Impact of Time to Metastasis (Synchronous vs. Metachronous) on Outcomes in Metastatic Renal Cell Carcinoma Patients Treated with First Line Immune-Checkpoint Inhibitors (ICI)-based Combinations

BACKGROUND: Metastatic renal cell carcinoma (RCC) can present as synchronous metastatic disease, where primary metastases are detected at the time of diagnosis, or metachronous disease, where metastases appear during follow-up after initial RCC diagnosis. The effect of time to metastasis on patient outcomes is not well characterized in the era of immune checkpoint inhibitor (ICI)-based combinations. Herein, we assess the differences in clinical outcomes between patients with synchronous and metachronous mRCC. METHODS: Data for mRCC patients treated with first line ICI-based combination therapies between 2014 and 2023 were retrospectively collected from two NCI-designated comprehensive cancer centers. Patients were categorized as having synchronous or metachronous disease based on the time of presentation of metastases. Synchronous disease was defined as the presence of metastases at the time of RCC diagnosis or within 3 months thereafter. The study endpoints were time to treatment failure (TTF), overall survival (OS), and disease control rate (DCR). TTF and OS were estimated by Kaplan-Meier method and compared based on the time of presentation of metastases using log-rank tests. Univariable and multivariable Cox proportional hazard models and logistic regression models were used to examine the impact of sex, IMDC risk score, histology, and age at treatment start on TTF, OS and DCR. RESULTS: A total of 223 patients (126 synchronous and 97 metachronous) diagnosed with mRCC were included in the analysis. No significant difference was seen in gender distribution or age at first line treatment between these two groups. Although not statistically significant, the synchronous group had a higher proportion of patients with non-clear cell histology compared to those with metachronous disease (21% vs. 11%, P = 0.057). The median TTF was shorter in patients with synchronous disease but did not reach statistical significance (9 vs. 19.8 months for synchronous and metachronous, respectively, HR 1.37, 95% CI [0.98, 1.92], P = 0.064). Median OS was significantly shorter in patients with synchronous disease (28.0 vs. 50.9 months, adjusted HR 2.23, 95% CI [1.36, 3.65], P = 0.001). Similarly, patients with synchronous mRCC had a lower DCR than patients with metachronous (58.7% vs 78.4%, adjusted odds ratio (OR) 0.29, 95% CI [0.13, 0.64], P = 0.002). In the multivariable analysis, synchronous disease remained an independent factor associated with worse OS and DCR. CONCLUSIONS: Patients with metastatic disease at the time of RCC diagnosis who were treated with first line ICI-based combinations have a poorer OS, and worse DCR than those who develop metastatic disease during follow-up. Although further validation is needed, these findings could be valuable in designing clinical trials and selecting patients for treatment escalation and closer clinical follow-up. CDMRP DOD Funding: no