TOKYO: Eisai Co., Ltd. and Merck & Co., Inc., Kenilworth, N.J., U.S.A. (known as MSD outside the United States and Canada) announced new investigational data from two trials under the LEAP (LEnvatinib And Pembrolizumab) clinical program evaluating LENVIMA, the orally available multiple receptor tyrosine kinase inhibitor discovered by Eisai, plus KEYTRUDA, Merck’s anti-PD-1 therapy. In the Phase 2 LEAP-004 trial, the LENVIMA plus KEYTRUDA showed an objective response rate (ORR) of 21.4% (95% confidence interval (CI): 13.9-30.5) in patients with unresectable or advanced melanoma who had previously progressed on an anti-PD-1/PD-L1 therapy. In the Phase 2 LEAP-005 trial, LENVIMA plus KEYTRUDA demonstrated an ORR that ranged from 9.7-32.3% (95% CI: 2.0- 51.4) in previously treated patients with triple-negative breast cancer (TNBC), ovarian cancer, gastric cancer, colorectal cancer (non-microsatellite instability-high [non-MSI-H]/mismatch repair proficient [pMMR]), glioblastoma multiforme (GBM) and biliary tract cancer (BTC). Results from LEAP-004 (Abstract #LBA44) and LEAP-005 (Abstract #LBA41) were accepted as late-breaking abstracts and are being presented in proffered paper presentations at the European Society for Medical Oncology (ESMO) Virtual Congress 2020.
“These new data from our LEAP clinical program show encouraging activity across several aggressive cancer types and expand our knowledge about the potential of KEYTRUDA plus LENVIMA to help a range of patients with these cancers,” said Dr. Scot Ebbinghaus, Vice President, Clinical Research, Merck Research Laboratories. “This is the first time that clinical data from two LEAP trials are being presented, reflecting important progress we are making to explore the potential of this combination for patients in need of new options, particularly those with advanced melanoma who have progressed on an anti-PD-1 or PD-L1 therapy.”
“We are encouraged by the growing body of research that we have seen to date, now in 13 different cancers, supporting the potential of the LENVIMA plus KEYTRUDA combination, which we’re currently evaluating in 19 clinical trials,” said Dr. Takashi Owa, Chief Medicine Creation and Chief Discovery Officer, Oncology Business Group at Eisai. “These data not only help advance our understanding of the regimen but also fuel our deep-seated determination to work to address the unmet needs of these patients.”
Lenvatinib (len) plus pembrolizumab (pembro) for advanced melanoma (MEL) that progressed on a PD-1 or PD-L1 inhibitor: initial results of LEAP-004 (Abstract #LBA44) LEAP-004 (ClinicalTrials.gov, NCT03776136) is a Phase 2, single-arm, open-label trial evaluating LENVIMA in combination with KEYTRUDA in patients with unresectable or advanced melanoma who had progressed on an anti-PD-1/PD-L1 therapy within 12 weeks. Patients were treated with LENVIMA 20 mg orally once daily until unacceptable toxicity or disease progression in combination with KEYTRUDA 200 mg intravenously every three weeks for up to 35 cycles (approximately two years). The primary endpoint is ORR per Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 as assessed by blinded independent central review (BICR). Secondary endpoints include progression-free survival (PFS) and
duration of response (DOR) per RECIST v1.1 by BICR, overall survival (OS) and safety.
At data cutoff (June 10, 2020), a total of 103 patients were enrolled and treated. With a median duration of follow-up of 12 months (range: 8.7-15.6), LENVIMA plus KEYTRUDA demonstrated an overall ORR by BICR of 21.4% (n=22) (95% CI: 13.9-30.5), with a complete response rate of 1.9% (n=2) and a partial response rate of 19.4% (n=20). In the total study population, the median DOR was 6.3 months (range: 2.1+ to 11.1+), with 72.6% (95% CI: 46.2-87.6) of responses lasting for at least six months. Median PFS was 4.2 months (95% CI: 3.5-6.3), with 73.8% of patients experiencing disease progression or death, and the nine- month PFS rate was 26.2% (95% CI: 17.4-35.9). Median OS was 13.9 months (95% CI: 10.8- not reached [NR]), with death occurring in 44.7% of patients, and the nine-month OS rate was
65.4% (95% CI: 55.2-73.8).
The exploratory analysis showed that specifically, in the 29 patients whose disease progressed after an anti-PD-1/L1 therapy plus an anti-CTLA-4 therapy, the ORR by BICR was 31% (95% CI: 15.3-50.8), with a complete response rate of 3.4% (n=1) and a partial response rate of 27.6% (n=8). Disease control rate (DCR) by BICR in these patients was 62.1% (95% CI: 42.3-79.3). In the total study population, the DCR by BICR was 65% (95% CI: 55.0-74.2).
Treatment-related adverse events (TRAEs) led to discontinuation of LENVIMA and/or KEYTRUDA in 7.8% of patients. Grade 3-5 TRAEs occurred in 44.7% of patients (Grade 3: 39.8%; Grade 4: 3.9%; Grade 5: 1.0%), and serious TRAEs occurred in 18.4% of patients. The most common TRAEs of any grade occurring in at least 30% of the overall study population, were hypertension (56.3%), diarrhea (35.9%) nausea (34.0%), hypothyroidism (33.0%) and decreased appetite (31.1%).
LEAP-005: Phase 2 Study of Lenvatinib Plus Pembrolizumab in Patients (Pts) With Previously Treated Advanced Solid Tumors (Abstract #LBA41)
LEAP-005 (ClinicalTrials.gov, NCT03797326) is a Phase 2, single-arm, open-label trial evaluating LENVIMA in combination with KEYTRUDA in patients with select previously treated advanced solid tumors. The study cohorts are TNBC, ovarian cancer, gastric cancer, colorectal cancer (non-MSI-H/pMMR), GBM and BTC. Patients have treated with LENVIMA 20 mg orally once daily until unacceptable toxicity or disease progression in combination with KEYTRUDA 200 mg intravenously every three weeks for up to 35 cycles (approximately two years). The primary endpoints are ORR per RECIST v1.1 as assessed by BICR or Response Assessment in Neuro-Oncology (RANO) criteria (for GBM only) as assessed by BICR, and safety. Secondary endpoints include DCR per RECIST v1.1 by BICR or RANO (for GBM only) by BICR, DOR per RECIST v1.1 by BICR or RANO (for GBM only) by BICR, PFS per RECIST v1.1 by BICR or RANO (for GBM only) by BICR, and OS.
The most common TRAEs of any grade occurring in at least 20% of the overall study population were hypertension (39.0%), fatigue (29.4%), diarrhea (26.7%), decreased appetite (25.1%), hypothyroidism (27.8%) and nausea (21.9%). Based on these initial results, the trial will expand to enroll approximately 100 patients in each cohort.