Abstract CT102: Interim results of a first-in-human, dose escalation and expansion study of PLB-1004, an irreversible inhibitor of exon 20 insertion mutations in patients with non-small cell lung cancer
Authors: Yang Jinji , Wu Yilong , Huang Meijuan , Zhao Yanqiu , Zhao Jun , Zhou Jianying , Mao Ying , Wang Huimin , Fan Yun , Chung David , Schaab Kevin 
Published: April 2023

Abstract
Background: PLB1004, a novel mono-anilino-pyrimidine small molecule inhibitor of EGFR, potently and irreversibly targets exon 20 insertion mutations with IC50 values ranging from 25.67-316.6 nM. The molecule also potently targets classical EGFR mutations ExDel19, L858R and T790M with a high degree of selectivity over wild-type EGFR.
Methods: The study is a multi-center, open-label, dose escalation and expansion study conducted entirely in China, to assess the safety, tolerability, pharmacokinetics, and anti-tumor effect of PLB1004, administered orally once per day, in patients with advanced non-small cell lung cancer. The primary objective of the study is to assess the safety profile of PLB1004 and determine the RP2D of the molecule.
Results: Dose escalation ranged from a starting dose of 10 mg QD to a top dose of 480 mg QD in 11 cohorts of patients. Dose expansion is ongoing at two dose levels, 320 mg QD and 400 mg QD. At the cutoff date for this abstract, July 31, 2022, a total of 65 patients (32 in escalation and 33 in expansion) had received treatment with PLB1004. The median age of the patients is 58 years old (range 31 to 77). Most patients are women (60%) with adenocarcinoma (95%) and good performance status (ECOG 0-1 in 90%). Prior therapy for NSCLC included platinum-based chemotherapy in 54% of patients and TKI therapy in 58%. Of note 58% of patients had intra-cranial metastases at baseline. The most frequent treatment related adverse events included diarrhea in 75% of patients (18% Grade 3), rash in 60% of patients (11% Grade 3), mouth ulceration in 43% of patients (1.5% Grade 3), elevated serum creatinine in 43% of patients (0% Grade 3) and elevated aspartate aminotransferase in 41% of patients (3% Grade 3). The criteria for DLT were not reported at any dose level and thus an MTD was not determined during cycle 1 of drug administration. Beyond Cycle 1, at the highest dose levels, frequent dose interruptions and reductions due to toxicity were observed, and further dose escalation was not attempted above 480 mg QD. A more complete summary of safety data will be presented at the meeting. Across all dose groups, a total of 38 subjects had EGFR Ex20ins mutations, including 29 at doses ≥ 160 mg QD, among whom 26 completed at least 1 tumor assessment. In these 26 patients the confirmed response rate was 57.7% (15/26) and the disease control rate (DCR) was 100% (26/26). Duration of response exceeded 6 months in 40% of responders.
Conclusion: In the ongoing Phase 1 study, PLB1004 appears to be safe and well-tolerated with promising anti-tumor activity in patients with NSCLC harboring EGFR exon 20 insertion mutations.
Citation Format: Jinji Yang, Yilong Wu, Meijuan Huang, Yanqiu Zhao, Jun Zhao, Jianying Zhou, Ying Mao, Huimin Wang, Yun Fan, David Chung, Kevin Schaab. Interim results of a first-in-human, dose escalation and expansion study of PLB-1004, an irreversible inhibitor of exon 20 insertion mutations in patients with non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT102.