Immunotherapy-based combination of pembrolizumab plus lenvatinib as first-line treatment for patients with advanced non-clear cell renal cell carcinoma

• Published in The Lancet Oncology ⁽¹⁾ and co-authored by VHIO’s Cristina Suarez, results from the single-arm phase II KEYNOTE-B61 clinical trial support the use of pembrolizumab plus lenvatinib in patients with previously untreated advanced non-clear cell renal cell carcinoma (nccRCC).
• Directed by Laurence Albiges at the Institut Gustave Roussy, Villejuif (France), this study is the largest clinical trial to date to investigate a combination of immune checkpoint inhibitors in patients with previously untreated nccRCC.

Non-clear cell renal cell carcinoma (nccRCC), accounting for around 25% of all RCC, is a heterogeneous group of kidney cancers, encompassing multiple histologies with different molecular features. Over recent years, there have been several advances in the treatment of advanced nccRCC, but due to the infrequency of these tumors, the improved management of these patients has been limited. Developing more effective treatment strategies for this patient population therefore represents an unmet clinical need.

Combined therapy with pembrolizumab, a PD-1 blocking immunotherapy that triggers T-cells to find and kill cancer cells, with targeted therapy lenvatinib, a multireceptor tyrosine kinase inhibitor, has previously shown improved response rates, progression-free survival, and overall survival compared with sunitinib as first line therapy in patients with ccRCC ⁽²⁾. In nccRCC, first-line pembrolizumab as monotherapy has shown promising antitumor activity in this patient population ⁽³⁾.

“Based on the promising results from these previous studies, the phase II single-arm KEYNOTE-B61 study was designed to evaluate pembrolizumab plus lenvatinib in patients with non-clear cell renal cell carcinoma, first results of which were presented at the 2022 annual ESMO Congress in Paris,” says Cristina Suarez, a KEYNOTE-B61 investigator and co-author of this study.

Led by Laurence Albiges, Institut Gustave Roussy, Villejuif (France), the KEYNOTE-B61 multicenter study, conducted at 48 sites (hospitals and cancer centers) in 14 countries, enrolled 158 patients with previously untreated advanced nccRCC. The primary endpoint was confirmed overall response rate to this novel combinatorial treatment strategy.

Now published in The Lancet Oncology ⁽¹⁾, results show that 78 of the 158 patients included in this study had a confirmed objective response, with an overall response rate of 49%. 75% of patients remained free from disease progression at 12 months. Survival data were also promising with a 12-month progression-free survival of 63% and an overall survival of 82% at 12 months. The investigators also reported a manageable safety profile, with no new safety signals.

“Considering the high heterogeneity of these tumors, our results are encouraging, particularly given the different molecular alterations and their clinical and therapeutical implications. Data support the use of pembrolizumab plus lenvatinib as a first-line treatment option for these patients,” concludes Cristina Suarez.

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References:

1. Laurence Albiges, Howard Gurney, Vagif Atduev, Cristina Suarez, Miguel A Climent, David Pook, Piotr Tomczak, Philippe Barthelemy,Jae Lyun Lee, Viktor Stus, Thomas Ferguson, Pawel Wiechno, Erhan Gokmen, Louis Lacombe, Craig Gedye, Rodolfo F Perini, Manish Sharma, Xiang Peng, Chung-Han Lee. Lancet Oncol. July 11, 2023. DOI: https://doi.org/10.1016/S1470-2045(23)00276-0.
2. Motzer R, Alekseev B, Rha SY, Porta C, Eto M, Powles T, Grünwald V, Hutson TE, Kopyltsov E, Méndez-Vidal MJ, Kozlov V, Alyasova A, Hong SH, Kapoor A, Alonso Gordoa T, Merchan JR, Winquist E, Maroto P, Goh JC, Kim M, Gurney H, Patel V, Peer A, Procopio G, Takagi T, Melichar B, Rolland F, De Giorgi U, Wong S, Bedke J, Schmidinger M, Dutcus CE, Smith AD, Dutta L, Mody K, Perini RF, Xing D, Choueiri TK; CLEAR Trial Investigators. Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma. N Engl J Med. 2021 Apr 8;384(14):1289-1300.
3. McDermott DF, Lee JL, Ziobro M, Suarez C, Langiewicz P, Matveev VB, Wiechno P, Gafanov RA, Tomczak P, Pouliot F, Donskov F, Alekseev BY, Shin SJ, Bjarnason GA, Castellano D, Silverman RK, Perini RF, Schloss C, Atkins MB. Open-Label, Single-Arm, Phase II Study of Pembrolizumab Monotherapy as First-Line Therapy in Patients With Advanced Non-Clear Cell Renal Cell Carcinoma. J Clin Oncol. 2021 Mar 20;39(9):1029-1039.