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Antibody-Drug Conjugate Prolongs Survival in Metastatic Breast Cancer

— Positive outcome with sacituzumab govitecan leads to questions about ADC sequencing

Ƶ MedicalToday

PARIS -- Patients with heavily pretreated metastatic breast cancer had clinically meaningful improvement in overall survival (OS) if they received the antibody-drug conjugate (ADC) sacituzumab govitecan (Trodelvy) instead of chemotherapy, according to updated results of a randomized trial.

Median OS increased from 11.2 months with physician's choice of chemotherapy to 14.4 months with the ADC. Objective response rate (ORR), duration of response (DOR), and quality of life all improved among patients who received sacituzumab govitecan.

The results added to a previously reported improvement in progression-free survival (PFS) with the ADC, said Hope S. Rugo, MD, of the University of California San Francisco, at the European Society for Medical Oncology (ESMO) annual congress.

"This statistically significant and clinically meaningful benefit of sacituzumab over TPC [therapy of physician's choice] in the TROPiCS-02 study supports the use of sacituzumab as a novel therapy for patients with pretreated, endocrine-resistant, hormone receptor-positive, HER2-negative metastatic breast cancer," Rugo said in conclusion.

In light of the OS analysis, combined with a previously favorable report on PFS, the TROPiCS-02 trial should be considered definitive, said ESMO invited discussant Meritxell Bellet-Ezquerra, MD, PhD, of Vall d'Hebron Institute of Oncology in Barcelona.

"This is the largest late-line trial specifically conducted in ER-positive, HER2-negative metastatic breast cancer," she said. "In my opinion, the results are clinically meaningful and should lead to regulatory approval. A weakness of the trial is the substantial proportion of screening failures, about 30% [ineligible for enrollment], so these results may not apply to at least one-third of patients with metastatic breast cancer in this setting."

Sacituzumab consists of a monoclonal antibody against human trophoblast cell-surface antigen 2 (Trop-2) -- expressed by the vast majority of breast cancer cells and associated with disease progression and poor prognosis -- linked to a topoisomerase I inhibitor. In studies of metastatic triple-negative breast cancer (TNBC), treatment with the ADC significantly improved PFS and OS versus chemotherapy, leading to FDA approval.

The success in metastatic TNBC led to evaluation of sacituzumab govitecan in metastatic hormone receptor-positive/HER2-negative breast cancer. At the American Society of Clinical Oncology (ASCO) meeting in June, Rugo reported results from the primary analysis of the randomized phase III TROPiCS-2 trial, which showed significant improvement in PFS with the ADC versus physician's choice of chemotherapy. The ESMO presentation focused on the key secondary endpoint of OS, as assessed at a planned interim analysis.

TROPiCS-2 involved 543 patients with metastatic hormone receptor-positive/HER2-negative breast cancer that had progressed on prior treatment including endocrine therapy, chemotherapy, and CDK4/6 inhibition in most cases. The patients had received a median of three prior chemotherapy regimens for metastatic disease.

The primary analysis showed a modest but statistically significant improvement in median PFS, from 4.0 months with chemotherapy to 5.5 months with sacituzumab govitecan. At the time of the ASCO presentation, OS data remained immature but showed a trend favoring the ADC.

With additional follow-up, a statistically significant 3.2-month improvement in OS emerged (HR 0.79, 95% CI 0.64-0.96, P=0.02). A subgroup analysis showed a consistent advantage for treatment with sacituzumab govitecan, with the exception of the small group of patients without visceral metastases at enrollment (~5% of the study population). That group had more than a twofold greater risk of death with the ADC, although the difference did not achieve statistical significance (P=0.064).

Sacituzumab govitecan led to a significantly higher ORR (57% vs 36%, P=0.035) and clinical benefit rate (92% vs 60%, P=0.003), DOR (8.1 vs 5.6 months), and quality of life including global health status (P=0.006) and fatigue (P=0.002).

Grade ≥3 adverse events (AEs) occurred more often with sacituzumab govitecan (74% vs 60%), but discontinuation associated with treatment-emergent AEs occurred at a similar rate in both groups (6% vs 4%). Two fatal AEs occurred during the trial, both in the the sacituzumab govitecan group. One of the two deaths was considered treatment-related.

Following the presentation, an unidentified member of the audience asked Rugo what the results imply for choosing between sacituzumab govitecan and trastuzumab deruxtecan (T-DXd, Enhertu), which has demonstrated a significant survival benefit for patients with hormone receptor-positive breast cancer and low HER2 expression.

"I think most of us would agree -- maybe all of us -- that in a patient with HER2-low, hormone receptor-positive disease in the second-line setting, we would choose T-DXd because that's where it was tested," Rugo replied. "For patients who have HER2-zero disease, I would use sacituzumab govitecan. We have no data for T-DXd."

"I would consider using sequential antibody-drug conjugate therapy for the specific reason that we know the efficacy of these drugs is related to the antibody target, as well as the toxin. Even though the toxins are in the same class, they're different. The antibodies are clearly different, and there are marked differences in the toxicity between these drugs. So, I think sequential therapy should be studied, and it is a treatment option for our patients, as well," she continued.

Bellet-Ezquerra also touched on the sequencing issue in her discussion.

"Sacituzumab activity after trastuzumab deruxtecan is unknown," she said. "Other ADCs are being developed, such as datopotamab deruxtecan, which has shown efficacy after sacituzumab, but the reverse sequence has not been investigated. The questions are, what is the optimal compound and the optimal sequencing. The same questions apply to non-Trop ADCs that are showing interesting or provocative activity in the hormone receptor-positive, HER2-negative patient population and sequencing."

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    Charles Bankhead is senior editor for oncology and also covers urology, dermatology, and ophthalmology. He joined Ƶ in 2007.

Disclosures

The TROPiCS-02 trial was supported by Gilead Sciences.

Rugo disclosed relationships with Puma Biotechnology, Mylan, Samsung, Bioepis, Macrogenics, OBI Pharma, Pfizer, Novartis, Lilly, Merck, Odonate Therapeutics, Daiichi Sankyo, Seattle Genetics, Sermonix Pharmaceuticals, AstraZeneca, Gilead Sciences, and Ayala Pharmaceuticals.

Billet-Ezquerra disclosed relationships with Pfizer, Novartis, and Lilly.

Primary Source

European Society for Medical Oncology

Rugo HS, et al "Overall survival results from the phase III TROPiCS-02 study of sacituzumab govitecan vs treatment of physician's choice in patients with HR+/HER2- metastatic breast cancer" ESMO 2022; Abstract LBA76.