Phase 1, pharmacogenomic, dose-expansion study of pegargiminase plus pemetrexed and cisplatin in patients with ASS1-deficient non-squamous non-small cell lung cancer

Introduction We evaluated the arginine-depleting enzyme pegargiminase (ADI-PEG20; ADI) with pemetrexed (Pem) and cisplatin (Cis) (ADIPemCis) in ASS1-deficient non-squamous non-small cell lung cancer (NSCLC) via a phase 1 dose-expansion trial with exploratory biomarker analysis. Methods Sixty-seven chemonaïve patients with advanced non-squamous NSCLC were screened, enrolling 21 ASS1-deficient subjects from March 2015 to July 2017 onto weekly pegargiminase (36 mg/m2) with Pem (500 mg/m2) and Cis (75 mg/m2), every 3 weeks (four cycles maximum), with maintenance Pem or pegargiminase. Safety, pharmacodynamics, immunogenicity, and efficacy were determined; molecular biomarkers were annotated by next-generation sequencing and PD-L1 immunohistochemistry. Results ADIPemCis was well-tolerated. Plasma arginine and citrulline were differentially modulated; pegargiminase antibodies plateaued by week 10. The disease control rate was 85.7% (n = 18/21; 95% CI 63.7%–97%), with a partial response rate of 47.6% (n = 10/21; 95% CI 25.7%–70.2%). The median progression-free and overall survivals were 4.2 (95% CI 2.9–4.8) and 7.2 (95% CI 5.1–18.4) months, respectively. Two PD-L1-expressing (≥1%) patients are alive following subsequent pembrolizumab immunotherapy (9.5%). Tumoral ASS1 deficiency enriched for p53 (64.7%) mutations, and numerically worse median overall survival as compared to ASS1-proficient disease (10.2 months; n = 29). There was no apparent increase in KRAS mutations (35.3%) and PD-L1 (<1%) expression (55.6%). Re-expression of tumoral ASS1 was detected in one patient at progression (n = 1/3). Conclusions ADIPemCis was safe and highly active in patients with ASS1-deficient non-squamous NSCLC, however, survival was poor overall. ASS1 loss was co-associated with p53 mutations. Therapies incorporating pegargiminase merit further evaluation in ASS1-deficient and treatment-refractory NSCLC

The potential of using circulating tumour cells and their gene expression to predict docetaxel response in metastatic prostate cancer

Background: Docetaxel improves overall survival (OS) in castration-resistant prostate cancer (PCa) (CRPC) and metastatic hormone-sensitive PCa (mHSPC). However, not all patients respond due to inherent and/or acquired resistance. There remains an unmet clinical need for a robust predictive test to stratify patients for treatment. Liquid biopsy of circulating tumour cell (CTCs) is minimally invasive, can provide real-time information of the heterogeneous tumour and therefore may be a potentially ideal docetaxel response prediction biomarker. Objective: In this study we investigate the potential of using CTCs and their gene expression to predict post-docetaxel tumour response, OS and progression free survival (PFS). Methods: Peripheral blood was sampled from 18 mCRPC and 43 mHSPC patients, pre-docetaxel treatment, for CTC investigation. CTCs were isolated using the epitope independent Parsortix® system and gene expression was determined by multiplex RT-qPCR. We evaluated CTC measurements for post-docetaxel outcome prediction using receiver operating characteristics and Kaplan Meier analysis. Results: Detection of CTCs pre-docetaxel was associated with poor patient outcome post-docetaxel treatment. Combining total-CTC number with PSA and ALP predicted lack of partial response (PR) with an AUC of 0.90, p= 0.037 in mCRPC. A significantly shorter median OS was seen in mCRPC patients with positive CTC-score (12.80 vs. 37.33 months, HR= 5.08, p= 0.0005), ≥3 total-CTCs/7.5mL (12.80 vs. 37.33 months, HR= 3.84, p= 0.0053), ≥1 epithelial-CTCs/7.5mL (14.30 vs. 37.33 months, HR= 3.89, p= 0.0041) or epithelial to mesenchymal transitioning (EMTing)-CTCs/7.5mL (11.32 vs. 32.37 months, HR= 6.73, p= 0.0001). Significantly shorter PFS was observed in patients with ≥2 epithelial-CTCs/7.5mL (7.52 vs. 18.83 months, HR= 3.93, p= 0.0058). mHSPC patients with ≥5 CTCs/7.5mL had significantly shorter median OS (24.57 vs undefined months, HR= 4.14, p= 0.0097). In mHSPC patients, expression of KLK2, KLK4, ADAMTS1, ZEB1 and SNAI1 was significantly associated with shorter OS and/or PFS. Importantly, combining CTC measurements with clinical biomarkers increased sensitivity and specificity for prediction of patient outcome. Conclusion: While it is clear that CTC numbers and gene expression were prognostic for PCa post-docetaxel treatment, and CTC subtype analysis may have additional value, their potential predictive value for docetaxel chemotherapy response needs to be further investigated in large patient cohorts