Gilead's First-in-Class TROP-2 ADC Trodelvy Demonstrates Significant Survival Benefit in Metastatic Triple-Negative Breast Cancer

December 14, 2020 /BioValleyBIOON/ -- Gilead Sciences recently announced the use of the targeted anticancer drug Trodelvy (sacituzumab govitecan-hziy) for the treatment of metastatic triple-negativeBreast CancerNew data from the Phase 3 ASCENT trial in metastatic triple-negative breast cancer (mTNBC). The results continue to confirm that Trodelvy demonstrates high clinical activity compared with chemotherapy, regardless of TROP-2 expression levels, in patient populations traditionally associated with poor outcomes.

Trodelvy is a novel, first-in-class antibody-drug conjugate (ADC) targeting TROP-2, developed by Immunomedics. Gilead acquired Immunomedics for $21 billion this September, thereby adding Trodelvy to its portfolio. The core of Immunomedics’ proprietary ADC platform is the use of a novel linker that does not require enzymes to release the payload, enabling it to function within tumor cells andTumorDelivering active drugs to the microenvironment, thereby generating a bystander effect.

The active pharmaceutical ingredient of Trodelvy is sacituzumab govitecan, which consists of a humanized IgG1 antibody targeting the TROP-2 antigen conjugated to SN-38, the metabolically active product of the chemotherapy drug irinotecan (a topoisomerase I inhibitor), with a drug-to-antibody ratio as high as 7.6:1. Trop-2 is a cell surface protein expressed in many solid tumors and is present in over 90% of triple-negative breast cancer (TNBC) cases. Trodelvy binds specifically to Trop-2 and delivers the anticancer agent SN-38 to kill cancer cells.

In April this year, Trodelvy received accelerated approval from the U.S. FDA for adult patients with metastatic triple-negative breast cancer (mTNBC) who had previously received at least two therapies for metastatic disease. Notably, Trodelvy is the first antibody-drug conjugate (ADC) approved by the FDA specifically for the treatment of recurrent or refractory mTNBC, and alsoFDAThe first approved Trop-2-targeted antibody-drug conjugate (ADC). This approval was based on data from a single-arm, multicenter Phase II study, including an overall response rate (ORR) of 33.3% and a median duration of response (DOR) of 7.7 months.

Based on the overall efficacy and safety results of Trodelvy in the Phase 3 ASCENT trial, Gilead has submitted to the U.S.FDASubmitted a supplemental Biologics License Application (sBLA) to convert the accelerated approval of Trodelvy for the mTNBC indication to full approval.

Loretta M. Itri, Chief Medical Officer of Immunomedics, a wholly owned subsidiary of Gilead Sciences, stated, “These new data and analyses from the ASCENT trial continue to demonstrate the benefits of Trodelvy in patients with refractory disease and reinforce the role of Trodelvy as an important treatment option for patients with metastatic triple-negative breast cancer (mTNBC).”

ASCENT (NCT02574455) is an international, open-label, Phase III study that enrolled more than 500 patients with metastatic triple-negative breast cancer (mTNBC) who had previously received at least two prior therapies for metastatic disease. In the study, patients were randomized into two groups: one receiving Trodelvy and the other receiving physician’s choice of chemotherapy. The primary endpoint was progression-free survival (PFS), and secondary endpoints included overall survival (OS), objective response rate (ORR), duration of response (DOR), time to response, safety, and tolerability. The study was conducted inFDADesigned under the Special Protocol Assessment (SPA), the study aims to confirm the promising efficacy and safety profile of Trodelvy demonstrated in the Phase II study that supported its approval.

Data released in July this year showed that the study met its primary and key secondary endpoints: Trodelvy demonstrated a statistically significant improvement in progression-free survival (PFS) compared with chemotherapy (median PFS: 5.6 months [95% CI: 4.3–6.3] vs. 1.7 months [95% CI: 1.5–2.6]), with a 59% significant reduction in the risk of disease progression (HR=0.41, 95% CI: 0.32–0.52, p<0.0001). Furthermore, the study also met key secondary endpoints: median overall survival (OS) (12.1 months vs. 6.7 months) and objective response rate (ORR) (35% vs. 5%).

The exploratory analysis released this time shows:Regardless of Trop-2 expression, Trodelvy induces clinical benefit compared with chemotherapy; however,In patients with moderate or high Trop-2 expression levels, greater therapeutic benefit was observed with Trodelvy.The specific PFS data were as follows: high Trop-2 expression subgroup (median PFS: 6.9 months vs. 2.5 months), moderate Trop-2 expression subgroup (median PFS: 5.6 months vs. 2.2 months), and low Trop-2 expression subgroup (median PFS: 2.7 months vs. 1.6 months). The specific OS data were: Trop-2 high-expression subgroup (median OS: 14.2 months vs. 6.9 months), Trop-2 moderate-expression subgroup (median OS: 14.9 months vs. 6.9 months), Trop-2 low-expression subgroup (median OS: 9.3 months vs. 7.6 months).

Furthermore, Trodelvy demonstrated superior efficacy compared to chemotherapy, regardless of germline BRCA1/2 mutation status. These new data confirm the results from the prior Phase II clinical trial, indicating that Trodelvy has the potential to change the standard of care for metastatic triple-negative breast cancer (mTNBC) and provide a new alternative to commonly used agents in clinical practice. Importantly, the study also validated the manageable safety profile of Trodelvy, making it a favorable partner for combination therapy with other treatments, including immunotherapy.

Breast cancer is the most common type of cancer in women, with over 2 million new cases diagnosed globally each year. Triple-negative breast cancer (TNBC) accounts for approximately 15% of all breast cancers and is more prevalent in women under the age of 50 compared to other breast cancer subtypes. TNBC is specifically defined by the negative expression of estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptor 2 (HER-2). It progresses rapidly, carries a very poor prognosis, and has a 5-year survival rate of less than 15%. TNBC does not respond to hormonal therapy or HER2-targeted therapies (such as Roche’s Herceptin), leaving clinical treatment options very limited and primarily reliant on chemotherapy.

In the treatment of TNBC, in March 2019, Roche's PD-L1TumorImmunotherapy Tecentriq (brand name: Taishengqi; generic name: atezolizumab) approved by the U.S.FDAApproval granted for the use of combination chemotherapy (Abraxane) as first-line treatment for patients with PD-L1-positive locally advanced or metastatic triple-negative breast cancer (TNBC). This approval makes the Tecentriq + Abraxane regimen the first cancer immunotherapy approach for the treatment of TNBC.

In November this year, Merck & Co.’s Keytruda (Keytruda, generic name: pembrolizumab) received U.S.FDAApproval, combination chemotherapy treatmentTumorPatients with locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC) expressing PD-L1 (Combined Positive Score [CPS] ≥10). Notably, this marks the first approval of Keytruda in the field of breast cancer, as well as its 27th regulatory approval in the United States. (Bioon.com)

Original Source: Sacituzumab Govitecan Induces Clinical Benefit in Metastatic TNBC, Irrespective of Trop-2 Expression