Abstract 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 2.5 mm slice interval provides the least measurement variability. Among the three techniques, 2D has the greatest measurement variability compared to 1D and 3D.
•Adavosertib is a selective small molecule inhibitor of the tyrosine kinase WEE1.•Few clinical trials of adavosertib have focused specifically on Japanese patients.•We assessed adavosertib ...monotherapy in Japanese patients with advanced solid tumors.•Adavosertib 200 mg once daily was well tolerated, with no new safety concerns.•Adavosertib monotherapy had limited antitumor activity in this patient population.
We aimed to assess the safety, pharmacokinetic profile, and antitumor activity of adavosertib monotherapy in Japanese patients with advanced solid tumors.
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.
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.
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.
ClinicalTrials.gov, NCT04462952
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.
Osimertinib is a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) that is selective for EGFR-TKI-sensitizing and
T790M resistance mutations. Evidence suggests ...that the addition of chemotherapy may extend the benefits of EGFR-TKI therapy.
In this phase 3, international, open-label trial, we randomly assigned in a 1:1 ratio patients with
-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.
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.
First-line treatment with osimertinib-chemotherapy led to significantly longer progression-free survival than osimertinib monotherapy among patients with
-mutated advanced NSCLC. (Funded by AstraZeneca; FLAURA2 ClinicalTrials.gov number, NCT04035486.).
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.
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.
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.
Patients were randomized 1:1; 254 to receive selumetinib + docetaxel and 256 to receive placebo + docetaxel.
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.
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%).
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.
clinicaltrials.gov: NCT01933932.
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/m
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.
Abstract Adavosertib (AZD1775) is a potent small‐molecule inhibitor of Wee1 kinase. This analysis utilized pharmacokinetic data from 8 Phase I/II studies of adavosertib to characterize the population ...pharmacokinetics of adavosertib in patients (n = 538) with solid tumors and evaluate the impact of covariates on exposure. A nonlinear mixed‐effects modeling approach was employed to estimate population and individual parameters from the clinical trial data. The model for time dependency of apparent clearance (CL) was developed in a stepwise manner and the final model validated by visual predictive checks (VPCs). Using an adavosertib dose of 300 mg once daily on a 5 days on/2 days off dosing schedule given 2 weeks out of a 3‐week cycle, simulation analyses evaluated the impact of covariates on the following exposure metrics at steady state: maximum concentration during a 21‐day cycle, area under the curve (AUC) during a 21‐day cycle, AUC during the second week of a treatment cycle, and AUC on day 12 of a treatment cycle. The final model was a linear 2‐compartment model with lag time into the dosing compartment and first‐order absorption into the central compartment, time‐varying CL, and random effects on all model parameters. VPCs and steady‐state observations confirmed that the final model satisfied all the requirements for reliable simulation of randomly sampled Phase I and II populations with different covariate characteristics. Simulation‐based analyses revealed that body weight, renal impairment status, and race were key factors determining the variability of drug‐exposure metrics.
To define a simple radiologic biomarker of prognosis in patients with advanced epithelial ovarian carcinoma on first-line chemotherapy.
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.
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.
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.
To characterize clinical outcomes of women with advanced/recurrent endometrial cancer (AEC) in routine practice using electronic health records from a real-world database.
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).
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.
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.
•This retrospective cohort study characterized real-world outcomes of women with advanced endometrial cancer in the USA.•Most women received platinum-based combination chemotherapy as first systemic treatment for advanced/recurrent disease.•Survival outcomes were poor overall, particularly in women with advanced uterine serous carcinoma.•Black/African American women had worse outcomes than white women despite similar demographics and treatment pathways.
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