Sherman, Eric J.

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 .

3594 Background: Selpercatinib (LOXO-292) is a highly selective and potent small molecule RET kinase inhibitor. Here we report an update on the efficacy and safety of selpercatinib in RET-mutant medullary thyroid cancer (MTC). Methods: Patients with RET-mutant MTC were enrolled to the Phase 1/2 LIBRETTO-001 trial (NCT03157128), a global, multicenter trial (16 countries, 89 sites). Following the Phase 1 dose escalation portion of the trial, patients received the recommended dose of 160 mg orally twice daily. Each cycle was 28 days. The primary endpoint was objective response rate (ORR) per RECIST 1.1. Secondary endpoints included duration of response (DoR) and safety. Per health authority agreement, the primary analysis set was defined as the first 55 consecutively enrolled patients previously treated with multikinase inhibitors cabozantinib and/or vandetanib. Patients naïve to cabozantinib and vandetanib treatment were analyzed separately. All analyses were based on a 16-Dec-2019 data cutoff date. Results: In the primary analysis set of prior cabozantinib and/or vandetanib-treated patients with MTC (n = 55), the ORR by investigator assessment was 62% (95% CI 47.7–74.6, n = 34/55) and the median DoR was not reached (95% CI 18.4 months–not estimable) despite a median follow-up of 14.8 months. In cabozantinib/vandetanib treatment-naïve patients (n = 88), the ORR by investigator assessment was 69% (95% CI 58.6–78.7, n = 61/88, including 2 responses pending confirmation). Of the 59 confirmed responding patients, with a median follow-up of 8 months, responses were ongoing for 57 responders at the time of the analysis. In the safety analysis set consisting of all selpercatinib dosed patients (N = 702), the most common treatment-related adverse events (TRAEs) that occurred in ≥15% of patients were dry mouth (33.3%), increased AST (24.5%), increased ALT (23.8%), hypertension (23.2%), diarrhea (19.7%), and fatigue (16.8%). Only 2% (14 of 702) of patients discontinued selpercatinib for TRAEs. Conclusions: Selpercatinib use was associated with marked and durable antitumor activity in prior cabozantinib and/or vandetanib-treated patients and in cabozantinib/vandetanib-naïve patients with RET-mutant MTC, with the majority of responses ongoing in both cohorts. Selpercatinib was well tolerated. Efficacy data assessed by independent review committee based on the 16-Dec-2019 data cutoff date will be presented. Clinical trial information: NCT03157128 .

6020 Background: A subset of salivary gland cancer (SGCs) express the androgen receptor (AR). This phase II trial evaluated the anti-androgen enzalumatide (Astellas) for patients with AR+ SGCs. Methods: Locally advanced/unresectable or metastatic AR+ SGCs were enrolled (AR status was centrally confirmed). Prior therapy with AR-targeted drugs was allowed. Enzalutamide 160 mg orally once daily was given (1 cycle= 28 days). The primary endpoint was confirmed response (RR) according to RECIST v1.1 within the first 8 cycles. Secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety. A Simon-Optimal two-stage design was used to detect a 20% RR (vs. 5%) (alpha = 5%; beta = 90%). > 1 response(s) in the first 21 would trigger accrual to 41; > 4 responses would be considered promising. Results: 46 eligible patients (pts) were enrolled (40 M, 6 F; median age 65) in 22 months. In the first 21 pts, we initially had 2 confirmed PRs allowing for full study accrual, though one was later changed to stable disease. Among the 46 pts, 7 had PR as best response, though only 2 were confirmed within the first 8 cycles (4% (95% CI: 0.5-15%). Two other PRs did not count towards the primary endpoint due to 1) development beyond 8 cycles (cycles 12-18) and 2) a confirmatory scan completed <4 weeks apart. The other 3 pts with unconfirmed PR developed progression of disease (PD) after the first PR scan. 24 pts had stable disease; 15 pts PD as best response. Among 11 pts previously treated with AR-targeted therapy, best responses were 1 confirmed PR, 7 SD, 3 PD. With a median follow-up of 11.7 months (mo), OS at 12 mo was 66% (95% CI: 52-83%), PFS at 12 mo was 24% (95% CI: 14-42%), and median PFS was 5.5 mo (95% CI: 3.7-7.3). Conclusions: This is the first prospective trial evaluating an antiandrogen alone for AR+ SGCs. The failure to meet the protocol-defined measure of success was due in part to the lack of durability of initial responses. The clinical activity observed suggests the AR-dependence of AR+ SGCs, even among those previously treated with other hormonal therapies. Support: U10CA180821, U10CA180882; Astellas; https://acknowledgments.alliancefound.org. Clinical trial information: NCT02749903.

Pazopanib and paclitaxel produce cytotoxic synergy in thyroid cancer models through inhibition of aurora kinase A.