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

Cancer Med. 2021 Oct;10(19):6642-6652. doi: 10.1002/cam4.4196. Epub 2021 Aug 12.

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.

Publication types

  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Cisplatin / pharmacology
  • Cisplatin / therapeutic use*
  • Cohort Studies
  • Female
  • Humans
  • Hydrolases / pharmacology
  • Hydrolases / therapeutic use*
  • Lung Neoplasms / drug therapy*
  • Male
  • Middle Aged
  • Pemetrexed / pharmacology
  • Pemetrexed / therapeutic use*
  • Polyethylene Glycols / pharmacology
  • Polyethylene Glycols / therapeutic use*

Substances

  • Pemetrexed
  • Polyethylene Glycols
  • Hydrolases
  • ADI PEG20
  • Cisplatin

Associated data

  • ClinicalTrials.gov/NCT02029690