Eisai And Merck to Collaborate on Lenvatinib Mesylate

Roger M. Perlmutter, MD, PhD

Lenvatinib mesylate (Lenvima) will be developed and commercialized in a collaboration between its creator, Japan’s Eisai Co. Ltd, and the pharmaceutical giant Merck.

The two companies announced the agreement to work together on the development of the oral tyrosine kinase inhibitor (TKI) as both monotherapy and in combination with Merck’s pembrolizumab (Keytruda), a PD-1 inhibitor in a press release March 7.

“Together with Eisai, we aim to maximize the value of Lenvima for its current indications while jointly pursuing additional approvals in combination with Keytruda across a wide range of cancers,” Roger M. Perlmutter, MD, PhD, president of Merck Research Laboratories, said in a statement. “There is strong scientific evidence supporting synergistic effects of Keytruda when used in combination with Lenvima, and the companies have already received Breakthrough Therapy designation from the US FDA for the Keytruda/Lenvima combination in renal cell carcinoma.”

Under the agreement, Eisai will book product sales globally for the TKI, while Eisai and Merck will share gross profits equally. All expenses, including trials and studies, will be shared equally between the 2 companies.

Per the established contract, Merck will pay Eisai $300 million upfront and up to $650 million for certain option rights through March 2021. Merck is also required to pay $450 million as reimbursement for research and development expenses. Eisai could receive another $385 million in clinical and regulatory milestones, and up to $3.97 billion if it achieves certain sales benchmarks.

The FDA in January granted the combination a Breakthrough Therapy designation for the treatment of patients with advanced and/or metastatic renal cell carcinoma (RCC), based on the ongoing phase Ib/II Study 111/KEYNOTE-146 trial.

Thirteen patients, including 8 with RCC that progressed after treatment with approved therapies and who had an ECOG performance status ≤1, enrolled phase Ib portion of the study. Patients began treatment with 24 mg of daily lenvatinib but the dosage was reduced to 20 mg per day based on toxicity.

This dosage of lenvatinib advanced to the phase 2 portion, which included 22 RCC patients with measurable disease who had undergone up to 2 prior lines of systemic therapy. The combination induced an objective response rate (ORR) of 83% after 24 weeks in treatment-naïve patients. The ORR was 50% in previously treated patients. All responses were partial responses, and an additional 10 patients achieved stable disease. Neither cohort had reached the median duration of response. The median duration of response was 8.5 months in the pretreated cohort.

Patients in phase II who experienced intolerable toxicities to lenvatinib could have their lenvatinib dose interrupted, with successive dose reductions to 14 mg, 10 mg, 8 mg, and 4 mg, if necessary. Dose re-escalation was not allowed. Toxicities related to pembrolizumab were managed with dose interruptions. Pembrolizumab was administered at 200 mg every 3 weeks in both phases.

The combined phase Ib and phase II results (N = 30) had a data cutoff of March 1, 2017. Tumor assessments were performed using irRECIST criteria every 6 weeks until week 24, and then every 9 weeks.

Investigators assessed PD-L1 status in 26 patients. Using a 1% staining cutoff for positivity, 12 patients (40%) were PD-L1-positive.

Twelve patients (40%) were treatment-naïve and therefore treated in the first-line setting. Ten patients (33%) had one prior systemic therapy, 3 (10%) had 2 prior systemic therapies, and 5 (17%) had ≥3. Sixteen (53%) patients had at least 1 prior VEGF-targeted therapy, with the most common agents being sunitinib (n = 9), pazopanib (Votrient; n = 8), and axitinib (Inlyta; n = 6). Five patients were previously treated with an mTOR-targeted agent and 4 patients were previously treated with other agents.

The median duration of therapy was 9.5 months. The mean dosage of lenvatinib received was 15.8 mg/day, with patients receiving 78.3% of the intended starting dose. The mean dosage of pembrolizumab administered was 191.9 mg per cycle, with patients receiving 95.9% of the intended doses.

ORR at 24 weeks was 83% (95% CI, 52-98) in the treatment-naïve cohort, and 50% in those patients who received previous treatment. All responses were partial responses. Two patients in the treatment-naïve group and 8 in the previously-treated population had stable disease. One patient in each cohort had primary progressive disease.

The median duration of response was not yet reached for the total cohort and the treatment-naïve cohort. The median duration of response was 8.5 months in the pretreated cohort.

When stratified by PD-L1 staining status, investigators observed similar objective responses in the PD-L1—positive (58%) and PD-L1–negative populations (71%).

At the time of data cutoff, the median progression-free survival (PFS) had not yet been reached (95% CI, 9.9 months-not evaluable). Tumor responses assessed by a modified RECIST v1.1 were the same as with irRECIST. The median PFS by RECIST v1.1 was also not yet evaluable.

Ten of 12 patients in the treatment-naïve cohort remain on treatment.

Twenty-eight of 30 patients experienced tumor shrinkage, and Lee said there was a tendency for greater tumor shrinkage in the treatment-naïve patients. Tumor shrinkage was observed in both PD-L1—positive and PD-L1–negative patients, with no clear association between changes in tumor size and PD-L1 staining status.

Treatment-emergent adverse events (TRAEs) led to lenvatinib dose reductions in 18 patients. Five patients (17%) discontinued at least 1 study drug.

The most common TRAEs of any grade were diarrhea (83%), fatigue (70%), hypothyroidism (67%), stomatitis (60%), hypertension (57%), and nausea (57%). No new safety signals were found. The 2 grade-5 TRAEs were related to disease progression and not considered related to the study drugs.

Lenvantinib is currently FDA approved as monotherapy for patients with thyroid cancer and in combination with everolimus (Afinitor) for the treatment of patients with RCC who have failed previous therapies. Eisai has filed for regulatory approval for lenvatinib monotherapy the treatment for patients with hepatocellular carcinoma in the United States, Europe, Japan, and China.

Lee C, Makker V, Rasco D, et al. A phase 1b/2 trial of lenvatinib plus pembrolizumab in patients with renal cell carcinoma. Presented at ESMO 2017 Congress; September 8-12, 2017; Madrid, Spain. Abstract 847O.