Context Incidence and awareness of endocrine-related adverse events (ERAE) associated with use of immune checkpoint inhibitors (ICI) has grown with increased ICI use, yet mechanisms for ERAE prediction, surveillance, and development are not well established. Objective We prospectively evaluated the impact of endocrine autoimmunity on ERAE development and overall survival (OS). Design, Setting, Participants Adults ≥18 years of age prescribed ICI treatment for advanced or metastatic solid tumors and no known active/past endocrine disorders were eligible for enrollment. Thyroid, adrenal, and pancreatic antibodies as well as hormone levels were assessed prior to ICI treatment and at 8-9 weeks and 36 weeks post treatment. Main outcomes ERAE in relation to presence and changes in endocrine-specific antibodies, hormone levels, and OS. Results Sixty patients were enrolled and ERAE were detected in 14 (23.3%), with a median onset of 52 days (IQR 38.5-71.5) after first ICI dose. Hypothyroidism occurred in 12 (20%) patients, and 2 (3.33%) patients developed hypophysitis; diabetes and primary adrenal insufficiency were not observed. Antibodies were detected in 14 patients (11 at baseline, 3 developed during follow up) and their presence was significantly associated with ERAE (R 2 59.3%, p<0.001). Thyroid peroxidase antibody (20%) and thyroid stimulating immunoglobulin (3.3%) were most common, and anti-GAD was present in 1 patient. The presence of ERAE was associated with a more favorable OS (p=0.001). Conclusions Endocrine-specific autoantibodies play an important role in ERAE pathogenesis and may serve as predictive markers for early identification and treatment of ICI-induced endocrinopathies.
11565 Background: TAPUR is a phase II basket study evaluating anti-tumor activity of commercially available targeted agents in pts with advanced cancers with genomic alterations. Results in a cohort of STS pts with CDK4 amplification treated with P are reported. Methods: Eligible pts had advanced STS, no standard treatment options, measurable disease, ECOG PS 0-2, and adequate organ function. Genomic testing was performed in CLIA-certified, CAP-accredited site selected labs. Pts received P at 125 mg orally once daily for 21 days, followed by 7 days off until disease progression. Pts matched to P had CDK4 amplification and no RB mutations. Simon 2-stage design tested the null disease control (DC) - defined as partial (PR), complete response (CR) or stable disease at 16+ weeks (SD 16+) - rate of 15% vs. 35% (power = 0.85; α = 0.10). If ≥2 of 10 pts in stage 1 have DC, 18 more pts are enrolled. If ≥7 of 28 pts have DC, the null DC rate is rejected. Secondary endpoints are progression-free survival (PFS), overall survival (OS) and safety. Results: 29 pts (66% male) with STS with CDK4 amplification were enrolled from July 2016 to Nov 2019. 1 pt was not evaluable and excluded from efficacy analyses. Demographics and outcomes are summarized in Table. One pt with partial response (PR) and 12 pts with SD16+ were observed for DC and objective response (OR) rates of 48% (95% CI: 31%, 62%) and 3.7% (95% CI: 0.1%, 19%), respectively, and the null DC rate of 15% was rejected (p<0.001). 9/13 pts with DC continued on treatment for >32 weeks. 14 pts had at least one grade 3-4 AE at least possibly related to P with the most common being low WBC/platelets. Other grade 3 AEs included increased alanine aminotransferase, anemia, and fatigue. Conclusions: Monotherapy P demonstrated anti-tumor activity in heavily pre-treated pts with STS with CDK4 amplification. Additional study is warranted to confirm the efficacy of P in pts with STS with CDK4 amplification. Clinical trial information: NCT02693535. [Table: see text]
TPS401 Background: XL092 is a novel oral multi-targeted inhibitor of receptor tyrosine kinases MET, VEGFR2, and TAM kinases (AXL, MER), which are important in tumor growth, neovascularization, and immune modulation of the tumor microenvironment. XL092 as a single-agent and in combination with an anti-PD-1 antibody showed antitumor activity in xenograft tumor models (Hsu et al. 2020). This first-in-human study is evaluating safety, pharmacokinetics (PK), and preliminary antitumor activity of XL092 with or without (w/wo) ICIs in pts with advanced solid tumors. Presented here are the trial design and details of GU cohorts. Methods: In this phase 1, multicenter, open-label, dose-escalation and expansion study (NCT03845166), pts will receive escalating doses of XL092 w/wo atezolizumab (ATEZO) 1200 mg Q3W or avelumab (AVE) 800 mg Q2W. The dose-escalation stage is enrolling pts with inoperable locally advanced or metastatic solid tumors using a 3+3 (single-agent) or rolling 6 (combination) design; the primary objective is to determine maximum tolerated dose and/or recommended dose of XL092 for further evaluation when administered w/wo ICIs; secondary objective is to evaluate plasma PK of XL092 and its metabolites alone and in combination with ICIs. Primary objectives for the expansion stage are to evaluate preliminary efficacy of XL092 w/wo ICIs by estimating objective response rate (ORR) by investigator (Inv) per RECIST 1.1 and for specific cohorts by estimating the % of pts with PFS at 6 months by Inv per RECIST 1.1; secondary objective is safety of XL092 w/wo ICIs via monitoring nonserious and serious adverse events (AEs) including immune related AEs and AEs of special interest. For GU cohorts in expansion stage, single-agent XL092 will be tested in: (i) previously treated advanced clear cell (cc) renal cell carcinoma (RCC; progression on 1-3 prior systemic regimens w/wo a sarcomatoid component); (ii) previously treated advanced non-cc RCC (progression on 1-3 prior systemic regimens); (iii) metastatic castration resistant prostate cancer (mCRPC; prior treatment with ≥1 novel hormonal therapy and taxane-based chemotherapy, ≤4 prior systemic regimens). XL092 + ATEZO will be tested in non-cc RCC and mCRPC cohorts. Pts with advanced urothelial carcinoma will be enrolled in 3 cohorts: (i) pts with ongoing CR/PR/SD after 4-6 cycles of first-line chemotherapy (gemcitabine + cisplatin and/or gemcitabine + carboplatin) will receive XL092 + AVE; (ii) pts with progression on/after prior ICI therapy (≤2 prior systemic therapies) will be randomized 1:1 to XL092 + AVE or single-agent XL092; (iii) pts with progression on/after first-line platinum-based chemotherapy will receive XL092 + AVE. The study is currently enrolling pts. Clinical trial information: NCT03845166.
associated with high response rates and decreased rates of neurotoxicity compared with higher dose WBRT. Our treatment policy for PCL patients with residual disease following chemotherapy is whole-brain irradiation to a total dose of 23.4 Gy in 13 fractions of 1.8 Gy followed by a sequential boost up to 45-50 Gy in 25 fractions of 1.8-2 Gy to the primary site/residual tumor. We propose a new methodology in order to limit the dose to the healthy brain to the prescribed dose by using composite planning (bias dose planning). Materials/Methods: We treated two patients with PCL and residual disease after chemotherapy using our methodology. First, we prepared a "standard plan", where the WBRT dose was planned first for volumetric arc therapy (VMAT) using the Monoco TPS (Elekta), followed by the sequential boost dose plan; second, a "bias plan" where the sequential boost dose was planned first, and only thereafter the WBRT dose using the bias dose planning option with the Monaco TPS in order to have a final composite plan corresponding to the prescribed doses. Results: Treatment plans resulting from bias dose planning had a markedly reduced dose to the brain outside of the boost. The mean dose to the brain minus the boost volume was of 25.00 Gy AE 0.5 Gy (Bias plan) vs 30.00 AE 0.6 Gy (standard plan). Conclusion: Composite planning of the boost first and only thereafter planning the dose to the brain taking the boost plan into account allows a reduction of 5 Gy to the healthy brain. To our knowledge, in lymphoma treatment, the total delivered dose is important, rather than the dose per fraction. We recommend this procedure for PCL radiations that have a sequential boost.
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