Episode 5: The KEYNOTE-B61 study

Professors Vulsteke from Maria Middelares Gent and Emmanuel Seront from UCL Louvain will be discussing the findings of the KEYNOTE-B61 study in non-clear cell renal carcinoma, presented at ASCO.

The regimen which combines lenvatinib with pembrolizumab, has become well-established in medical oncology as a treatment for endometrial cancer. This combination also demonstrated efficacy in clear cell renal cancer, leading to its recent reimbursement in that context due to a robust response rate of 71%. Treatments proven effective in clear cell cancer are subsequently evaluated in non-clear cell cancers. However, they typically demonstrate modest response rates, usually falling within the range of 10-30% compared to sunitinib. In most trials, cohort comprises a mix of tumour types including papillary, chromophobe, unclassified, translocation and other histologies, contributing to confusion and an overall response rate lower than that seen in clear cell cases.

In the KEYNOTE-B61 all patients with their various histologies received oral 20 mg of lenvatinib, a dose comparable to that used in clear cell cases, alongside pembrolizumab every three weeks. ORR across all tumour types hovered around 40-50%. Exclusion of chromophobe RCC cases increased the response rate to 49%, confirming the regimen is less effective in this subtype. Conversely, in sarcomatoids, the response rate exceeded 50%. Median PFS stood at 18 months, an improvement over the historical control arm’s PFS of less than a year. In conclusion, this regimen may be considered for non-clear cell renal cancer treatment based on these phase 2 single-arm trial data.

Experts deliberated on whether lenvatinib pembrolizumab should be the standard of care for non-clear cell cancer patients in daily practice. They acknowledged its efficacy but noted the regimen’s significant side effects, particularly those associated with lenvatinib. Considering the diverse histological variants, they stressed the importance of a central pathological review to ensure accurate diagnosis and treatment decisions.

With a response rate of 30% in chromophobe cases, experts advocate for using the combination in such patients given the limited alternatives. Future randomized phase 3 trials must determine the optimal control arm. Suggestions include incorporating the new approach as the control arm or potentially adding a third agent like belzutifan to non-clear cell treatment.