Positive trend towards improved OS in the TROPiCS-02 had now firmed up and reached statistical significance

Hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer is the most common type of breast cancer and accounts for approximately 70% of all new cases, or nearly 400,000 diagnoses worldwide each year. Almost one in three cases of early-stage breast cancer eventually become metastatic, and among patients with HR+/HER2- metastatic disease, the five-year relative survival rate is 30%. Trodelvy, a drug called an antibody-drug conjugate, is approved in more than 35 countries, with multiple additional regulatory reviews underway worldwide. Gilead is currently conducting a Phase III (TROPiCS-02) trial of Trodelvy. TROPiCS-02 enrolled patients with HR+/HER2- metastatic breast cancer who were refractory to or relapsed after at least 2 prior systemic chemotherapy regimens for metastatic disease, including at least 1 prior anticancer hormonal treatment and at least 1 CDK4/6 inhibitor administered in the metastatic setting.

Back in June at the ASCO 2022 conference, Trodelvy's 1.5-month improvement in reducing tumor progression or death was universally regarded as clinically insignificant. Trodelvy reduced the probability of death by 16% while extending life expectancy by only 1.6 months at the time, according to data at the time. 

The TROPiCS-02 study had previously met its primary endpoint of statistically significant PFS benefit with sacituzumab govitecan. The median PFS with TROPiCS-02 was 5.5 months and the 12-month PFS rate was 21% versus treatment of physician’s choice, in which the median PFS was 4.0 months, and the 12-month PFS rate was 7%. 

After dismal tumor progression results, the drug has made a surprising return in HR-positive, HER2-negative breast cancer, with a life extension benefit exceeding industry expectations. A statistically significant improvement in OS was observed with sacituzumab govitecan versus treatment of physician’s choice. The median OS with sacituzumab govitecan was 14.4 months versus 11.2 months with the physician's choice therapy. The OS rates at 12 months were 61% and 47%, respectively. Significant improvements in ORR and quality of life (QoL) and manageable safety were also observed. 

The ORR was higher in the sacituzumab govitecan arm versus the physician's choice group (21% vs 14%). The median duration of response was 8.1 months and 5.6 months, respectively. And, the clinical benefit rate for patients given sacituzumab govitecan was 34%, whereas the rate for those given therapy of physician's choice was 22%. 

Along with this, a longer time-to-deterioration (TTD) in the EORTC QoL questionnaire (QLQ)-C30 global health scale/QoL was noticed. It was 4.3 months in the case of sacituzumab govitecan versus 3.0 months with the treatment of the physician’s choice. The median TTD for fatigue was 2.2 months in the sacituzumab govitecan arm and 1.4 months in the comparator arm. With this data, Trodelvy has now proven a survival advantage in both pre-treated HR+/HER2- metastatic breast cancer and second-line metastatic TNBC - two difficult-to-treat types of breast cancer.

Gilead has submitted a supplemental Biologics License Application (sBLA) to the US FDA based on TROPiCS-02 data. The discussion concerning its competitive profile against AstraZeneca and Daiichi Sankyo's Enhertu, on the other hand, is far from done. The Destiny-Breast04 trial was carried out in a comparable ER-positive but purportedly Her2-negative group. ASCO was astounded by the result, which also established the notion of Her2-low disease.

Although most investors are comparing the two studies side by side, a straight comparison of the two datasets is flawed: Trodelvy's TROPiCS-02 enrolled a more advanced cohort that had a median of three prior chemotherapies, versus one for Enhertu's DESTINY-Breast04. Furthermore, in TROPiCS-02, all enrolled patients had prior CDK4/6 inhibitor treatment, but in the Enhertu trial, 30% did not. It is not unlikely that Trodelvy could have achieved a more competitive outcome in an earlier setting. However, doing so would be costly, and Gilead is already under fire to defend the $21 billion it spent to purchase the drug from Immunomedics. Gilead is emphasizing triple-negative breast cancer since Trodelvy has previously approved in the third-line setting  for this type of cancer. In light of Enhertu, that seems like a sensible market segment to occupy, but the company may be excused for betting.

Expert Opinion: “These data show that sacituzumab govitecan – targeting the Trop-2 molecule – is an extremely promising treatment option for those with heavily pre-treated metastatic breast cancer”

For more insight into the breast cancer domain, visit: HR+/HER2- Breast Cancer, Triple Negative Breast Cancer, HR+/HER2+ Breast Cancer