Lenvatinib/Pembrolizumab Combo Shows Promising Antitumor Activity in mRCC


Pembrolizumab plus lenvatinib demonstrated antitumor activity and a manageable safety profile in patients with metastatic renal cell carcinoma who have previously received immune checkpoint inhibitor therapy.

Pembrolizumab (Keytruda) plus lenvatinib (Lenvima) demonstrated antitumor activity and a manageable safety profile in patients with metastatic renal cell carcinoma (mRCC) who have previously received immune checkpoint inhibitor (ICI) therapy, according to data published in The Lancet Oncology.

The study 111/KEYNOTE-146 trial (NCT02501096), an open-label, single-group, multicenter, phase 1b/2, had 3 groups of patients: a treatment-naïve group receiving this combination as first-line treatment; those previously treated with 1 or more lines of therapy, but not an anti-PD-1 or anti-PD-L1 ICI; and patients previously treated with at least 1 anti-PD-1 or anti-PD-L1 ICI. Objective response rate (ORR) at 24 weeks using immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) was the primary end point. Patients received pembrolizumab at 200 mg intravenously every 3 weeks and lenvatinib at a starting dose of 20 mg until disease progression, unacceptable toxicity, or withdrawal from the trial.

“The ORR at week 24 by investigator assessment per irRECIST was high in all 3 groups of patients,” the investigators wrote in their discussion. “ORRs were generally similar regardless of response criteria, whereas progression-free survival [PFS] and duration of response varied (potentially due to unconfirmed progression). Lenvatinib plus pembrolizumab resulted in promising overall objective response rates irrespective of previous treatment regimens.”

In the treatment-naïve population, 16 of the 22 patients (72.7%) had an objective response at week 24; 7 patients (41.2%) of the 17 patients who were previously treated and ICI naïve achieved 24-week objective response; and of the 104 ICI-pretreated patients, 58 had an objective response at 24 weeks.

Overall, 17 treatment-naïve patients had objective responses; all 17 were partial responses (PRs), 5 had stable disease (SD), and none had progressive disease (PD). Nine ICI-naïve patients had an objective response overall, 9 PRs, 7 with SD, and 1 with PD. There were 65 ICI-pretreated patients with objective response, all of which were PRs, 31 had SD, and 4 had PD; another 4 patients in this group were not evaluable for response. None of the patients on the trial achieved complete response.

There was a median duration of response of 24.2, 9.0, and 12.5 months for treatment-naïve, pretreated ICI-naïve, and ICI-pretreated patients, respectively. Disease control was observed in 100%, 94.1%, and 92.3% of patients. Twenty patients (90.9%), 13 patients (76.5%), and 81 patients (77.9%) had clinical benefit among the 3 groups. The median times to response were 1.4, 2.8, and 2.7 months, respectively.

In the ICI-pretreated population, 101 out of 104 had baseline and post-baseline target lesion assessments. Regardless of previous treatment, there was a decrease in tumor size for most patients. In each group, at least a quarter of patients had a maximum 50% decrease of their tumor size by investigator assessment. Three ICI-pretreated patients, 1 treatment naïve, and 1 ICI naïve had 100% reduction in their target lesions.

There was an 18.9-month median follow-up for investigator-assessed progression-free survival (PFS) by irRECIST. In the 3 groups, 68% treatment-naïve, 71% ICI-naïve, and 57% ICI-pretreated patients experienced disease progression or death. The median PFS was 24.1, 11.8, and 12.2 months, respectively.

The median overall survival was not reached (NR) for those who were treatment naïve (95% CI, 28.6–NR; median follow up 29.5 months), 30.3 months for patients previously treated and ICI naïve (95% CI, 28.7–NR; median follow-up 50.8 months), and NR for patients pretreated with an ICI (95% CI, NR–NR; median follow-up 16.6 months).

Treatment-related adverse events (TRAEs) were observed in 99% of all patients on the trial (n = 145), with grade 3 TRAEs in 57%, and grade 4 TRAEs in 7%. Fatigue, diarrhea, and hypertension were the most common any-grade TRAEs, and hypertension was the most common grade 3 TRAE in 21% of all patients.

Serious TRAEs occurred in 25% of patients, and there were 3 treatment-related deaths. These grade 5 TRAEs included 1 treatment-naïve patient with pneumonia and 2 ICI-pretreated patients, 1 with upper gastrointestinal hemorrhage, and 1 with sudden death that was not otherwise specified.

Overall, 28 of the 145 patients (19%) discontinued pembrolizumab, lenvatinib, or both due to TRAEs. Thirteen percent discontinued lenvatinib only, 14% discontinued pembrolizumab only, and 7% discontinued both. TRAEs required 110 patients to have dose interruptions and 94 patients to have dose reductions. Fatigue and diarrhea were the most common TRAEs leading to dose reductions of lenvatinib.

Immune-mediated AEs occurred in 54% of patients, with the most common being hypothyroidism. Twelve patients who experienced immune-mediated AEs had previously received high-dose systemic steroids of 40 mg or more of prednisone or the equivalent.

“To address this need, this study evaluated a large group of patients who had progressed on or after treatment with ICI-based regimens. The anti-tumor activity results of lenvatinib plus pembrolizumab in ICI-pretreated patients were encouraging,” the investigators wrote. “…However, there is a need to further explore the role of maintaining ICI-combination treatment as second-line treatment for mRCC.”


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:S1470-2045(21)00241-2. doi:10.1016/S1470-2045(21)00241-2

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