Data from three pivotal phase 3 trials—KEYNOTE-426, CheckMate-9ER, and CLEAR—underscore the efficacy of immuno-oncology (IO)/TKI doublets as first-line treatments for metastatic clear cell renal cell carcinoma (ccRCC). These studies consistently demonstrate improved progression-free survival (PFS) across various risk groups as defined by the International mRCC Database Consortium. While overall survival (OS) benefits are more pronounced in intermediate- and poor-risk patients, the combinations offer a viable option for managing this challenging cancer.
Consistent PFS Improvement Across Risk Groups
According to Yousef Zakharia, MD, medical oncologist, vice chair of the Genitourinary Malignancy Disease Group at the Mayo Clinic Comprehensive Cancer Center, the trials show consistent improvement in PFS across the International mRCC Database Consortium risk groups. The three regimens include pembrolizumab plus axitinib (KEYNOTE-426), cabozantinib plus nivolumab (CheckMate-9ER), and pembrolizumab plus lenvatinib (CLEAR).
KEYNOTE-426: Pembrolizumab Plus Axitinib
The KEYNOTE-426 trial randomized patients with first-line ccRCC to either pembrolizumab (200 mg every 3 weeks) plus axitinib (5 mg twice daily) or sunitinib. Pembrolizumab was administered for up to 2 years, while axitinib continued until disease progression or unacceptable toxicity. Long-term data favor the pembrolizumab/axitinib combination for PFS. While an OS benefit was not observed in favorable-risk patients, the combination demonstrated superiority to sunitinib in intermediate- and poor-risk subgroups.
Biomarker data presented at the 2024 ASCO Annual Meeting revealed that patients with enriched T-cell infiltration tended to respond better to pembrolizumab plus axitinib. Higher angiogenesis gene expression was associated with improved outcomes in the sunitinib arm, and PD-L1 CPS was negatively associated with OS within the sunitinib arm.
CheckMate-9ER: Cabozantinib Plus Nivolumab
In the CheckMate-9ER trial, patients were randomized to receive either cabozantinib plus nivolumab or sunitinib. Both nivolumab and cabozantinib were continued until disease progression or unacceptable toxicity. The trial enrolled 651 patients. Similar to other IO/TKI regimens, PFS was superior with the combination compared to sunitinib in the favorable-risk population. However, OS was not superior in this group, unlike the intermediate- and poor-risk populations, where both PFS and OS favored the doublet. The overall response rate (ORR) with the combination was 55.7% (95% CI, 50.1%-61.2%).
Subgroup analysis presented at the 2024 Genitourinary Cancers Symposium indicated that the combination of cabozantinib and nivolumab was generally superior to sunitinib, irrespective of whether the site of metastasis was in the liver, bone, or lungs.
CLEAR: Pembrolizumab Plus Lenvatinib
The CLEAR study compared pembrolizumab plus lenvatinib versus lenvatinib plus everolimus versus sunitinib in metastatic ccRCC, with the primary analysis focusing on pembrolizumab/lenvatinib versus sunitinib. The OS benefit favored the combination over sunitinib, primarily in intermediate- and poor-risk patients. While no OS signal was observed in the favorable-risk population, PFS and ORR outcomes still favored the combination. The ORR with the combination was 71% (95% CI, 66.3%-75.7%).
Managing Adverse Effects
Effective management of adverse effects is crucial for maintaining patients on these treatments long-term. Early interruption and dose reduction of the TKI component, especially for patients experiencing grade 3/4 toxicity, are essential strategies.
Conclusion
The collective data from these phase 3 trials support the use of IO/TKI doublets as standard first-line therapy for metastatic ccRCC, particularly in intermediate- and poor-risk patients. While the benefit in favorable-risk patients is less pronounced regarding overall survival, the improved progression-free survival and overall response rates make these combinations a valuable option. Careful management of adverse events is critical to optimize treatment outcomes.
