In 2023, renal cell carcinoma (RCC) was ranked the seventh most common type of cancer, accounting for 4.2% of all new cancer cases [1]. In the USA alone, there are ∼82 000 new cases and nearly 15 000 deaths annually [2]. The 5-yr survival rate for patients with kidney cancer significantly improved to >75% from 2013 to 2019 [1]. Similarly, median overall survival (OS) in metastatic RCC (mRCC) improved from approximately 26 mo in 2009 [3] to 55 mo in 2022 [4]. Immune checkpoint inhibitor (ICI)-based combinations currently represent the standard of care for mRCC management in first-line setting. Specifically, combinations such as ipilimumab + nivolumab, lenvatinib + pembrolizumab, cabozantinib + nivolumab, and pembrolizumab + axitinib, have demonstrated significant improvements in both progression-free survival (PFS) and OS in clinical trials [4], [5], [6], [7]. Consequently, these ICI-based combinations are the cornerstone for mRCC management [8].

The Surveillance, Epidemiology and End Results (SEER) registry of the US National Cancer Institute provides data regarding the RCC disease stage at presentation. According to the latest data, 82% of cases have localized disease (65%) or locally advanced disease involving regional lymph nodes (17%), while 16% of cases present with metastatic disease (known as synchronous mRCC) [1]. It has been reported that ∼20-50% of patients initially diagnosed with localized disease might subsequently progress to metastatic disease, known as metachronous mRCC [9], [10], [11], [12], [13]. It has been shown that synchronous mRCC was associated with less favorable outcomes in comparison to metachronous mRCC in patients treated with targeted tyrosine kinase inhibitors (TKIs) [14].

Numerous prognostic factors for mRCC have been previously identified. The International mRCC Database Consortium (IMDC) score is a validated tool that is widely used for stratifying patients according to their prognosis. This scoring system incorporates baseline factors, including anemia, thrombocytosis, neutrophilia, hypercalcemia, Karnofsky performance status, and time from diagnosis to initiation of systemic treatment, all of which have demonstrated independent associations with inferior OS [15]. The time from diagnosis to initiation of systemic treatment is sometimes perceived as a surrogate for synchronous versus metachronous mRCC. However, this inference is imperfect; as one example, there may be patients with small-volume synchronous mRCC for whom treatment is deferred.

Given the limited literature on the specific impact of time to metastasis on ICI-based treatment outcomes, we sought to evaluate the impact of synchronous versus metachronous mRCC on survival outcomes in patients treated with ICI-based combinations. We hypothesized that patients with synchronous mRCC will have poorer survival outcomes than those with metachronous mRCC.