Lenvatinib/Pembrolizumab Deemed Safe and Effective in Select GI Cancers

Hyun Cheol Chung, MD

In multiple gastrointestinal tumor types, including advanced gastric cancer, advanced metastatic microsatellite instability-high (MSI-H) or mismatch repair (MMR) colorectal cancer, and advanced biliary tract cancers, the combination of the anti-angiogenic multikinase inhibitor lenvatinib (Lenvima) plus the anti-PD-1 antibody pembrolizumab (Keytruda) demonstrated promising antitumor activity and a manageable safety profile, according to data presented at the 2021 ASCO Gastrointestinal Cancers Symposium.¹

The combination of the anti-angiogenic multikinase inhibitor lenvatinib (Lenvima) plus the anti-PD-1 antibody pembrolizumab (Keytruda) demonstrated promising antitumor activity and a manageable safety profile in previously treated patients with advanced gastric cancer, advanced metastatic microsatellite instability-high (MSI-H) or mismatch repair (MMR) colorectal cancer, and advanced biliary tract cancers, according to data presented at the 2021 ASCO Gastrointestinal Cancers Symposium.

Given the duo’s performance in previous phase 2 studies, the multicohort LEAP-005 study (NCT03797326) set out to evaluate the combination’s safety and efficacy in a number of solid tumor types, enrolling patients in 7 different cohorts. Data specific to the combination’s performance in patients with 3 types of gastrointestinal cancers were presented at this meeting.

Gastric Cancer Cohort Results

The gastric cancer cohort1 enrolled 31 patients (87% male) with metastatic or unresectable gastric cancer who had received at least 2 prior lines of therapy. More than half (58%) of the patients were 65 years old or younger, and 71% had a PD-L1 combined positive score (CPS) of 1.

Patients received lenvatinib 20 mg once daily plus pembrolizumab 200 mg every 3 weeks for up to 35 cycles (approximately 2 years) of pembrolizumab or until disease progression, unacceptable toxicity, or consent withdrawal. In patients who experienced a clinical benefit, treatment with lenvatinib could continue beyond 2 years.

Overall response rate (ORR) and safety were the primary endpoints of the study, with secondary endpoints including disease control rate (DCR; which included complete response [CR], partial response [PR], and stable disease [SD]), duration of response (DOR), progression-free survival (PFS), and overall survival (OS)).

While 19 patients (61%) discontinued treatment, at the time of data reporting, the ORR was 10% (95% CI, 2-26). One patient had a CR (3%), 2 had a PR (6%), and 12 patients (39%) had SD, leading to a DCR of 48% (95% CI, 30.67). Median PFS was 2.5 months (95% CI, 1.8-4.2) and median OS was 5.9 months (95% CI, 2.6-8.7), however, median DOR was not reached (range, 2.1+ to 2.3+ months).

Follow-up imaging was done every 9 weeks for 54 weeks, then every 12 weeks until week 102, and every 24 weeks beyond that. In a presentation on the data, lead author Hyun Cheol Chung, MD, noted the antitumor activity findings of this cohort.

“Among 26 patients who completed at least one baseline tumor assessment, 50% had a decrease from baseline in the size of their target lesions, and 15% of patients showed a decreased tumor size of more than 30%,” said Chung.

In terms of safety, 90% of patients experienced treatment-related AEs, 13 (42%) of whom experienced grade 3-5 AEs. One patient died as a result of a treatment-related hemorrhage. Immune-mediated AEs were less frequent, found in 8 patients (26%), and included hypothyroidism (n = 5), hyperthyroidism (n = 2), and pneumonitis (n = 1). There were no infusion-related reactions.

Overall, Chung concluded, “In patients with advanced gastric cancer who failed 2 prior lines of therapy, lenvatinib plus pembrolizumab demonstrated promising antitumor activity and a manageable safety profile. Based on these data, enrollment in the gastric cancer cohort has been expanded to 100 patients.”

Colorectal Cancer Cohort Results

Given pembrolizumab’s approval in both the first-line treatment of patients with unresectable or MSI-H or MMR deficient colorectal cancer, as well as for patients who have progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan, the colorectal cancer cohort examined the combination therapy this patient population².

Similar to the gastric cancer cohort, 32 patients received lenvatinib 20 mg once daily plus pembrolizumab 200 mg every 3 weeks for the same amount of time, noting that treatment with lenvatinib could continue beyond 2 years in patients who saw clinical benefit with it. In a presentation of the data, lead author Carlos Gomez-Roca, MD, noted that the median age of all participants was 56 years, and 91% of patients (n=29) received 2 prior lines of therapy.

The study’s primary endpoints were ORR and safety, with secondary endpoints including DCR, DOR, PFS, and OS. The median time from first dose to data cutoff was 10.6 months (range, 5.9-13.1 months).

At data cutoff, the ORR was 22% (95% CI, 9-40), and the DCR was 47% (95% CI, 29-65). Median PFS was 2.3 months (95% CI, 2.0-5.2) and median OS was 7.5 months (95% CI, 3.9-NR). Median DOR was not reached (2.1+-10.4+).

Safety data found that grade 3-5 treatment-related AEs occurred in 16 (50%) pts. Three patients discontinued treatment as a result of treatment-related AEs, including a grade 2 ischemic stroke (n = 1), grade 3 increased liver transaminases (n = 1), and grade 5 intestinal perforation (n = 1).

Overall, the authors noted, lenvatinib plus pembrolizumab showed promising antitumor activity and a manageable safety profile in patients with previously treated, advanced non–MSI-H/pMMR colorectal cancer, leading researchers to expand enrollment in the colorectal cohort to 100 patients.

Biliary Tract Cancer Cohort Results

The biliary tract cancer cohort³ included 31 patients with metastatic and/or unresectable disease with progression after 1 prior line of therapy. The treatment schedule was the same as in the gastric and colorectal cancer cohorts, with primary endpoints of ORR and safety. Secondary endpoints included the combined DCR, DOR, PFS and OS.

The median time from first dose to data cutoff was 9.5 months (range, 3.1-11.9), with 16 patients remaining on treatment at data cutoff. There were 3 (10%) PRs and 18 (58%) SDs. ORR was 10% (95% CI, 2-26), and DCR was 68% (95% CI, 49-83). Median DOR was 5.3 months (range, 2.1+ to 6.2). Median PFS was 6.1 months (95% CI, 2.1-6.4) and median OS was 8.6 months (95% CI, 5.6 to NR).

In terms of safety, 30 patients (97%) experienced treatment-related AEs, 15 (48%) of whom had grade 3-4 AEs. In a presentation on the findings, lead author Luis Villanueva, MD, noted that the most frequent treatment-related AEs included hypertension (42%), dysphonia (39%), diarrhea (32%), fatigue (32%), and nausea (32%).

“Fourteen patients (45%) experienced immune-mediated AEs, including hypothyroidism (n=11, 36%), hyperthyroidism (n=2, 6%), and hepatitis (n=2, 6%).” One patient (3%) had an infusion-related reaction, and two patients (6%) discontinued treatment due to treatment-related AEs of myocarditis and pyrexia (n = 1 each). There were no treatment-related deaths.

Based on these findings, Villanueva concluded, enrollment in the biliary tract cancer cohort has been expanded to 100 patients.

_References:

_{1. Chung HC, Lwin Z, Gomez-Roca C, et al. LEAP-005: A phase II multicohort study of lenvatinib plus pembrolizumab in patients with previously treated selected solid tumors: Results from the gastric cancer cohort. Presented at: 2021 ASCO Gastrointestinal Cancers Symposium. Abstract 230.}

_{2. Gomez-Roca C, Yanez E, Im S, et al. LEAP-005: A phase II multicohort study of lenvatinib plus pembrolizumab in patients with previously treated selected solid tumors—Results from the colorectal cancer cohort. Presented at: 2021 ASCO Gastrointestinal Cancers Symposium. Abstract 94.}

_{3. Villanueva L, Lwin Z, Chung HC, et al. Lenvatinib plus pembrolizumab for patients with previously treated biliary tract cancers in the multicohort phase II LEAP-005 study. Presented at: 2021 ASCO Gastrointestinal Cancers Symposium. Abstract 321.}