Data describing the safety/efficacy of targeted therapies in combination with stereotactic radiotherapy (SRS/SRT) for brain metastases are limited. We leverage a bicentric cohort to evaluate rates of intracranial failure and radiation necrosis in patients receiving targeted therapy and SRS. Patients with intact brain metastases at two institutions treated with SRS/SRT and concurrent central nervous system (CNS)-active targeted therapy were identified. Concurrent targeted therapy was defined as receipt of targeted therapy starting before and continuing through receipt of radiation therapy, except for a brief washout interval of 3–7 days. Patients were followed for a minimum of 3 months after SRS/SRT with brain MRI. Kaplan-Meier analysis was performed to evaluate overall survival and cumulative rates of symptomatic radiation necrosis (sRN). Variables associated with radiation necrosis on univariable analysis (p < 0.2) were included in a multivariable logistic regression model for adjusted analysis. The study included 93 patients with 306 metastases, and median follow-up was 17 months. The overall rate of sRN per-metastasis and per-patient was 16/306 (5
Background: Baseline lymphopenia is common among advanced solid tumors and may influence the efficacy/safety of immune checkpoint inhibitors (ICIs), but large real-world evidence is limited. We evaluated the association between baseline absolute lymphocyte count (ALC) and clinical outcomes in adults with solid tumors treated with ICIs in routine practice. Methods: We performed a retrospective cohort study using TriNetX. Adults with solid tumors who received pembrolizumab, nivolumab, or atezolizumab (ICI-Naïve) between January 2015 and June 2026 were included. Baseline ALC was measured within 30 days before first treatment and was classified as lymphopenic (ALC < 1.5 × 109/L) or non-lymphopenic (ALC ≥ 1.5 × 109/L). Propensity score matching (1:1) yielded 5249 patients per group. The index date was the first immunotherapy date, and outcomes were assessed at 6, 12, 24, 36 months, and 5 years. The primary outcome was 24-month overall survival (OS); secondary outcomes were OS at 6 and 12 months and 6-month risks of healthcare utilization, immune-related adverse events (irAEs), and serious infections; and exploratory outcomes included OS at 36 months and 5 years. All outcomes were analyzed using Kaplan-Meier analysis, Cox proportional hazards models, and risk ratios. Subgroup analysis included OS stratified by solid tumor subtypes and prior lines of therapy. Results: After matching, patients with baseline lymphopenia had consistently worse OS. Compared with patients without lymphopenia, the lymphopenia cohort had lower OS at 6 months (HR 1.29, 95% CI 1.22-1.37), 12 months (HR 1.28, 95% CI 1.21-1.35), 24 months (HR 1.26, 95% CI 1.2-1.33), and, in exploratory analyses with substantial right censoring and limited observed follow-up, 36 months (HR 1.26, 95% CI 1.2-1.33) and 5 years (HR 1.26, 95% CI 1.2-1.33), though these estimates should be considered hypothesis-generating only. At 6 months, baseline lymphopenia was associated with a greater healthcare utilization (RR 1.05, 95% CI 1.02-1.09), a higher infection risk (RR 1.08, 95% CI 1.01-1.15), and similar rates of clinically coded irAEs (RR 1.0, 95% CI 0.93-1.09), an observation subject to competing risk from early mortality in the lymphopenic cohort. Subgroup analysis, stratified by tumor subtypes and prior lines of therapy, showed consistently lower OS in the lymphopenia group, consistent with the primary outcome results. Conclusions: In this large propensity-matched real-world analysis of 10,498 patients with diverse solid tumors, baseline lymphopenia at ICI initiation was associated with persistently inferior OS at 6, 12, and 24 months (primary and secondary endpoints), greater early healthcare utilization, and a higher serious infection risk. Critically, lymphopenic patients developed irAEs at an identical rate to non-lymphopenic patients despite worse survival, a dissociation suggesting that baseline ALC stratifies patients along mortality risk and immune activation capacity as partially independent axes. These findings could support the use of baseline ALC as a simple, universally available biomarker that informs not only survival prognosis but also the anticipated toxicity profile of ICI therapy and highlight the need for competing-risk analyses and prospective immune phenotyping to characterize this relationship fully.
Zelenectide pevedotin (zele; formerly BT8009) is a Bicycle® Drug Conjugate (BDC®) comprised of a highly selective bicyclic peptide targeting Nectin-4 linked to monomethyl auristatin E (MMAE) via a cleavable linker. With low molecular weight and a short plasma half-life, zele has the potential to rapidly penetrate solid tumours with minimal exposure to healthy tissue. The ongoing Phase 1/2 Duravelo-1 trial (NCT04561362; BT8009-100) has shown preliminary antitumour activity and a manageable safety profile of zele monotherapy in patients (pts) with breast cancer (BC). This open-label, multicentre, Phase 2 Duravelo-3 study (NCT06840483; BT8009-201) aims to further evaluate the efficacy and safety of zele monotherapy in pts with recurrent, unresectable, or metastatic NECTIN4 amplified (amp) BC. The trial will enrol pts into 2 cohorts: pts with hormone receptor (HR)+/human epidermal growth factor receptor 2 (HER2)– BC who have received ≤3 prior lines of nonendocrine-based therapy in the metastatic setting (Cohort A; n≈33) and pts with triple-negative BC who have received 1–3 prior lines of systemic therapy in the metastatic setting (Cohort B; n≈33). NECTIN4 amp is defined as a NECTIN4:CEN1 ratio ≥2.0 or NECTIN4 copy number ≥6, per fluorescence in situ hybridization. All pts must have ECOG performance status 0–1 and adequate organ function. Pts previously treated with MMAE will be excluded. All pts will receive zele 6 mg/m2 IV on Days 1 and 8 of a 21-day cycle. The primary endpoint is objective response rate. Secondary endpoints are duration of response, clinical benefit rate, disease control rate, progression-free survival, overall survival, time to progression, and incidence of adverse events. Efficacy endpoints will be investigator-assessed per RECIST v1.1. Exploratory endpoints will include assessment of baseline tumour biomarkers, including Nectin-4 expression and surrogates of NECTIN4 amp, and peripheral blood biomarkers such as circulating Nectin-4 protein and tumour DNA. Pharmacokinetics, correlation of efficacy and safety with biomarkers of NECTIN4 amp, and measurement of antidrug antibody are additional exploratory endpoints. This study is actively recruiting. P. A. Kaufman, P. Aftimos, J. Cortes, G. Curigliano, F. Dalenc, M. Danso, K. Jhaveri, M. Rimawi, C. Saura, P. Savas, P. Schmid, J. Ricker, K. Josephs, C. Xu, E. Hamilton. A Phase 2 study of zelenectide pevedotin, a Bicycle Drug Conjugate, in patients with NECTIN4 amplified advanced breast cancer (Duravelo-3) [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 PS5-09-23.
The standard of care for patients with high-risk, early-stage triple-negative breast cancer (TNBC) is neoadjuvant pembrolizumab + chemotherapy followed by adjuvant pembrolizumab. Patients with HR-low+/HER2− breast cancer are often managed according to TNBC recommendations. There is a need for improved neoadjuvant therapy to increase the rate of pathological complete response (pCR), as patients who do not achieve pCR have a high risk of recurrence, and to reduce risk of long-term toxicities associated with cyclophosphamide and anthracyclines. HER3 is frequently expressed in breast cancer and overexpression is associated with drug resistance. Patritumab deruxtecan (HER3-DXd) is an antibody-drug conjugate comprising a fully human anti-HER3 IgG1 monoclonal antibody linked to a topoisomerase I inhibitor (DXd) via a stable tetrapeptide-based linker that is selectively cleaved within tumor cells. In a phase 2 study, HER3-DXd monotherapy showed antitumor activity and manageable safety in heavily pretreated participants with HER3-high expressing TNBC. This phase 2 study (NCT06797635) is evaluating neoadjuvant HER3-DXd + pembrolizumab administered before or after carboplatin + paclitaxel + pembrolizumab for early-stage TNBC or HR-low+/HER2− breast cancer. Eligible participants are adults (≥18 y) with untreated, locally advanced nonmetastatic (AJCC stage cT1c, N1-N2 or cT2-cT4, N0-N2) TNBC or HR-low+/HER2− breast cancer. Participants (N ≥10 and ≤30) in Part 1 of the study (safety lead-in) will receive neoadjuvant HER3-DXd + pembro followed by carboplatin + paclitaxel + pembro (Table) followed by surgery. Dose-limiting toxicity evaluation and dose finding for HER3-DXd (up to three dose levels of 5.6 mg/kg Q3W, 4.8 mg/kg Q3W and 3.2 mg/kg Q3W) during cycle 1 of neoadjuvant HER3-DXd + pembrolizumab will be performed in Part 1 to determine an optimal dose of HER3-DXd for Part 2. Participants (N ∼342) in Part 2 will be randomly assigned 1:1:1 to Arm A, B or C (Table) for neoadjuvant treatment. Randomization will be stratified by cancer type (TNBC vs HR-low+/HER2−) and, in the TNBC subgroup, PD-L1 status (combined positive score ≥10 vs <10), overall clinical stage (II vs III) and HER3 expression per IHC (low vs high). After neoadjuvant treatment, participants will undergo surgery (with postoperative radiotherapy if clinically indicated) and receive adjuvant pembrolizumab 400 mg Q6W for 5 cycles. Participants with residual disease may receive additional adjuvant treatment of physician’s choice. Primary endpoints are safety (Part 1 and 2) and pCR (ypT0/Tis ypN0) rate (Part 2). Enrollment is ongoing. J. O'Shaughnessy, J. M. Collins, L. Yao, K. L. Smith, J. A. Mejia, M. Danso. Herthena-breast03: a phase 2, randomized, open-label study evaluating neoadjuvant patritumab deruxtecan (HER3-DXd) + pembrolizumab before or after pembrolizumab + chemotherapy for early-stage TNBC or HR-low+/HER2− breast cancer [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 PS5-12-21.
