Abstract 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, ρ = 0.553 for 50 HU; P < 0.001, ρ = 0.565 for 60 HU; P < 0.001, ρ = 0.553 for 70 HU; P = 0.001, ρ = 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, ρ = 0.336) and 70 HU (P = 0.042; ρ = 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.
TPS5612 Background: There is a high unmet medical need for therapies treating uterine serous carcinoma (USC), an aggressive type of endometrial carcinoma with an increased likelihood of recurrence and limited therapeutic options. 5-year overall survival (OS) for USC is estimated to be 35–50% for women with stage I–II disease and 0–15% for women with stage III–IV disease (Acharya et al. Lancet Oncol 2005). USC exhibits high rates of mutation in TP53 ( > 90% of cases), as well as mutations or amplifications in other cell-cycle regulators or oncogenes, including CCNE1, FBXW7, MYC, RB1, and KRAS/ NRAS (Zhao et al. PNAS 2013; Levine DA et al. Nature 2013), which may contribute to increased replication stress and susceptibility to inhibition of the tyrosine kinase WEE1. WEE1 inhibition is expected to release a tumor cell from DNA-damage-induced arrest at the G2/M boundary, so that unrepaired DNA damage may be taken into mitosis, leading to cell death. A Phase II study of the WEE1 inhibitor adavosertib in 34 women with recurrent or persistent USC reported an objective response rate (ORR) of 29.4% and a median duration of response (DoR) of 9.0 months; further correlative analysis and a translational biopsy cohort are planned (Liu et al. J Clin Oncol 2020). This Phase IIb study, ADAGIO, a single-arm, multicenter, global study (NCT04590248), aims to expand on these findings and will evaluate the efficacy and safety of adavosertib in women with recurrent or persistent USC who have previously received platinum-based chemotherapy. Methods: Women aged ≥18 years with histologically confirmed recurrent or persistent USC who have previously received at least one platinum-based chemotherapy regimen for the management of USC and have evidence of measurable disease according to RECIST v1.1 are eligible for this study. Participants with carcinosarcomas are not eligible. Prior receipt of immune checkpoint inhibitors, vascular endothelial growth factor inhibitors and human epidermal growth factor receptor 2 targeted therapy is permitted, with no restriction on the number of prior lines of systemic therapy a participant may have previously received. Approximately 120 eligible participants will receive oral adavosertib 300 mg qd on days 1–5 and 8–12 of a 21-day treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent, or another discontinuation criterion is met. The primary outcome measure is ORR, defined as the percentage of patients with measurable disease at baseline who have a confirmed complete or partial response, as determined by blinded independent central review (RECIST v1.1 assessment every 6 weeks for the first 48 weeks, then every 9 weeks). Secondary outcome measures include DoR, depth of response, progression-free survival, OS, disease control rate, biomarkers, safety, tolerability, and pharmacokinetics. Clinical trial information: NCT04590248.
e13596 Background: Response Evaluation Criteria In Solid Tumors (RECIST) is widely used to evaluate the efficacy of anticancer therapies. However, relying upon a unidimensional length to approximate change in tumor burden may be biased. The purpose of this study was to compare tumor responses/changes assessed by volumetric and RECIST unidimensional measurements. Methods: CT scans of chest, abdomen and pelvis were acquired at 5mm slice thickness as per study protocol, from 49 patients enrolled in early phase oncology trials. Baseline and the first follow-up scans (~6 weeks) were analyzed. Tumor greatest diameter was manually measured by a radiologist and tumor volume by semi-automated computer algorithms. Results: 144 individual sites of metastatic disease were analysed, including from liver, lung and lymph nodes. As expected, the magnitude of tumor burden change was larger for volume than unidimensional measurements: 32/49 (65%) patients had an increase in tumor volume of more than 30% compared to 6/49 (12%) for unidimensional measurements. Based upon RECIST and mathematical equivalence (assuming spherical tumors) of partial response (PR) and progressive disease (PD) for volume, 9/49 (18%) patients were discordant. Out of these 9 cases, 6/9 (67%) were classified as stable disease (SD) using unidimensional measurements and PD using volume, 2/9 (22%) were classified as PD for unidimensional measurements and SD using volume, and 1/9 (11%) was classified as a PR using unidimensional measurements and SD using volume. Comparing tumor burden changes from baseline with 95% limits of agreement (derived from repeat scan reads; ECR 2011) for unidimensional measurements (-12.4, 20.4%) and volumetric measurements (-9.6, 18.0%), 20/49 (41%) patients were discordant. Out of these 20 cases, 19/20 (95%) were classified as having ‘no change’ using unidimensional and ‘change’ using volume (3/20 [15%], decrease; 16/20 [80%], increase). 1/20 (5%) patient was classified as having ‘no change’ using volume and ‘change’ (a decrease) using unidimensional measurements. Conclusions: There was some evidence to suggest that volume is more sensitive than unidimensional measurements in identifying tumor changes for individual patients.
EFFORT, a randomized noncomparative phase II study of adavosertib (WEE1 inhibitor) +/- olaparib [poly (ADP-ribose) polymerase inhibitor (PARPi)] in patients with PARPi-resistant ovarian cancer (OC), demonstrated efficacy and moderate toxicity. We report updated progression-free survival (PFS) and clinical/molecular features associated with clinical benefit from adavosertib (A) +/- olaparib (O).
Methods
Eligible patients had recurrent OC after progression on PARPi, measurable disease, and adequate end-organ function. Primary endpoint was objective response rate (ORR) per RECIST v1.1. Secondary endpoints included PFS and clinical benefit (ORR/stable disease > 4 months) based on BRCA status, homologous recombination deficiency (HRD), platinum sensitivity, and intervening alternate therapy after prior PARPi before trial enrollment. Replication stress and HRD are being assessed using novel pRPA32 and Rad51 foci.
Results
There were 35 evaluable patients on each arm. Patients received a median of 4 prior therapies (range 1–11), including olaparib (41%). Median PFS was 5.5 months (95% CI, 3.9–6.9) from A and 6.8 months (95% CI, 4.3–8.3) from A/O. Table 1 demonstrates clinical benefit based on clinical/molecular features. Clinical benefit was observed on both arms regardless of BRCA status, platinum sensitivity, or use of intervening therapy after PARPi. Figure 1 demonstrates clinical benefit based on platinum sensitivity, with intriguing activity in platinum-resistant disease.
Conclusion/Implications
Efficacy of adavosertib +/- olaparib was retained across multiple clinical cohorts of PARPi-resistant OC, including BRCAwt and platinum-resistant disease. Ongoing analysis using a novel functional HRD assay consisting of concordant measurement of Rad51, gH2AX and geminin foci will elucidate the role of HRD in clinical benefit.
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.
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 <6). One squamous NSCLC patient in the C1 arm, with high copy number FGFR 1 amplification and who had received 2 previous lines of anti-cancer therapy, experienced a partial response lasting 12 weeks (patient discontinued study treatment due to RECIST disease progression at 24 weeks). An additional 4 patients in Part C1 had long periods of disease stabilization (?24 weeks; advanced breast cancer [n=1], squamous NSCLC [n=1] and transitional cell carcinoma [n=2]). Pharmacokinetic data were generally both predictable and linear. The most common adverse events (AEs) reported were hyperphosphataemia, dry skin and mucous membranes, and retinal pigmented epithelial detachment (RPED). AEs were generally mild to moderate and reversible. Parts C2 (squamous NSCLC) and C3 (gastric cancer) are ongoing.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.
11010 Background: AZD4547 is a selective inhibitor of FGFR 1, 2, and 3, with activity in patient-derived explant models with FGFR gene amplification. Study 1C1 assessed safety and clinical activity of AZD4547 (80 mg bid continuous dosing), in patients with advanced solid tumors, prospectively selected for amplification of FGFR 1 or 2. FGFR gene amplification status was determined using fluorescent in situ hybridization (FISH) analysis of archival tumor tissue. Methods: Analysis of FFPE diagnostic tumor samples included FGFR expression by IHC, expression analysis of ~200 pathway related genes by Nanostring and targeted Next Generation Sequencing (NGS) of a 287 gene panel at Foundation Medicine. Results: Of 21 patients dosed with AZD4547, seven had high FGFR amplification (ratio FGFR:Centromeric probe ≥ 3.0) and three of these, a squamous NSCLC, breast and bladder cancer patients, had target lesion shrinkage or prolonged (≥24 weeks) disease stabilization. NGS analysis of tumor from a partial response squamous NSCLC patient, confirmed high FGFR1 amplification together with amplification of 11q13 genes FGF3/4/19 and CCND1. A breast cancer patient, with 25% reduction in target lesions, was highly FGFR1 amplified by NGS and expressed FGFR1 protein. Four patients with high FGFR gene amplification by FISH had little sign of efficacy. Of these, one patient was not confirmed FGFR amplified by NGS analysis, likely due to tumor heterogeneity. The other three patient tumors had an additional Receptor Tyrosine Kinase (RTK) amplification (IGF1R, HER2 or EGFR), with accompanying high expression. Two out of three bladder cancer patients experienced prolonged disease stabilization, both with marked FGFR1 and FGFR3 expression, one with high FGFR1amplification while an FGFR3 ligand binding domain mutation was found in tumor from the other. Conclusions: In this AZD4547 Phase I study, evidence of FGFR pathway expression was observed in tumor samples from advanced cancer patients with signs of efficacy. Co-amplification of RTKs may confer resistance to AZD4547. FGFR1/3 expression, amplification and mutation are potential selection markers for bladder cancer patients. Clinical trial information: NCT00979134.
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