In a phase II trial, the combination of lenvantinib and pembrolizumab demonstrated a manageable safety profile and encouraging antitumor activity in patients with selected advanced solid tumors. The decision to combine the agents was based on preclinical data, which suggested that VEGF and FGF signaling may enhance the therapeutic efficacy of lenvatinib.
In a phase II trial, the combination of lenvantinib (Lenvima) and pembrolizumab (Keytruda) demonstrated a manageable safety profile and encouraging antitumor activity in patients with selected advanced solid tumors.1The decision to combine the agents was based on preclinical data, which suggested that VEGF and FGF signaling may enhance the therapeutic efficacy of lenvatinib.2
The study included 124 patients with either renal cell carcinoma (RCC), endometrial cancer, squamous cell carcinoma of the head and neck (SCCHN), melanoma, nonsmall cell lung cancer (NSCLC), and urothelial cancer. The primary end point was objective response rate (ORR) at week 24. The secondary end points were a number of participants with treatment-emergent adverse events, progression-free survival (PFS), overall survival, duration of response (DOR), disease control rate, durable stable disease rate, and clinical benefit rate.
Best responses were observed in the RCC cohort. Among the 19 evaluable patients with RCC, the ORR was 63% (95 CI, 43%-80.1%) at week 24 and climbed to 70% (95 CI, 50.6%-85.3%) in 21 out of 30 patients at the time of data cutoff. The median DOR in this cohort was 20.0 months (95% CI, 9.0-22.8 months), and the median PFS was 19.8 months (95% CI, 9.9-24.1 months).
In 12 evaluable patients from the endometrial cancer cohort (n = 23), the 24-week ORR of 52% (95% CI, 30.6%-73.2%). The median DOR was not reached in this group (95% CI, 2.6 months to not evaluable [NE]). The median PFS achieved in patients with endometrial cancer was 9.7 months (95% CI, 4.2 months-NE).
The melanoma cohort included 21 patients, 10 of whom were evaluable for the primary end points. This cohort had a 24-week ORR and overall ORR of 48% (95% CI, 25.7%-70.2%). The median DOR was 12.5 months (95% CI, 2.7 months-NE), and the PFS was 5.5 months (95% CI, 2.6-15.8 months).
Eight out of 22 patients from the SCCHN cohort were evaluable for the 24-week ORR end points, which was 36% (95% CI, 17.2%-59.3%). The overall ORR was 46% in 10 out of 22 patients (95% CI, 24.4%-67.8%). This cohort had a median DOR of 8.2 months (95% CI, 2.2-12.6 months), and a median PFS of 4.7 months (95% CI, 4.0-9.8 months).
There were 21 patients with NSCLC in the study, 7 of whom were evaluable for the 24-week ORR. In this cohort, the ORR at 24 weeks was 33% (95% CI, 14.6%-57.0%). The median DOR was 10.9 months (95% CI, 2.4 months-NE), and the median PFS was 5.9 months (95% CI, 2.3-13.8 months).
A 25% ORR at week 24 was achieved in the urothelial cancer cohort (95% CI, 8.7%-49.1%), which included 5 evaluable patients out of 20. The median DOR in this cohort was not reached (95% CI, 6.5 months-NE), and the median PFS was 5.4 months (95% CI, 1.3 months-NE).
At the time of data cutoff, a percentage of patients from the RCC (30%), endometrial cancer (30%), melanoma (10%), SCCHN (14%), NSCLC (29%), urothelial cancer (15%) were still receiving treatment.
Complete and partial responses occurred in 47% of patients overall (n = 65). Additionally, all cohorts had a decrease in tumor size as a result of treatment.
Taylor MH et al found these data to be promising based on prior evidence with both drugs as monotherapies and compared with data observed with similar agents.
“Across cohorts, ORRs ranged from 25% to 70%, with the most favorable responses seen among patients with RCC (70%), endometrial cancer (52%), and melanoma (48%). These encouraging response rates are particularly interesting when viewed in the context of clinical trial results with either lenvatinib or pembrolizumab given as monotherapies to patients with these tumor types. Lenvatinib monotherapy resulted in an ORR of 27% in the second-line treatment of RCC in a previously reported study. The Keynote 427 trial that evaluated pembrolizumab as first-line therapy in patients with advanced clear-cell RCC showed an ORR of 34%. Additionally, response rates in our trial for patients with RCC were promising compared with the response rates of recently approved tyrosine kinase/immune checkpoint inhibitor combinations,” the authors wrote.
The majority of patients in the study (97%) experienced treatment-related adverse events (TRAEs). The most common TRAES across all grade levels were fatigue (58%), diarrhea (52%), hypertension (47%), hypothyroidism (42%), and decreased appetite (39%). Sixty-seven percent of patients experienced grade 3/4 TRAEs, with the most common being hypertension (20%), fatigue (12%), diarrhea (9%), proteinuria (8%), and increased lipase levels (7%).
Eighty-five percent of patients had the dosage of lenvatinib treatment reduced or treatment interrupted due to TRAEs. Lenvatinib was discontinued in 13% of patients and pembrolizumab was discontinued in 15% of patients. Doses of pembrolizumab were also lowered in 45% of patients as a result of TRAEs.
Overall, 21 patients died during the study, with 2 deaths related to treatment. One of these patients had been in the NSCLC cohort and experienced a pulmonary hemorrhage and the other was in the urothelial cancer cohort and succumbed to gastrointestinal hemorrhage.
To enroll in the phase II study, patients were required to have measurable disease, an ECOG performance status of 0 to 1, adequately controlled blood pressure (BP) with or without antihypertensive medication, and adequate renal function, bone marrow function, blood coagulation function, and liver function. Some individuals were also excluded from the study due to diseases and infections that may have interfered with lenvatinib or pembrolizumab treatment, or because they had prior anticancer treatment within 28 days of first dosing in the study.
The study investigators concluded from this study that the combination of lenvatinib and pembrolizumab is effective and tolerable for patients with selected advanced solid tumors. Multiple phase III studies have been launched to further this research.