Gilead's First-in-Class TROP-2 Targeting Drug Trodelvy Under EMA Review for Triple-Negative Breast Cancer; Everest Medicines Brings It to China

March 27, 2021/BioValleyBIOON/--Gilead Sciences recently announced that the European Medicines Agency (EMA) has accepted the marketing authorization application (MAA) for the targeted anticancer drug Trodelvy (sacituzumab govitecan-hziy, SG), indicated for the treatment of unresectable locally advanced or metastatic triple-negative breast cancer in patients who have previously received at least two therapies, including at least one therapy for locally advanced or metastatic disease.Breast Cancer(mTNBC) adult patients. Currently, a supplemental Biologics License Application (sBLA) for Trodelvy in the treatment of mTNBC is under review by the U.S.FDAreview, aimed at converting accelerated approval to full approval.

Trodelvy is a first-in-class therapy targeting Trop-2. Trop-2 is a protein expressed in various epithelialTumor(a protein frequently expressed in TNBC), where high expression is associated with improved survival rates and lower recurrence rates. Currently, in the European Union, no standard treatment regimen has been proven to provide an overall survival (OS) benefit for patients with previously treated metastatic triple-negative breast cancer (mTNBC).

Based on the Phase 3 ASCENTClinical Trialspositive results, the EMA granted accelerated assessment of the MAA. In addition to the European Union, regulatory reviews of Trodelvy for the treatment of mTNBC are ongoing in the United Kingdom, Canada, Switzerland, and Australia. Through its partner Everest Medicines, Trodelvy for the treatment of mTNBC is also undergoing regulatory review in Singapore. Furthermore, a new indication application for Trodelvy is currently under review by the U.S.FDAReview: For the treatment of adult patients with locally advanced or metastatic urothelial carcinoma (UC) who have previously received platinum-containing chemotherapy and a PD-1 inhibitor or PD-L1 inhibitor in the neoadjuvant/adjuvant or metastatic setting.

Trodelvy is a novel, first-in-class antibody-drug conjugate (ADC) targeting TROP-2, developed by Immunomedics. In September 2020, Gilead Sciences acquired Immunomedics for $21 billion, thereby adding Trodelvy to its portfolio. At the core of Immunomedics’ proprietary ADC platform is a novel linker that does not require enzymatic cleavage to release the payload, enabling release within tumor cells andTumorDelivering active drugs to the microenvironment, thereby generating a bystander effect.

In April 2019, Everest Medicines entered into an agreement with Immunomedics to acquire the rights to Trodelvy in Greater China, South Korea, Mongolia, and Southeast Asian countries and regions.

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 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 2020, 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 relapsed 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 from the Phase 3 ASCENT trial, Gilead Sciences submitted a supplemental Biologics License Application (sBLA) to the U.S. FDA, aiming to convert the accelerated approval of Trodelvy for the treatment of metastatic triple-negative breast cancer (mTNBC) to full approval. Currently, this sBLA is under review by the U.S.FDAreview.

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 atFDADesigned under the Special Protocol Assessment (SPA), the study aimed to confirm the promising efficacy and safety of Trodelvy demonstrated in the Phase II trial that supported its approval.

Data published in July 2020 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%).

Exploratory analysis published in December 2020 showed that Trodelvy induced clinical benefit compared with chemotherapy, regardless of Trop-2 expression; however, greater therapeutic benefit was observed with Trodelvy in patients with moderate or high Trop-2 scores. Specific PFS data were as follows: high Trop-2 subgroup (median PFS: 6.9 months vs. 2.5 months), moderate Trop-2 subgroup (median PFS: 5.6 months vs. 2.2 months), and low Trop-2 subgroup (median PFS: 2.7 months vs. 1.6 months). Specific OS data were as follows: high Trop-2 subgroup (median OS: 14.2 months vs. 6.9 months), moderate Trop-2 subgroup (median OS: 14.9 months vs. 6.9 months), and low Trop-2 subgroup (median OS: 9.3 months vs. 7.6 months).

Furthermore, Trodelvy demonstrated superior efficacy compared with 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 subtypes. TNBC is defined by the negative expression of estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptor 2 (HER-2). It is characterized by rapid progression and a poor prognosis, with a 5-year survival rate of less than 15%. TNBC does not respond to hormonal therapies 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 (Taishengqi, generic name: atezolizumab) approved in the United StatesFDAApproval 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 approved for the treatment of TNBC.

In November 2020, Merck’s Keytruda (brand name: 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 also marks the first approval of Keytruda in the field of breast cancer. (Bioon.com)

Original Source:European Medicines Agency Validates Marketing Authorization application for Sacituzumab Govitecan-Hziy for the Treatment of Metastatic Triple-Negative Breast Cancer