Combination therapies involving immunotherapy (IO) and tyrosine kinase inhibitors (TKI) are showing promising results in the treatment of non-clear cell renal cell carcinoma (nccRCC), according to recent clinical trial data. These findings are shifting treatment paradigms and offering new hope for patients with this rare and heterogeneous group of cancers.
KEYNOTE-B61 Trial: Pembrolizumab Plus Lenvatinib
The phase 2 KEYNOTE-B61 trial (NCT04704219) evaluated the combination of pembrolizumab and lenvatinib in patients with treatment-naive, locally advanced or metastatic nccRCC. The study, which included 158 patients, demonstrated a 50% overall response rate (ORR) per RECIST by blinded central review. Notably, 8% of patients achieved complete responses (CRs). The median duration of response (DOR) was 19.5 months, with 50.6% of patients experiencing a DOR of 18 months or greater.
The patient population included various nccRCC subtypes, with papillary histology being the most prevalent (n = 93), followed by chromophobe (n = 28), unclassified (n = 20), translocation (n = 6), and other subtypes (n = 10). Median progression-free survival (PFS) in the total population was approximately 17.9 months, with the chromophobe subgroup showing a median PFS of about 26 months. Median overall survival (OS) was not reached in the total population or in the papillary and chromophobe subgroups.
"I find it good to consider the more than 50% ORR. If you look at the depths of the response in the waterfall plot, the majority of patients had some shrinkage of their disease, and some of these responses are durable," said Yousef Zakharia, MD, Medical Oncologist/Hematologist, Mayo Clinic Arizona.
The FDA granted approval for pembrolizumab plus lenvatinib as a first-line treatment for nccRCC based on these results, and the combination is now an NCCN-preferred regimen. The adverse event (AE) profile was consistent with what is typically observed with IO/TKI combinations, including hypertension, diarrhea, and hand-foot syndrome. Grade 4 AEs were documented in 5 patients, but no unexpected safety signals emerged.
Cabozantinib Plus Nivolumab: An Alternative IO/TKI Regimen
Another phase 2 single-arm trial (NCT03635892) investigated the combination of cabozantinib plus nivolumab in nccRCC. This trial differed from KEYNOTE-B61 in that it allowed patients who were treatment-naive or had received one prior line of therapy. The primary endpoint was ORR, with multiple secondary endpoints also assessed. The trial included two cohorts: cohort 1 consisted of patients with papillary, unclassified, or translocation nccRCC (n = 40), while cohort 2, intended for patients with chromophobe histology, was closed early due to a lack of efficacy (0% ORR; n = 7).
The ORR across the groups was 54%, suggesting that a significant number of patients benefited from the combination. The median PFS in the intention-to-treat population was 13 months, with 11 months in the first-line setting and 13 months in the second-line setting. The AE profile was similar to that observed with lenvatinib/pembrolizumab, including fatigue, hand-foot syndrome, diarrhea, dry mouth, and hypertension.
Dosing Considerations and Toxicity Management
Managing the toxicities associated with TKI therapy is crucial for maintaining patients on treatment and optimizing outcomes. "Usually, having a low threshold to hold the dose and lower the dose is key in order to keep the patient for a longer period on these treatments," Dr. Zakharia noted. He added that real-world data with axitinib and pembrolizumab have shown that patients who undergo dose interruption and receive lower doses tend to have better long-term outcomes.
Cabozantinib is typically administered at 40 mg in combination with nivolumab, although many patients require dose reductions to 20 mg or even lower due to tolerability issues. Similarly, lenvatinib is often started at 20 mg with pembrolizumab but may need to be de-escalated to 14 mg, 10 mg, or even 8 mg to manage AEs.
Lenvatinib Plus Everolimus: An Alternative for Immunotherapy-Ineligible Patients
While IO/TKI combinations are now preferred first-line treatments for nccRCC, lenvatinib plus everolimus remains an alternative option, particularly for patients who are not eligible for immunotherapy due to contraindications such as autoimmune disease. A smaller study evaluating this combination as a first-line treatment for nccRCC showed that 70% of patients with papillary histology had stable disease, although the results were not as impressive as those seen with IO/TKI combinations.
Evolving Treatment Landscape
The treatment landscape for nccRCC is rapidly evolving, with IO/TKI combinations emerging as effective first-line options. Ongoing research is focused on further refining treatment strategies and identifying biomarkers that can help predict response to therapy. As Dr. Zakharia noted, "It's reassuring to see that these 2 regimens are not total opposites of each other. You're seeing a 50% ORR with both regimens and quite good numbers of CR rates. This is almost mimicking the data in clear cell RCC."
