4117 Background: Patients (pts) with advanced CCA who progressed on or after first line chemotherapy have no approved treatment options. Fibroblast growth factor receptor (FGFR) gene alterations are observed in many tumor types including 14-17% in CCA. Erdafitinib, an orally bioavailable, selective pan-FGFR kinase inhibitor, has shown clinical activity against solid tumors with FGFR alterations. Methods: LUC2001 is an open-label, multicenter, Ph2a study in advanced CCA pts with FGFR alterations (FoundationOne), who progressed after ≥ 1 prior treatment. The primary endpoint is objective response rate (ORR; RECIST 1.1). The secondary endpoints are disease control rate (DCR), progression free survival (PFS), duration of response (DOR), safety and pharmacokinetics (PK). Disease is evaluated every 8 weeks until disease progression (PD). Results: As of 3 Dec 2018, 222 CCA pts were molecularly screened; 34 had FGFR alterations, of whom 14 (8 FGFR2 fusion, 3 FGFR2 mutation, 1 FGFR3 fusion, 2 FGFR3 mutation) were dosed 8 mg once daily with up titration option. Median age was 51.5 years. 13/14 and 12/14 pts had prior platinum or gemcitabine based therapy respectively, 7/14 pts got re-treated with platinum or gemcitabine based therapy, and 9/14 pts had ≥2 prior lines of therapy. Median number of treatment cycles was 5.0 (range: 1; 22) and treatment duration was 4.83 (range: 0.5; 20.3) months. In 12 evaluable pts, there were 6 confirmed partial response (PR), 4 stable disease (SD) and 2 PD; ORR (CR+PR) was 6/12 (50.0%), DCR (CR+PR+uCR+uPR+SD) was 10/12 (83.3%); median DOR was 6.83 months (95% CI: 3.65; 12.16); median PFS was 5.59 months (95% CI: 1.87, 13.67). In 10 evaluable FGFR2+ pts, ORR was 6/10 (60.0%); DCR was 10/10(100%); median PFS was 12.35 months (95% CI: 3.15, 19.38). The most common TEAEs ( > 30%) were hyperphosphatemia, dry mouth, stomatitis, and dry skin. 9 pts had ≥ Grade 3 AEs (8 Grade 3,1 Grade 5), of which 7 drug related. TEAE led to treatment 1 discontinuation, 6 dose reductions and 1 death (not drug related). The results of PK and PK/PD relationship were consistent with other erdafitinib studies in different ethnic background pts. Conclusions: Asian advanced CCA pts with FGFR alterations treated with erdafitinib had encouraging efficacy and acceptable safety profile similar to experience in other tumor types and populations. Clinical trial information: NCT02699606.
217 Background: Durvalumab (D) and tremelimumab (T), monoclonal antibodies against PD-L1 and CTLA-4 immune checkpoints, have shown efficacy as monotherapy/combination therapy in multiple cancer types. Herein, we report a randomized phase 2 study to evaluate efficacy and safety of D monotherapy with or without T (D+T) in previously treated mPDAC. Methods: Part A was a lead-in safety and signal-seeking study with plans to expand to Part B as a nonrandomized or randomized controlled study pending efficacy signal. Eligible pts had progressive disease (PD) following front-line 5-FU- or gemcitabine-based therapy. In Part A, pts were randomized to D (1.5 g IV Q4W) or D+T (D 1.5 g IV + T 75 mg IV Q4W × 4 doses → D 1.5 g IV Q4W) for up to 12 months (mo) or until confirmed PD or unacceptable toxicity. Primary endpoint was investigator-assessed objective response rate per RECIST 1.1. Results: In Part A, 65 pts were randomized to D (n = 33) or D+T (n = 32). Due to a pretreatment death, 64 pts received therapy. Eleven pts (34.4%) in D+T and 10 (31.3%) in D had treatment-related adverse events (trAEs); 7 (22%) in D+T and 2 (6%) in D had grade ≥3 trAEs. Common trAEs: fatigue (12.5%), diarrhea (12.5%), and hypothyroidism (9.4%) in D+T; fatigue (9.4%), diarrhea (6.3%), and pruritus (6.3%) in D. Grade ≥3 trAEs were diarrhea (9.4%), fatigue (6.3%) in D+T and ascites (3.1%), hepatitis (3.1%), and increased lipase (3.1%) in D. In D+T, 3 (9.4%) pts and 1 (3.1%) in D discontinued therapy due to trAEs. No trAEs resulted in death. In D+T, 1 (3.1%) pt had a durable confirmed partial response (PR) > 12 mo and disease control rate (DCR) was 9.4%. In D, 2 (6.1%) pts had unconfirmed PRs, and the DCR was 6.1%. Median PFS in both arms was 1.5 mo, and median OS was 3.1 mo in D+T and 3.6 mo in D. Biomarker analyses (tumor mutation burden, PD-L1 and microsatellite status) are currently being evaluated. Conclusions: Typical safety profiles were observed for D or D+T in mPDAC. Part B was not enrolled as the threshold for efficacy was not met in Part A. D and D+T had modest activity in second-line non-selected mPDAC, underpinning the need for multimodal immune-based combinations to overcome intrinsic resistance in this disease. Clinical trial information: NCT02558894.
Abstract Background: Isocitrate dehydrogenase 1/2 (IDH1/2) is mutated in a subset of cholangiocarcinoma (CCA), gliomas, and other solid tumors. LY3410738 is a potent, selective, covalent, dual inhibitor of IDH1/2 mutations (IDH1/2m). LY3410738 binds covalently at a novel binding site, enabling continued potency in preclinical models in the setting of second site IDH resistance mutations. We present initial results from the first-in-human phase 1 study of oral LY3410738 in patients (pts) with IDH1/2m CCA, and IDH1m glioma or other solid tumors. Methods: Dose escalation (3+3 design) evaluated LY3410738 monotherapy in advanced IDHm CCA and other solid tumors (NCT04521686). Key objectives included determining the RP2D, safety, PK, PD (inhibition of plasma D-2-HG), and preliminary antitumor activity. Results: As of 28 July 2022, 80 pts including 42 with CCA (33 IDH1m, 9 IDH2m), 27 with glioma (IDH1m), and 11 other tumor types (IDH1m) received LY3410738 dosed at 25-600 mg QD or 300 mg BID. Pts were median 52 years of age (range, 23-80) with a median of 2 prior therapies (range, 1-7). 19% of CCA pts had received prior IDH1 inhibitor. Median time on treatment was 3.7 months (range, 0.1-19). No DLTs or treatment related deaths were observed; the MTD was not reached. Treatment emergent adverse events (TEAEs) ≥15% included nausea (35%), vomiting (21%), and decreased appetite (19%) and were mostly grade 1-2. Most frequent grade ≥3 TEAEs >2% were anemia (4%), cholangitis (3%), headache (3%), decreased lymphocyte count (3%), and hyponatremia (3%). LY3410738 exposure was dose proportional. In pts with IDH1m cancers, LY3410738 achieved sustained D-2-HG inhibition at all dose levels, including in pts who received prior IDH1 inhibitor. In pts with IDH2m cancers, a higher dose (≥150 mg daily dose) was required for D-2-HG inhibition. Among the 42 pts with R/R CCA, the best response included 1 PR and 22 SD. Of the 22 glioma pts with contrast enhancing tumors, best response included 3 PR and 9 SD. Conclusions: LY3410738 demonstrated a favorable safety profile with potent and sustained D-2-HG inhibition in pts with IDH1/2m advanced solid tumors. Consistent with the expectations for IDH inhibitor monotherapy in this setting, CCA and glioma pts exhibited prolonged stable disease. RP2D evaluation is ongoing. Updated data on LY3410738 monotherapy will be presented at the meeting. Citation Format: Jordi Rodon, Lipika Goyal, Teresa Macarulla Mercade, Masafumi Ikeda, Shunsuke Kondo, Do-Youn Oh, Li-Yuan Bai, Makoto Ueno, Antoine Italiano, Kyriakos Papadopoulos, David Spigel, Sani H. Kizilbash, Rasha Cosman, Joon Oh Park, Li-Tzong Chen, Tomoya Yokota, Anita A. Turk, Chih-Yi Liao, Rachna Shroff, Anthony El-Khoueiry, Taroh Satoh, Antoine Hollebecque, Mitesh J. Borad, Nilofer Azad, Kurt A. Jaeckle, Herbert H. Loong, Jorge Adeva, Wei Peng Yong, Junjie Zhao, Hui Liu, Anna M. Szpurka, Ivelina Gueorguieva, Kamnesh R. Pradhan, Xiaojian Xu, James J. Harding. A first-in-human phase 1 study of LY3410738, a covalent inhibitor of mutant IDH, in advanced IDH-mutant cholangiocarcinoma and other solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT098.
Trastuzumab emtansine (T-DM1) is an antibody–drug conjugate incorporating the human epidermal growth factor receptor 2 (HER2)–targeted antitumor properties of trastuzumab with the cytotoxic activity of the microtubule-inhibitory agent DM1. The antibody and the cytotoxic agent are conjugated by means of a stable linker.
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