| Autor: |
Tolaney, Sara M, DeMichele, Angela, Takano, Toshimi, Rugo, Hope S, Perou, Charles, Lynce, Filipa, Parsons, Heather Anne, Santa-Maria, Cesar Augusto, Rocque, Gabrielle Betty, Yao, Wenliang, Sun, Shawn W, Mocci, Simonetta, Partridge, Ann H, Carey, Lisa A |
| Zdroj: |
Future Oncology; 2024, Vol. 20 Issue 31, p2343-2355, 13p |
| Abstrakt: |
Patients with early-stage triple-negative breast cancer (TNBC) with residual invasive disease after neoadjuvant therapy have a high risk of recurrence even with neoadjuvant and adjuvant treatment with pembrolizumab. Sacituzumab govitecan, a Trop-2-directed antibody–drug conjugate with a topoisomerase I inhibitor payload, improved progression-free survival (PFS) and overall survival (OS) versus chemotherapy in patients with pre-treated metastatic TNBC. Moreover, preclinical data suggest that topoisomerase I inhibitors may enhance the effects of immune checkpoint inhibitors through activation of the cGAS-STING pathway. Here we describe the international randomized phase III AFT-65/ASCENT-05/OptimICE-RD trial, which evaluates the efficacy and safety of sacituzumab govitecan plus pembrolizumab versus treatment of physician's choice (pembrolizumab ± capecitabine) among patients with early-stage TNBC with residual invasive disease after neoadjuvant therapy. Clinical Trial Registration:NCT05633654 (ClinicalTrials.gov) Other Study ID Number(s): Gilead Study ID: GS-US-595-6184 Registration date: 1 December 2022 Study start date: 12 December 2022 Recruitment status: Recruiting Plain Language Summary AFT-65/ASCENT-05/OptimICE-RD is an ongoing clinical trial that is testing a new treatment combination for patients with stage II or III triple-negative breast cancer (TNBC). Stage II–III means the cancer is confined to the breast and/or nearby lymph nodes and can be surgically removed. However, there remains a risk that the cancer could recur after surgery. To reduce this risk, patients with stage II–III TNBC receive anti-cancer medication before and after surgery. For some patients, receipt of anti-cancer medication before surgery produces a pathologic complete response (pCR), meaning there is no observable cancer left behind at surgery. Patients with a pCR have a lower risk of recurrence than patients with residual disease. The AFT-65/ASCENT-05/OptimICE-RD trial includes people with stage II-III TNBC who have residual cancer after completing their course of pre-surgery anti-cancer medication. All participants have any remaining cancer in their breast and/or lymph nodes removed surgically, after which they are randomly assigned to receive one of two treatments. The experimental therapy consists of pembrolizumab along with a medication called sacituzumab govitecan, which kills cancer cells directly and may strengthen the anti-cancer immune response. Pembrolizumab strengthens the anti-cancer immune response, so the hypothesis of this trial is that the two medications will be more effective together. The control therapy consists of pembrolizumab, alone or in combination with a chemotherapy medication called capecitabine, which is the current standard of care. To study the effectiveness of each treatment, the researchers are following up with all participants to learn if and when their breast cancer returns. Article highlights Background Patients with stage II-III triple-negative breast cancer (TNBC) with residual invasive disease after neoadjuvant therapy have a high risk of recurrence with current standard-of-care adjuvant therapy regimens. Trop-2 is a transmembrane protein that is highly expressed on epithelial cancers, including TNBC. Sacituzumab govitecan is an antibody–drug conjugate consisting of an anti-Trop-2 antibody conjugated to SN-38 (the active metabolite of the DNA topoisomerase I inhibitor irinotecan) via a hydrolizable linker. This formulation facilitates release of SN-38 intracellularly as well as outside of cancer cells in the tumor microenvironment, creating a bystander killing effect. Preclinical evidence suggests that sacituzumab govitecan and anti-PD-1/PD-L1 agents exert synergistic activity. DNA-damaging agents activate cGAS-STING signaling, which results in recruitment of anti-tumor immune cells through type I interferon signaling. Immune cell activity is enhanced by the immune checkpoint inhibitor. AFT-65/ASCENT-05/OptimICE-RD Trial The randomized, open-label, phase III AFT-65/ASCENT-05/OptimICE-RD trial investigates the combination of sacituzumab govitecan plus pembrolizumab versus treatment of physician's choice (TPC; pembrolizumab alone or in combination with capecitabine) in patients with stage II-III TNBC with residual invasive disease in the breast or lymph nodes after completion of neoadjuvant therapy. Patients must be at least 18 years old with histologically confirmed TNBC, clinical stage T1, N1-2 or T2-4, N0-2. Patients must have received at least 6 cycles of neoadjuvant anthracycline and/or taxane-containing chemotherapy with or without an immune checkpoint inhibitor. Approximately 1514 patients will be randomized 1:1 to receive sacituzumab govitecan 10 mg/kg IV on day 1 and day 8, every 21 days for 8 cycles, plus pembrolizumab 200 mg IV on day 1 every 21 days for 8 cycles, or TPC, which consists of pembrolizumab 200 mg IV on day 1 every 21 days for 8 cycles with or without capecitabine 1000 mg/m2 orally twice daily on day 1–14 every 21 days for 8 cycles. The primary end point is iDFS. Secondary end points include overall survival, recurrence-free survival and safety and tolerability. Exploratory end points include analysis of Trop-2 and PD-L1 expression on tumor tissue and correlation with clinical outcomes. Patient-reported outcomes (PROs) include the FACT-B, EQ-5D-5L and PRO-CTCAE. Conclusion Results from the randomized phase III AFT-65/ASCENT-05/OptimICE-RD trial will provide efficacy and safety data for sacituzumab govitecan plus pembrolizumab versus pembrolizumab (alone or in combination with capecitabine) that could lead to a novel, more effective therapeutic combination to prevent disease recurrence in patients with stage II-III TNBC with residual invasive disease after the completion of neoadjuvant therapy. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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