Lenvatinib/Pembrolizumab Combo Shows Antitumor Activity in Previously Treated Advanced Solid Tumors – OncLive

Lenvatinib (Lenvima) plus pembrolizumab (Keytruda) showed early antitumor activity and tolerability in previously treated patients with advanced solid tumors, according to interim results from the phase 2 LEAP-005 trial (NCT03797326) presented during the virtual 2020 ESMO Congress.1

Results showed that the objective response rate (ORR) with the combination per RECIST v1.1 criteria and blinded independent central review (BICR) was 29.0% (95% CI, 14.2%-48.0%) in 31 patients with triple-negative breast cancer (TNBC) who received treatment in the second- or third-line setting. The ORR was even higher, at 32.3% (95% CI, 16.7%-51.4%) in 21 patients with ovarian cancer who received the combination as their fourth line of treatment.

Moreover, the ORRs were 9.7% (95% CI, 2.0%-25.8%) in 21 patients with third-line gastric cancer, 21.9% (95% CI, 9.3%-40.0%) in 32 patients with third-line colorectal cancer (CRC), and 9.7% (95% CI, 2.0%-25.8%) in 31 patients with second-line biliary tract cancer. In 31 patients with second-line glioblastoma multiforme, the ORR was 16.1% (95% CI, 5.5%-33.7%).

“The prespecified futility efficacy criteria for cohort expansion were met and toxicity was manageable in all cohorts,” Zarnie Lwin, MD, lead investigator of the trial and medical oncologist in the Department of Medical Oncology at the Royal Brisbane and Women’s Hospital, of the University of Queensland, in Australia, said in a virtual presentation during the meeting. “LEAP-005 will continue to assess the efficacy and safety of lenvatinib plus pembrolizumab in patients with previously treated advanced solid tumors in expanded cohorts of 100 patients each.”

Investigators hypothesized that the combination of the antiangiogenic multikinase inhibitor lenvatinib with the PD-1 immunotherapy pembrolizumab would result in dual immunomodulatory effects.2 The combination has already demonstrated encouraging antitumor activity in early-phase trials done in patients with several cancers.3

In September 2019, lenvatinib plus pembrolizumab received regulatory approval from the FDA for use in patients with previously treated advanced endometrial cancer that was not microsatellite instability–high (MSI-H)/or mismatch repair deficient (dMMR) who were not candidates for curative surgery or radiation. The decision was based on data from a study comprised of 94 patients and the combination elicited an ORR of 38.8%.4

In the multicenter, open-label phase 2 trial, investigators set out to examine the safety and efficacy of lenvatinib plus pembrolizumab in patients with previously treated solid tumors. In order to be eligible for participation, patients had to be 18 years of age or older and have histologically or cytologically advanced solid tumors that fell into the following cohorts with the appropriate lines of treatment: TNBC (second or third line), ovarian (fourth line), gastric (third line), CRC (non–MSI-H/proficient MMR; third line), biliary tract (second line), and glioblastoma multiforme (second line).

Patients also had to have measurable disease per RECIST v1.1 criteria, an ECOG performance status of 0 or 1, and tissue available for PD-L1 evaluation.

A total of 30 patients were enrolled to each cohort on the study and they received pembrolizumab at an intravenous dose of 200 mg every 3 weeks in combination with lenvatinib at an oral dose of 20 mg once daily for up to 35 treatment cycles.

The primary end points of the trial were ORR per RECIST v1.1 criteria, as well as safety and tolerability. Response in the glioblastoma cohort was per RANO criteria, and all responses were evaluated by BICR. Key secondary end points included disease control rate (DCR), duration of response (DOR), and progression-free survival (PFS).

Patient response was evaluated every 9 weeks until week 54 and then every 12 weeks until week 102; it was examined every 24 weeks thereafter.

The first 187 patients were enrolled to LEAP-005 and they received at least 2 doses of the combination, said Lwin. At the time of the data cutoff, which was April 10, 2020, 13% to 48% of patients were still receiving treatment with lenvatinib/pembrolizumab. The median study follow-up, defined as the time from initiation of the study combination to data cutoff, was 8.6 months (range, 1.9-13.1).

Across the 6 cohorts examined, the median age of participants ranged from 56 years to 65 years and the majority of patients had an ECOG performance status of 1. Moreover, all patients received previous standard therapies, and some had received multiple lines. Sixty-three percent of patients (n = 20) in the CRC cohort received previous bevacizumab (Avastin), along with 61% (n = 19) in the ovarian cohort, and 3% (n = 1) in the TNBC cohort.

Additional results showed that the best overall response in the TNBC cohort was a complete response (CR) in 3% of patients, a partial response (PR) in 26%, and stable disease (SD) in 29%. Twenty-six percent of patients experienced disease progression. The best overall response in the ovarian cohort included a 3% CR rate, 29% PR rate, and a 42% SD rate. The DCRs in the TNBC and ovarian arms were 58.1% (95% CI, 39.1%-75.5%) and 74.2% (95% CI, 55.4%-88.1%), respectively. Sixteen percent of patients had progressive disease. The DOR in both cohorts had not yet been reached.

In the gastric cancer cohort, 3% experienced a CR, 6% had a PR, 39% had SD, and 35% experienced disease progression; in the CRC cohort, these rates were 0%, 22%, 25%, and 38%, respectively. In the biliary tract cancer cohort, 0% achieved a CR, 10% had a PR, and 58% experienced SD; 23% had progressive disease. The DCRs in the gastric, CRC, and biliary tract cancer cohorts were 48.4% (95% CI, 30.2%-66.9%), 46.9% (95% CI, 29.1%-65.3%), and 67.7% (95% CI, 48.6%-83.3%), respectively. The DOR had not yet been reached in the gastric and CRC cohorts; it was 5.3 months in the biliary tract cancer cohort.

The best overall response achieved in the glioblastoma cohort by RANO criteria was a PR in 16.1% of patients and SD in 42%. Thirty-five percent of patients experienced disease progression in this subgroup. Moreover, the DCR was 58.1% (95% CI, 39.1%-75.5%) in these patients, and the DOR was 3.2 months.

The median PFS per RECIST v1.1 by BICR in the TNBC cohort was 4.2 months (95% CI, 1.9–not reached [NR]), and the estimated 6-month PFS rate was 48.9%. In the ovarian cohort, the median PFS was 4.4 months (95% CI, 4.0-8.5) and the estimated PFS rate at 6 months was 47.1%.

The median PFS was 2.5 months (95% CI, 1.8-4.2) in the gastric cancer cohort, 2.3 months (95% CI, 2.0-5.2) in the CRC cohort, and 6.1 months (95% CI, 2.1-6.4) in the biliary tract cancer cohort. The estimated 6-month PFS rates in the gastric, CRC, and biliary tract cancer cohorts were 22.2%, 30.5%, and 56.5%, respectively.

The median PFS per RANO criteria by BICR in the glioblastoma cohort was 2.8 months (95% CI, 1.6-4.0) with an estimated 6-month PFS rate of 11.5%.

With regard to safety, 1 or more treatment-related adverse effect (TRAE) occurred in most patients in each cohort. Grade 3 to 5 TRAEs were reported in approximately half of patients in each cohort, although the incidence of these toxicities was 68% in the ovarian cohort and 35% in the glioblastoma cohort.

Grade 3 to 5 TRAEs that resulted in treatment discontinuation were reported in 10% of those in the TNBC cohort, 13% in the ovarian cohort, 6% in the gastric cohort, 9% in the CRC cohort, 6% in the biliary tract cancer cohort, and 6% in the glioblastoma cohort. One patient in each cohort, with the exception of the biliary tract cancer cohort, experienced a TRAE that resulted in death.

Immune-mediated toxicities were reported in 48% of those in the TNBC cohort, 48% in the ovarian cohort, 26% in the gastric cohort, 44% in the CRC cohort, 45% in the biliary tract cancer cohort, and 29% in the glioblastoma cohort. Grade 3 to 5 immune-mediated toxicities occurred in 3%, 3%, 3%, 6%, 6%, and 3%, of patients across the 6 cohorts, respectively.

Infusion reactions were reported in a total of 3 patients across the cohorts: 1 in the TNBC cohort, 1 in the ovarian cohort, and 1 in the biliary tract cancer cohort; only 1 of these effects, the 1 reported in the ovarian cohort, was grade 3 to 5 in severity.

Hypertension was the most commonly experienced adverse effect in all cohorts except for gastric cancer, where diarrhea and fatigue were the most frequently experienced toxicities. Overall, the safety profile of the combination was found to be consistent with what has previously been reported, concluded Lwin.


1. Lwin Z, Gomez-Roca C, Saada-Bouzid E, et al. LEAP-005: phase 2 study of lenvatinib plus pembrolizumab in patients with previously treated advanced solid tumors. Presented at: 2020 ESMO Virtual Congress; September 19-21, 2020; Virtual. Abstract LBA41.

2. Kimura T, Kato Y, Ozawa Y, et al. Immunomodulatory activity of lenvatinib contributes to antitumor activity in the Hap1-6 hepatocellular model. Cancer Sci. 2018;109(21):3993-4002. doi:10.111/cas.13806

3. Taylor M, Dutcus CE, Schmidt E, et al. A phase 1b trial of lenvatinib (LEN) plus pembrolizumab (PEM) in patients with selected solid tumors. Ann Oncol. 2016;27(suppl 6):vi266-vi295. doi:10.1093/annonc/mdw373.4

4. FDA takes first action under new international collaboration with Australia and Canada designed to provide a framework for concurrent review of cancer therapies, approving treatment for patients with endometrial carcinoma. News release. FDA. September 17, 2019. Accessed September 20, 2020. https://bit.ly/2kqmAGq.

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Lenvatinib/Pembrolizumab Combo Shows Antitumor Activity in Previously Treated Advanced Solid Tumors – OncLive

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