For advanced breast cancer that is hormone receptor–positive and HER2-negative, sacituzumab govitecan-hziy significantly reduced the risk of disease progression by 34% over physician’s choice of treatment, based on the results of the phase III TROPiCS-02 trial.1 The heavily pretreated patients in the study had received a median of three prior therapies for metastatic disease. The primary progression-free survival analysis of TROPiCS-02 and the first of three planned overall survival analyses were presented at the 2022 ASCO Annual Meeting by Hope S. Rugo, MD, FASCO, Professor of Medicine at the University of California San Francisco.
“In the landmark analysis, three times more women were progression-free at the 1-year mark when treated with sacituzumab govitecan compared with treatment of physician’s choice (21% vs 7%). Sacituzumab govitecan should be considered a potential treatment option for these patients,” said Dr. Rugo.
Meeting the primary endpoint, the study showed a statistically significant improvement in progression-free survival by independent review. Median progression-free survival was 5.5 months with sacituzumab govitecan and 4.0 months with chemotherapy (hazard ratio [HR] = 0.66; P = .0003).
Hope S. Rugo, MD, FASCO
Jane Lowe Meisel, MD
ASCO expert in breast cancer Jane Lowe Meisel, MD, of Emory University School of Medicine, Atlanta, commented on the findings at a press briefing: “We’ve all been eagerly awaiting the results of this trial. We’ve seen how dramatically sacituzumab govitecan works in triple-negative breast cancer. These estrogen receptor–positive, endocrine-resistant patients can be difficult to treat and an area of great unmet need.”
“The idea that a patient with heavily pretreated disease could walk into your clinic and you could offer her an option that would allow a one in five chance of not having disease progression at 1 year is huge from a clinical standpoint. In our incremental options, we need drugs that may be better than chemotherapy. This study represents a step forward for the field,” Dr. Meisel stated.
Difficult-to-Treat Population
Sacituzumab govitecan, an anti-Trop2 antibody-drug conjugate, is approved for patients with metastatic triple-negative breast cancer after at least two prior treatments (one or more for metastatic disease). The findings from TROPiCS-02 suggest the drug may be useful in women with hormone receptor–positive tumors as well.
As Dr. Rugo pointed out, hormone receptor–positive/HER2-negative tumors account for about 70% of metastatic disease. International guidelines recommend sequential endocrine therapy, starting with first-line endocrine therapy in combination with cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors. When resistance to endocrine therapy develops, the next step is sequential single-agent chemotherapy.
“This is associated with declining efficacy and increased toxicity,” Dr. Rugo noted. “With limited chemotherapy options in later-line settings, there remains a high unmet clinical need.”
About TROPiCS-02
TROPiCS-02 is a global, open-label, randomized phase III study that enrolled 543 patients who had received a median of three prior regimens in the metastatic setting. Most of them had visceral metastases (95%) and had a median time from initial metastatic diagnosis to randomization of approximately 4 years.
Patients were required to have received at least one endocrine therapy and a CDK4/6 inhibitor and to have been treated with two to four lines of chemotherapy for metastatic disease. Baseline characteristics were balanced between the arms.
Investigators randomly assigned patients to receive sacituzumab govitecan (10 mg/kg on days 1 and 8 every 21 days) or treatment of physician’s choice: capecitabine, eribulin, vinorelbine, or gemcitabine. The primary endpoint was progression-free survival by blinded independent review.
Landmark Analysis
Median progression-free survival was 5.5 months with sacituzumab govitecan vs 4.0 months with standard chemotherapy (HR = 0.66; P = .0003). The benefit was consistent across subgroups, including patients who had received at least three prior chemotherapy regimens in the metastatic setting (HR = 0.70), had visceral metastases (HR = 0.66), and were aged 65 or older (HR = 0.59).
Response rates were 21% with sacituzumab govitecan and 14% with chemotherapy (odds ratio [OR] = 1.63; P = .03), and the clinical benefit rates were 34% and 22%, respectively (OR = 1.84; P = .002). Overall survival data were immature, but a numerical trend for improvement was seen, with median overall survival of 13.9 months vs 12.3 months (HR = 0.84; P = .14), respectively. Progression-free survival rates for sacituzumab govitecan vs chemotherapy were 46% vs 30% at 6 months and 21% vs 7% at 12 months, she reported.
“A subset of these heavily pretreated patients had rapid disease progression in the first 2 months on treatment; therefore, we analyzed progression-free survival at several key landmark time points,” Dr. Rugo said. “The Kaplan-Meier curves separated early and were consistent over time, with a higher proportion of patients on sacituzumab govitecan alive and progression-free at all landmark time points.”
Asked to explain the discordance between the 1.5-month benefit in progression-free survival and the more robust hazard ratio and P value (HR = 0.66; P = .0003), Dr. Rugo explained that patients with very resistant and aggressive disease have rapid disease progression, “even before they go to their first scan,” and she noted the proportion of such patients was parallel between the arms. This scenario has been observed in several trials in the metastatic setting. The result is a more modest progression-free survival that does not reflect the real benefit in patients able to complete treatment.
“This is where the landmark analysis helps us. We can see three times as many patients are progression-free at 12 months with sacituzumab govitecan,” she added.
Safety and Quality of Life
The safety profile of sacituzumab govitecan in this study was consistent with that observed in previous trials. Grade ≥ 3 treatment-emergent adverse events were observed in 74% of that arm and in 60% of the chemotherapy arm. The most common toxicities associated with sacituzumab govitecan were diarrhea (5%), febrile neutropenia (4%), neutropenia (3%), and neutropenic colitis (2%). There were no events of interstitial lung disease with sacituzumab govitecan (vs 1% with chemotherapy) and no cases of cardiac failure or left-ventricular dysfunction in either arm. One death related to sacituzumab govitecan was reported, from septic shock due to neutropenic colitis.
“Sacituzumab govitecan also demonstrated an overall health-related quality-of-life benefit over chemotherapy, with delayed deterioration in fatigue and global health status/quality-of-life scales,” she further reported.
Explaining the Benefit in ‘Hormone Receptor–Positive’ Tumors
Patients in TROPiCS-02 were required to have hormone receptor–positive tumors, although this was not centrally confirmed. Ideally, hormone receptor status would have been tested within a year of enrollment, but Dr. Rugo acknowledged that some testing could have occurred much earlier in the disease course.
In other words, hormone receptor status could have changed over time, so some patients’ tumors now leaned toward negative. These “shifts” in subtypes are being observed more frequently now that sequential biopsies are performed more often. “As patients develop more visceral involvement and resistance to treatment, we do see falling estrogen receptor expression…. In those patients, we may be better able to overcome resistance by using these more effective drugs,” she said.
DISCLOSURE: Dr. Rugo has received honoraria from or served as a consultant or advisor to Mylan, Puma Biotechnology, Samsung Bioepis, and Napo Pharmaceuticals. Dr. Meisel has received honoraria from Medscape and Total Health Conferencing; has served as a consultant or advisor to AstraZeneca, Curio Science, Genentech, GlaxoSmithKline, Novartis, and Seattle Genetics; has received research funding from Pfizer and Seattle Genetics; and has been reimbursed for travel, accommodations, or other expenses from Pfizer, Puma Biotechnology, and Total Health Conferencing.
REFERENCE
1. Rugo HS, Bardia A, Marmé F, et al: Primary results from TROPiCS-02. 2022 ASCO Annual Meeting. Abstract LBA1001. Presented June 4, 2022.
