Virginia Oncology Associates

AC699 is a novel, orally bioavailable chimeric estrogen receptor-α (ERα) degrader that induces proteasome-dependent ERα degradation via cereblon E3 ligase recruitment. Here we report findings from a first-in-human, phase 1, dose-escalation study of once-daily AC699 (100-600 mg) in patients with heavily-pretreated, locally-advanced/metastatic ER-positive/HER2-negative breast cancer (ClinicalTrials.gov Identifier: NCT05654532). Primary objectives are to assess dose-limiting toxicities and treatment-emergent adverse events (TEAEs). Secondary objectives are to evaluate pharmacokinetics, objective response rate (ORR), clinical benefit rate (CBR, including stable disease ≥24 weeks), duration of response (DOR), and progression-free survival (PFS). Among 37 treated patients, TEAEs occurred in 78% of patients, most commonly nausea (19%), fatigue (16%), and neutropenia (16%). All treatment-related adverse events were Grade 1/2, with no dose reductions/discontinuations; the maximum tolerated dose was not reached. Of 26 efficacy-evaluable patients, 4 (15%) achieved partial responses and CBR was 23%. In exploratory analysis of patients with ESR1 mutations, ORR and CBR were 40% and 45%, respectively. Median DOR and PFS were 6.5 and 3.6 months overall, and 6.5 and 7.4 months in ESR1-mutant patients. AC699 steady-state exposure increased approximately dose-proportionally between 100-400 mg, plateauing at 600 mg. AC699 demonstrated favorable safety, predictable PK, and encouraging antitumor activity, particularly in ESR1-mutant disease.

Secondary medication delivery using large-volume smart pumps offers important workflow and safety benefits. However, the widely used linear peristaltic large-volume smart pumps rely on sufficient head-height differential for accurate secondary infusion, leading to underdelivery risks. This article outlines common clinician workarounds used to mitigate these risks, including delivering secondary medications via primary mode, programming excess volume to be infused, clamping primary lines, and using short-set primary delivery. Although intended to ensure full medication delivery, these strategies introduce safety risks, increase alert burden, and heighten cognitive load. In contrast, cassette-based large-volume smart pumps use valve-controlled fluid delivery, eliminating the need for head-height differential and reducing the potential for human error. This review evaluates the risks and rewards of these workarounds and offers guidance to support informed decision-making while advocating for long-term technology solutions that improve safety, reduce clinician burden, and align with best practices in infusion therapy.

6516 Background: ASC2ESCALATE (NCT05384587) is the first prospective trial of ASC in CML-CP after 1 TKI (2L) with dose escalation for pts with suboptimal response; ASC is also being assessed in a separate newly diagnosed (1L) cohort. A previous IA of the 2L cohort reported ASC’s safety (n=71) and wk 24 efficacy (n=28; BCR::ABL1 IS ≤1%, 85.7%; major molecular response [MMR], 42.9%). We report updated safety (n=101) and wk 24 efficacy (n=63) results. Methods: ASC2ESCALATE is a phase 2, single-arm, open-label US study of ASC in adults with 1L or 2L CML-CP without the T315I mutation. In the 2L cohort, eligible pts had discontinued their prior TKI due to warning or failure per ELN2020 or intolerance with BCR::ABL1 IS >0.1% at screening. Pts received ASC 80 mg once daily (QD). If BCR::ABL1 IS >1% at wk 24, dose was increased to 200 mg QD. If BCR::ABL1 IS >0.1% at wk 48, dose was increased from 80 to 200 mg QD or from 200 mg QD to 200 mg twice daily, or pts could be taken off study. If pts had any grade 3/4 or persistent grade 2 toxicity refractory to optimal management, they were ineligible for dose escalation at wk 24 and/or 48 and continued the same dose. Results: This IA included all 101 pts enrolled with 2L CML-CP; all pts had received ≥1 ASC dose by the cutoff (Nov 15, 2024). Prior treatment (Tx) included dasatinib (44.6%), imatinib (42.6%), nilotinib (9.9%), or bosutinib (5.0%); 66.3% of pts had received prior Tx for ≥12 mo. Pts discontinued prior Tx due to lack of efficacy (56.4%) or intolerance (43.6%). By the cutoff, 92 pts (91.1%) remained on ASC; 9 pts (8.9%) discontinued ASC, mostly due to adverse events (AEs; n=4) and pt decision (n=3). Median duration of ASC exposure was 26.1 (range, 6-100) wk. Pts evaluable for all efficacy analyses completed assessments for the respective timepoint or discontinued earlier (wk 4, n=94; wk 12, n=86; wk 24, n= 63). At wk 4, 12, and 24, 46.8%, 84.9%, and 82.5% pts, respectively, had BCR::ABL1 IS ≤1%. Deeper responses were also achieved at wk 12 (MMR, 39.5%; MR 4 , 11.6%; MR 4.5 , 2.3%) and 24 (MMR, 44.4%; MR 4 , 25.4%; MR 4.5 , 9.5%). Seven pts had dose escalation from 80 to 200 mg QD per their response level at wk 24 (n=3) and 48 (n=4). All-grade AEs ≥20% were headache (22.8%) and nausea (20.8%). Grade ≥3 AEs ≥5% were hypertension (8.9 %), thrombocytopenia (6.9%), and neutropenia (5.9%). AEs led to dose adjustment/interruption in 27 pts (26.7%). AEs led to discontinuation in 4 pts; 1 of these AEs occurred >30 d after last ASC dose. No arterial-occlusive events or on-Tx deaths occurred. Conclusions: 2L ASC demonstrated high molecular response rates at wk 24 and safety consistent with previously established ASC data across Tx lines; no new or worsening safety signals arose. ASC was tolerable with few AEs leading to discontinuation. These IA results support ASC as a Tx option in 2L CML-CP. The impact of dose escalation continues to be explored. Clinical trial information: NCT05384587 .

In non-small-cell lung cancer (NSCLC), activating human epidermal growth factor receptor 2 (HER2) mutations are found in a small subset of patients and are associated with a higher incidence of brain metastases (BMETSs), conferring poor survival outcomes. Trastuzumab deruxtecan (T-DXd) was recently approved as a second-line agent for use in patients with previously treated, unresectable, or metastatic HER2-mutated NSCLC. We present a case of HER2-mutated NSCLC with BMETS, treated with T-DXd to defer whole-brain radiotherapy (WBRT) because of the concern of long-term neurotoxicity. He initially also received bevacizumab to address the cerebral edema, which allowed stopping corticosteroids. After the first two doses, the patient had remarkable clinical and imaging (brain and systemic) responses without progression after more than 1 year of treatment. T-DXd may be an effective and durable therapy for patients with HER2-mutated NSCLC with brain metastases in situations where intracranial disease would otherwise warrant WBRT. Clinical trials are needed to understand the efficacy and durability of T-DXd in NSCLC with BMETS and the optimal sequence of available therapies.