NCCN Guidelines Weigh New Data for Combinations: A Deep Dive into Immunotherapy and Tyrosine Kinase Inhibitors
In a recent live event, Moshe C. Ornstein, MD, MA, delved into the recommended regimens for non-clear cell renal cell carcinoma (nccRCC) and evaluated the findings on dual immunotherapy in this setting. The NCCN guidelines now list immunotherapy (IO) and tyrosine kinase inhibitor (TKI) combinations for advanced nccRCC, based on the efficacy of lenvatinib (Lenvima) plus pembrolizumab (Keytruda) and cabozantinib (Cabometyx) plus nivolumab (Opdivo), despite the results coming from single-arm trials.
Dr. Ornstein, a genitourinary oncologist at the Cleveland Clinic, discussed the rationale behind these regimens during a virtual Case-Based Roundtable. He also reviewed the older regimen of lenvatinib/everolimus and considered the interpretation of another recent trial for the dual IO regimen of ipilimumab (Yervoy)/nivolumab. The event was part of a two-part series from a Case-Based Roundtable event.
Key Takeaways from the Studies of Lenvatinib/Pembrolizumab and Cabozantinib/Nivolumab
- The lenvatinib/pembrolizumab study was larger, with primary endpoints of overall response rates (ORRs) in the low 50% range, similar across both studies and by histology.
- Median overall survival (OS) was longer in the lenvatinib/pembrolizumab study, with a median progression-free survival (PFS) of about 18 months for frontline patients.
- Treatment-related adverse events leading to discontinuation of either study drug are crucial for safety considerations.
NCCN-Recommended Combination: Lenvatinib Plus Everolimus
- Some physicians still use lenvatinib plus everolimus for nccRCC, particularly for chromophobe RCC, based on a small study with a 44% response rate.
- Data support the role of mTOR mutations or TSC mutations, suggesting a potential for mTOR inhibition in chromophobe RCC.
Incorporating Phase 2 Studies into NCCN Guidelines
- Questions arose about including single-arm phase 2 trials in NCCN guidelines, especially since cabozantinib had a randomized study. However, data showing PFS of 18 months and median OS not reached at follow-ups of 34-36 months supported their inclusion.
- Insurance companies have not raised issues with coverage, and future clinical trial designs may need to consider cabozantinib as a control arm.
Other Regimens with Supporting Data
- The NCCN guidelines do not include ipilimumab plus nivolumab, despite meeting its primary endpoint of 12-month OS rate at almost 87%.
- Response rates were lower for ipilimumab/nivolumab (25%) compared to lenvatinib/pembrolizumab (50%) and cabozantinib/nivolumab (50%).
- More than one-third of patients with nccRCC who received ipilimumab/nivolumab experienced primary disease progression, with a short PFS of only 5.5 months.
Disclosure and References
- Ornstein has reported consulting or advisory roles for various pharmaceutical companies and served on speakers' bureaus.
- References include studies on lenvatinib/pembrolizumab, cabozantinib/nivolumab, and ipilimumab/nivolumab, with details on study designs, endpoints, and results.
