First-in-Class ADC Has Benefit Across mTNBC Subgroups

But Data Not Definitive

Liam Davenport

December 14, 2020

The antibody–drug conjugate sacituzumab govitecan (SG) (Trodelvy) appears to be effective across biomarker subgroups for women with metastatic triple-negative breast cancer (mTNBC) that has progressed after multiple lines of therapy, a biomarker evaluation from the phase 3 ASCENT trial shows.

But both an observer and the lead study author cautioned that the results were hypothesis generating.

Nonetheless, the data suggest the drug yields good survival outcomes in comparison with placebo in both BRCA1/2-positive and -negative patients and is effective even for those with low expression of the target protein, trophoblast cell surface antigen 2 (Trop-2).

The research was presented last week at the San Antonio Breast Cancer Symposium (SABCS) 2020.

Study presenter Sara Hurvitz, MD, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, urged caution in interpreting the data, given the small sample sizes in the Trop-2 low subgroup and germline BRCA1/2-positive subgroup.

Jennifer K. Litton, MD, University of Texas MD Anderson Cancer Center, Houston, Texas, who was not involved in the research, echoed those comments.

She told Medscape Medical News that the numbers, particularly for the BRCA1/2 analysis, were "very small."

She added: "This was not a prespecified group, so it represents an interesting analysis to be hypothesis-generating for future studies but not anything applicable to current clinical practice."

Nevertheless, Litton said that the data from the primary analysis of ASCENT remain "practice changing" for women with mTNBC who have received at least two previous lines of therapy.

As to whether SG will eventually move beyond this advanced setting, she emphasized that "more trials would need to be done and reported evaluating its role in other settings, and hopefully expanding its usefulness for patients."

SG is a first-in-class drug comprising an antibody directed at Trop-2, which is highly expressed in breast cancer, and linked to SN-38, the active metabolite of irinotecan.

On the basis of positive phase 1/2 trial data, SG was granted accelerated approval by the US Food and Drug Administration for patients with mTNBC who experience disease progression after at least two prior therapies.

As reported by Medscape Medical News, primary results from ASCENT that were presented at the 2020 annual meeting of the European Society for Medical Oncology showed that SG improved progression-free survival (PFS) by nearly 4 months and overall survival by more than 5 months for women with pretreated mTNBC compared to chemotherapy.

Study Details

At SABCS, Hurvitz presented an exploratory biomarker evaluation of data from the trial regarding the association between SG efficacy and Trop-2 expression, as well as germline BRCA1/2 mutation status.

She reminded the audience that in ASCENT, 529 patients with mTNBC who had experienced disease progression after undergong at least two chemotherapy regimens for advanced disease were randomly assigned in a 1:1 ratio to receive intravenous SG on days 1 and 8 of a 21-day cycle or physician's choice of treatment.

Treatment was continued until disease progression or unacceptable toxicity occurred.

For the current analysis, which focused on patients who did not have brain metastases, the team studied primary or metastatic archival biopsy or surgical specimens collected at study entry.

These were analyzed using a validated immunohistochemistry assay. Tumors were categorized as Trop-2 low, medium, or high expressers on the basis of H-score, which is a weighted summation of percent staining.

In addition, germline BRCA1/2 mutation status was determined at baseline.

Mutation status was known for 149 SG patients and 143 control patients. Of those, the majority (57% and 54%, respectively) were BRCA1/2 negative.

Among 151 SG patients for whom Trop-2 expression status was available, 56% had tumors of high expression; 26%, medium expression; and 18%, low expression.

In the control group, Trop-2 expression was known in 139 patients, of whom 52% had tumors of high expression; 25%, medium expression; and 23%, low expression.

Hurvitz reported that although median PFS among patients given SG decreased with decreasing Trop-2 expression, it remained longer than that seen with control treatment.

In patients with tumors of Trop-2 high status, median PFS was 6.9 months with SG, vs 2.5 for patients who underwent control treatment. This fell to 5.6 months vs 2.2 months in the Trop-2 medium group and 2.7 months vs 1.6 months in Trop-2 low group.

A similar pattern was seen for overall survival.

In the Trop-2 high group, median overall survival was 14.2 months with SG, vs 6.9 months with control therapy; 14.9 months vs 6.9 months in the Trop-2 medium group; and 9.3 months vs 7.6 months in the Trop-2 low group.

Again, the objective response rate fell from 44% to 38% and then to 22% with SG in the Trop-2 high, medium, and low groups, compared with 1%, 11%, and 6%, respectively, with control treatment.

There did not seem to be any interaction between Trop-2 expression and treatment-related adverse events of special interests. Rates of neutropenia, diarrhea, and anemia were consistently higher in SG-treated patients than in those given placebo.

Hurvitz said that the objective response rate was markedly higher with SG vs control treatment in both BRCA1/2-positive and -negative patients, at 19% vs 6% in the positive group and 33% vs 6% in the negative group.

This was reflected in improved median PFS with SG in both subgroups, at 4.6 months vs 2.5 months with control therapy in BRCA1/2-positive patients and 4.9 months vs 1.6 months in BRCA1/2-negative patients.

Overall survival was 15.6 months with SG, vs 4.4 months with control treatment in BRCA1/2-positive patients. In BRCA1/2-negative patients, the respective figures were 10.9 months and 7.0 months.

The study was sponsored by Immunomedics Inc. Hurvitz has financial ties to Immunomedics and multiple other pharmaceutical companies. Litton has financial ties to multiple pharmaceutical companies, including those with breast cancer therapies.

San Antonio Breast Cancer Symposium (SABCS) 2020: Abstract GS3-06. Presented December 10, 2020.

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