Lenvatinib in combination with everolimus improved progression-free survival in patients with advanced renal cell carcinoma compared with sunitinib, meeting the primary end point of the phase 3 KEYNOTE-581/CLEAR clinical trial. Pembrolizumab added to lenvatinib, another experimental arm of the trial, also achieved a satisfactory overall response rate, meeting a key secondary end point.
Lenvatinib (Lenvima) in combination with everolimus (Afinitor) improved progression-free survival in patients with advanced renal cell carcinoma (RCC) compared with sunitinib (Sutent), meeting the primary end point of the phase 3 KEYNOTE-581/CLEAR clinical trial (Study 307, NCT02811861). Pembrolizumab added to lenvatinib, another experimental arm of the trial, also achieved a satisfactory overall response rate (ORR), meeting a key secondary end point.
It was announced by Merck and Eisai in a press release that these combinations also achieved the overall survival (OS) secondary end point. Taken together, these achievements represent a significant and clinical meaningful improvement in outcomes with lenvatinib/everolimus versus with sunitinib as well as lenvatinib plus pembrolizumab versus sunitinib in the intention-to-treat population of the study. Full results from the study will be presented at an upcoming medical meeting.
“The results from KEYNOTE-581/CLEAR (Study 307) support the potential use of Keytruda plus Lenvima for the first-line treatment of advanced RCC. These data also support the potential first-line use of Lenvima plus everolimus, which is already approved in advanced RCC following prior antiangiogenic therapy,” said Takashi Owa, PhD, vice president, chief Medicine Creation and chief discovery officer, Oncology Business Group at Eisai, in a statement. “These findings energize our efforts as we continue to advance our understanding and address the unmet needs of patients with difficult-to-treat cancers.”
Regarding lenvatinib plus pembrolizumab, Gregory Lubiniecki, MD, associate vice president, Oncology Clinical Research, Merck Research Laboratories, stated; “The results for Keytruda plus Lenvima versus sunitinib, which showed a statistically significant improvement in progression-free survival, overall survival and objective response rate, build on the growing scientific evidence that supports the investigation of Keytruda-based combinations for the first-line treatment of advanced renal cell carcinoma.”
In addition to demonstrating efficacy as treatment of patients with advanced RCC, lenvatinib plus everolimus or pembrolizumab showed safety profiles that were consistent with the profiles observed in previous studies. Specifically, the kinase inhibitor, lenvatinib, has led to hypertension, cardiac dysfunction, arterial thromboembolic events, hepatotoxicity, renal failure or impairment, proteinuria, diarrhea, and other adverse events in previous RCC clinical trials.
In combination with everolimus, the most common adverse events (AEs) observed with lenvatinib in clinical trials included diarrhea (81%), fatigue (73%), arthralgia/myalgia (55%), decreased appetite (53%), vomiting (48%), nausea (45%), stomatitis (44%), hypertension (42%), peripheral edema (42%), cough (37%), abdominal pain (37%), dyspnea (35%), rash (35%), decreased weight (34%), hemorrhagic events (32%), and proteinuria (31%).
The most common AEs observed to the combination of lenvatinib and pembrolizumab in prior studies were fatigue (65%), musculoskeletal pain (65%),hypertension (65%), diarrhea (64%), decreased appetite (52%), hypothyroidism (51%), nausea (48%), stomatitis (43%), vomiting (39%), decreased weight (36%), abdominal pain and headache (33% each), constipation (32%), urinary tract infection (31%), dysphonia (29%), hemorrhagic events (28%), hypomagnesemia (27%), palmar-plantar erythrodysesthesia syndrome (26%), dyspnea (24%), and cough and rash (21% each).
KEYNOTE-581/CLEAR (Study 307) is active with 1050 participants enrolled and is not currently recruiting patients. The patients enrolled had histologically or cytologically confirmed RCC with a clear-cell component, at least 1 measurable lesion per RECIST v1.1, Karnofsky performance status of ≥70, as well as adequate controlled blood pressure and organ function. Patients are being treated with lenvatinib 18 mg once daily plus everolimus 5 mg once daily or lenvatinib 20 mg once daily plus pembrolizumab 200 mg once daily, in the experimental arms. Patients in the comparator arm are receiving sunitinib 50 mg once daily.
The partnership between Merck and Eisai to further development lenvatinib and pembrolizumab is currently underway with 19 clinical trials in 13 different disease states. The tumor types being explored include endometrial carcinoma, hepatocellular carcinoma, melanoma, non–small cell lung cancer, squamous cell carcinoma of the head and neck, urothelial cancer, biliary tract cancer, colorectal cancer, gastric cancer, glioblastoma, ovarian cancer and triple-negative breast cancer, as well as RCC.
Keytruda® (pembrolizumab) Plus Lenvima® (lenvatinib) demonstrated statistically significant improvement in progression-free survival (PFS), overall survival (OS) and objective response rate (ORR) versus sunitinib as first-line treatment for patients…News release. Merck and Eisai. November 10. 2020. Accessed November 10, 2020. https://bit.ly/36g1m1C