Lenvatinib Plus Pembrolizumab Shows Clinically Meaningful Response Rates in Unresectable HCC, Advanced RCC


Lenvatinib (Lenvima, Eisai) plus pembrolizumab (Keytruda, Merck) showed significant response rates in unresectable hepatocellular carcinoma and in patients with metastatic clear cell renal cell carcinoma who progressed following immune checkpoint inhibitor therapy.

New data from a pair of clinical trials evaluating lenvatinib (Lenvima, Eisai), an oral multiple receptor tyrosine kinase inhibitor, plus pembrolizumab (Keytruda, Merck), an anti-PD-1 therapy, showed clinically significant objective response rates (ORR) in patients with unresectable hepatocellular carcinoma (HCC) with no prior systemic therapy and in patients with metastatic clear cell renal cell carcinoma (ccRCC) who progressed following immune checkpoint inhibitor therapy.

Results from the KEYNOTE-524 trial and results from the KEYNOTE-146 trial were presented during an oral abstract session of the Virtual Scientific Program of the 2020 American Society of Clinical Oncology Annual Meeting.

“As data from our combination trials continue to read out, our enthusiasm for and belief in the potential of Keytruda plus Lenvima are strengthened by the growing body of evidence observed in multiple advanced cancers,” said Takashi Owa, PhD, chief medicine creation and chief discovery officer, Oncology Business Group at Eisai, in a press release. “Our ongoing clinical study efforts on this combination exemplify our commitment to following the science and exploring possible solutions for patients affected by difficult-to-treat cancers.”

In KEYNOTE-524 (ClinicalTrials.gov, NCT03006926), a phase 1b, open-label, single-arm trial, lenvatinib plus pembrolizumab combination was evaluated in 100 patients with unresectable HCC with no prior systemic therapy.

Patients were administered pembrolizumab 200 mg intravenously every 3 weeks in combination with lenvatinib 8 or 12 mg orally once daily. The primary endpoints were ORR and duration of response (DOR) by modified Response Evaluation Criteria in Solid Tumors (mRECIST) and RECIST v1.1 per independent imaging review.

Secondary endpoints included progression-free survival (PFS), time to progression (TTP), and overall survival (OS). As of the data cutoff date, October 31, 2019, with a median duration follow-up of 10.6 months (95% CI: 9.2-11.5), 37 patients were still on lenvatinib plus pembrolizumab (n=34) and lenvatinib monotherapy (n=3). Median duration of treatment exposure to the lenvatinib plus pembrolizumab combination was 7.9 months (range: 0.2-31.1).

The study showed an ORR of 36% (n=36) (95% CI: 26.6-46.2) in those treated with lenvatinib plus pembrolizumab, with a complete response rate of 1% (n=1) and a partial response rate of 35% (n=35). The median DOR was 12.6 months (95% CI: 6.9-not estimable [NE]), using RECIST v1.1 criteria per IIR. The lenvatinib plus pembrolizumab combination demonstrated an ORR of 46% (n=46) (95% CI: 36.0-56.3), with a complete response rate of 11% (n=11), a partial response rate of 35% (n=35), and a median DOR of 8.6 months (95% CI: 6.9-NE), as assessed using mRECIST criteria.

Adverse events (AEs) that led to discontinuation of lenvatinib plus pembrolizumab were observed in 6% of patients, with discontinuation of pembrolizumab in 10% of patients and discontinuation of lenvatinib in 14% of patients.

Grade ≥3 AEs were observed in 67% of patients (grade 3: 63%; grade 4: 1%; grade 5: 3%). There was 1 grade 4 AE (leukopenia/neutropenia), and 3 grade 5 treatment-related deaths from acute respiratory failure/acute respiratory distress syndrome, intestinal perforation, and abnormal hepatic function, according to the study.

The most common AEs of any grade (≥20%) were hypertension (36%), diarrhea (35%), fatigue (30%), decreased appetite (28%), hypothyroidism (25%), palmar-plantar erythrodysesthesia syndrome (23%), decreased weight (22%), dysphonia (21%), increased aspartate aminotransferase (20%), and proteinuria (20%).

The KEYNOTE-146 (ClinicalTrials.gov, NCT02501096) was a phase 1b/2, open-label, single-arm trial that evaluated the lenvatinib/pembrolizumab combination in 104 patients with metastatic ccRCC who experienced disease progression following PD-1/PD-L1 immune checkpoint inhibitor therapy using RECIST v1.1 criteria.

Patients were treated with pembrolizumab 200 mg intravenously every 3 weeks in combination with lenvatinib 20 mg orally once daily until unacceptable toxicity or disease progression.

As of April 9, 2020, results showed an ORR at week 24 of 51% (95% CI: 41-61) with the lenvatinib/pembrolizumab combination. ORR was 55% (95% CI: 45-65), with a partial response rate of 55%, a stable disease rate of 36%, and a progressive disease rate of 5%. Median DOR was 12 months (95% CI: 9-18), median PFS was 11.7 months (95% CI: 9.4-17.7), and the 12-month PFS rate was 45% (95% CI: 32-57).

Median OS was not reached (95% CI:16.7-NR) and the 12-month OS rate was 77% (95% CI: 67-85).

AEs in this population that led to discontinuation of lenvatinib/pembrolizumab were observed in 15% of patients, with discontinuation of pembrolizumab in 12% of patients, and discontinuation of lenvatinib in 12% of patients. The most common AEs that led to dose reduction of lenvatinib were fatigue (14%), diarrhea (10%), and proteinuria (9%).

Grade 4 AEs included diverticulitis, large intestine perforation, and myocardial infarction.

Two grade 5 treatment-related deaths were reported from upper gastrointestinal hemorrhage and sudden death. The most common AEs of any grade (≥20%) were fatigue (53%), diarrhea (46%), proteinuria (39%), dysphonia (35%), hypertension (34%), nausea (32%), stomatitis (32%), arthralgia (29%), decreased appetite (28%), palmar-plantar erythrodysesthesia syndrome (25%), hypothyroidism (23%) and headache (22%).

“The tumor response rates demonstrated with Keytruda plus Lenvima in these studies underscore the potential of this combination regimen in certain types of hepatocellular and renal cell carcinoma,” said Jonathan Cheng, MD, vice president, Oncology Clinical Research, Merck Research Laboratories, in a press release. “Keytruda plus Lenvima is an important pillar of our broad oncology research program, and we continue to advance the study of the combination across multiple types of cancers and stages of disease.”


KEYTRUDA® (pembrolizumab) plus LENVIMA® (lenvatinib) Combination Demonstrated Clinically Meaningful Tumor Response Rates in Unresectable Hepatocellular Carcinoma and Advanced Renal Cell Carcinoma. [News Release]. Kenilworth, NJ, and Woodcliff Lake, NJ. May 28, 2020. https://www.eisai.com/news/2020/news202023.html.

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