of 20 April 2014, 17 pts were evaluable (8 female; median age 63; 8 adenocarcinoma, 8 squamous, 1 non-squamous histology) to the following treatment cohorts: gem + cis + sel50, n = 3; gem + cis + sel75, n = 1; gem + carb + sel50, n = 7; pem + carb + sel50, n = 2; pem + carb + sel75, n = 4. Median total selumetinib exposure was 78 days (range 16–224). The majority of adverse events (AEs) were CTCAE Grade 1 or 2. Selumetinib-related AEs of Grade ≥3 were seen in 7 pts: gem + cis + sel50, 0/3; gem + cis + sel75, 0/1; gem + carb + sel50, 6/7; pem + carb + sel50, 1/2; pem + carb + sel75, 0/4. One DLT of thrombocytopenia was observed in the gem + carb + sel50 cohort. Combination therapy did not appear to show any marked effect on the PK profile of selumetinib. Across all cohorts, partial responses were seen in 6/17 (35%) pts evaluable for response, and 4/17 (24%) had stable disease. Conclusions: The AE profile of selumetinib in combination with these chemotherapy regimens for NSCLC was consistent with the known profiles. Two tolerated dose regimens have been confirmed: gem + cis + sel50 and pem + carb + sel50. The activity of platinum-based regimens seems to be preserved in this unselected population. Dose escalation and expansion is ongoing; updated data including the RP2D and PK will be presented. Disclosure: F. Blackhall: Research funding: AstraZeneca; R. Califano: Consultancy/honoraria: Roche, Lilly, Boehringer Ingelheim, Pfizer; D. Ghiorghiu: Employment and stock ownership: AstraZeneca; A. Dymond: Employment and stock ownership: AstraZeneca; I. Smith: Employment and stock ownership: AstraZeneca R. Plummer: Consultancy agreement (no remuneration to date): AstraZeneca. Institutional trial costs. All other authors have declared no conflicts of interest.