Osimertinib after Chemoradiotherapy in Stage III EGFR-Mutated NSCLC.

BACKGROUND: Osimertinib is a recommended treatment for advanced non-small-cell lung cancer (NSCLC) with an epidermal growth factor receptor (EGFR) mutation and as adjuvant treatment for resected EGFR-mutated NSCLC. EGFR-tyrosine kinase inhibitors have shown preliminary efficacy in unresectable stage III EGFR-mutated NSCLC. METHODS: In this phase 3, double-blind, placebo-controlled trial, we randomly assigned patients with unresectable EGFR-mutated stage III NSCLC without progression during or after chemoradiotherapy to receive osimertinib or placebo until disease progression occurred (as assessed by blinded independent central review) or the regimen was discontinued. The primary end point was progression-free survival as assessed by blinded independent central review. RESULTS: A total of 216 patients who had undergone chemoradiotherapy were randomly assigned to receive osimertinib (143 patients) or placebo (73 patients). Osimertinib resulted in a significant progression-free survival benefit as compared with placebo: the median progression-free survival was 39.1 months with osimertinib versus 5.6 months with placebo, with a hazard ratio for disease progression or death of 0.16 (95% confidence interval [CI], 0.10 to 0.24; P<0.001). The percentage of patients who were alive and progression free at 12 months was 74% (95% CI, 65 to 80) with osimertinib and 22% (95% CI, 13 to 32) with placebo. Interim overall survival data (maturity, 20%) showed 36-month overall survival among 84% of patients with osimertinib (95% CI, 75 to 89) and 74% with placebo (95% CI, 57 to 85), with a hazard ratio for death of 0.81 (95% CI, 0.42 to 1.56; P = 0.53). The incidence of adverse events of grade 3 or higher was 35% in the osimertinib group and 12% in the placebo group; radiation pneumonitis (majority grade, 1 to 2) was reported in 48% and 38%, respectively. No new safety concerns emerged. CONCLUSIONS: Treatment with osimertinib resulted in significantly longer progression-free survival than placebo in patients with unresectable stage III EGFR-mutated NSCLC. (Funded by AstraZeneca; LAURA ClinicalTrials.gov number, NCT03521154.).

Safety, tolerability, pharmacokinetics, and antitumor activity of adavosertib in Japanese patients with advanced solid tumors: A phase I, open-label study.

INTRODUCTION: We aimed to assess the safety, pharmacokinetic profile, and antitumor activity of adavosertib monotherapy in Japanese patients with advanced solid tumors. MATERIALS AND METHODS: This was a single-center, open-label, phase I study with two consecutive cohorts (250 mg and 200 mg cohorts). Patients received adavosertib at 250 mg or 200 mg, orally once daily for 5 days on and 2 days off for Weeks 1 and 2 of a 21-day cycle. RESULTS: Dose-limiting toxicities (Grade 3 febrile neutropenia) occurred in 2/6 patients in the 250 mg cohort. None of the three patients in the 200 mg cohort developed dose-limiting toxicities. The most frequent treatment-emergent adverse event was nausea (250 mg: 83.3 %; 200 mg: 100.0 %). Median time to peak drug concentration was 4.03 and 2.08 h after the first dose and 2.82 and 1.90 h after multiple dosing in the 250 and 200 mg cohorts, respectively; respective mean terminal elimination half-lives were 7.36 and 7.30 h (first dose) and 10.55 and 8.88 h (multiple dosing). Systemic exposure increased in a slightly more than dose-proportional manner. No RECIST v1.1 response was observed. Disease control rate was 0 % and 33.3 % in the 250 and 200 mg cohorts, respectively. One patient (33.3 %) in the 200 mg cohort showed a best overall response of stable disease at ≥ 8 weeks; the rest showed progressive disease. CONCLUSIONS: Adavosertib 200 mg once daily was well tolerated in this patient population and no safety concerns were raised. Exposure increased in a slightly more than dose-proportional manner and limited antitumor activity was shown. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04462952.

CNS Efficacy of Osimertinib With or Without Chemotherapy in Epidermal Growth Factor Receptor-Mutated Advanced Non-Small-Cell Lung Cancer.

PURPOSE: We report CNS efficacy of first-line osimertinib plus chemotherapy versus osimertinib monotherapy in patients with epidermal growth factor receptor (EGFR)-mutated advanced non-small-cell lung cancer (NSCLC) from the phase III FLAURA2 study according to baseline CNS metastasis status. METHODS: Patients were randomly assigned to osimertinib plus platinum-pemetrexed (combination) or osimertinib monotherapy until disease progression or discontinuation. Brain scans were performed in all patients at baseline and progression and at scheduled assessments until progression for patients with baseline CNS metastases; scans were assessed by neuroradiologist CNS blinded independent central review (BICR). RESULTS: On the basis of baseline CNS BICR, 118 of 279 (combination) and 104 of 278 (monotherapy) randomly assigned patients had ≥one measurable and/or nonmeasurable CNS lesion and were included in the CNS full analysis set (cFAS); 40 of 118 and 38 of 104 had ≥one measurable target CNS lesion and were included in the post hoc CNS evaluable-for-response set (cEFR). In the cFAS, the hazard ratio (HR) for CNS progression or death was 0.58 (95% CI, 0.33 to 1.01). In patients without baseline CNS metastases, the HR for CNS progression or death was 0.67 (95% CI, 0.43 to 1.04). In the cFAS, CNS objective response rates (ORRs; 95% CI) were 73% (combination; 64 to 81) versus 69% (monotherapy; 59 to 78); 59% versus 43% had CNS complete response (CR). In the cEFR, CNS ORRs (95% CI) were 88% (73 to 96) versus 87% (72 to 96); 48% versus 16% had CNS CR. CONCLUSION: Osimertinib plus platinum-pemetrexed demonstrated improved CNS efficacy compared with osimertinib monotherapy, including delaying CNS progression, irrespective of baseline CNS metastasis status. These data support this combination as a new first-line treatment for patients with EGFR-mutated advanced NSCLC, including those with CNS metastases.

Osimertinib with or without Chemotherapy in EGFR-Mutated Advanced NSCLC.

BACKGROUND: Osimertinib is a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) that is selective for EGFR-TKI-sensitizing and EGFR T790M resistance mutations. Evidence suggests that the addition of chemotherapy may extend the benefits of EGFR-TKI therapy. METHODS: In this phase 3, international, open-label trial, we randomly assigned in a 1:1 ratio patients with EGFR-mutated (exon 19 deletion or L858R mutation) advanced non-small-cell lung cancer (NSCLC) who had not previously received treatment for advanced disease to receive osimertinib (80 mg once daily) with chemotherapy (pemetrexed [500 mg per square meter of body-surface area] plus either cisplatin [75 mg per square meter] or carboplatin [pharmacologically guided dose]) or to receive osimertinib monotherapy (80 mg once daily). The primary end point was investigator-assessed progression-free survival. Response and safety were also assessed. RESULTS: A total of 557 patients underwent randomization. Investigator-assessed progression-free survival was significantly longer in the osimertinib-chemotherapy group than in the osimertinib group (hazard ratio for disease progression or death, 0.62; 95% confidence interval [CI], 0.49 to 0.79; P<0.001). At 24 months, 57% (95% CI, 50 to 63) of the patients in the osimertinib-chemotherapy group and 41% (95% CI, 35 to 47) of those in the osimertinib group were alive and progression-free. Progression-free survival as assessed according to blinded independent central review was consistent with the primary analysis (hazard ratio, 0.62; 95% CI, 0.48 to 0.80). An objective (complete or partial) response was observed in 83% of the patients in the osimertinib-chemotherapy group and in 76% of those in the osimertinib group; the median response duration was 24.0 months (95% CI, 20.9 to 27.8) and 15.3 months (95% CI, 12.7 to 19.4), respectively. The incidence of grade 3 or higher adverse events from any cause was higher with the combination than with monotherapy - a finding driven by known chemotherapy-related adverse events. The safety profile of osimertinib plus pemetrexed and a platinum-based agent was consistent with the established profiles of the individual agents. CONCLUSIONS: First-line treatment with osimertinib-chemotherapy led to significantly longer progression-free survival than osimertinib monotherapy among patients with EGFR-mutated advanced NSCLC. (Funded by AstraZeneca; FLAURA2 ClinicalTrials.gov number, NCT04035486.).

Real-world outcomes in patients with advanced endometrial cancer: A retrospective cohort study of US electronic health records.

OBJECTIVES: To characterize clinical outcomes of women with advanced/recurrent endometrial cancer (AEC) in routine practice using electronic health records from a real-world database. METHODS: Adult women diagnosed with AEC (stage III/IV, or early stage with locoregional/distant recurrence) between January 1, 2013 and September 30, 2020, inclusive, were eligible provided they received platinum-based chemotherapy at any time following diagnosis and had ≥2 clinical visits. Follow-up was from initiation of systemic treatment after advanced diagnosis (index) until March 30, 2021, last available follow-up, or death, whichever occurred first. Outcomes, by histological subtype, included Kaplan-Meier estimates of overall survival (OS) and time to first subsequent therapy or death (TFST). RESULTS: Of the 2202 women with AEC, most were treated in a community setting (82.7%) and presented with stage III/IV disease at initial diagnosis (74.0%). The proportion with endometrioid carcinoma, uterine serous carcinoma (USC), and other AEC subtypes was 59.8%, 25.0%, and 15.2%, respectively. The most common first systemic treatment following advanced/recurrent diagnosis was platinum-based combination chemotherapy (82.0%). Median OS (95% CI) from initiation of first systemic treatment was shorter with USC (31.3 [27.7-34.3] months) and other AECs (29.4 [21.4-43.9] months) versus endometrioid carcinoma (70.8 [60.5-83.2] months). Similar results were observed for TFST. Black/African American women had worse OS and TFST than white women. CONCLUSIONS: Women with AEC had poor survival outcomes, demonstrating the requirement for more effective therapies. To our knowledge, this is the most comprehensive evaluation of contemporary treatment of AEC delivered in a community setting to date.

A Randomized, Double-Blind, Placebo- and Positive-Controlled, Three-Way Crossover Study in Healthy Participants to Investigate the Effect of Savolitinib on the QTc Interval.

Savolitinib (AZD6094, HMPL-504, volitinib) is an oral, bioavailable, selective MET-tyrosine kinase inhibitor. This randomized, double-blind, 3-way, crossover phase 1 study of savolitinib versus moxifloxacin (positive control) and placebo-evaluated effects on the QT interval after a single savolitinib dose. Healthy non-Japanese men were randomized to 1 of 6 treatment sequences, receiving single doses of savolitinib 600 mg, moxifloxacin 400 mg, and placebo. The primary end point was time-matched, placebo-adjusted change from baseline in the QT interval corrected for the time between corresponding points on 2 consecutive R waves on electrocardiogram (RR) by the Fridericia formula (ΔΔQTcF). Secondary end points included 12-lead electrocardiogram (ECG) variables, pharmacokinetics, and safety. All 3 treatment periods were completed by 44 of 45 participants (98%). Baseline demographics were balanced across treatment groups. After a single savolitinib 600-mg dose, the highest least-squares mean ΔΔQTcF of 12 milliseconds was observed 5 hours postdose. Upper limits of the 2-sided 90% confidence interval for ΔΔQTcF exceeded 10 milliseconds (the prespecified International Council for Harmonisation limit) 3-6 hours postsavolitinib but otherwise remained less than the threshold. Savolitinib showed no additional effect on PR, QRS, QT, or RR intervals. A positive ΔΔQTcF signal from the moxifloxacin group confirmed study validity. Savolitinib was well tolerated, with a low incidence of adverse events. In this thorough QT/QTc study, QTcF prolongation was observed with a single savolitinib 600-mg dose. ECG monitoring will be implemented in ongoing and future studies of savolitinib to assess the clinical relevance of the observed QT changes from this study.

A Comprehensive Methodology to Systematically Identify Drug Hypersensitivity and Anaphylactic Reactions in Clinical Trial Databases.

BACKGROUND: The incidence of drug hypersensitivity or anaphylactic reactions in clinical trial databases is thought to be underestimated due to variable clinical presentations and lack of clear definitions. OBJECTIVE: Our objective was to develop a more comprehensive, systematic methodology for retrospectively identifying potential hypersensitivity or anaphylactic reactions reported in patients treated with investigational drugs in clinical trials and to accurately assess and characterise the risk. METHODS: A three-step approach was developed to identify hypersensitivity or anaphylactic reactions: clinical trial database search, medical review, and adjudication to confirm or rule out cases. The database search strategy consisted of the narrow search for Standardized MedDRA Query (SMQ) Hypersensitivity, a modified MedDRA query based on SMQ Anaphylactic reaction, and pyrexia-related MedDRA Preferred Terms. The cases identified from the search were further medically reviewed taking into consideration the temporal relationship, seriousness, severity, course, and management of the events, action taken, and outcomes of adverse events. Those cases deemed to have potentially drug-related hypersensitivity were then adjudicated to be confirmed or ruled out. RESULTS: The method was applied to a clinical trial database containing safety data for 421 patients treated with an investigational drug. Application of the methodology led to 19 hypersensitivity cases being identified. Of these, 12 were classified as immediate reactions and 7 as non-immediate reactions. CONCLUSION: This three-step method provided a thorough and robust way to identify hypersensitivity reactions, including anaphylaxis, in a clinical trial database. This method could be applied to investigational drugs to improve early detection and monitoring of potential safety concerns, subsequent patient safety management strategies, and potentially programme-wide drug development decisions. Algorithmic tools and narrow and/or broad SMQs should be considered when evaluating safety concerns. The authors also recommend a revision of the MedDRA SMQ of Anaphylactic reaction.

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.

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.

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.

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.

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.

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.

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

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.

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.

Enhancing fraction predicts clinical outcome following first-line chemotherapy in patients with epithelial ovarian carcinoma.

PURPOSE: To define a simple radiologic biomarker of prognosis in patients with advanced epithelial ovarian carcinoma on first-line chemotherapy. EXPERIMENTAL DESIGN: Twenty-seven patients receiving platinum-based chemotherapy with >2 cm residual disease [International Federation of Gynecology and Obstetrics (FIGO) stages IIIC or IV] after surgery were identified. The proportion of enhancing tumor tissue--the enhancing fraction--was calculated on pre-chemotherapy computed tomography scans at four Hounsfield unit (HU) thresholds and assessed for correlation with CA125 response, Response Evaluation Criteria in Solid Tumors (RECIST) radiologic response, and time to progression. Discriminative power was assessed by leave-one-out discriminant analysis. RESULTS: Pre-chemotherapy residual tumor volume did not correlate with clinical outcome. Pre-chemotherapy enhancing fraction at all thresholds significantly correlated with CA125 response (P < 0.001, rho = 0.553 for 50 HU; P < 0.001, rho = 0.565 for 60 HU; P < 0.001, rho = 0.553 for 70 HU; P = 0.001, rho = 0.516 for 80 HU). Significant correlations were also shown for radiologic response at all thresholds. Enhancing fraction predicted CA125 response with 81.9% to 86.4% specificity and Response Evaluation Criteria in Solid Tumors response with 74.9% to 76.8% specificity at 95% sensitivity (dependent on threshold). Enhancing fraction correlated with time to progression at the 60 HU (P = 0.045, rho = 0.336) and 70 HU (P = 0.042; rho = 0.340) thresholds. CONCLUSION: Pre-chemotherapy enhancing fraction is a simple quantitative radiologic measure. Further evaluation in larger trials is required to confirm the potential of enhancing fraction as a predictive factor, particularly for patients who may benefit from the addition of antiangiogenic therapy.

[Role of computerized tomography in the diagnosis of transitional cell carcinoma of the upper urinary tract]. / Rolul tomografiei computerizate în diagnosticul carcinomului tranzitional de uroteliu superior.

PURPOSE: To evaluate the computed tomography (CT) semiological criteria used in the diagnosis of transitional cell carcinoma of the upper urinary tract. MATERIALS AND METHODS: 26 patients with transitional cell carcinoma of the upper urinary tract underwent preoperative CT. In all cases nephroureterectomy was performed and CT and histopathologic findings were compared. RESULTS: 16 tumors were infiltrative and 10 tumors were sessile. The smallest tumour had 7 mm diameter and the largest one 13 cm. Associated focal hydronephrosis appeared in 11 cases and diffuse hydronephrosis in 7 cases. The vast majority of these tumors (69.23%) had a 21 to 50 Hounsfield Units enhancement. CONCLUSIONS: CT is a powerful tool to diagnose transitional cell carcinoma of the upper urinary tract when data acquired in intravenous urography and echography are equivocal.

[Renal cell carcinoma- diagnosis by computed tomography]. / Rolul tomografiei computerizate în diagnosticul cancerului renal chistic.

In approximately 10% of cases, renal cell carcinoma (RCC) could present as a fluid- filled cystic mass. There are three mechanisms by which RCC may become cystic: extensive cystic necrosis, intrinsic cystic growth and origin from the epithelium lining a simple renal cyst. Simple renal cysts are very common. Uncommonly these cysts are complicated by hemorrhage, infection and possibly ischemia. The goal of the radiologist in evaluating these cystic lesions is to distinguish malignant neoplastic cystic masses from non-neoplastic complicated cysts so that appropriate management can be undertaken: RCC is best treated by surgical excision while non-neoplastic complicated cysts do not require surgery. The radiologic findings in these cystic masses which must be carefully evaluated include calcification, abnormal density, septations, nodularity, wall thickening and enhancement.