As reported in The Lancet Oncology by Chung-Han Lee, MD, and colleagues, findings in a cohort of the phase Ib/II Study 111/KEYNOTE-146 trial showed that the combination of lenvatinib and pembrolizumab produced high response rates among patients with metastatic clear cell renal cell carcinoma categorized as treatment-naive, immune checkpoint inhibitor–naive, and pretreated with an immune checkpoint inhibitor.

Chung-Han Lee, MD

Study Details

The study enrolled 143 patients from sites in the United States and Europe between July 2015 and October 2019, including 22 who were treatment-naive; 17 who had received one or more lines of prior treatment, excluding anti–PD-1 and anti–PD-L1 immune checkpoint inhibitors; and 104 who had received prior anti–PD-1 or anti–PD-L1 immune checkpoint inhibitor treatment. Patients received oral lenvatinib at 20 mg once daily and pembrolizumab at 200 mg once every 3 weeks, with treatment continuing until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed objective response rate at week 24 on immune-related Response Evaluation Criteria in Solid Tumors (irRECIST).

Responses

Median follow-up was 19.8 months (interquartile range [IQR] = 14.3–28.4 months).

At week 24, objective responses (all partial) were observed in:

• 16 of 22 treatment-naive patients (72.7%, 95% confidence interval [CI] = 49.8%–89.3%)
• 7 of 17 previously treated but immune checkpoint inhibitor–naive patients (41.2%, 95% CI = 18.4%–67.1%)
• 58 of 104 immune checkpoint inhibitor–pretreated patients (55.8%, 95% CI = 45.7%–65.5%).

At data cutoff (August 2020), an objective response was observed in 17 (77.3%), 9 (52.9%), and 65 (62.5%) patients, respectively. Median response durations were 24.2 months (95% CI = 10.3–37.7 months) in the treatment-naive responders, 9.0 months (95% CI = 3.5 months to not reached) in the previously treated immune checkpoint inhibitor–naive responders, and 12.5 months (95% CI = 9.1–17.5 months) in the immune checkpoint inhibitor–pretreated responders.

Median progression-free survival (per irRECIST) was 24.1 months (95% CI = 11.7–31.7 months) among treatment-naive patients, 11.8 months (95% CI = 5.5–21.9 months) among previously treated immune checkpoint inhibitor–naive patients, and 12.2 months (95% CI = 9.5–17.7 months) among immune checkpoint inhibitor–pretreated patients. Median overall survival was not reached (95% CI = 28.6 months to not reached; median follow-up = 29.5 months) in treatment-naive patients, 30.3 months (95% CI = 28.7 months to not reached; median follow-up = 50.8 months) in previously treated immune checkpoint inhibitor–naive patients, and not reached (95% CI = not reached to not reached; median follow-up = 16.6 months) in immune checkpoint inhibitor–pretreated patients.

Adverse Events

Among 145 treated patients (including 2 with non–clear cell disease excluded from efficacy analysis), grade 3 or 4 (7%) treatment-related adverse events occurred in 63%, with the most common being hypertension (21%, all grade 3), increased lipase (11%, 3% grade 4), proteinuria (9%, all grade 3), and diarrhea (7%, all grade 3). Immune-mediated adverse events of any grade occurred in 54% of patients, with the most common being hypothyroidism (40%, all grade 1–2). Treatment-related serious adverse events occurred in 25% of patients. Treatment-related adverse events led to discontinuation of any component of study treatment in 19% (13%, lenvatinib; 14%, pembrolizumab; 7%, both). Three treatment-related deaths occurred, due to upper gastrointestinal hemorrhage, sudden death, and pneumonia.

The investigators concluded: “Lenvatinib plus pembrolizumab showed encouraging antitumor activity and a manageable safety profile and might be an option for post–immune checkpoint inhibitor treatment of metastatic renal cell carcinoma.”

Dr. Lee, of the Department of Medicine, Memorial Sloan Kettering Cancer Center, is the corresponding author of The Lancet Oncology article.

Disclosure: The study was funded by Eisai and Merck Sharp & Dohme. For full disclosures of the study authors, visit thelancet.com.