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TROPiCS-02 Trial Sees Progression-Free Survival Edge for Trodelvy-Treated Advanced Breast Cancers

NEW YORK – An international team led by investigators at the University of California, San Francisco has found evidence pointing to progression-free survival benefits for advanced, extensively pretreated breast cancer patients with hormone receptor (HR)-positive, HER2-negative disease who are treated with Gilead Sciences' antibody-drug conjugate Trodelvy (sacituzumab govitecan).

The drug, which targets a cell surface protein called Trop-2 that is highly expressed in tumor cells in roughly 80 percent of breast cancer cases, received accelerated approval from the US Food and Drug Administration for treating advanced triple-negative breast cancer in 2020 and full approval from the US regulator in 2021. It has since received approval from regulators in other countries, too, for metastatic or unresectable cases of triple-negative breast cancer, based on results from the Phase III ASCENT study.

While that form of breast cancer is relatively rare, HR-positive, HER2-negative breast cancer cases are among the most common, making up roughly 70 percent of diagnosed breast cancer cases.

At the American Society of Clinical Oncology's annual meeting in Chicago on Saturday, Hope Rugo, director of the breast oncology clinical trials program at the University of California, San Francisco's Helen Diller Family Comprehensive Cancer Center, shared findings from a randomized, open-label Phase III clinical trial of Trodelvy in previously treated metastatic or locally recurrent, inoperable cases of HR-positive, HER2-negative disease.

For the Gilead-sponsored trial, dubbed TROPiCS-02, investigators evaluated progression-free survival, overall survival, and other outcomes in 543 advanced HR-positive/HER2-negative patients randomized to receive either Trodelvy or physician's choice of chemotherapy until disease progression or treatment discontinuation due to toxicity.

"The majority of patients in both arms discontinued treatment due to disease progression," Rugo noted.

The current standard of care for metastatic HR-positive, HER2-negative breast cancer is sequential endocrine therapy, along with CDK4/6 inhibitors, she said, followed by a series of single-agent chemotherapy treatments when endocrine therapy resistance arises.

"This is associated with sequentially declining efficacy and increased toxicity," she noted, adding that "with limited chemotherapy options in later-line settings, there remains a high unmet clinical need."

TROPiCS-02 participants ranged in age from 27 to 86 years old; the median age of study participants was 56 years. They had all received multiple lines of chemotherapy and/or CDK4/6 inhibitors, as well as at least one line of endocrine therapy. More than half of the patients had received at least three prior chemotherapy lines, and the median time between a diagnosis of metastatic disease and randomization was around four years.

The team found that the primary endpoint of median progression-free survival stretched out to 5.5 months among 272 patients randomized to receive Trodelvy compared to a median of four months to disease progression in the 271 patients randomized to receive physician's choice of drugs such as capecitabine, vinorelbine, gemcitabine, or eribulin.

In the first six months after treatment, the TROPiCS-02 investigators found that 46 percent of Trodelvy-treated patients remained progression-free, compared to 30 percent of those in the control arm. At nine months, progression-free survival rates came in at 33 percent in the Trodelvy arm and 17 percent in the arm receiving chemotherapy, they reported. Progression-free survival rates dipped to 21 percent in the Trodelvy group and 7 percent in the chemotherapy group at the one-year mark.

Rugo noted that patients on Trodelvy appeared to have a 34 percent reduction in the risk of disease progression or death, along with improved quality-of-life assessments. From these and other findings so far, she suggested that the antibody-conjugate drug "should be considered potential treatment in this heavily pretreated population."

"As clinicians, we've seen how well and how dramatically sacituzumab govitecan works in triple-negative breast cancer patients," Jane Lowe Meisel, a medical oncologist at Emory University who was not involved in the study, said during a briefing with reporters at the ASCO conference. "As Dr. Rugo points out, these estrogen-positive, endocrine-resistant patients really are an area of great unmet need, and their cancers can be very difficult to treat."

"Even though the median progression-free survival difference — 5.5 months versus four months — may not seem clinically significant, it is important to look at the landmark analyses," she added. "A lot of patients in both arms progressed quickly, but when you look at the patients who do respond on sacituzumab govitecan, it seems that they tend to respond better and longer."

For her part, Rugo suggested that the Trop-2-targeting drug is not intended to replace other therapies for advanced HR-positive, HER2-negative breast cancer but points to an additional therapy to offer patients in sequence, particularly patients who may have exhausted many other options.

Patients in the study reported adverse events such as diarrhea, nausea, and low white blood cell counts, she noted, and one treatment-related death was reported in the Trodelvy arm of the trial.

When it came to the secondary endpoint of overall survival, meanwhile, the team saw slightly longer median survival in the patients receiving Trodelvy in an interim analysis — 13.9 months compared to 12.3 months in the chemotherapy group — though this increase did not reach statistical significance, and the data is not yet mature. Two more overall survival analyses are planned in the TROPiCS trial.

Gilead acquired Immunomedics, the company that developed Trodelvy, in 2020. Earlier this year, the Foster City, California-based company reported a significant rise in sales of the antibody-conjugate drug for triple-negative breast cancer in the last quarter of 2021 relative to the same time period in 2020.

Following an interim analysis of progression-free survival data from TROPiCS-02 in March, Gilead said it was aiming to expand breast cancer indications to include advanced HR-positive, HER2-negative disease.

"Clearly the trial met its primary endpoint," said Veronique Dieras, from the Eugene Marquis Center, speaking at an ASCO conference session that included data from TROPiCS-02 and other advanced breast cancer studies.

While she acknowledged that the TROPiCS-02 trial achieved statistically significant results in a high-need patient group that is known for poor prognoses, Dieras expressed concerns about the clinical impact of delaying disease progression by a median of a month and a half.

Consequently, she suggested that additional data are needed to not only explore the overall survival effects of the antibody-conjugate drug in the longer term, but also quality-of-life measures for metastatic breast cancer patients.