Background: The standard first-line treatment for metastatic renal cancer (mRCC) combines immune checkpoint- (ICI) and tyrosine kinase inhibitors (TKI). While TKI therapy continues until disease progression, ICI treatment is typically stopped after 24 months or 35 cycles, aligning with approval study criteria. However, in real-world practice, the decision to discontinue ICI therapy upon achieving a positive response can be distressing for both patients and healthcare providers; thus ICIs are not stopped. We conducted an initial analysis of prolonged pembrolizumab (Pem) use in axitinib-pembrolizumab (Axi-Pem) combination therapy to evaluate its effects and toxicity. Methods: We retrospectively analyzed data from mRCC patients treated with first-line Axi-Pem in 10 German tertiary care centers between 2019 and 2023. After completing 35 cycles or 24 months of Pem, patients were offered continued ICI therapy if positive response was assessed. We calculated objective response rate (ORR) and progression-free survival (PFS) from the treatment start to achievement of 36 therapy months. Adverse events (irAEs) were reported following CTCAE 5.0 criteria. Results: Out of 72 patients, 27 met strict eligibility criteria from the Keynote-426 study (NCT02853331), with a response at 24 months and continuous Pem therapy. Patients had a median age of 65.7 years (range: 34-84), and IMDC risk was favorable/intermediate/poor in 22.2%/55.5%/18.5%. Median follow-up was 33.2 months (range: 25.3-48.4). At the 36-mos landmark, median PFS was not reached (PFS 64.7%), ORR was 63.6%, with complete response, partial response, and stable disease observed in 9.1%(1)/54.5%(6)/9.1%(1) of cases, respectively. Permanent Pem discontinuation occurred due to progressive disease in two cases and complete response in one case. Another case led to Pem discontinuation due to immune-related toxicity. Conclusions: In our selected real-world patient cohort seeking prolonged ICI therapy, responders who received continuous Pem beyond 24 months achieve sustained efficacy in first-line treatment. Furthermore, the incidence of irAEs does not increase with prolonged exposure to ICI therapy. Additional results beyond the 36-month landmark are urgently needed to further support the clinical necessity and feasibility of ongoing ICI treatment in light of its impact on the overall financial burden of cancer care.