Authors: Vaibhav Sahai, Paul Eliezer Oberstein, Smitha S. Krishnamurthi, Nashat Y. Gabrail, Christos Fountzilas, Warren S. Brenner, Zev A. Wainberg, Hongxia Yan, Gail McIntyre, Charles D. Lopez, Niharika B. Mettu, Robert B. Geller
Published: 2023-06-04
DOI: 10.1200/jco.2023.41.16_suppl.e16258
Source: Full article
e16258 Background: PDAC is a deadly aggressive cancer characterized by up to 80% tumor stroma enriched by macrophages, fibroblasts, and collagen deposition that influences resistance to therapy. Tyrosine kinase receptor AXL and ligand expression of growth arrest specific protein 6 (GAS6) produce tumor associated macrophages and fibroblasts and correlate with poor prognosis. GAS6 blockade partially reverses epithelial-to-mesenchymal transition of tumor and supports NK cell activation, inhibiting metastasis. As a novel decoy FC fusion protein, batiraxcept (BT) binds to GAS6 and demonstrates highly potent and specific AXL inhibition. Preclinical studies showed a relationship between AXL signaling and response to DNA damage in PDAC models. Methods: This dose escalation study tested BT 15 mg/kg on day 1 and 15 in combination with G 1000 mg/m2 and NP 125 mg/m2 days 1, 8, 15 of a 28-day cycle. Primary endpoints are safety and objective response rate (ORR) using RECIST v1.1; key secondary endpoints are progression free survival (PFS) and overall survival (OS); pharmacokinetic data were collected to determine exposure-PFS response (E-R) relationship. Results: As of January 17, 2023, 21 patients (pts) received BT/G/NP of which 10 (48%) were male and 3 (14%) received prior neoadjuvant/adjuvant therapy. BT-related AEs > 10% pts included fatigue (n=7, 33%), diarrhea (n=4, 19%), infusion related reaction and neutropenia (n=3, 14% each). Grade ≥ 3 BT-related AE occurred in 6 pts (29%). BT administration reduced GAS6 to non-quantifiable levels until treatment ended. 18 pts (86%) discontinued treatment, primarily due to toxicity (n=2) and progressive disease (n=13). Median (m) BT/G/NP treatment duration was 13.1 weeks (range 0.1─74.7). ORR is 29%; mPFS and mOS were 5.4 mo (2.1, 5.6) and 12.3 mo (4.11─NE) respectively. BT efficacy results are described by a minimally efficacious concentration (MEC) of 14.5 mg/L identified by E-R modeling. Conclusions: BT/G/NP combination was well tolerated, and the BT safety profile is consistent with prior trials. Patients with BT trough > MEC had longer PFS and OS. In addition, in these patients OS appears longer than historical data of 8.5 months. Due to increased stroma seen in PDAC, a higher BT MEC may be required to maximize efficacy. Higher BT dose levels in combination with G/NP are under study. Clinical trial information: NCT04983407 . [Table: see text]