Lenvatinib Plus Pembrolizumab Deemed Valid Treatment for Renal Cell Carcinoma


“The results that we’ve seen do suggest that there is some interaction between the two drugs, despite ongoing debate of whether this regimen after progression on a PD-1 inhibitor could be beneficial in clear cell renal cell carcinoma."

During treatment for clear cell renal cell carcinoma (ccRCC), the activity of immune checkpoint inhibitors is often impacted by angiogenesis inhibition caused by vascular endothelial growth factor (VEGF)-mediated immune suppression modulation. Thus, combination therapy is needed to allow patients to derive benefit from immune checkpoint inhibitors, even after they have progressed. A phase Ib/II study of lenvatinib (Lenvima) and pembrolizumab (Keytruda) aimed to provide a solution for treating patients with advanced solid tumors, including a cohort of patients with ccRCC.

Final results from the study were presented at the 2020 Genitourinary Cancers Symposium (GU 2020) and showed a 63% overall response rate (ORR) in the 30 patients with ccRCC (95% CI, 43.9-80.1%).

“The results that we’ve seen do suggest that there is some interaction between the two drugs, despite ongoing debate of whether this regimen after progression on a PD-1 inhibitor could be beneficial in ccRCC,” Chung Han Lee, MD, told Targeted Oncology.

Lenvatinib in combination with pembrolizumab was granted FDA Breakthrough Therapy Designation back in 2018 and further FDA action is anticipated as the results from this study show validity for the combination, according to Lee.

In an interview with Targeted Oncology, Lee, a medical oncologist at Memorial Sloan Kettering Cancer Center, discussed the ccRCC cohort in the study of lenvatinib plus pembrolizumab in advanced solid tumors.

TARGETED ONCOLOGY: What are the current options for patients with ccRCC who progress after a PD-1 or PD-L1 inhibitor?

Lee: Currently, when we talk about people who have progressed on PD-L1 or PD-1 therapy, the options include single agent tyrosine kinase inhibitors (TKIs), or TKIs in combination with an mTOR targeted agent or even single-agent mTOR targeted therapy.

TARGETED ONCOLOGY: What was the rationale for the phase 2 study pf lenvatinib plus pembrolizumab in this patient population?

Lee: In the first-line setting as a proof-of-concept, we have seen outstanding efficacy for combinations of anti-VEGF and immune checkpoint inhibitors. There was extreme interest in understanding whether or not these types of regimens can still be effective after progression on a PD-1 inhibitor. There has been speculation regarding whether or not of the addition of an immune checkpoint inhibitor after progression on prior immune checkpoint inhibitor can still be beneficial.

TARGETED ONCOLOGY: What were the results of the interim analysis? What safety profile was observed with the combination in patients with ccRCC?

Lee: The interim analysis was an analysis of approximately 30 patients with the primary and point being the objective response rate, and as a best response rate, we saw partial responses in 64% of patients at 24 weeks. We were also able to demonstrate a progression-free survival of approximately 11.2 months.

Overall, there were no new safety signals that were identified. The toxicities related to the combination of lenvatinib plus pembrolizumab were in line with what we've seen with other TKI/immunotherapy combinations. The toxicities were generally well-tolerated in patients.

In terms of the type of grade 3 and grade 4 toxicities, we saw incidences of fatigue, hypertension, and proteinuria. We also observed that about 39% of patients had some sort of immune-related toxicity of special interest with the most common toxicity being hypothyroidism.

TARGETED ONCOLOGY: What is the key takeaway from this study?

Lee: The most important thing is to remember about this regimen is that we have to think about it as a regimen as opposed to patients getting 1 TKI and 1 immunotherapy agent separately. The results that we’ve seen suggest that there is some interaction between the 2 drugs, despite the ongoing debate of whether this regimen after progression on a PD-1 inhibitor could be beneficial in ccRCC.

TARGETED ONCOLOGY: What challenges do you anticipate with giving a combination like this into the community setting?

Lee: The main challenge that we're facing first is whether or not the FDA will approve this combination in the first-line setting. With these new data for patients who have progressed on a PD-1 inhibitor, I believe this will be considered a valid combination. This represents the first prospective data that we have looking at the combination of a TKI and an immunotherapy agent.

TARGETED ONCOLOGY: What are the next steps with this research?

Lee: We are looking at completing the cohort. The trial is fully accrued at this point, and we are looking forward to final readouts for the broader cohort.

TARGETED ONCOLOGY: Looking at the kidney cancer space more broadly, what exciting data is being discussed among oncologists right now?

Lee: This is certainly an exciting time. Oncologists are most excited to see the extensive biomarker data that has come out and also further discussion about novel targets that may be relevant for kidney cancer.


Taylor MH, Lee CH, Makker V, et al. Phase IB/II Trial of Lenvatinib Plus Pembrolizumab in Patients With Advanced Renal Cell Carcinoma, Endometrial Cancer, and Other Selected Advanced Solid Tumors. J Clin Oncol. 2020; 38 (11); 1154-1163. doi: 10.1200/JCO.19.01598

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