Dabak, Vrushali

Abstract Background: Endocrine therapy (ET) with aromatase inhibitors (AIs) plus ovarian function suppression (OFS) is a standard endocrine strategy for premenopausal women with ER+/HER2- breast cancer. However, poor tolerability to AI+OFS limits its use, leaving tamoxifen as the only alternative. Prospective studies demonstrated that premenopausal women treated with neoadjuvant ET whose tumors exhibit Ki-67 ≤ 10% following 4 weeks of therapy achieve 5-year distant disease-free survival > 96%. Problematically, only 41% of patients reach this threshold with tamoxifen compared to 78% with AI+OFS (Nitz JCO 2022). (Z)-endoxifen (ENDX) is a potent selective estrogen receptor modulator that dually targets ERα and PKCβ1. At plasma concentrations of 3-5 ng/mL, it inhibits ERα; at ≥ 500 ng/mL, it targets PKCβ1, leading to AKT suppression. The EVANGELINE trial aims to examine endocrine sensitivity in terms of Week 4 Ki-67 in premenopausal women whose baseline Ki-67 > 10%, and objective response rate after 24 weeks of ENDX + goserelin in premenopausal women with baseline Ki-67≤ 10%. Methods: EVANGELINE (NCT05607004) is a multicenter, open-label, Phase 2 study comprised of three parts. Eligible patients are premenopausal women with Stage IIA/IIB ER+/HER2- breast cancer. • Part 1 (PK Run-in): assessed 40mg vs 80mg ENDX (+/- OFS) in 22 patients. • Part 2: patients with baseline Ki-67 >10% were randomized to 40 mg ENDX + goserelin or exemestane + goserelin for 6 months with the primary objective being 4-week ESD rate. Patients with a baseline Ki-67 ≤10% were assigned to a single-arm cohort of 40 mg ENDX monotherapy (no OFS) to evaluate the 24-week endocrine sensitivity disease rate. • Part 3 (replaces Part 2): all patients are treated with ENDX 40mg daily + goserelin every 28 days. A two stage Phase II design was chosen to assess outcomes as follows: Part 3a: Up to 45 patients with baseline Ki-67> 10% to assess Week 4 Ki-67≤ 10% rate is at least 65%. If 9 or more of these patients have a Week 4 Ki-67>10%, enrollment will be stopped due to futility. Otherwise, enrollment will continue. Part 3b: Up to 20 patients enrolled with baseline Ki-67≤ 10% to assess Week 24 objective response rate. Ki-67 levels are determined by central laboratory and images are centrally reviewed. Secondary objectives include safety, tolerability, surgical outcomes, and biomarker analysis using paired biopsies (baseline, week 4) and surgical specimens. Results: The PK run-in (completed Fall 2024) enrolled 22 patients and assessed ENDX doses (40 mg daily vs 80 mg daily (+/-OFS)). The Week 4 Ki-67 ≤ 10% rate with ENDX was 86% and did not differ according to dose. Early safety, PK, efficacy and compliance data supported the selection of 40 mg ENDX daily as the optimal dose. Enrollment in Part 2 began in May 2025. Part 3 will replace Part 2 with simplification of the trial design. Conclusions: EVANGELINE is the first trial to evaluate (Z)-endoxifen + OFS as neoadjuvant therapy in premenopausal ER+/HER2- breast cancer. By targeting both ER and PKC pathways, ENDX may offer a well-tolerated alternative to AI-based regimens and expand endocrine therapy options for this population. Clinical Trial Registration: NCT05607004 Citation Format: M. P. Goetz, V. J. Suman, C. Lopez, H. Erickson, L. Beaulieu, S. S. Hammer, L. Mina, R. Leon-Ferre, K. N. Hunt, M. Piltin, A. Degnim, J. N. Ingle, J. C. Boughey, B. A. Sarah, J. M. Reid, M. Schellenberg, J. R. Hawse, P. Advani, K. Giridhar, F. Batalini, D. Flora, J. M. Jones, N. A. Bagegni, J. Jakub, V. Abramson, V. Dabak, W. J. Irvin, E. Sima, K. Seema, S. C. Quay. A Phase 2 Trial of (Z)-endoxifen + Goserelin as Neoadjuvant Treatment for Premenopausal Women with ER+, HER2-, Breast Cancer (EVANGELINE) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-12-16.

7522 Background: Elranatamab (ELRA) is a humanized BCMA-CD3 bispecific antibody. In the phase 2 registrational MagnetisMM-3 (MM-3) trial, SC ELRA was given as 2 step-up priming doses (12 mg on C1D1 and 32 mg on C1D4) followed by 76 mg QW in patients (pts) with RRMM. Overall, 56.3% of pts had CRS (grade 2, 14.3%; no grade ≥3). Most events occurred after doses 1 (44.5%), 2 (20.2%), and 3 (5.9%); 0.8% (1 pt) had CRS with doses 4+. Recurrent CRS (>1 event) occurred in 15.1% of pts (Lesokhin Nat Med 2023). Methods: MagnetisMM-9 (MM-9; NCT05014412) is a phase 1/2, open-label, nonrandomized study of ELRA examining an alternative 2-dose step-up priming regimen (4 and 20 mg on C1D1 and C1D4, respectively). Eligible pts had RRMM and were refractory to ≥1 IMiD, ≥1 PI, and ≥1 anti-CD38 antibody. After the priming doses, ELRA 76 mg was given QW for 6 cycles (Part 1) or for 1 cycle followed by 116 or 152 mg Q2W for 5 cycles (Part 2A). The RP2D from Part 2A (152 mg) was evaluated in Part 2B (dose expansion). The rate of grade ≥2 CRS per ASTCT criteria during C1 is the primary endpoint for both parts. Secondary endpoints include evaluation of AEs and PK. Here, we report the overall safety and CRS profile associated with the 4/20 mg priming regimen. Results: For 85 treated pts, median age was 64.0 y; 49.4% were male; 23.5% had EMD; 31.8% had high-risk cytogenetics. Pts had a median of 5.0 (range, 1-12) prior LOTs; 85.9% had triple-class refractory disease. After a median follow-up of 7.4 mo, the most common (>50%) AEs were CRS (63.5%; grade ≥2, 15.3%) and neutropenia (54.1%; all grade ≥2). ICANS occurred in 4.7% of pts (all grade ≤2). The grade ≥2 CRS rate in C1 was 14.1% (90% CI, 8.4-21.9). CRS rates after the first 3 doses are in the the table. For doses 4+, any grade (grade ≥2) CRS was observed in 10.6% (3.5%) of pts overall, 12.1% (3.0%) of pts continuing to receive 76 mg (n=33), 25.0% (0%) of pts receiving 116 mg (n=12), and 5.0% (5.0%) of pts receiving 152 mg (RP2D; n=40). Overall, recurrent CRS was observed in 20.0% of pts. The geometric means (CV%) of free ELRA concentrations 24 h (Cmax-24h) after step-up doses 1 and 2 were 85.64 (48%) and 242.8 (55%). Conclusions: The 4/20 mg step-up priming regimen and alternative dosing schedules resulted in similar safety and incidence of overall and grade ≥2 CRS events vs the regimen used in MM-3 (12/32 mg), with no new safety signals identified. However, the CRS profile in this study differed, with more CRS after doses 2, 3, and 4+ and a higher prevalence of recurrent CRS. The Cmax-24h of free ELRA (CV%) after the priming doses were lower than those in MM-3 (107.4 [47%] and 405.1 [72%], respectively). Thus, the priming regimen used in MM-3 remains the optimal regimen for mitigating CRS. Future analyses of ongoing studies will be used to confirm these results. Clinical trial information: NCT05014412 . [Table: see text]

ABSTRACT Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder that primarily causes the growth of tumors along nerves. Additionally, the germline mutations involved in NF1 predispose patients to develop further malignancies. The mainstay initial treatment for these malignancies is surgical removal at diagnosis, although targeted therapies are under evaluation in the relapsed setting. We report a case of malignant peripheral nerve sheath tumor (MPNST), gastrointestinal stromal tumor (GIST), and pheochromocytoma in a patient with NF1 who presented with an infected right shoulder lesion that was confirmed to be spindle cell sarcoma via biopsy. She was treated with antibiotics; however, she rapidly deteriorated and opted for hospice care. NF1 germline mutations increase the risk of patients developing various types of cancer. Recent studies have shown that there is a role for using MEK inhibitors such as selumetinib for treating patients with NF1.

ABSTRACT Primary splenic or hepatic angiosarcomas are ultra-rare and aggressive malignancies associated with poor prognosis. The mainstay treatments are surgical resection and chemotherapy. We report a case of angiosarcoma in a 50-year-old woman who presented with bruising, fatigue, ecchymosis, and hepatosplenomegaly. She was treated with the multi-kinase inhibitor sunitinib for 4 weeks before developing a splenic hemorrhage and succumbing. Recent studies have demonstrated the clinical benefit of immunotherapies in angiosarcomas. Additionally, sequencing techniques have showcased the diverse molecular aberrations involved in angiosarcomas, which offer opportunities for precision-matched targeted therapies such as inhibitors of the VEGF/VEGFR axis and PI3K/Akt/mTor pathway.