Gianoukakis, Andrew G.

Abstract Purpose: Lenvatinib, a potent multikinase inhibitor, improves progression-free survival (PFS) in patients with radioiodine (RAI)-refractory differentiated thyroid cancer; however, most patients experience disease progression, warranting further therapy. We evaluated the efficacy and safety of lenvatinib plus pembrolizumab in these patients. Patients and Methods: We enrolled patients with progressive, RAI-refractory differentiated thyroid cancer who were either naïve to multikinase inhibitors (cohort 1) or who had progressed on lenvatinib (cohort 2). Patients received oral lenvatinib daily (cohort 1, 20 mg; cohort 2, dose at progression) and intravenous pembrolizumab (200 mg) every 21 days. Results: In cohorts 1 and 2, 30 and 27 patients were enrolled, respectively. Adverse events were consistent with those observed in other cancers. In cohort 1, the confirmed overall response rate was 65.5%. There were no complete responses (primary endpoint). The 12- and 18-month PFS were 72.0% and 58.0%, respectively, and the median PFS was 26.8 months. In cohort 2, the confirmed overall response rate was 16% (primary endpoint), and the median PFS was 10.0 months (95% confidence interval, 7.0–17.9 months). Tumor histology, driver mutations, and immune-related biomarkers, including PD-L1 expression, thyroid-specific antibody levels, and CD8+ T-cell tumor infiltrate, did not correlate with response to therapy. Increased baseline peripheral blood monocytes and neutrophil to lymphocyte ratio were associated with a worse PFS in cohort 1. Conclusions: Lenvatinib plus pembrolizumab may enhance the durability of lenvatinib monotherapy in lenvatinib-naïve patients. Furthermore, the addition of pembrolizumab may be a viable salvage therapy for patients who have progressed on lenvatinib.

6512 Background: Lenvatinib is an approved therapy for patients with RAIR DTC. While the overall response rate (ORR) is high, few patients achieve a complete response (CR) and most patients eventually have progressive disease (PD). Combination lenvatinib and pembrolizumab is being explored in many different cancers, and this combination has been approved for advanced endometrial carcinoma. Methods: Patients with RAIR DTC with Response Evaluation Criteria in Solid Tumor (RECIST v1.1) measurable PD (<14 months (mo) prior to registration) were enrolled in this single-arm multicenter phase II study. Patients were excluded if they had received previous VEGFR-directed multikinase therapy. The lenvatinib starting dose was 20 mg/day orally and pembrolizumab was 200mg IV every 3 weeks. The primary endpoint was CR. ORR, progression-free survival (PFS) and safety graded by Common Terminology Criteria for Adverse Events v4.0 were secondary endpoints. Results: Thirty patients were enrolled. The median age was 62.5 years, and 53% of the patients were women. Seventy percent of patients had grade 3 adverse events (AEs) and 10 percent had grade 4 AEs. There were no treatment-related deaths. The most common > grade 3 AEs were hypertension (47%), weight loss (13%), maculopapular rash (13%), leukopenia (7%), diarrhea (7%) and oral mucositis (7%). Twenty-one patients (70%) required lenvatinib dose reduction. Of 29 evaluable patients, 18 (62%) had a partial response (PR) and 10 (35%) had stable disease (SD). The clinical benefit rate (ORR +SD) was 97%. Median time to tumor nadir was 7.4 mo (1.6-17.8 mo). Median PFS was not yet reached. The PFS at 12 months was 74%. Median time on therapy was 9.9 mo (3.2-18.9 mo). Fourteen patients are continuing therapy (7.6-18.9 mo). Six of these patients (43%) have not yet reached tumor size nadir. Three patients (10%) had > 80% target tumor shrinkage. Conclusions: Lenvatinib plus pembrolizumab is reasonably tolerated in patients with RAIR DTC. To date, there have been no documented complete responses. Combination lenvatinib plus pembrolizumab therapy has a high ORR in patients with RAIR DTC. Continuation of this study will help determine the depth and length of the responses. Clinical trial information: NCT02973997 .