Abstract 684P
Background
The presence of glandular metastases (GM) is associated with improved survival in metastatic clear cell renal cell carcinoma (m-ccRCC), but underlying molecular mechanisms remain to be elucidated.
Methods
We performed whole transcriptome RNA sequencing of 47 primary tumors of patients with at least one GM (pancreas, thyroid or adrenal) and 113 primary tumors of patients who did not, as well as 32 metastatic lesions in glandular organs and 258 metastatic lesions in non-glandular organs. We calculated the IMmotion 150 Angio, Teff and Myeloid gene expression signatures (GES) and the JAVELIN RENAL 101 Angio and Immuno GES, which correlate with outcome on therapy. Differences in GES were tested using Mann-Withney U tests with Bonferroni correction. Overall (OS) and progression-free survival (PFS) was studied using Kaplan-Meier survival analysis and Cox regression models.
Results
Primary tumors of patients with GM had higher IMmotion Angio (p=0.0001) and JAVELIN Angio (p=0.004) GES than those without GM. Metastatic lesions in glandular organs had higher IMmotion Angio (p=0.003) and JAVELIN Angio (p=0.007) GES, compared to lesions in non-glandular organs. Immune-related GES were not different between either primary tumors or metastatic lesions. Patients with GM had better OS (HR 0.46, 95% CI 0.30-0.70, p=0.0003) and PFS on first-line vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) (HR 0.64, 95% CI 0.41-0.98, p=0.04) than patients with non-GM. PFS on first- or later line immunotherapy (IO) was not different. IMmotion Angio and JAVELIN Angio GES were associated with better OS and PFS on first-line VEGFR-TKIs, but not PFS on first-line IO.
Conclusions
Patients with m-ccRCC who develop GM have higher angiogenesis-related GES in both primary tumors and metastatic lesions, while differences in immune-related GES are not apparent. Patients with GM have longer OS and PFS on first-line VEGFR-TKIs but no different PFS on first- or later line IO. Glandular tropism is thus likely to be an indicator of heightened angiogenesis, better prognosis, and better outcomes on VEGFR-TKIs. Therefore, the preferential first-line therapy for m-ccRCC patients with GM would be a VEGFR/IO combination rather than ipilimumab/nivolumab.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
BMS.
Disclosure
All authors have declared no conflicts of interest.