Pembrolizumab plus lenvatinib shows promise metastatic kidney cancer

Combining the PD-1 inhibitor pembrolizumab (Keytruda) with the TKI lenvatinib (Lenvima) showed promising efficacy across treatment lines in patients with metastatic renal cell carcinoma (RCC), according to data from the phase 1b/2 KEYNOTE-146 study published in Lancet Oncology.1

Of particular note, the combination achieved an objective response rate (ORR) of 55.8% at week 24 among patients previously treated with immune checkpoint inhibitors. The ORR was 72.7% among treatment-naïve patients and 41.2% among previously treated immune checkpoint inhibitor–naïve patients.

“This large trial of the TKI lenvatinib in combination with pembrolizumab demonstrated encouraging antitumor activity with a manageable safety profile, irrespective of previous therapies,” the study’s investigators wrote. “Lenvatinib plus pembrolizumab might, therefore, be a future potential standard-of-care treatment for patients with metastatic clear cell RCC after disease progression with [immune checkpoint therapy].”

The study’s patient population included 145 patients in the RCC cohort enrolled between July 21, 2015, and October 16, 2019. Investigators focused on the patients with clear cell histology and included 22 patients in the treatment-naïve group, 17 patients in the previously treated immune checkpoint inhibitor–naïve group, and 104 patients in the immune checkpoint inhibitor–pretreated group.

Patients aged 18 years or older with select solid tumors and an ECOG performance status of 0 or 1 were enrolled in the study. The patient population was treated with lenvatinib 20 mg orally once daily with pembrolizumab 200 mg intravenously once every 3 weeks.

Patients who were pretreated with an immune checkpoint inhibitor had received 2 or more doses of an immune checkpoint inhibitor and progressed on or after treatment. Among this group, 92% of patients reported that an immune checkpoint inhibitor was their most recent therapy. The median duration of treatment for patients who were previously treated with an immune checkpoint inhibitor therapy was 6.8 months, and 1.6 months for the median time from the end of the most recent immune checkpoint inhibitor regimen to the first dose of the experimental combination.

The overall objective response rate at the data cutoff point of August 18, 2020, was 77.3% among treatment-naïve patients, 52.9% among previously treated immune checkpoint inhibitor–naïve patients, and 62.5% among immune checkpoint inhibitor–pretreated patients.

After a median follow up of 18.9 months, the median progression-free survival assessed by investigators was 24.1 months for treatment-naive patients, 11.8 months for previously treated immune checkpoint inhibitor–naïve patients, and 12.2 months for immune checkpoint inhibitor–pretreated patients. At the data cutoff, 68%, 71%, and 57% of patients in each respective group had disease progression or died.

With a median follow-up of 29.5 months, the median overall survival (OS) among the treatment-naïve patient population was not reached (NR; 95% CI, 28.6-NR). Additionally, the median OS was 30.3 months (95% CI, 28.7-NR) with a median follow-up of 50.8 months for previously treated immune checkpoint inhibitor–naïve patients and was NR (95% CI, NR-NR) at a median follow-up of 16.6 months for pretreated patients.

In terms of safety, all but 1 of the 145 patients analyzed experienced at least 1 treatment-related adverse effect (TRAE). Of those events, 57% of patients experienced a grade 3 TRAE and 7% of patients experienced a grade 4 TRAE. Common TRAEs included fatigue, diarrhea, and hypertension, with hypertension (21%) being the most common grade 3 TRAE. Serious TRAEs were observed in 25% of patients, and 3 treatment-related deaths were reported.

“The results from this study provide evidence of preliminary efficacy and safety of lenvatinib plus pembrolizumab in patients with metastatic clear cell renal cell carcinoma, irrespective of previous therapies,” the investigators concluded. “This combination is being further investigated in phase 3 trials involving patients with various tumor types, including a study in advanced or metastatic renal cell carcinoma.”

The study’s limitations included its non-randomized design and heterogenous patient population. Efficacy-related conclusions were limited due to the small sample size of treatment-naïve and previously treated ICI-naïve patients.


1. Lee CH, Shah AY, Rasco D, et al. Lenvatinib plus pembrolizumab in patients with either treatment-naive or previously treated metastatic renal cell carcinoma (Study 111/KEYNOTE-146): a phase 1b/2 study. Lancet Oncol. 2021;22(7):946-958. doi:10.1016/S1470-2045(21)00241-2

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