ABSTRACT
Background: Datopotamab deruxtecan (Dato-DXd) is an antibody-drug conjugate (ADC) consisting of a humanized anti-TROP2 IgG1 monoclonal antibody covalently linked to a highly potent topoisomerase I (Topo I) inhibitor payload via a stable, tumor-selective, tetrapeptide-based cleavable linker. Dato-DXd demonstrated compelling single-agent antitumor activity in heavily pretreated patients (pts) with metastatic triple-negative BC (Krop, SABCS 2021). This is the first report of results from the TROPION-PanTumor01 study in pts with unresectable or metastatic hormone receptor- positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-;including HER2-low and HER2-zero) BC. Method(s): TROPION-PanTumor01 (NCT03401385) is a phase 1, multicenter, open-label, 2-part doseescalation/expansion study evaluating Dato-DXd in previously treated pts with solid tumors. Based on previous clinical findings and exposure-response results from pts with NSCLC, Dato-DXd 6 mg/kg IV Q3W is being evaluated in pts with unresectable or metastatic HR+/HER2- BC that progressed on standard therapies. The primary objectives were safety and tolerability. Tumor responses, including ORR (complete response [CR] + partial response [PR]) and DCR (CR + PR + stable disease [SD]), were assessed per RECIST version 1.1 by blinded independent central review. Result(s): As of the April 29, 2022, data cutoff, 41 pts had received Dato-DXd (median follow-up, 10.9 mo [range, 7-13]);9 pts were ongoing. The primary cause of treatment discontinuation was disease progression (63% progressive disease [PD] or clinical progression). Median age was 57 y (range, 33- 75);54% had de novo metastatic disease. Pts were heavily pretreated (Table) with a median of 5 (range, 3-10) prior regimens in the advanced setting;95% had prior CDK4/6i (adjuvant/metastatic). Median time from initial treatment for metastatic disease to the first dose of Dato-DXd was 42.7 mo (range, 10.2-131.1). Treatment-emergent adverse events (TEAEs;all cause) were observed in 98% (any grade) and 41% (grade >=3) of pts. Most common TEAEs (any grade, grade >=3) were stomatitis (80%, 10%), nausea (56%, 0%), fatigue (46%, 2%), and alopecia (37%, 0%). Serious TEAEs were observed in 6 pts (15%);1 pt died due to dyspnea, which was not considered to be treatment related. Dose reductions occurred in 5 pts due to stomatitis (n=3), fatigue (n=2), keratitis (n=1), and decreased appetite (n=1) (>1 AE per pt);14 pts had treatment delayed due to stomatitis (n=8), retinopathy (n=1), dysphagia (n=1), fatigue (n=1), malaise (n=1), COVID-19 (n=1), cellulitis (n=1), urinary tract infection (n=1), decreased lymphocyte count (n=1), and nasal congestion (n=1;>1 AE per pt). Three pts discontinued treatment due to keratitis (n=1) and pneumonitis (n=2);1 case of pneumonitis was adjudicated as grade 2 drug-related interstitial lung disease. The ORR was 29% (11 confirmed PRs;1 pending confirmation), the DCR was 85% (35/41), and the clinical benefit rate (CR + PR + SD >=6 mo) was 41% (17/41). Conclusion(s): Dato-DXd demonstrated a manageable safety profile and encouraging antitumor activity, with high disease control in heavily pretreated pts, the majority having received prior CDK4/6i. Based on these findings, the TROPION-Breast01 (NCT05104866) randomized phase 3 study comparing 2L+ Dato-DXd vs investigator's choice chemotherapy is currently enrolling pts with HR+/HER2- BC.
ABSTRACT
Background: HER2+ mBC remains incurable, with a need for new HER2-directed therapies and regimens, including chemotherapy-free options. Zanidatamab (zani) is a novel HER2-targeted bispecific antibody that binds HER2 in a unique trans configuration, driving multiple mechanisms of antitumor activity, including complement-dependent cytotoxicity. A CDK4/6 inhibitor combined with endocrine therapy is an approved treatment for HER2-negative/HR+ mBC and this combination has also demonstrated encouraging antitumor activity when paired with HER2-targeted therapy(ies) in HER2+/HR+ mBC. Here, we report results from ZWI-ZW25-202 (NCT04224272), an ongoing singlearm phase 2 study of zani combined with palbociclib (palbo) and fulvestrant (fulv) in pts with HER2+/HR+ mBC. Method(s): Eligibility requirements include: HER2+/HR+ unresectable, locally advanced BC or mBC;ECOG PS of 0 or 1;prior treatment with trastuzumab, pertuzumab and T DM1 (additional prior HER2-targeting agents are permitted);and no prior treatment with CDK4/6 inhibitors. Part 1 of the study evaluated the safety and tolerability of the zani/palbo/fulv combination and determined the recommended doses for use in Part 2, where the antitumor activity of the combination is being evaluated. Endpoints include safety outcomes, progression-free survival at 6 months (PFS6), confirmed objective response rate (cORR) per RECIST v1.1;disease control rate (DCR=complete response [CR] plus partial response [PR] plus stable disease [SD]);duration of response (DOR);PFS;and overall survival. Result(s): As of 24 Feb 2022, 34 pts (33 HER2+/HR+ per central analysis) with a median age of 52 (range 36-77) have been treated. In the metastatic setting, pts had received a median (range) of 4 (1-10) prior systemic regimens, including 3 (1-8) different prior HER2 targeted therapies, and 1 (0-4) endocrine therapy. Seven pts (20%) had prior T DXd treatment and 7 pts had prior fulv treatment. All pts received zani (20 mg/kg Q2W) and standard doses of palbo and fulv. Eighteen pts (53%) remained on treatment;median duration of zani treatment was 6.9 mo (range 0.5- 16.3). A dose-limiting toxicity (DLT) of neutropenia occurred in 1 of 7 DLT-evaluable pts in Part 1. Among all pts (n=34), the most common (>20%) treatment (zani, palbo and/or fulv)-related adverse events (TRAEs) were diarrhea (74%), neutrophil count decreased/neutropenia (62%), stomatitis (41%), asthenia (26%), nausea (24%), and anemia (21%). Grade (Gr) >=3 TRAEs in 2 or more pts included neutrophil count decreased/neutropenia (50%), anemia (6%), diarrhea (6%), and thrombocytopenia (6%). AEs of special interest were all Gr <=2 and included 4 pts with cardiac events (LVEF decrease of >=10% from baseline) and 1 pt with infusion-related reaction. There were no treatment-related serious AEs. Palbo was discontinued for 1 pt due to an AE (AST increase);no pt discontinued zani treatment as a result of AEs. Two deaths occurred: 1 due to disease progression and 1 due to an unrelated AE of pneumonia caused by COVID-19. In 29 pts with measurable disease, the cORR was 34.5% (95% CI: 17.9, 54.3), all responses were cPRs, of which 1 is pending CR confirmation. DOR ranged from 2.3 to 14.9+ mo, with 8 confirmed responses ongoing, and the DCR was 93.1% (95% CI: 77.2, 99.2). Interim median PFS was 11.3 mo (range 0.03-16.7;95% CI: 5.6, not estimable). PFS6 analysis is planned following the completion of enrollment. Conclusion(s): Zani in combination with palbo and fulv shows encouraging antitumor activity with durable responses in heavily pretreated pts and a manageable safety profile. This regimen has the potential to be a chemotherapy-free treatment option in pts with HER2+/HR+ mBC. Enrollment in the study is continuing.
ABSTRACT
The COVID-19 Pandemic adversely impacted the nation's blood supply such that blood suppliers could not fill standing orders. To address the dwindling blood supply, the American Red Cross (ARC) implemented daily thresholds, which distributed red blood cells (RBCs) based on clients' historical blood orders and the ARC's inventory. The threshold system left the blood bank to devise a process to judiciously allocate the reduced RBC supply across our institution. Herein, we describe an internal RBC utilization audit, the data from which we used to devise an algorithm to predict our ability to meet transfusion requirements for operating room (OR) procedures. An OR adjudication committee used our report to prioritize elective surgical cases taking places the following day. Thirtyone non-consecutive days of blood inventory release slips were reviewed across three months of recent transfusions. Weekdays were disproportionally investigated to predict the blood utilization for days with scheduled OR procedures. For all RBCs released, the blood type requested and the final disposition (transfused vs returned to blood bank) of the units were recorded. Average use was calculated as well as interquartile range (IQR) to account for transfusion variability. Utilization data was then used to develop a worksheet-based tool to predict ability to meet RBC requirements. Overall, the hospital transfused an average of 80 RBC units each weekday (IQR: 64-92 units). Approximately 40% of all requested RBC units were released to the OR. In turn, the OR transfused only 39% of the RBCs released to them, which represented 20% of transfusions hospital-wide. The OR requested an average of 41 RBC units each weekday (IQR: 25-57 units). The OR transfused an average of 16 units of RBCs each weekday (IQR: 9-21 units). The outpatient cancer center infusion clinic used less than 15% of total RBCs. The biggest user of RBCs were inpatients, who were transfused 65% of RBCs during the week and 82% of transfusions during the weekend. These percentages and the averageto-third-quartile range were used to devise a blood allocation algorithm to inform the OR if the blood bank could support anticipated use. The data was also used to devise a blood allocation worksheet for the on-call transfusion medicine physicians to predict our ability to provide adequate blood for emergent, non-elective procedures that require transfusion support such as liver transplants and aortic repairs. The audit of RBC disposition informed blood inventory management practices during a time of remarkable shortage. Within the confines of the threshold system, the transfusion medicine service allocated the expected number of units based on historical request and transfusion data to predict whether inventory levels could support scheduled and nonscheduled OR procedures.