Here, we will discuss what are the advantages of Trodelvy, and which is superior in the field of breast cancer treatment, Trodelvy vs. Dato-DXd, Enhertu?

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Trodelvy: Any Chance Against Dato-DXd and
Enhertu?
Trodelvy (sacituzumab govitecan-hziy) is a First-in-class Trop-2-directed
antibody-drug conjugate (ADC) indicated for the treatment of metastatic
triple-negative breast cancer (mTNBC) and metastatic urothelial cancer (mUC).
Here, we will discuss what are the advantages of Trodelvy, and which is
superior in the field of breast cancer treatment, Trodelvy vs. Dato-DXd,
Enhertu?
What is Trodelvy?
Trodelvy is a targeted (biological) therapy, which is composed of 3
components:
1. Monoclonal antibody: The humanized monoclonal antibody, hRS7 IgG1κ,
that binds to Trop-2, a transmembrane calcium signal transducer that is
overexpressed in many epithelial cancers, including triple-negative breast
cancer (TNBC)
2. Cytotoxic drug: The camptothecin-derived agent, SN-38, a topoisomerase I
inhibitor act by interfering with the replicative capacity of cancer cells.
3. Linker: A hydrolyzable linker, with a short PEGylated unit.
Figure 1. Structure of Trodelvy
Trodelvy® was developed by Immunomedics, and Gilead acquired ownership
of Trodelvy® in September 2020 through its $21 billion acquisition of
Immunomedics. Trodelvy's first clinical trial began in 2012 and has a
substantial clinical evidence base. Even without the aura of Gilead's huge
acquisition, Trodelvy had previously been terminated early with stunning
clinical data and received accelerated approval for triple-negative breast

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cancer (TNBC) nearly 2 months ahead of the scheduled approval date, making
it a potential star drug.
Trodelvy has been approved in more than 35 countries and is undergoing
multiple additional regulatory reviews worldwide for the treatment of adult
patients with unresectable locally advanced or metastatic triple-negative
breast cancer who have received two or more prior systemic therapies. Gilead
Sciences has submitted a supplemental Biologics License Application to the
U.S. FDA.
In addition to breast cancer, Trodelvy® has shown positive performance in
several cancer types including uroepithelial cancer, lung cancer, and prostate
cancer. Phase II clinical studies for single-agent second-line treatment of
uroepithelial carcinoma showed an ORR of 28%, and this indication has been
approved for marketing by the FDA.

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Figure 2. Pipelines of Trodelvy, source: Gilead official website
Trodelvy vs. Dato-DXd, Enhertu
Trodelvy's sales were $380 million in 2021. According to analysts, Trodelvy's
sales need to peak at $4 billion in order for Gilead to recover the cost of the
acquisition. But the potential competition is also fierce and challenging for
Trodelvy's subsequent growth. Currently, the two products with the most
competition are Dato-DXd and Enhertu.
Dato-DXd
In terms of same-target ADC products, there are more than 20 TROP-2 ADCs
in development worldwide. Its main competitor, Datopotamab deruxtecan
(DS-1062/Dato-DXd) from Daiichi Sankyo/AstraZeneca, is already in Phase III
clinical development.
Figure 3. Stucture of Dato-DXd, and comparison between Dato-DXd &
Trodelvy

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Dato-DXd is designed and developed based on Daiichi Sankyo's proprietary
DXd-ADC technology platform, which uses DNA topoisomerase I to inhibit
DXd with high activity and is able to kill nearby cancer cells through the
"bystander effect" with short half-life and low toxic side effects. The linker is
highly stable and can be specifically cleaved by enzymes in the tumor tissue,
avoiding the killing effect on normal tissue.
On December 7, 2021, Daiichi Sankyo disclosed at SABCS the latest data
from the TROPION-PanTumor01 TNBC cohort, a clinical phase I trial of
Dato-DXd, showing that Dato-DXd demonstrated sustained remission and
disease control in patients with metastatic triple-negative breast cancer who
experienced disease progression after standard therapy.
Specific results showed that of the 44 patients treated with Dato-DXd (6 mg/kg
[n=42] and 8 mg/kg [n=2]) 15 patients achieved objective remission with an
ORR of 34%. After a median follow-up of 7.6 months (4-13 months), 14
patients were confirmed to have achieved complete/partial remission, with a
median duration of remission not yet reached as most patients remained in
remission, for a disease control rate of 77%. In the subgroup of 27 patients
with measurable disease and not previously treated with topoisomerase I
inhibitor-ADC drugs, the ORR in the Dato-DXd group was 52%, and after a
median follow-up of 8.8 months (4-13 months), 13 patients were confirmed to
have achieved CR/PRs, 1 patient with CR/PRs yet to be confirmed, and
another 9 patients had stable disease. The DCR for this subgroup of patients
was 81%. With regard to safety, treatment-related adverse events occurred in
≥15% of patients including: nausea, stomatitis, vomiting, fatigue, hair loss,
mucosal inflammation, constipation, headache, lymphopenia, neutropenia,
fever, anemia, pruritus, hypokalemia, diarrhea, and cough. 23% of patients
experienced ≥ grade 3 treatment-related adverse events. There were no cases
of interstitial lung disease (ILD).
Enhertu
One of Trodelvy's indications, HR+/HER2- breast cancer, has been challenged
by a strong rival, Enhertu, although the patient populations are not the same,
but there is some degree of overlap. Trodelvy's Phase III TROPiCS-02 study
included patients with HR+/HER2- metastatic breast cancer who had received
endocrine therapy, CDK4/6 inhibitors and 2-4 lines of chemotherapy, including
patients with HER2-low and IHC 0 status.
At the 2022 ASCO meeting, data from Enhertu's DESTINY-Breast04 and
Trodelvy's TROPiCS-02 were both released. DESTINY-Breast04, which
defines a new breast cancer staging that distinguishes low HER2 expression
(IHC 1+ or IHC2+/ISH negative) from the HER2-negative population, was
approved by the FDA for priority review in approximately two weeks.
TROPiCS-02, despite meeting clinical endpoints and being included in the

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NCCN guidelines as a Class 2A recommendation based on positive data, did
not yield the expected results. Detailed data can be found in the chart below.
Figure 4. Tropics-02: KM-curve for progression free survival (primary endpoint)
Figure 5. DESTINY-Breast04 results

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References:
[1] Bardia A, Hurvitz SA, Tolaney SM, et al. Sacituzumab Govitecan in
Metastatic Triple-Negative Breast Cancer. N Engl J Med.
2021;384(16):1529-1541. doi:10.1056/NEJMoa2028485
[2]https://www.cancernetwork.com/view/positive-response-activity-seen-with-d
atopotamab-deruxtecan-in-advanced-tnbc
[3] https://www.medscape.com/viewarticle/974274
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