After four years of follow-up, KEYTRUDA plus LENVIMA reduced the risk of death by 21% versus sunitinib in the pivotal Phase 3 CLEAR (Study 307)/KEYNOTE-581 trial

Final results will be presented at ASCO 2023 in an oral abstract session

Merck (NYSE: MRK), known as MSD outside of the United States and Canada, and Eisai today announced data from the final pre-specified overall survival (OS) analysis of the pivotal Phase 3 CLEAR (Study 307)/KEYNOTE-581 trial investigating KEYTRUDA, Merck’s anti-PD-1 therapy, plus LENVIMA, the orally available multiple receptor tyrosine kinase inhibitor discovered by Eisai, for the first-line treatment of patients with advanced renal cell carcinoma (RCC). These data will be presented on Monday, June 5 at 12:54 p.m. EDT during an oral abstract session at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting (Abstract #4502). After four years of follow-up, KEYTRUDA plus LENVIMA maintained a clinically meaningful OS benefit versus sunitinib, reducing the risk of death by 21% (HR=0.79 [95% CI, 0.63-0.99]). The 24- and 36-month estimated OS rates were 80.4% and 66.4% for KEYTRUDA plus LENVIMA versus 69.6% and 60.2% for sunitinib, respectively. Results from the final pre-specified OS analysis were consistent with the superior results versus sunitinib from the primary OS analysis of the CLEAR/KEYNOTE-581 trial.

Additionally, KEYTRUDA plus LENVIMA reduced the risk of disease progression or death by 53% (HR=0.47 [95% CI, 0.38-0.57]), with a median progression-free survival (PFS) of 23.9 months (95% CI, 20.8-27.7) versus 9.2 months (95% CI, 6.0-11.0) for sunitinib; the objective response rate (ORR) was 71.3% (95% CI, 66.6-76.0) with a complete response (CR) rate of 18.3% for KEYTRUDA plus LENVIMA versus an ORR of 36.7% (95% CI, 31.7-41.7) with a CR rate of 4.8% for sunitinib.

There were no new safety signals and the safety profile at the final OS analysis was consistent with the primary analysis. Grade ≥3 treatment-related adverse events (TRAE) occurred in 74.1% of patients who received KEYTRUDA plus LENVIMA versus 60.3% of patients who received sunitinib. The six most common TRAEs of any grade of patients in the KEYTRUDA plus LENVIMA arm were diarrhea (56.0%), hypertension (54.3%), hypothyroidism (44.9%), decreased appetite (35.5%), fatigue (34.1%) and stomatitis (32.7%). In the sunitinib arm, the six most common TRAEs of any grade were diarrhea (45.3%), hypertension (40.3%), stomatitis (37.4%), palmar-plantar erythrodysesthesia (36.2%), fatigue (32.9%) and nausea (28.2%).

“KEYTRUDA plus LENVIMA continues to demonstrate durable clinical benefit as a first-line treatment for patients with advanced renal cell carcinoma, as shown by the clinically meaningful improvement in overall survival sustained with four years of follow up,” said Dr. Thomas Hutson, DO, Pharm.D., FACP, Director of the Urologic Oncology Program and Co-chair of the Urologic Cancer Research and Treatment Center, Texas Oncology at Baylor Sammons Cancer Center. “Furthermore, these data also showed clinically meaningful improvements in median PFS and ORR compared to sunitinib. These findings reinforce the important role of KEYTRUDA plus LENVIMA as a first-line standard of care treatment option for patients with advanced renal cell carcinoma.”

“Long-term follow up data from the CLEAR/KEYNOTE-581 trial show the responses to first-line use of KEYTRUDA plus LENVIMA were durable for many of these patients,” said Dr. Gregory Lubiniecki, Vice President, Global Clinical Development, Merck Research Laboratories. “Through our joint clinical development program with Eisai, we’re continuing to advance our research evaluating KEYTRUDA plus LENVIMA for other challenging cancers as we strive to help even more patients.”

“At the final pre-specified analysis, KEYTRUDA plus LENVIMA continued to demonstrate clinically meaningful efficacy across PFS, ORR and OS, providing patients and their physicians with new information about treating people living with advanced renal cell carcinoma,” said Corina Dutcus, M.D., Senior Vice President, Clinical Development, Oncology at Eisai Inc. “These results are a testament to our steadfast commitment to people living with advanced cancers, and we are grateful for the support from the patients, families and healthcare provider community for their participation in this research.”

KEYTRUDA plus LENVIMA is approved in the U.S., the EU, Japan and other countries for the treatment of advanced RCC and certain types of advanced endometrial carcinoma. Lenvatinib is marketed as KISPLYX^® for advanced RCC in the EU. Merck and Eisai are studying the KEYTRUDA plus LENVIMA combination through the LEAP (LEnvatinib And Pembrolizumab) clinical program in various tumor types, including but not limited to endometrial carcinoma, hepatocellular carcinoma, non-small cell lung cancer, RCC, head and neck cancer, gastric cancer and esophageal cancer across multiple clinical trials.

Study design and additional data from CLEAR/KEYNOTE-581

The CLEAR/KEYNOTE-581 trial is a multicenter, randomized, open-label Phase 3 trial (ClinicalTrials.gov, NCT02811861) evaluating LENVIMA in combination with KEYTRUDA or in combination with everolimus versus sunitinib for the first-line treatment of patients with advanced RCC. The major efficacy outcome measures were PFS, as assessed by independent radiologic review (IRC) according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1), and OS. Additional efficacy outcome measures included confirmed ORR as assessed by IRC, health-related quality of life (HRQoL) and safety.

The trial enrolled 1,069 patients who were randomized 1:1:1 to receive KEYTRUDA (200 mg intravenously every three weeks for up to 24 months) plus LENVIMA (20 mg orally once daily), or LENVIMA (18 mg orally once daily) plus everolimus (5 mg orally once daily), or sunitinib (50 mg orally once daily for four weeks on treatment, followed by two weeks off treatment). KEYTRUDA was administered for up to 35 cycles (approximately two years) or until protocol-specified discontinuation criteria were met. After completing two years of combination therapy, LENVIMA may have been administered as a single agent until protocol-specified discontinuation criteria were met.

This final pre-specified OS analysis was event driven and was triggered by approximately 304 OS target events in the two treatment arms (149 events out of 355 patients for KEYTRUDA plus LENVIMA versus 159 events out of 357 patients for sunitinib).

The median duration of response was 26.7 months (95% CI, 22.8-34.6) for KEYTRUDA plus LENVIMA versus 14.7 months (95% CI, 9.4-18.2) for sunitinib.

Efficacy results were consistent across the pre-specified Memorial Sloan Kettering Cancer Center (MSKCC) risk groups (favorable, intermediate and poor) and International Metastatic RCC Database Consortium (IMDC) risk groups. Across the pre-specified Memorial Sloan Kettering Cancer Center (MSKCC) risk groups (favorable, intermediate and poor), OS and PFS were improved with KEYTRUDA plus LENVIMA versus sunitinib. Interpretation OS in favorable risk patients is limited by low number of events.

Fewer patients who were treated with KEYTRUDA plus LENVIMA received subsequent anti-cancer therapies (181 out of 355 patients, 51.0%) versus those who were treated with sunitinib (246 out of 357 patients, 68.9%), with 56 patients (15.8%) and 195 patients (54.6%) who went on to receive PD-1/PD-L1 checkpoint inhibitors, respectively. In an exploratory analysis using a 2-stage model, KEYTRUDA plus LENVIMA reduced the risk of death by 45% versus sunitinib when adjusted for subsequent anticancer medications (HR=0.55 [95% CI, 0.44-0.69]).