Background: Loss of the metabolic tumor suppressor argininosuccinate synthetase 1 (ASS1) sensitizes non-squamous non-small cell lung cancer (NSCLC) cells to arginine deprivation with pegylated arginine deiminase (ADI-PEG20), which also disrupts thymidine pools and potentiates pemetrexed (Pem) cytotoxicity. In the phase I dose-escalation TRAP study (NCT02029690) we showed that ADI-PEG20 with first-line PEM and cisplatin (Cis) chemotherapy (ADIPemCis) produced a 100% disease control rate (DCR) (n = 9) of ASS1-deficient thoracic cancers, with no additional toxicity (Beddowes et al., 2017). Here, we present the TRAP expansion cohort experience in non-squamous NSCLC.

Methods: Good-performance (ECOG 0-1) NSCLC patients (pts) with nonresectable disease were enrolled in a phase I TRAP expansion cohort at the maximum tolerated dose (MTD) of ADIPemCis, using tumoral ASS1 loss as a selection biomarker. Pem (500mg/m2) and Cis (75mg/m2) were given every 3 weeks with weekly IM ADI-PEG20 (36mg/m2) for a maximum of 4 cycles with maintenance ADI-PEG20 or Pem in responding pts. Primary endpoint was tumor response rate (RECIST 1.1), with secondary endpoints including progression-free survival (PFS), overall survival (OS), and toxicity. We measured plasma arginine and citrulline concentrations, ADI-PEG20 antibodies, early molecular responses by 18-FLT-PET/CT, and biopsied pts on progression to explore resistance mechanisms.

Results: 21 ASS1-deficient non-squamous NSCLC pts (median age 60) were enrolled out of 70 screened pts; 14% (3/21) had stable brain metastases at entry. Plasma arginine decreased with a reciprocal increase in plasma citrulline. The partial response rate was 48% (n=10/21) with a DCR of 85.7% (n=18/21). Median PFS was 2.6 months and median OS was 5.3 months. 23.8% (n=5/21) pts experienced grade 3/4 treatment-related toxicities, the most common being non-febrile neutropenia (14.3%). A partial metabolic response was detected in 57.1% (n=4/7) pts by 24 hrs of arginine deprivation using 18-FLT-PET/CT with EORTC response criteria. Upregulation of ASS1 expression was observed in 1/3 biopsies on progression.

Conclusions: The ADIPemCis regimen is active in ASS1-deficient non-squamous NSCLC pts with a higher than expected response rate. However, the short survival (PFS and OS) compared with ASS1-agnostic historical controls indicates that ASS1 loss selects for a biologically more aggressive phenotype of NSCLC. Further studies are warranted exploring rationale combinations with ADIPemCis in patients with ASS1-deficient non-squamous NSCLC.

Citation Format: Melissa Phillips, Teresa Szyszko, Peter Hall, Sukaina Rashid, Ramsay Khadeir, Louise Lim, Jeremy Steele, John Conibear, Paula Wells, Stephen Ellis, Xiaoxing Feng, Jim Thomson, Amanda Johnston, Bor-Wen Wu, John Bomalaski, Simon Pacey, Gary Cook, Peter Szlosarek. Expansion study of pegylated arginine deiminase (ADI-PEG20), pemetrexed, and cisplatin in patients with ASS1-deficient non-squamous non-small cell lung cancer (TRAP) [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr B33.