The National Comprehensive Cancer Network (NCCN) has recommended the combination use of lenvatinib (Lenvima) plus pembrolizumab (Keytruda) for the frontline treatment of renal cell carcinoma (RCC).1
This recommendation is key for urologists to be aware of, in particular, because of the role of themultidisciplinary approach to cancer care. “The urologist should be aware of these data in particular because of the question of whether cytoreductive nephrectomy is appropriate or not,” Eric Jonasch, MD, professor in the Department of Genitourinary Medical Oncology in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston, Texas, and vice-chair of the NCCN Guidelines Panel for Kidney Cancer, said in an interview with Urology Times.
“Even with less powerful regimens, the role of cytoreductive nephrectomy has decreased , so that for individuals who have intermediate and poor risk disease, in particular, systemic therapy should be the frontline choice for most patients.”
The panel comprised by the organization based its category 1 recommendation on findings from the phase 3 CLEAR trial (NCT02811861), designed to evaluate the combination of lenvatinib with either pembrolizumab or everolimus (Afinitor), compared with sunitinib (Sutent) for the treatment of patients with advanced RCC receiving therapy in the frontline setting.2
Patients were randomized in a 1:1:1 fashion to receive either 20 mg oral lenvatinib once daily plus 200 mg IV pembrolizumab once every 3 weeks (n = 355); 18 mg oral lenvatinib once daily plus 5 mg oral everolimus once daily (n = 357); or 50 mg oral sunitinib once daily for 4 weeks on and 2 weeks off (n = 357).
Progression-free survival (PFS) by Independent Review Committee (IRC) per RECIST v1.1 was the primary end point. Secondary end points included overall survival (OS), objective response rate (ORR) by IRC per RECIST v1.1, safety and health-related quality of life (HRQoL).
The median PFS with lenvatinib and pembrolizumab was 23.9 months (95% CI, 20.8-27.7) compared to 9.2 months (95% CI, 6-11) with single-agent sunitinib (HR, 0.39; 95% CI, 0.32-0.49; P <.001). The lenvatinib plus everolimus treatment arm achieved a median PFS of 14.7 months (95% CI, 11.1-16.7) compared to the 9.2 months in the sunitinib arm (HR, 0.65; 95% CI, 0.53-0.8; P <.001).
A median OS was not reached in any of the three treatment arms; however, the data indicated the end point was significantly longer in the lenvatinib and pembrolizumab arm compared to the sunitinib arm (HR, 0.66; 95% CI, 0.49-0.88; P = .005).
ORR was higher in both the lenvatinib plus pembrolizumab (71%; 95% CI, 66.3-75.7) and lenvatinib plus everolimus (53.5%; 95% CI, 48.3-58.7) treatment arms compared to sunitinib (36.1%; 95% CI, 31.2-41.1). In particular, Jonasch noted that the 16% CR rate with lenvatinib plus pembrolizumab was impressive.
Lastly, patients in the lenvatinib plus pembrolizumab arm achieved the longest median DOR at 25.8 months (95% CI, 22.1-27.9), compared to 16.6 months (95% CI, 14.6-20.6) in the lenvatinib plus everolimus arm and 14.6 months (95% CI, 9.4-16.7) in the sunitinib arm.
“This trial basically showed various, very strong results in all of these domains. … All of these factors, together, show that this is one of the strongest regimens that's been tested so far in advanced kidney cancer,” Jonasch explained. “And so the NCCN panel felt that these data deserve preferred status.”
Although systemic therapy is recommended, Jonasch continued that there could still be the integration of therapy – highlighting the need for a multidisciplinary approach. “[With this recommendation], the integration of surgery and systemic therapy becomes even more important,” he said. “The timing of one versus the other is also important for the patient’s well-being, especially when you can get such rapid response with systemic therapy. But it doesn't, in any way, diminish the role of the surgeon in the team. The team consists of the medical oncologist, the surgeon, the radiation oncologist and the nursing staff, as it has before.”
Moreover, this recommendation highlights the need for open patient-physician communication. “…the patient or therapy-related details a skilled oncologist evaluates to make these decisions can prioritize those therapies, even within the preferred category. Or there might be some circumstances that will make a preferred regimen not appropriate for a particular patient,” he explained. “So, this is obviously a conversation that needs to occur between the patient and the physician. The physician can then explain what the different regimens are in these various categories, explain why one would be chosen over the other and whether there may be other choices that are not preferred, but that might actually be ideal for that particular patient for various reasons.”
1. National Comprehensive Cancer Network. Kidney Cancer. Version 3.2021. https://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf.
2. Motzer RJ, Alekseev B, Rha S.-Y., et al. Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma. Published online February 13, 2021. N Engl J Med. doi:10.1056/NEJMoa2035716.