Eric Jonasch, MD

Recent updates to the National Comprehensive Cancer Network’s (NCCN) guidelines for renal cell carcinoma (RCC) reflect quick integration of new agents and combination regimens to provide patients with RCC with more treatment options and the most up-to-date options.¹

Incorporated into the latest guidelines update, released March 23, 2021, are the use of lenvatinib (Lenvima) and pembrolizumab (Keytruda) as frontline systemic therapy for patients with clear cell RCC, both for favorable and poor-/intermediate-risk disease. The combination received a preferred, category 1 recommendation from the NCCN. Phase 3 clinical trial results supporting the regimen were recently presented at the 2021 Genitourinary Cancers Symposium in February.²

The NCCN quickly took into account the levels of evidence with these treatments to provide recommendations for oncologists treating patients with RCC.

“This is just a way of allowing physicians to understand where, based on these expert recommendations, these particular treatments lie in the treatment armamentarium…and [lenvatinib/pembrolizumab] is one of the preferred regimens because the strength of the evidence is such that we would want to see this being prioritized,” said vice chair of the NCCN Guidelines Panel for Kidney Cancer, Eric Jonasch, MD, in an interview with Targeted Oncology.

The preferred status for lenvatinib and pembrolizumab was supported by findings from the multicenter, open-label, randomized phase 3 CLEAR trial (NCT02811861), in which the combinations of lenvatinib and pembrolizumab as well as lenvatinib and everolimus (Afinitor) were compared with sunitinib (Sutent) monotherapy in the frontline treatment of patients with advanced clear cell RCC.

Notably, the lenvatinib and everolimus combination is also included in the NCCN guidelines with a category 1 recommendation as a subsequent therapy option.¹

A total of 1069 patients were randomized equally between the 3 arms to receive oral lenvatinib 20 mg once daily plus intravenous pembrolizumab 200 mg every 3 weeks (n = 355), lenvatinib 18 mg once daily plus oral everolimus 5 mg once daily (n = 357), or oral sunitinib 50 mg once daily for 4 weeks on and 2 weeks off (n = 357).^2,3

The primary end point was progression-free survival (PFS) by independent review committee per RECIST 1.1 criteria, and secondary end points included overall survival (OS), objective response rate (ORR), safety, and health-related quality of life.

PFS for the lenvatinib/pembrolizumab combination was 23.9 months (95% CI, 20.8-27.7) in comparison with 9.2 months (95% CI, 6-11) with sunitinib monotherapy (HR, 0.39; 95% CI, 0.32-0.49; P < .001). Comparatively, the median PFS for lenvatinib and everolimus was 14.7 months (95% CI, 11.1-16.7).

The median OS was not reached in any of the arms but indicated a trend in favor of lenvatinib/pembrolizumab over sunitinib (HR, 0.66; 95% CI, 0.49-0.88; P = .005).

ORR was also significantly higher in the lenvatinib/pembrolizumab arm at 71% (95% CI, 66.3%-75.7%) versus 36.1% (95% CI, 31.2%-41.1%) in the sunitinib arm. Complete responses were reported in 16.1% of the lenvatinib/pembrolizumab combination arm versus in 4.2% of the monotherapy arm.

Median duration of response was 25.8 months (95% CI, 22.1-27.9) with lenvatinib/pembrolizumab versus 14.6 months (95% CI, 9.4-16.7) with sunitinib.

In terms of safety, there were more treatment-related adverse events leading to dose reductions or treatment discontinuations in the combinations arms versus the monotherapy arm, but the combinations were still considered to have a manageable toxicity profile.

“These are very, very strong data,” Jonasch, professor in the Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, said. “This is one of the strongest regimens that's been tested so far in this particular setting in advanced kidney cancer. And so the [NCCN] panel felt that these data deserve preferred status.”

_References:

_{1. NCCN Clinical Practice Guidelines in Oncology. Kidney Cancer. March 23, 2021. Accessed April 14, 2021. https://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf}

_{2. Motzer RJ, Porta C, Eto M, et al. Phase 3 trial of lenvatinib (LEN) plus pembrolizumab (PEMBRO) or everolimus (EVE) versus sunitinib (SUN) monotherapy as a first-line treatment for patients (pts) with advanced renal cell carcinoma (RCC) (CLEAR study). J Clin Oncol. 2021; 39(suppl6):269. doi: 10.1200/JCO.2021.39.6_suppl.269.}

_{3. Motzer RJ, Alekseev B, Rha SY, et al; CLEAR Trial Investigators. Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma. N Engl J Med. 2021;384:1289-1300. doi:10.1056/NEJMoa2035716}