ORCID Profile
0000-0002-4910-4615
Current Organisations
Campbelltown Hospital
,
NHMRC Clinical Trials Centre
,
Prince of Wales Hospital
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Publisher: MDPI AG
Date: 30-12-2022
Abstract: Women with advanced endometrial carcinoma (EC) with mismatch repair (MMR) deficiency have improved outcomes when treated with immune checkpoint inhibitors however, additional biomarkers are needed to identify women most likely to respond. Scores for programmed death ligand 1 (PD-L1), immunohistochemical staining of tumor (TC+), immune cells (IC+) and presence of tumor-associated immune cells (ICP) on MMR deficient (n = 34) and proficient (n = 33) EC from women treated with durvalumab in the PHAEDRA trial (ANZGOG1601/CTC0144) (trial registration number ACTRN12617000106336, prospectively registered 19 January 2017) are reported and correlated with outcome. Receiver operating characteristic (ROC) analyses and area under the ROC curve were used to determine optimal cutpoints. Performance was compared with median cutpoints and two algorithms a novel algorithm derived from optimal cutpoints (TC+ ≥ 1 or ICP ≥ 10 or IC+ ≥ 35) and the Ventana urothelial carcinoma (UC) algorithm (either TC+ ≥ 25, ICP 1 and IC+ ≥ 25 or ICP = 1 and IC+ = 100). The cutpoint ICP ≥ 10 had highest sensitivity (53%) and specificity (82%), being prognostic for progression-free survival (PFS) (p = 0.01), while the optimal cutpoints algorithm was associated with overall survival (p = 0.02) these results were not significant after adjusting for MMR status. The optimal cutpoints algorithm identified non-responders (p = 0.02) with high sensitivity (88%) and negative predictive value (92%), remaining significant after adjustment for MMR. Although MMR status had the strongest association with response, further work to determine the significance of ICP ≥ 10 and the novel optimal cutpoint algorithm is needed.
Publisher: Wiley
Date: 05-01-2022
DOI: 10.1002/CNCR.34085
Abstract: Overall survival (OS) is the gold‐standard end point for oncology trials. However, the availability of multiple therapeutic options after progression and crossover to receive investigational agents confound and delay OS data maturation. Progression‐free survival 2 (PFS‐2), defined as the time from randomization to progression on first subsequent therapy, has been proposed as a surrogate for OS. Using a meta‐analytic approach, the authors aimed to assess the association between OS and PFS‐2 and compare this with progression‐free survival 1 (PFS‐1) and the objective response rate (ORR). An electronic literature search was performed to identify randomized trials of systemic therapies in advanced solid tumors that reported PFS‐2 as a prespecified end point. Correlations between OS and PFS‐2, OS and PFS‐1, and OS and ORR as hazard ratios (HRs) or odds ratios (ORs) were assessed via linear regression weighted by trial size. Thirty‐eight trials were included, and they comprised 19,031 patients across 8 tumor types. PFS‐2 displayed a moderate correlation with OS ( r = 0.67 95% confidence interval [CI], 0.08‐0.69). Conversely, correlations of ORR ( r = 0.12 95% CI, 0.00‐0.13) and PFS‐1 ( r = 0.21 95% CI, 0.00‐0.33) were poor. The findings for PFS‐2 were consistent for subgroup analyses by treatment type (immunotherapy vs nonimmunotherapy: r = 0.67 vs 0.67), survival post progression ( vs ≥12 months: r = 0.86 vs 0.79), and percentage not receiving subsequent treatment ( % vs ≥50%: r = 0.70 vs 0.63). Across erse tumors and therapies, the treatment effect on PFS‐2 correlated moderately with the treatment effect on OS. PFS‐2 performed consistently better than PFS‐1 and ORR, regardless of postprogression treatment and postprogression survival. PFS‐2 should be included as a key trial end point in future randomized trials of solid tumors.
Publisher: BMJ
Date: 2022
DOI: 10.1136/BMJOPEN-2021-057663
Abstract: There is a strong theoretical rationale for combining checkpoint blockade with cytotoxic chemotherapy in pleural mesothelioma and other cancers. Two recent single-arm, phase 2 trials [DuRvalumab with chEmotherapy as first-line treAtment in advanced pleural Mesothelioma (DREAM) and Phase II multicenter study of anti-PD-L1, durvalumab, in combination with cisplatin and pemetrexed for the first-line treatment of unresectable malignant pleural mesothelioma (PrE0505)] combining the programmed death ligand-1 (PD-L1) inhibitor durvalumab with standard first-line chemotherapy exceeded prespecified safety and activity criteria to proceed to a phase 3 confirmatory trial to assess this combination. We present the protocol of the DREAM3R trial. This multicentre open-label randomised trial will recruit 480 treatment-naïve adults with advanced pleural mesothelioma, randomised (2:1) to either 3-weekly durvalumab 1500 mg plus 3-weekly doublet chemotherapy (cisplatin 75 mg/m 2 or carboplatin, Area Under the Curve,AUC 5 and pemetrexed 500 mg/m 2 ) 4–6 cycles, followed by 4-weekly durvalumab 1500 mg until disease progression, unacceptable toxicity or patient withdrawal OR doublet chemotherapy alone for 4–6 cycles, followed by observation. The target accrual time is 27 months, with follow-up for an additional 24 months. This provides over 85% power if the true HR for overall survival (OS) is 0.70, with two-sided alpha of 0.05, assuming a median OS of 15 months in the control group. Randomisation is stratified by age (18–70 years vs ), sex, histology (epithelioid vs non-epithelioid), platinum agent (cisplatin vs carboplatin) and region (USA vs Australia/New Zealand vs Other). The primary endpoint is OS. Secondary endpoints include progression-free survival, objective tumour response (by mRECIST V.1.1 and iRECIST), adverse events, health-related quality of life and healthcare resource use. Tertiary correlative objectives are to explore and validate potential prognostic and/or predictive biomarkers (including features identified in the DuRvalumab with chEmotherapy as first-line treAtment in advanced pleural Mesothelioma (DREAM) and PrE0505 studies, PD-L1 expression, tumour mutational burden, genomic characteristics and human leukocyte antigen subtypes) in tissue and serial blood s les. An imaging databank will be assembled for validation of radiological measures of response, and studies of possible radiomic biomarkers in mesothelioma. The protocol was approved by human research ethics review committees for all participating sites. Results will be disseminated in peer-reviewed journals and at scientific conferences. AstraZeneca. CTC 0231 / TOGA 18/001 / PrE0506 3.0, 29 July 2021. ClinicalTrials.gov Identifier: NCT04334759 ACTRN 12620001199909.
Publisher: Asian Society of Gynecologic Oncology; Korean Society of Gynecologic Oncology and Colposcopy
Date: 2019
Publisher: Elsevier BV
Date: 04-2021
No related grants have been discovered for Peey Sei Kok.