KEYTRUDA? (pembrolizumab) Plus LENVIMA? (lenvatinib) Demonstrated Superior Progression-Free Survival (PFS) and Overall Survival (OS) Versus Sunitinib as First-Line Treatment for Patients With
KENILWORTH, N.J. & WOODCLIFF LAKE, N.J.--(BUSINESS WIRE)-- Merck (NYSE: MRK), known as MSD outside the United States and Canada, and Eisai today announced the first presentation of new investigational data from the pivotal Phase 3 CLEAR study (KEYNOTE-581/Study 307) in an oral presentation session (Abstract #269) at the virtual 2021 Genitourinary Cancers Symposium (ASCO GU) and simultaneously published in the?New England Journal of Medicine. The trial evaluated the combinations of KEYTRUDA, Merck?s anti-PD-1 therapy, plus LENVIMA, the orally available multiple receptor tyrosine kinase inhibitor discovered by Eisai, and LENVIMA plus everolimus versus sunitinib for the first-line treatment of patients with advanced renal cell carcinoma (RCC). KEYTRUDA plus LENVIMA demonstrated statistically significant and clinically meaningful improvements in progression-free survival (PFS; HR=0.39 [95% CI: 0.32-0.49]; p<0.001), overall survival (OS; HR=0.66 [95% CI: 0.49-0.88]; p=0.005) and objective response rate (ORR; relative risk=1.97 [95% CI: 1.69-2.29]; p<0.001) versus sunitinib. LENVIMA plus everolimus also showed statistically significant improvements in PFS (HR=0.65 [95% CI: 0.53-0.80]; p<0.001) and ORR (relative risk=1.48 [95% CI: 1.26-1.74]; p<0.001) versus sunitinib. In an exploratory analysis, results for PFS and OS were consistent across prespecified Memorial Sloan Kettering Cancer Center (MSKCC) risk groups (favorable, intermediate and poor). Full MSKCC risk group data can be found in the?New England Journal of Medicine?article entitled ?Lenvatinib Plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma,? published today. The safety profiles of both KEYTRUDA plus LENVIMA and LENVIMA plus everolimus were consistent with previously reported studies.
?Continued efforts to improve outcomes in patients with advanced renal cell carcinoma are critical, considering that the number of people diagnosed with the disease has more than doubled over the last 50 years, and almost one-third of these patients are diagnosed at an advanced stage,? said Dr. Robert Motzer, Medical Oncologist, Kidney Cancer Section Head, Genitourinary Oncology Service, Memorial Sloan Kettering Cancer Center. ?KEYTRUDA plus LENVIMA demonstrated a median progression-free survival of nearly two years, and seven in 10 patients experienced an objective response. This combination also significantly improved overall survival compared with sunitinib, with a 34% reduction in risk of death. These results suggest that this combination has the potential to impact clinical practice for this type of devastating cancer.?
In the trial?s primary endpoint of PFS, as assessed by independent review per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, KEYTRUDA plus LENVIMA reduced the risk of disease progression or death by 61% (HR=0.39 [95% CI: 0.32-0.49]; p<0.001), with a median PFS of 23.9 months (95% CI: 20.8-27.7) versus 9.2 months (95% CI: 6.0-11.0) for patients who received sunitinib. In the trial?s key secondary endpoints, KEYTRUDA plus LENVIMA reduced the risk of death by 34% (HR=0.66 [95% CI: 0.49-0.88]; p=0.005) versus patients who received sunitinib. Median OS was not reached in either treatment arm after a median follow-up of 27 months. Treatment with KEYTRUDA plus LENVIMA resulted in an ORR of 71.0% (95% CI: 66.3-75.7), with a complete response (CR) rate of 16.1% and a partial response (PR) rate of 54.9%, versus an ORR of 36.1% (95% CI: 31.2-41.1), with a CR rate of 4.2% and a PR rate of 31.9%, for patients who received sunitinib (relative risk=1.97 [95% CI: 1.69-2.29]; p<0.001). Median duration of response (DOR) for patients who received KEYTRUDA plus LENVIMA was 25.8 months (95% CI: 22.1-27.9) versus 14.6 months (95% CI: 9.4-16.7) for patients who received sunitinib.
?These promising results are a testament to our company?s commitment to help improve outcomes for patients diagnosed with cancer,? said Dr. Gregory Lubiniecki, Vice President, Oncology Clinical Research, Merck Research Laboratories. ?In this trial, KEYTRUDA plus LENVIMA demonstrated superior efficacy benefits compared with sunitinib. If approved, we believe this combination has the potential to be an important new treatment option for patients with advanced renal cell carcinoma in the first-line setting.?
In the trial?s second experimental treatment arm, LENVIMA plus everolimus reduced the risk of disease progression or death by 35% (HR=0.65 [95% CI: 0.53-0.80]; p<0.001), with a median PFS of 14.7 months (95% CI: 11.1-16.7) versus 9.2 months (95% CI: 6.0-11.0) for patients who received sunitinib. LENVIMA plus everolimus did not demonstrate an improvement in OS compared with sunitinib (HR=1.15 [95% CI: 0.88-1.50]; p=0.3). Median OS was not reached in either treatment arm after a median follow-up of 27 months. The ORR was 53.5% (95% CI: 48.3-58.7), with a CR rate of 9.8% and a PR rate of 43.7%, for patients who received LENVIMA plus everolimus versus 36.1% (95% CI: 31.2-41.1), with a CR rate of 4.2% and a PR rate of 31.9%, for patients who received sunitinib (relative risk=1.48 [95% CI: 1.26-1.74]; p<0.001). Median DOR for patients who received LENVIMA plus everolimus was 16.6 months (95% CI: 14.6-20.6) versus 14.6 months (95% CI: 9.4-16.7) for patients who received sunitinib.
?These investigational data from the CLEAR study (KEYNOTE-581/Study 307) represent a significant milestone in our clinical research efforts in advanced renal cell carcinoma, with encouraging Phase 3 results in this population for the KEYTRUDA plus LENVIMA combination and with more than 700 patients having received LENVIMA plus everolimus in the clinical trial setting,? said Dr. Takashi Owa, Vice President, Chief Medicine Creation and Chief Discovery Officer, Oncology Business Group at Eisai. ?Our progress thus far also reflects the significant contributions of dedicated patients, healthcare staff and researchers who continued to support this study during the global pandemic, to whom we extend our deepest gratitude.?
In the KEYTRUDA plus LENVIMA arm, treatment-related adverse events (TRAEs) led to discontinuation of KEYTRUDA in 25.0% of patients, of LENVIMA in 18.5% of patients, and of both in 9.7% of patients. In the LENVIMA plus everolimus arm, TRAEs led to discontinuation of LENVIMA in 16.1% of patients, of everolimus in 19.2% of patients, and of both in 13.5% of patients. In the sunitinib arm, TRAEs led to discontinuation of sunitinib 10.0% of patients. Grade 5 TRAEs occurred in 1.1% of patients in the KEYTRUDA plus LENVIMA arm, in 0.8% of patients in the LENVIMA plus everolimus arm, and in 0.3% of patients in the sunitinib arm. Grade =3 TRAEs occurred in 71.6% of patients in the KEYTRUDA plus LENVIMA arm, in 73.0% of patients in the LENVIMA plus everolimus arm, and in 58.8% of patients in the sunitinib arm. The most common TRAEs of any grade occurring in at least 20% of patients in the KEYTRUDA plus LENVIMA arm were diarrhea (54.5%), hypertension (52.3%), hypothyroidism (42.6%), decreased appetite (34.9%), fatigue (32.1%) and stomatitis (32.1%). In the LENVIMA plus everolimus arm, the most common TRAEs of any grade occurring in at least 20% of patients were diarrhea (59.7%), stomatitis (45.6%), hypertension (43.1%), fatigue (36.6%), decreased appetite (34.9%) and proteinuria (31.8%). In the sunitinib arm, the most common TRAEs of any grade occurring in at least 20% of patients were diarrhea (44.4%), hypertension (39.1%), stomatitis (37.4%), hand-foot syndrome (35.9%), fatigue (32.1%) and nausea (27.6%).
CLEAR Study (KEYNOTE-581/Study 307) Trial Design (Abstract #269)
The CLEAR study (KEYNOTE-581/Study 307) is a Phase 3, multicenter, randomized, open-label 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 primary endpoint is PFS by independent review per RECIST v1.1. Key secondary endpoints include OS, ORR and safety. A total of 1,069 patients were randomized to one of three treatment arms to receive:
- LENVIMA (20 mg orally once daily) in combination with KEYTRUDA (200 mg intravenously every three weeks); or
- LENVIMA (18 mg orally once daily) in combination with everolimus (5 mg orally once daily); or
- Sunitinib (50 mg orally once daily for four weeks on treatment, followed by two weeks off treatment).
- solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options, or
- colorectal cancer that has progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan.