TRODELVY: OL Video Series

ADC Landscape Transcript 

INDICATIONS
TRODELVY® (sacituzumab govitecan-hziy) is a Trop-2-directed antibody and topoisomerase inhibitor conjugate indicated for the treatment of adult patients with:

• Unresectable locally advanced or metastatic triple-negative breast cancer (mTNBC) who have received two or more prior systemic therapies, at least one of them for metastatic disease.
• Unresectable locally advanced or metastatic hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative (IHC 0, IHC 1+ or IHC 2+/ISH–) breast cancer who have received endocrine-based therapy and at least two additional systemic therapies in the metastatic setting.

IMPORTANT SAFETY INFORMATION
TRODELVY has a boxed warning.
TRODELVY can cause severe, life-threatening, or fatal neutropenia. Withhold TRODELVY for absolute neutrophil count below 1500/mm3 or neutropenic fever. Monitor blood cell counts periodically during treatment. Primary prophylaxis with G-CSF is recommended for all patients at increased risk of febrile neutropenia. Initiate anti-infective treatment in patients with febrile neutropenia without delay. 

TRODELVY can cause severe diarrhea. Monitor patients with diarrhea and give fluid and electrolytes as needed. At the onset of diarrhea, evaluate for infectious causes and, if negative, promptly initiate loperamide. If severe diarrhea occurs, withhold TRODELVY until resolved to ≤Grade 1 and reduce subsequent doses.

Please see full Prescribing Information, including BOXED WARNING, at TRODELVYhcp.com.

VR: Doctors, it’s good to see you both. I’m glad we get this opportunity to sit down together and have a conversation about antibody drug conjugates.

VKG: Yeah, so happy to be here.

MD: Yeah, it’s good to see you both. 

VR: So why don’t we just dive right in and talk about the unmet needs for patients with HR-positive, HER2-negative metastatic breast cancer and triple-negative metastatic breast cancer. 

VKG: Yeah, I think when we talk about unmet need, the truth is those patients still pass from that disease. And as long as that’s the case, we got to keep working. We got to keep finding new ideas, new mechanisms of actions, new drugs, new agents, and then work towards prioritizing those as fast as we can get them to be available to patients, as appropriate. 

VR: What are your thoughts about using ADCs for metastatic breast cancer patients? 

MD: I think we have to understand who are the patients that benefit the most…We don’t have much data that really helps us delineate most optimal therapies. 

VR: Yeah, couldn’t agree more. Something I find difficult to navigate with patients is talking about sequencing for ADCs. So that’s really an area that I wish we had more data. 

MD: I think the notion is that we still have a lot to learn. We lose patients in between lines of therapy. Many patients don’t progress from one line to the next and don’t have the opportunity to receive another agent. So we want to use what we have identified as the best possible opportunity used in the first possible setting. And I think this will require us to really tear down some of our old paradigms and replace them with new evidence-based strategies that have really changed the way we think about sequencing. 

VKG: So let’s talk about one of the available ADCs, TRODELVY, and its MOA. 

VR: For TRODELVY, we should note that the mechanism of action is suggested based on preclinical data, which may not correlate to clinical outcomes. 

VR: TRODELVY was designed to deliver a potent cytotoxic payload called SN-38 to Trop-2 expressing cells, which includes cancer cells. 

VR: Trop-2 is a trophoblast cell-surface antigen…And SN-38 is a topoisomerase-1 inhibitor that prevents repair of DNA damage and leads to apoptosis and cell death. 

MD: It also has a high drug-to-antibody ratio of about 8:1. 

MD: Specifically, what makes TRODELVY unique from other ADCs is the payload is bound to a humanized monoclonal antibody by a hydrolyzable CL2A linker. So when TRODELVY binds to Trop-2 and gets internalized by the cell, the CL2A linkers will release the cytotoxic payload to kill tumor cells. 

VKG: The payload can act on both Trop-2 expressing cells and surrounding cells after intracellular release, enabling a so-called bystander effect. 

MD: Some people may think that all ADCs work the same, but they don’t. 

VKG: Yeah, I spent a lot of time thinking about these drugs and they’re unique. And part of how that uniqueness happens is there’s multiple components to these drugs. First you have the antibody that hones in on whatever the target is, then you have the linker and the drug. And those three important pieces all can differ from one ADC to the next. 

MD: Yeah, I think it’s important that when we target or select the target, it is ubiquitously expressed, at least in a high frequency so that we can find a whole number of patients that can benefit from the drug. 

VR: We’re not expecting people to repeat biomarker testing. We don’t have to be looking for Trop-2, we understand that it’s present on those cells. I think that’s a really important point when we’re thinking about which agent to choose between antibody-drug conjugates for patients. 

VR: Another thing differentiating TRODELVY in the antibody-drug conjugate landscape is the guidance from the NCCN. So why don’t we review the NCCN guidance and then we can discuss the significance on the other side. 

VR: Sacituzumab govitecan-hziy, or TRODELVY, is the only antibody-drug conjugate designated by the National Comprehensive Cancer Network, or NCCN®, as an NCCN Category 1 preferred regimen for both pretreated HR+/HER2– metastatic breast cancer and metastatic triple-negative breast cancer in the NCCN Clinical Practice Guidelines in Oncology. 

VR: Sacituzumab govitecan-hziy is recommended as a Category 1 preferred treatment option for adult patients with unresectable locally advanced or metastatic triple-negative breast cancer as second-line therapy. It may be considered for later line if not used as second-line therapy. 

VR: For HR+/HER2– metastatic breast cancer, sacituzumab govitecan-hziy is recommended as a Category 1 preferred treatment option for adult patients with unresectable locally advanced or metastatic HR+/HER2– breast cancer who have received prior treatment, including endocrine therapy, a CDK4/6 inhibitor, and at least 2 lines of chemotherapy, at least one of which was in the metastatic setting. It may be used in the second line if the patient isn’t a candidate for fam-trastuzumab deruxtecan-nxki. It may also be considered for later line if not used as a second-line therapy.

It’s important to note that the NCCN recommendations differ from the TRODELVY PI. 

VR: So that being said, what’s the importance of TRODELVY being the first and only ADC designated as an NCCN category one preferred option for HR-positive, HER2-negative metastatic breast cancer and metastatic triple-negative breast cancer? 

MD: Well, for me it’s important that NCCN is listing TRODELVY here with a strong emphasis as category one preferred agent. 

VKG: Yeah, when I think about the NCCN, I really do hold them in high esteem. They look at the data with cold, hard eyes and really evaluating the quality of the study, how the study was conducted, the results themselves, the safety profile, integrating all that information, putting it in the flow of how we’re going to treat our patients from one line to the next, and then giving recommendations based on that. Level one evidence is very hard to get. 

VR: Yeah. For many oncologists, I think the NCCN is the gold standard for understanding what treatment options we recommend.

VKG: So the other thing, of course, with the NCCN indicating that it was across HER2– status. I think is really important. With a drug like sacituzumab govitecan targeting Trop-2 that you don’t have a biomarker that you have to go search for, it’s another important distinction for this agent. 

VR: Well, I want to thank both of you. I think this has been a really wonderful conversation and I really appreciate learning from both of you, your insights. 

VKG: Yeah, likewise. Every time I sit with folks like you guys, I just learn so much as well each time. So this has been great. 

VR: Please keep watching for Important Safety Information. 

IMPORTANT SAFETY INFORMATION

TRODELVY is contraindicated for patients with severe hypersensitivity reactions to TRODELVY.

Warnings and precautions for TRODELVY include neutropenia, diarrhea, hypersensitivity and infusion-related reactions, nausea and vomiting, increased risk of adverse reactions in patients with reduced UGT1A1 activity, and embryo-fetal toxicity.

Neutropenia: Severe, life-threatening, or fatal neutropenia can occur as early as the first cycle of treatment and may require dose modification. Neutropenia occurred in 64% of patients treated with TRODELVY. Grade 3-4 neutropenia occurred in 49% of patients. Febrile neutropenia occurred in 6%. Neutropenic colitis occurred in 1.4%. Primary prophylaxis with G-CSF is recommended starting in the first cycle of treatment in all patients at increased risk of febrile neutropenia, including older patients, patients with previous neutropenia, poor performance status, organ dysfunction, or multiple comorbidities. Monitor absolute neutrophil count (ANC) during treatment. Withhold TRODELVY for ANC below 1500/mm³ on Day 1 of any cycle or below 1000/mm³ on Day 8 of any cycle. Withhold TRODELVY for neutropenic fever. Treat neutropenia with G-CSF and administer prophylaxis in subsequent cycles as clinically indicated or indicated in Table 2 of USPI.

Diarrhea: Diarrhea occurred in 64% of all patients treated with TRODELVY. Grade 3-4 diarrhea occurred in 11% of patients. One patient had intestinal perforation following diarrhea. Diarrhea that led to dehydration and subsequent acute kidney injury occurred in 0.7% of all patients. Withhold TRODELVY for Grade 3-4 diarrhea and resume when resolved to ≤Grade 1. At onset, evaluate for infectious causes and if negative, promptly initiate loperamide, 4 mg initially followed by 2 mg with every episode of diarrhea for a maximum of 16 mg daily. Discontinue loperamide 12 hours after diarrhea resolves. Additional supportive measures (for example, fluid and electrolyte substitution) may also be employed as clinically indicated. Patients who exhibit an excessive cholinergic response to treatment can receive appropriate premedication (for example, atropine) for subsequent treatments.

Hypersensitivity and Infusion-Related Reactions: TRODELVY can cause serious hypersensitivity reactions including life-threatening anaphylactic reactions. Severe signs and symptoms included cardiac arrest, hypotension, wheezing, angioedema, swelling, pneumonitis, and skin reactions. Hypersensitivity reactions within 24 hours of dosing occurred in 35% of patients. Grade 3-4 hypersensitivity occurred in 2% of patients. The incidence of hypersensitivity reactions leading to permanent discontinuation of TRODELVY was 0.2%. The incidence of anaphylactic reactions was 0.2%. Pre-infusion medication is recommended. Have medications and emergency equipment to treat such reactions available for immediate use. Observe patients closely for hypersensitivity and infusion-related reactions during each infusion and for at least 30 minutes after completion of each infusion. Permanently discontinue TRODELVY for Grade 4 infusion-related reactions.

Nausea and Vomiting: TRODELVY is emetogenic and can cause severe nausea and vomiting. Nausea occurred in 64% of all patients treated with TRODELVY and Grade 3-4 nausea occurred in 3% of these patients. Vomiting occurred in 35% of patients and Grade 3-4 vomiting occurred in 2% of these patients. Premedicate with a two or three drug combination regimen (for example, dexamethasone with either a 5-HT3 receptor antagonist or an NK1 receptor antagonist as well as other drugs as indicated) for prevention of chemotherapy-induced nausea and vomiting (CINV). Withhold TRODELVY doses for Grade 3 nausea or Grade 3-4 vomiting and resume with additional supportive measures when resolved to ≤Grade 1. Additional antiemetics and other supportive measures may also be employed as clinically indicated. All patients should be given take-home medications with clear instructions for prevention and treatment of nausea and vomiting.

Increased Risk of Adverse Reactions in Patients with Reduced UGT1A1 Activity: Patients homozygous for the uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1)*28 allele are at increased risk for neutropenia, febrile neutropenia, and anemia and may be at increased risk for other adverse reactions with TRODELVY. The incidence of Grade 3-4 neutropenia was 58% in patients homozygous for the UGT1A1*28, 49% in patients heterozygous for the UGT1A1*28 allele, and 43% in patients homozygous for the wild-type allele. The incidence of Grade 3-4 anemia was 21% in patients homozygous for the UGT1A1*28 allele, 10% in patients heterozygous for the UGT1A1*28 allele, and 9% in patients homozygous for the wild-type allele. Closely monitor patients with known reduced UGT1A1 activity for adverse reactions. Withhold or permanently discontinue TRODELVY based on clinical assessment of the onset, duration and severity of the observed adverse reactions in patients with evidence of acute early-onset or unusually severe adverse reactions, which may indicate reduced UGT1A1 function.

Embryo-Fetal Toxicity: Based on its mechanism of action, TRODELVY can cause teratogenicity and/or embryo-fetal lethality when administered to a pregnant woman. TRODELVY contains a genotoxic component, SN-38, and targets rapidly dividing cells. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with TRODELVY and for 6 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with TRODELVY and for 3 months after the last dose.

The following adverse reactions were observed with TRODELVY.

In the pooled safety population, the most common (≥ 25%) adverse reactions including laboratory abnormalities were decreased leukocyte count (84%), decreased neutrophil count (75%), decreased hemoglobin (69%), diarrhea (64%), nausea (64%), decreased lymphocyte count (63%), fatigue (51%), alopecia (45%), constipation (37%), increased glucose (37%), decreased albumin (35%), vomiting (35%), decreased appetite (30%), decreased creatinine clearance (28%), increased alkaline phosphatase (28%), decreased magnesium (27%), decreased potassium (26%), and decreased sodium (26%).

In the ASCENT study (locally advanced or metastatic triple-negative breast cancer), the most common adverse reactions (incidence ≥25%) were fatigue, diarrhea, nausea, alopecia, constipation, vomiting, abdominal pain, and decreased appetite. The most frequent serious adverse reactions (incidence >1%) were neutropenia (7%), diarrhea (4%), and pneumonia (3%). Serious adverse reactions were reported in 27% of patients, and 5% of patients discontinued therapy due to adverse reactions. The most common Grade 3-4 lab abnormalities (incidence ≥25%) in the ASCENT study were reduced neutrophils, leukocytes, and lymphocytes.

In the TROPiCS-02 study (locally advanced or metastatic HR-positive, HER2-negative breast cancer), the most common adverse reactions (incidence ≥25%) were diarrhea, fatigue, nausea, alopecia, and constipation. The most frequent serious adverse reactions (incidence >1%) were diarrhea (5%), febrile neutropenia (4%), neutropenia (3%), abdominal pain, colitis, neutropenic colitis, pneumonia, and vomiting (each 2%). Serious adverse reactions were reported in 28% of patients, and 6% discontinued therapy due to adverse reactions. The most common Grade 3-4 lab abnormalities (incidence ≥25%) in the TROPiCS-02 study were reduced neutrophils and leukocytes.

Drug interactions for TRODELVY include UGT1A1 inhibitors and UGT1A1 inducers. 

UGT1A1 Inhibitors: Concomitant administration of TRODELVY with inhibitors of UGT1A1 may increase the incidence of adverse reactions due to potential increase in systemic exposure to SN-38. Avoid administering UGT1A1 inhibitors with TRODELVY. 

UGT1A1 Inducers: Exposure to SN-38 may be reduced in patients concomitantly receiving UGT1A1 enzyme inducers. Avoid administering UGT1A1 inducers with TRODELVY. 

Please see full Prescribing Information, including BOXED WARNING, at TRODELVYhcp.com.

This information does not constitute the provision of medical advice and should not substitute for clinical decision-making. 

Presenters are paid consultants of Gilead. 

TRODELVY, the TRODELVY logo, GILEAD, and the GILEAD logo are trademarks of Gilead Sciences, Inc., or its related companies. All other marks are the property of their respective owners.
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