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

Peter W Szlosarek, Akhila G Wimalasingham, Melissa M Phillips, Peter E Hall, Pui Ying Chan, John Conibear, Louise Lim, Sukaina Rashid, Jeremy Steele, Paula Wells, Chiung-Fang Shiu, Chih-Ling Kuo, Xiaoxing Feng, Amanda Johnston, John Bomalaski, Stephen Ellis, Marianne Grantham, Michael Sheaff, Peter W Szlosarek, Akhila G Wimalasingham, Melissa M Phillips, Peter E Hall, Pui Ying Chan, John Conibear, Louise Lim, Sukaina Rashid, Jeremy Steele, Paula Wells, Chiung-Fang Shiu, Chih-Ling Kuo, Xiaoxing Feng, Amanda Johnston, John Bomalaski, Stephen Ellis, Marianne Grantham, Michael Sheaff

Abstract

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.

Trial registration: ClinicalTrials.gov NCT02029690.

Keywords: ADIPemCis; ASS1; KRAS; PD-L1; arginine; arginine deiminase; non-squamous NSCLC; p53.

Conflict of interest statement

PW Szlosarek received support from the Higher Education Funding Council for England (HEFCE) and research grant support from Polaris Group. Ms Shiu, Ms Kuo, Dr Bomalaski, Dr Johnson, and Dr Feng are paid employees of Polaris Pharmaceuticals. The remaining authors did not report any relevant conflict of interest.

© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Figures

FIGURE 1
FIGURE 1
CONSORT diagram
FIGURE 2
FIGURE 2
Pharmacodynamics and response. (A) Pharmacodynamics of arginine and citrulline in patients treated with ADIPemCis. Serum [arginine] and [citrulline] are shown by week of treatment (means ± SEM). (B) Serum levels of anti‐ADI‐PEG 20 antibodies in all patients by week of ADIPemCis (Mean ± SEM); Ab, Antibody. (C) Waterfall plot of response by RECIST 1.1. to ADIPemCis. (D) Spider plots showing response duration to ADIPemCis
FIGURE 3
FIGURE 3
Survival outcomes for ASS1‐deficient patients (A) Progression‐free survival. (B) Kaplan–Meier survival estimates
FIGURE 4
FIGURE 4
Survival outcomes for ASS1‐proficient patients Kaplan–Meier survival estimates for ASS1‐proficient patients screened as part of this study (n = 29) and treated with standard of care cisplatin and pemetrexed chemotherapy and compared to ASS1‐deficient patients receiving ADIPemCis (n = 21)

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