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TROP2 Targeted Therapy: Module

CME

TROP-2–Targeted Therapy: Redefining the Therapeutic Landscape in HER2-Negative Breast Cancer

Physicians: Maximum of 0.75 AMA PRA Category 1 Credit™

Released: February 22, 2024

Expiration: February 21, 2025

CME/CE Information

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Sacituzumab Govitecan: First-in-Class TROP-2–Targeted ADC

Sacituzumab govitecan is the first-in-class TROP-2‒targeted ADC to enter into the clinic.2 It comprises 3 important components: a humanized RS7 anti‒TROP-2 monoclonal antibody; a proprietary cleavable, hydrolysable linker (CL2A); and a cytotoxic payload (SN-38).3-5 SN-38 is a derivative of camptothecin, which is the active component of irinotecan, and it delivers as much as 136-fold more SN-38 to tumor cells compared with irinotecan, its parent compound. SN-38 induces cell death via the inhibition of topoisomerase-I (TOPO-I), and this interaction triggers double-strand DNA breaks when cells are in the S-phase of the cell cycle. With a high drug-to-antibody ratio of 7.6:1, sacituzumab govitecan is rapidly internalized, after which it is trafficked to the lysosome where the RS7 antibody is degraded, and the cytotoxic payload is released. However, because the linker (CL2A) is hydrolysable, it can be cleaved during trafficking, circumventing the requirement for lysosomal delivery for the release of its cytotoxic payload.5 Of note, the connection between CL2A and SN-38 is pH sensitive, and this enhances the rapid release of the cytotoxic payload in an acidic environment, such as that found in the lysosome or the tumor cell and its microenvironment. The characteristics of the CL2A linker also allow for a bystander tumor cell killing effect, in that the extracellular release of SN-38 from the RS7 antibody into the tumor microenvironment can result in the diffusion of the cytotoxic payload into neighboring TROP-2‒negative cells.

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ASCENT: Sacituzumab Govitecan vs Single-Agent Chemotherapy for Metastatic TNBC

ASCENT is a randomized phase III trial that investigated sacituzumab govitecan vs physician’s choice of single-agent chemotherapy (capecitabine, eribulin, gemcitabine, or vinorelbine) in 529 patients with metastatic TNBC who have received ≥2 prior chemotherapy regimens.6 Patients with disease progression within 12 months of neoadjuvant or adjuvant therapy and those with brain metastases if stable for ≥4 weeks before treatment also were eligible to enroll on this trial. Sacituzumab govitecan was administered intravenously at 10 mg/kg on Days 1 and 8 of 21-day cycles. The primary endpoint was progression-free survival (PFS) by blinded independent central review (BICR) among patients without brain metastases. The secondary endpoints included investigator-assessed PFS, overall survival (OS), objective response rate (ORR), duration of response, time to response, and safety. Per unanimous recommendation of the data and safety monitoring committee, the ASCENT trial was halted early based on the efficacy of sacituzumab govitecan.

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ASCENT: PFS and OS Among Patients Without Brain Metastases

Among 468 patients without brain metastases, the median PFS and OS were significantly longer with sacituzumab govitecan compared with chemotherapy.6,7 The median PFS with sacituzumab govitecan was 5.6 months vs 1.7 months with chemotherapy (hazard ratio: 0.41; 95% CI: 0.32-0.52; P <.001), and the median OS with sacituzumab govitecan was 12.1 months vs 6.7 months with chemotherapy (hazard ratio: 0.48; 95% CI: 0.38-0.59; P <.001). Based on the results of the ASCENT trial, sacituzumab govitecan received FDA approval for patients with unresectable locally advanced or metastatic TNBC who have received ≥2 prior systemic therapies, at least one of them for metastatic disease.2

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TROPiCS-02: Sacituzumab Govitecan vs TPC for HR-Positive/HER2-Negative Advanced Breast Cancer

The phase III TROPiCS-02 trial enrolled patients with HR-positive/HER2-negative inoperable, locally recurrent, or metastatic breast cancer.8,9 To be eligible for enrolment, patients must have experienced disease progression on 2-4 prior chemotherapy regimens in the metastatic setting. Prior treatments included ≥1 endocrine therapy, ≥1 taxane, and ≥1 CDK4/6 inhibitor in any setting. Patients with disease progression within 12 months of neoadjuvant or adjuvant therapy also were eligible for enrolment on the study. In total, 543 patients were randomly assigned to receive either intravenously administered sacituzumab govitecan at 10 mg/kg on Days 1 and 8 of 21-day cycles or physician’s choice of single-agent chemotherapy (capecitabine, eribulin, gemcitabine, or vinorelbine). The primary endpoint was PFS by BICR, and the secondary endpoints included OS, response, and safety. In the post hoc subgroup analysis, treatment efficacy was assessed in patients with HER2-low and HER2 IHC 0 advanced breast cancer.

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TROPiCS-02: Updated PFS (by BICR) and OS in Overall Patient Population

On the TROPiCS-02 trial, patients had received a median of 3 prior lines of chemotherapy, and 98% to 99% of patients on both arms had previously received a CDK4/6 inhibitor.9 Of importance, the median PFS and OS were longer with sacituzumab govitecan vs chemotherapy. The median PFS was 5.5 months with sacituzumab govitecan vs 4.0 months with chemotherapy (hazard ratio: 0.65; 95% CI: 0.53-0.81; P = .0001). In particular, the 18-month PFS rate was 3-fold higher with sacituzumab govitecan (14.4%) vs chemotherapy (4.7%). The risk of death with sacituzumab govitecan vs chemotherapy was reduced by 21%, with a median OS of 14.5 months with sacituzumab govitecan vs 11.2 months with chemotherapy (hazard ratio: 0.79; 95% CI: 0.65-0.95; P = .0133).

Based on the results of the TROPiCS-02 trial, which showed unprecedented PFS and OS improvement in heavily pretreated patients, the FDA approval of sacituzumab govitecan was extended to include patients with HR-positive/HER2-negative (IHC 0, IHC 1+ or IHC 2+/ISH-) unresectable locally advanced or metastatic breast cancer who have received endocrine-based therapy and ≥2 additional systemic therapies in the metastatic setting.2

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TROPiCS-02: PFS and OS by HER2 IHC Status

Exploratory analysis of efficacy by HER2 IHC status demonstrated that PFS and OS were numerically prolonged with sacituzumab govitecan vs chemotherapy among patients with HER2-low or HER2 IHC 0 disease.9 Among patients with HER2-low disease, the median PFS was 5.8 months with sacituzumab govitecan vs 4.2 months with chemotherapy (hazard ratio: 0.60; 95% CI: 0.44-0.82), and the median OS was 15.4 months with sacituzumab govitecan vs 11.5 months with chemotherapy (hazard ratio: 0.75; 95% CI: 0.57-0.97). Similarly, in the population of patients with HER2 IHC 0 and advanced breast cancer, the median PFS was 5.0 months with sacituzumab govitecan vs 3.4 months with chemotherapy (hazard ratio: 0.70; 95% CI: 0.51-0.98), and the median OS was 13.6 months with sacituzumab govitecan vs 10.8 months with chemotherapy (hazard ratio: 0.85; 95% CI: 0.63-1.14).

The TROPiCS-02 trial results have changed the treatment landscape for patients with HR-positive/HER2‑negative advanced breast cancer, especially for patients with HER2 IHC 0 disease, for whom there are limited treatment options, or those with heavily pretreated HR-positive/HER2-negative advanced disease.

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