Trodelvy and Keytruda Achieve Breakthrough Results, Ushering in a New Era for ADCs in Breast Cancer

Gilead Sciences has announced that the combination of Trodelvy® (sacituzumab govitecan-hziy) and Keytruda® (pembrolizumab) has demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) for patients with previously untreated PD-L1-positive (CPS ≥10) metastatic triple-negative breast cancer (mTNBC). This marks the first pivotal Phase 3 trial showing the superiority of a TROP-2 antibody-drug conjugate combined with an immuno-oncology agent over the standard of care in first-line mTNBC treatment.

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What drug is Trodelvy ?

Sacituzumab govitecan is an antibody-drug conjugate (ADC) that targets Trop-2, a transmembrane protein involved in calcium signaling and commonly overexpressed in various epithelial cancers, including triple-negative breast cancer (TNBC). It consists of a humanized IgG1-kappa monoclonal antibody linked to SN-38, the active metabolite of irinotecan and a potent topoisomerase I inhibitor, via a hydrolyzable linker.

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Once the ADC binds to Trop-2 on cancer cells, it is internalized, and the linker is hydrolyzed to release SN-38. SN-38 disrupts topoisomerase I function, preventing the repair of single-strand DNA breaks and inducing cell death. Notably, SN-38 is released both inside the tumor cells and into the surrounding tumor microenvironment, enhancing its cytotoxic effect.

Overview of TNBC

Triple-negative breast cancer (TNBC) is a biologically aggressive subtype of breast cancer that lacks expression of estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptor 2 (HER2). Because it does not express these common targets, TNBC does not respond to hormonal therapies or HER2-directed treatments, limiting systemic therapy options primarily to chemotherapy and, more recently, immunotherapy and antibody-drug conjugates.

TNBC accounts for approximately 10% to 15% of all breast cancer cases and is more commonly diagnosed in younger women, those of African descent, and individuals with BRCA1 mutations. It is characterized by high histologic grade, rapid proliferation, early recurrence, and a higher propensity for visceral and central nervous system metastases compared to other subtypes.

Despite being highly sensitive to chemotherapy, TNBC has historically been associated with poorer prognosis due to a higher rate of relapse within the first three to five years after diagnosis. However, recent advances have changed the treatment landscape.

In the metastatic setting, treatment decisions are guided by PD-L1 status, germline BRCA mutation status, and prior therapies. Options now include immune checkpoint inhibitors (e.g., pembrolizumab for PD-L1+ disease), PARP inhibitors for BRCA-mutant tumors, and antibody-drug conjugates like sacituzumab govitecan (Trodelvy) for heavily pretreated cases.

What is the standard treatment of TNBC?

In metastatic triple-negative breast cancer (mTNBC), treatment depends primarily on PD-L1 status, BRCA mutation status, prior treatments, and patient performance status. For patients whose tumors are PD-L1 positive (combined positive score ≥10), the standard first-line treatment is a combination of pembrolizumab (a PD-1 inhibitor) with chemotherapy. This approach is based on the KEYNOTE-355 trial, which demonstrated improved progression-free and overall survival compared to chemotherapy alone. Common chemotherapy partners include nab-paclitaxel, paclitaxel, or the combination of gemcitabine and carboplatin.

For patients with PD-L1 negative tumors or those who have progressed on immune checkpoint inhibitors, standard treatment involves single-agent chemotherapy. Common options include taxanes such as paclitaxel or docetaxel, eribulin, capecitabine, or platinum-based regimens like carboplatin or cisplatin.

For patients with germline BRCA1 or BRCA2 mutations, PARP inhibitors such as olaparib or talazoparib may be used, offering an alternative to traditional chemotherapy with targeted activity in DNA repair-deficient tumors.

Sacituzumab govitecan (Trodelvy), an antibody-drug conjugate targeting Trop-2, is approved for patients with mTNBC who have received at least two prior lines of therapy in the metastatic setting.

ADCs in Breast Cancer: A Historic Shift into a New Era.

Trodelvy (sacituzumab govitecan-hziy) received its first FDA approval in April 2020 under the accelerated approval pathway. It was indicated for adult patients with metastatic triple-negative breast cancer (mTNBC) who had received at least two prior therapies for metastatic disease. This marked a major milestone as Trodelvy became the first antibody-drug conjugate targeting Trop-2, delivering the active chemotherapy agent SN-38 directly to cancer cells.

In April 2021, the FDA converted Trodelvy’s accelerated approval to full approval after the confirmatory Phase 3 ASCENT trial demonstrated significant improvements in both progression-free survival (PFS) and overall survival (OS) compared to standard chemotherapy in previously treated mTNBC patients.

Also in April 2021, Trodelvy received an additional accelerated approval for the treatment of locally advanced or metastatic urothelial carcinoma. This indication applied to patients who had previously received platinum-based chemotherapy and a PD-1 or PD-L1 inhibitor. The approval was based on tumor response rates and duration of response.

In February 2023, Trodelvy was further approved for use in patients with unresectable or metastatic hormone receptor-positive, HER2-negative breast cancer. This indication was for patients who had received prior endocrine therapy and at least two additional systemic treatments. The approval was supported by results from the Phase 3 TROPiCS-02 trial, which showed statistically significant improvements in progression-free and overall survival.

In February 2023, Trodelvy was further approved for use in patients with unresectable or metastatic hormone receptor-positive, HER2-negative breast cancer. This indication was for patients who had received prior endocrine therapy and at least two additional systemic treatments. The approval was supported by results from the Phase 3 TROPiCS-02 trial, which showed statistically significant improvements in progression-free and overall survival.

Written by Sona Karamyan, MD