Abstract 69P
Background
Two phase III trials (SAPPHIRE and CONTACT-01) have evaluated the combination of TAM receptor tyrosine kinase inhibitors (TYRO3, AXL, MERTK, TAMi) and immune checkpoint inhibitors (ICB) in NSCLC patients who were resistant to previous ICB plus chemotherapy (Chemo). Although there is substantial preclinical evidence supporting the inhibition of TAM RTKs to enhance ICB efficacy, both trials failed to improve outcomes over docetaxel. We hypothesized that 1) moving TAMi plus ICB to the first-line setting may be more appropriate; 2) TAMi would be beneficial for tumors with high TAM RTK expression.
Methods
To preliminarily explore optimal biomarker and scenario for employing TAMi plus ICB, we assessed the association between TAM RTK mRNA expression and ICB efficacy and tumor microenvironment in our in-house phase III randomized controlled trials (ORIENT-11, NCT03607539) that compared PD-1 inhibitor Sintilimab plus Chemo (n=113) versus Chemo (n=58) in treatment-naïve non-squamous NSCLC. The 75th percentile of a gene was selected as cutoff for high expression.
Results
Among the three RTKs, high TYRO3 expression defined a subset of patients with no overall survival (OS; HR=0.92, P=0.8) and progression-free survival (PFS; HR=0.86, P=0.7) from ICB+Chemo over Chemo, while the advantage of OS (HR=0.59, P=0.02) and PFS (HR=0.29, P= 2.00E-08) both remained in patients with low TYRO3 expression. These reduced benefits were independently of PD-L1 expression and other clinical variables (P interaction=0.01). These findings suggested that TYRO3 could serve as a biomarker for identifying patients who may benefit from incorporation of TAMi in the first-line setting. Conversely, high AXL and MERTK expression did not curtail ICB+Chemo efficacy. High TYRO3 but not AXL and MERTK expression was associated with elevated T regulatory cell infiltration.
Conclusions
Future trials investigating TAMi plus ICB should in a biomarker-driven approach (high TAM RTK expression) in the first-line setting. Importantly, most TAMi developed to date are pan-TAM inhibitors, leading to significant off-target toxicities. Our findings emphasize the urgency of developing highly selective agents specifically targeting TYRO3.
Clinical trial identification
NCT03607539.
Legal entity responsible for the study
A. Li.
Funding
This study was supported by the National Natural Science Foundation of China (81972898, 82172713, and 81972556), the Guangdong Basic and Applied Basic Research Foundation (2023B1515020008), and the Fundamental Research Funds for the Central Universities, Sun Yat-sen University (22ykqb15).
Disclosure
All authors have declared no conflicts of interest.