Adding Lenvatinib to Pembrolizumab in Squamous Cell Head and Neck Cancer Shows Promise

Matthew H. Taylor, MD

Promising activity was seen in patients with squamous cell carcinoma of the head and neck (SCCHN) who were treated with lenvatinib (Lenvima) in addition to pembrolizumab (Keytruda) with an objective response rate (ORR) of 40.9%. The results of this ongoing open-label phase Ib/II clinical trial were presented at the ASCO Annual Meeting.¹

In the first 22 patients with SCCHN enrolled, there was an ORR in 9 patients. The median progression-free survival (PFS) was 8.2 months, reported Matthew H. Taylor, MD.

By comparison, the ORRs with pembrolizumab in the KEYNOTE-012,²KEYNOTE-040,³and KEYNOTE-055 studies were 18%, 15%, and 16%, respectively, and the median PFS for pembrolizumab alone was 2 months in each of these studies, noted Taylor, Director of the phase I clinical trials program at Knight Cancer Institute, Oregon Health and Science University, Portland.

“The next step will be to expand the cohort to 120 patients because these are still small numbers,” he said.

Lenvatinib is a multikinase inhibitor currently approved as monotherapy for radioiodine-refractory differentiated thyroid cancer and in combination with everolimus for the treatment of advanced renal cell carcinoma following anti-angiogenic therapy.

The data presented at the meeting were from the SCCHN cohort of the phase II portion of the study; the combination regimen is being studied in a total of 6 solid tumor cohorts. Patients in phase II received oral lenvatinib, 20 mg/day, and intravenous pembrolizumab, 200 mg every 3 weeks on a 21-day treatment cycle, until disease progression, development of unacceptable toxicity, withdrawal of consent, or discontinuation from the study.

The efficacy observed with the combination may be due to therapeutic effects on both the tumor and its microenvironment, Taylor said. “The study has a whole has been extremely successful. We have seen really good response rates in renal cell carcinoma, endometrial carcinoma, and even in the melanoma cohort, and that [efficacy] held up in the SCCHN cohort,” he said. “Pembrolizumab monotherapy only has a response rate of 15% to 18%, and in this combination, it was 41%, and we think it’s due to the combination and not the lenvatinib by itself. In a previous clinical trial, lenvatinib by itself had a response rate of less than 10%, so we think that it’s the combination that’s making the difference.”

The data cut-off for this analysis was December 1, 2017, at which time 22 patients with measurable, confirmed SCCHN had been treated. Their median age was 65.5 years and 18 patients (81.8%) were male. Per protocol, all patients had an ECOG Performance Status of 0 or 1. Fourteen patients (63.6%) received 1 prior line of anticancer therapy, 3 (13.6%) were treated with 2 previous lines, and 3 (13.6%) with 3 or more lines. Patients enrolled were not selected based on PD-L1 status. In the 17 patients in whom PD-L1 status was measured, all 17 were PD-L1-positive. PD-L1 status was not determined in 5 of the 22 patients.

Tumors were assessed by study investigators using immune-related RECIST (irRECIST). Of the 9 responses observed, the best overall response was a complete response in 1 patient (4.5%) and a partial response in 8 (36.4%). Eleven patients (50%) had stable disease. The ORR at 24 weeks, the primary endpoint of the study, was 36.4% (8 of 22). The median duration of response was 13.3 months. The 12-month PFS rate was 41.9%.

Most patients had a reduction in tumor size, with four patients having a reduction of 80% or greater. The median duration of exposure to lenvatinib was 5.0 months and the mean daily dose delivered was 11.7 mg/day, with a median of 54% of the intended dose delivered. The median pembrolizumab treatment duration was 5.9 months and the median number of pembrolizumab cycles received was 8.5. The mean dose delivered per cycle was 187.5 mg, with a median of 100% of the intended dose delivered.

“We didn’t see any additional immune-mediated toxicities. The pembrolizumab toxicity was basically as it would be with monotherapy, specifically in relation to immune-mediated adverse events [AEs],” Taylor said. “For lenvatinib toxicity, [it looked like the typical vascular endothelial growth factor receptor toxicities of hypertension and proteinuria.”

Grade 3 or 4 AEs occurred in 72.7% of patients. The most common treatment-related AEs were fatigue (50%; grade 3, 4.5%), hypertension (40.9%; grade 3, 18.2%), and diarrhea (36.4%; grade 3, 4.5%). Five patients had serious treatment-related AEs that included hypertension, acute kidney injury, dehydration, hemoptysis, and pulmonary edema.

References:

1. Taylor MH, Rasco DW, Brose MS, et al. A phase 1b/2 trial of lenvatinib plus pembrolizumab in patients with squamous cell carcinoma of the head and neck. Presented at: 2018 ASCO Annual Meeting; June 1-5, 2018; Chicago, IL. Abstract 6016. abstracts.asco.org/214/AbstView_214_224747.html.
2. Seiwert TY, Burtness B, Mehra R, et al. Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial.Lancet Oncol. 2016;17:956-965. doi: 10.1016/S1470-2045(16)30066-3.
3. Bauml J, Seiwert TY, Pfister DG, et al. Pembrolizumab for platinum- and cetuximab-refractory head and neck cancer: results from a single-arm, phase II study.J Clin Oncol. 2017;35(14):1542-1549. doi: 10.1200/JCO.2016.70.1524.