Tuan Zea Tan

Durvalumab versus Physician’s Choice Chemotherapy in Recurrent Ovarian Clear Cell Adenocarcinoma (MOCCA/APGOT-OV2/GCGS-OV3): A Multicenter, Randomized, Phase 2 Trial

Abstract Purpose: The optimal treatment of recurrent ovarian clear cell carcinoma (rOCCC) remains unknown. This is the first randomized trial to compare durvalumab with chemotherapy in rOCCC. Patients and Methods: MOCCA is a randomized, phase 2 trial conducted in Singapore, Korea, and Australia. Eligible patients had rOCCC with recurrence after platinum-based chemotherapy, Eastern Cooperative Oncology Group performance status ≤2, and no prior immune checkpoint blockade. Patients were randomly assigned (2:1) to durvalumab (1,500 mg every 4 weeks) or chemotherapy. Patients progressing on chemotherapy were allowed to cross over to durvalumab. The primary outcome was progression-free survival. Secondary outcomes included overall survival, objective response rates, and safety. Results: Forty-eight eligible women were assigned to durvalumab (N = 31) or chemotherapy (N = 17). The median progression-free survival was 7.6 [95% confidence interval (CI), 7.0–16.0] and 14.0 (95% CI, 7.0–32.9) weeks with durvalumab and chemotherapy, respectively (HR = 1.6; 95% CI, 0.8–3.0; P = 0.92). The median overall survival was 37.9 (95% CI, 21.7–143.0) and 40.6 (95% CI, 25.0–not reached) weeks, respectively (HR = 1.5; 95% CI, 0.7–3.3; P = 0.85). The difference in objective response rates between the groups was not statistically significant (durvalumab 9.7% vs. physician’s choice chemotherapy 18.8%; difference −9.1%; 95% CI, −31.3% to 12.9%; P = 0.83). Fewer all-grade (35.5% vs. 68.8%) and high-grade (9.7% vs. 31.3%) treatment-related adverse events were observed for durvalumab. PD-L1 combined positive score (CPS)+ was observed in 28.9% (CPS ≥1%) and 10.5% (CPS ≥10%) of patients. PIK3CA mutations were associated with time to progression on durvalumab ≥12 weeks [relative risk (mutated vs. wild-type) 2.83; 95% CI, 1.16–14.17]. Conclusions: Durvalumab was well-tolerated but did not improve efficacy outcomes compared with chemotherapy in rOCCC.

The effect of inhibition of receptor tyrosine kinase AXL on DNA damage response in ovarian cancer

Abstract AXL is a receptor tyrosine kinase that is often overexpressed in cancers. It contributes to pathophysiology in cancer progression and therapeutic resistance, making it an emerging therapeutic target. The first-in-class AXL inhibitor bemcentinib (R428/BGB324) has been granted fast track designation by the U.S. Food and Drug Administration (FDA) in STK11-mutated advanced metastatic non-small cell lung cancer and was also reported to show selective sensitivity towards ovarian cancers (OC) with a Mesenchymal molecular subtype. In this study, we further explored AXL’s role in mediating DNA damage responses by using OC as a disease model. AXL inhibition using R428 resulted in the increase of DNA damage with the concurrent upregulation of DNA damage response signalling molecules. Furthermore, AXL inhibition rendered cells more sensitive to the inhibition of ATR, a crucial mediator for replication stress. Combinatory use of AXL and ATR inhibitors showed additive effects in OC. Through SILAC co-immunoprecipitation mass spectrometry, we identified a novel binding partner of AXL, SAM68, whose loss in OC cells harboured phenotypes in DNA damage responses similar to AXL inhibition. In addition, AXL- and SAM68-deficiency or R428 treatment induced elevated levels of cholesterol and upregulated genes in the cholesterol biosynthesis pathway. There might be a protective role of cholesterol in shielding cancer cells against DNA damage induced by AXL inhibition or SMA68 deficiency.

Development and Validation of the Gene Expression Predictor of High-grade Serous Ovarian Carcinoma Molecular SubTYPE (PrOTYPE)

Abstract Purpose: Gene expression–based molecular subtypes of high-grade serous tubo-ovarian cancer (HGSOC), demonstrated across multiple studies, may provide improved stratification for molecularly targeted trials. However, evaluation of clinical utility has been hindered by nonstandardized methods, which are not applicable in a clinical setting. We sought to generate a clinical grade minimal gene set assay for classification of individual tumor specimens into HGSOC subtypes and confirm previously reported subtype-associated features. Experimental Design: Adopting two independent approaches, we derived and internally validated algorithms for subtype prediction using published gene expression data from 1,650 tumors. We applied resulting models to NanoString data on 3,829 HGSOCs from the Ovarian Tumor Tissue Analysis consortium. We further developed, confirmed, and validated a reduced, minimal gene set predictor, with methods suitable for a single-patient setting. Results: Gene expression data were used to derive the predictor of high-grade serous ovarian carcinoma molecular subtype (PrOTYPE) assay. We established a de facto standard as a consensus of two parallel approaches. PrOTYPE subtypes are significantly associated with age, stage, residual disease, tumor-infiltrating lymphocytes, and outcome. The locked-down clinical grade PrOTYPE test includes a model with 55 genes that predicted gene expression subtype with >95% accuracy that was maintained in all analytic and biological validations. Conclusions: We validated the PrOTYPE assay following the Institute of Medicine guidelines for the development of omics-based tests. This fully defined and locked-down clinical grade assay will enable trial design with molecular subtype stratification and allow for objective assessment of the predictive value of HGSOC molecular subtypes in precision medicine applications. See related commentary by McMullen et al., p. 5271

A multi‐ethnic analysis of immune‐related gene expression signatures in patients with ovarian clear cell carcinoma

AbstractLittle is known about the immune environment of ovarian clear cell carcinoma (OCCC) and its impact on various ethnic backgrounds. The aim of this OCCC immune‐related gene expression signatures (irGES) study was to address the interaction between tumour and immune environment of ethnically‐diverse Asian and Caucasian populations and to identify relevant molecular subsets of biological and clinical importance. Our study included 264 women from three different countries (Singapore, Japan, and the UK) and identified four novel immune subtypes (PD1‐high, CTLA4‐high, antigen‐presentation, and pro‐angiogenic subtype) with differentially expressed pathways, and gene ontologies using the NanoString nCounter PanCancer Immune Profiling Panel. The PD1‐high and CTLA4‐high subtypes demonstrated significantly higher PD1, PDL1, and CTLA4 expression, and were associated with poorer clinical outcomes. Mismatch repair (MMR) protein expression, assessed by immunohistochemistry, revealed that about 5% of OCCCs had deficient MMR expression. The prevalence was similar across the three countries and appeared to cluster in the CTLA4‐high subtype. Our results suggest that OCCC from women of Asian and Caucasian descent shares significant clinical and molecular similarities. To our knowledge, our study is the first study to include both Asian and Caucasian women with OCCC and helps to shine light on the impact of ethnic differences on the immune microenvironment of OCCC. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Quantitative imaging of RAD51 expression as a marker of platinum resistance in ovarian cancer

Early relapse after platinum chemotherapy in epithelial ovarian cancer (EOC) portends poor survival. A-priori identification of platinum resistance is therefore crucial to improve on standard first-line carboplatin-paclitaxel treatment. The DNA repair pathway homologous recombination (HR) repairs platinum-induced damage, and the HR recombinase RAD51 is overexpressed in cancer. We therefore designed a REMARK-compliant study of pre-treatment RAD51 expression in EOC, using fluorescent quantitative immunohistochemistry (qIHC) to overcome challenges in quantitation of protein expression in situ. In a discovery cohort (n = 284), RAD51-High tumours had shorter progression-free and overall survival compared to RAD51-Low cases in univariate and multivariate analyses. The association of RAD51 with relapse/survival was validated in a carboplatin monotherapy SCOTROC4 clinical trial cohort (n = 264) and was predominantly noted in HR-proficient cancers (Myriad HRDscore < 42). Interestingly, overexpression of RAD51 modified expression of immune-regulatory pathways in vitro, while RAD51-High tumours showed exclusion of cytotoxic T cells in situ. Our findings highlight RAD51 expression as a determinant of platinum resistance and suggest possible roles for therapy to overcome immune exclusion in RAD51-High EOC. The qIHC approach is generalizable to other proteins with a continuum instead of discrete/bimodal expression.

A phase 1b, multicentre, dose escalation, safety and pharmacokinetics study of tilvestamab (BGB149) in relapsed, platinum-resistant, high-grade serous ovarian cancer (PROC) patients

Abstract Background Tilvestamab is a highly selective humanised immunoglobulin G1 anti-AXL monoclonal antibody. This phase 1 study evaluated its optimal dose, safety, tolerability, immunogenicity and pharmacokinetics (PK) in relapsed platinum-resistant HGSOC patients. Methods Patients received tilvestamab in three dose levels (1 mg/kg, 3 mg/kg and 5 mg/kg) via IV infusion every 2 weeks. Primary objectives included safety, tolerability and PK. Exploratory objectives included overall response, progression-free survival (PFS) and quality-of-life measures. Pharmacodynamic included AXL expression, gene and protein changes by transcriptomic and proteomic analysis. Results Between 25 February 2021 and 4 February 2022, 16 patients were enroled across 8 sites in Singapore, Korea, United Kingdom, and Norway. Median treatment duration was 6.1 weeks. Grade 3 or higher treatment-emergent adverse events occurred in 62.5% patients, but none were tilvestamab-related. Common events included fatigue (38%), anorexia (38%) infections (31%), anaemia (25%) and dyspnoea (25%). No objective responses were observed, but 7 (44%) had stable disease at 6 weeks. PK showed dose-proportional exposure and steady-state by the second dose. Pharmacodynamic analyses revealed reduced fibrosis-related gene signatures and AXL protein expression. Epithelial-mesenchymal transition reversal was seen in 2 patients. Conclusion Tilvestamab was well-tolerated and further studies to examine the efficacy of AXL inhibition in other indications are required. Clinical trial registration This trial is registered at https://clinicaltrials.gov. Registration number: NCT04893551. EudraCT Number: 2020-001382-36

Comprehensive characterization of genomic features and clinical outcomes following targeted therapy and secondary cytoreductive surgery in OCCC: a single center experience

Ovarian clear cell carcinoma (OCCC) is associated with chemoresistance. Limited data exists regarding the efficacy of targeted therapies such as immune checkpoint inhibitors (ICI) and bevacizumab, and the role of secondary cytoreductive surgery (SCS). We retrospectively analyzed genomic features and treatment outcomes of 172 OCCC patients treated at our institution from January 2000 to May 2022. Next-generation sequencing (NGS) was performed where sufficient archival tissue was available. 64.0% of patients were diagnosed at an early stage, and 36.0% at an advanced stage. Patients with advanced/relapsed OCCC who received platinum-based chemotherapy plus bevacizumab followed by maintenance bevacizumab had a median first-line progression-free survival (PFS) of 12.2 months, compared with 9.3 months for chemotherapy alone (hazard ratio=0.69; 95% confidence interval [CI]=0.33, 1.45). In 27 patients who received an ICI, the overall response rate was 18.5% and median duration of response was 7.4 months (95% CI=6.5, 8.3). In 17 carefully selected patients with fewer than 3 sites of relapse, median PFS was 35 months (95% CI=0, 73.5) and median overall survival was 96.8 months (95% CI=44.6, 149.0) after SCS. NGS on 58 tumors revealed common mutations in Our study demonstrates encouraging outcomes with bevacizumab and ICI, and SCS in select relapsed OCCC patients. Prospective trials are warranted.

A Study of Tilvestamab (BGB149) in Relapsed, Platinum-resistant, High-grade Serous Ovarian Cancer (HGSOC) Participants

The primary purpose is to assess the safety and tolerability of tilvestamab following IV administration of multiple doses to participants with HGSOC who have been treated with at least 1 complete course of platinum-based chemotherapy and whose disease has relapsed with platinum resistance (\[PRR\]-HGSOC) and to determine the plasma pharmacokinetics (PK) exposure by comprehensive profiling (at single dose and steady-state) of multiple ascending doses of tilvestamab.