Immunotherapy, combo immuno/targeted therapy beat targeted Tx alone for clear cell renal cell carcinoma

Real-world results have verified previous findings from clinical trials that both first-line immunotherapy (IT) and treatment with combination tyrosine kinase-inhibiting targeted therapy (TT) and IT (TT/IT) improve overall survival (OS) in patients with metastatic clear cell renal cell carcinoma (RCC) compared with first-line TT. Results are published in JAMA Network Open.

“Renal cell carcinoma (RCC) is the sixth most common cancer among men and the eighth most common cancer among women in the U.S., accounting for 4.2% of all incident cancer cases and 2.4% of all cancer deaths each year. Approximately 30% of patients with RCC present with either regional or distant metastases, and 20% of individuals who receive an initial diagnosis of localized disease will eventually develop regional or distant metastases. Clear cell RCC is the most common histologic subtype, representing approximately 80% of all RCCs,” wrote researchers led by Nicholas H. Chakiryan, MD, Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.

With the proven efficacy of immune checkpoint blocking agents and their superiority to TT in improving OS and progression-free survival, first-line management of patients with metastatic clear cell RCC has moved to the use of IT as first-line therapy, the authors noted.

“Current guideline recommendations for preferred first-line IT-based therapy for metastatic clear cell RCC include both dual IT (e.g., ipilimumab plus nivolumab) and combination TT and IT (e.g., axitinib plus pembrolizumab) regimens. Although the safety and efficacy of IT-based regimens have been demonstrated in clinical trials, to our knowledge, their effectiveness among more generalizable populations has not yet been assessed,” they wrote and added. “Evaluating new treatments in comparative effectiveness studies is a critical part of validating clinical trial findings because patients enrolled in clinical trials tend to be younger and healthier than those encountered in real-world practice.10-12 Given the limited availability of effectiveness data for novel and increasingly used IT regimens for metastatic clear cell RCC, we sought to examine real-world survival outcomes for TT, IT, and combination TT and IT regimens using a generalizable cohort of patients with metastatic clear cell RCC.”

To this end, Chakiryan and colleagues conducted this propensity-matched cohort study in 5,872 patients with metastatic clear cell RCC from the National Cancer Database who were treated with first-line TT, IT, or combination TT/IT, but not included in a clinical trial. The primary outcome was OS from diagnosis to death or last follow-up.

“The year 2015 was chosen as the earliest date for the analysis because it was the first year of U.S. Food and Drug Administration (FDA) approval for an ICB agent (nivolumab, as second-line therapy) for the treatment of metastatic clear cell RCC,” they explained.

The 4,755 patients who comprised the TT group were mostly men (70%), with a median age of 64 years. Among the 638 patients in the IT group, 74% were men, with a median age of 61 years; and of the 479 patients treated with TT/IT, 67% were men, with a median age of 62 years. Patients treated with IT and TT/IT groups were younger, had fewer comorbid conditions compared with those in the TT group, and were more often treated at academic centers. A matched cohort of 1,437 patients were included.

Researchers found that both first-line IT and combination TT/IT were associated with improved OS compared with first line TT in these patients (HR for IT group: 0.60; 95% CI: 0.48-0.75; P˂0.001; HR for TT/IT group: 0.74; 95% CI: 0.60-0.91; P=0.005). They found no differences in survival between the IT and combination TT/IT groups (IT and combination TT HR: 1.24; 95% CI: 0.98-1.56; P=0.08).

Upon Kaplan-Meier analysis for survival distributions, researchers found a 12-month OS of 59% in the TT group, 73% in the IT group, and 68% in the combination TT/IT group.

“This analysis of a nationally representative real-world cohort demonstrated that both IT and combination TT and IT were associated with improved OS for patients with metastatic clear cell RCC compared with TT alone. These findings imply the broader generalizability of previously reported clinical trial outcomes,” concluded Chakiryan et al.

Study limitations included possible selection bias, short follow-up and the lack of specific information on the specific agents used for IT, subsequent treatments beyond first-line, and patient characteristics that may have affected survival.

  1. Overall survival benefits seen in clinical trials of first-line immunotherapy-based regimens compared with targeted therapy in patients with clear cell renal cell carcinoma have been validated in a real-world setting.

  2. These results suggest that outcomes from previous clinical trials may have a broader generalizability to patients with clear cell renal cell carcinomas.

Liz Meszaros, Deputy Managing Editor, BreakingMED™

Chakiryan reported no disclosures.

Cat ID: 120

Topic ID: 78,120,730,120,835,127,192,925