On June 5, 2023 Ellipses Pharma ("Ellipses"), a global drug development company focused on accelerating the development of new oncology treatments, reported its intention to expedite further global clinical development of the next generation selective RET inhibitor (SRI) EP0031/A400 following the publication of ‘very encouraging’ clinical data (Press release, Ellipses Pharma, JUN 5, 2023, View Source [SID1234632495]).

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Professor Tobias Arkenau, Global Head of Drug Development & CMO at Ellipses, commented:

"The data presented today gives everyone involved great confidence to further progress our clinical trial programme. The results have been marked in terms of significant tumour shrinkage across RET-altered tumours and importantly EP0031 had an encouraging safety and tolerability profile. This is an exciting development, and we look forward to rapidly advancing with our next phase of clinical work."

EP0031 is being developed in partnership with Kelun-Biotech Pharmaceutical Co. Ltd. (Kelun-Biotech) and is also known as A400 when in conjunction with Kelun-Biotech’s ongoing regional development.

Trial data of the Phase 1 Study of KL590586 (EP0031/A400), presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) conference in Chicago today, reported preliminary efficacy and safety for a total of 109 patients. A400/EP0031 was generally well tolerated with the majority of adverse events recorded as manageable grade 1 or 2. In the overall RET-altered tumour population, patients who received A400/EP0031 at doses between 40 and 120mg OD had an objective response rate of 60% with a disease control rate of 90%. Two specific treatment cohorts were highlighted at the meeting: i) patients, with previously untreated RET-fusion positive advanced NSCLC with an objective response rate of 80.8% (21/26 patients); and ii) patients with RET-fusion positive NSCLC who had received prior systemic treatment (median prior line 2, range 1-9), including chemo-immunotherapy, with an objective response rate of 69.7% (23/33 patients). Disease control rates of >96% were reported for each cohort. Importantly, evidence of clinical activity was also reported in cohorts of patients with brain metastases as well as patients that had received prior 1st generation SRI.

EP0031/A400 is the subject of a global, modular Phase 1/2 trial to evaluate safety, tolerability and efficacy in patients with advanced RET-altered tumours and has been under clinical investigation in China by Kelun-Biotech for patients with RET-altered cancers. Clinical dose expansion data from the latter study were reported at the ASCO (Free ASCO Whitepaper) conference today.

Professor Sir Christopher Evans, OBE, Chairman, Ellipses, commented:

"From the outset of Ellipses, we have remained firmly focused on the selection of only the most promising oncology discoveries through our global network of over 200 key opinion leaders and our unbiased vetting approach. We are delighted to see EP0031 progressing so well through its clinical trial journey. It offers great potential to address a significant unmet need in oncology and extend the treatment options for patients."

Dr Rajan Jethwa, Chief Executive Officer, Ellipses, commented:

"EP0031/A400 is a promising next generation SRI. We welcome the very striking clinical data presented by our partners at Kelun-Biotech, which marks an important step in the development of this agent. EP0031 offers the potential to further improve patient outcomes and the rapid pace at which its clinical programme is progressing provides further evidence that our approach accelerates drug development for the benefit of patients. Data presented today will be augmented by results from our Phase1/2 trial currently underway in the US, EU and UK."

Dr Junyou Ge, Chief Executive Officer of Kelun-Biotech, commented:

"EP0031/A400 offers a significant therapeutic potential for tumours with RET oncogene mutation/fusion and is hoped to bring new treatment options for patients. The clinical data presented today is extremely encouraging and Kelun-Biotech will continue to collaborate with Ellipses to promote the global development and subsequent potential commercialisation of this treatment to benefit more cancer patients around the world."

On June 5, 2023 MEDiC Life Sciences ("MEDiC"), a Silicon Valley biotech startup, reported that it entered into a research collaboration with Bristol Myers Squibb (NYSE:BMY) (Press release, MEDIC Life Sciences, JUN 5, 2023, View Source [SID1234632494]). In the collaboration, MEDiC is using its scalable 3-dimensional tumor models to perform CRISPR functional genomics screens in solid tumor indications of interest to Bristol Myers Squibb. MEDiC is also using its immune cell and tumor cell co-culture platform to identify novel genes relevant to immune cell killing of cancer cells.

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"We are very excited that Bristol Myers Squibb selected MEDiC as a collaborator to advance its oncology discovery programs," said Kyuho Han, Ph.D., co-founder and chief executive officer of MEDiC. "We look forward to working with Bristol Myers Squibb to identify novel oncology targets to advance potentially effective new medicines for cancer patients."

Under the terms of the agreement, MEDiC will receive upfront payments for the research collaboration and will be eligible for additional option payments on a target-by-target basis. MEDiC is also eligible for future development and regulatory milestone payments.

MEDiC has developed a proprietary CRISPR functional genomics platform that employs patient-tumor-like cancer models to identify optimal gene targets and biomarkers for cancer. While functional genomics approaches have been widely used to screen whole genomes for gene functions in cancer, MEDiC has demonstrated for the first time that using 3-dimensional tumor models, rather than traditional 2-dimensional cultures, may vastly improve the accuracy and translatability of CRISPR functional genomics. With this technology, MEDiC may identify novel cancer targets and biomarkers to develop drugs for solid tumor indications. MEDiC’s unique approach has already attracted partners seeking novel targets for drug development.

On June 5, 2023 Gilead Sciences, Inc. (Nasdaq: GILD) reported longer-term overall survival (OS) results from the Phase 3 TROPiCS-02 study evaluating Trodelvy (sacituzumab govitecan-hziy) versus comparator chemotherapy (physicians’ choice of chemotherapy, TPC) in patients with HR+/HER2- (IHC0, IHC1+, IHC2+/ISH-) metastatic breast cancer who received endocrine-based therapies and at least two chemotherapies (Press release, Gilead Sciences, JUN 5, 2023, View Source;Metastatic-Breast-Cancer [SID1234632493]). In this exploratory analysis, Trodelvy demonstrated a clinically meaningful improvement in median OS benefit compared to TPC (median OS: 14.5 months vs. 11.2 months; hazard ratio (HR): 0.79; [95% CI: 0.65-0.95]; nominal p=0.0133). These findings will be shared as an oral presentation at the 2023 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (Abstract #1003). This abstract has also been selected to be included in the 2023 Best of ASCO (Free ASCO Whitepaper) program, which will be held this summer following the ASCO (Free ASCO Whitepaper) Annual Meeting.

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"These longer-term results show the durable overall survival benefit of sacituzumab govitecan over traditional chemotherapy in pre-treated HR+/HER2- metastatic breast cancer," said Sara Tolaney, MD, MPH, Chief of the Division of Breast Oncology at the Dana-Farber Cancer Institute, and Associate Professor of Medicine, Harvard Medical School. "At this stage of disease, sequential chemotherapy is common, and benefits may become smaller with subsequent lines of therapy. The potential for a novel agent that may allow patients to live longer is especially meaningful."

Progression-free survival (PFS) rates for Trodelvy vs. TPC were consistently higher at landmark milestones of 6, 12 and 18 months (45.6% vs. 29.4%, 21.7% vs. 8.4% and 14.4 vs. 4.7%, respectively). Similarly, OS rates for Trodelvy vs. TPC were consistently higher at landmark milestones of 12, 18, and 24 months (60.9% vs. 47.1%, 39.2% vs. 31.7%, and 25.7% vs. 21.1%, respectively). Ninety-two percent of patients in TROPiCS-02 were also eligible for evaluation of OS by HER2 status, as measured by immunohistochemistry (HER2 IHC0, n=217; HER2-low, n=283). Patients treated with Trodelvy demonstrated improved OS versus TPC in both the HER2 IHC0 (median OS: 13.6 months vs. 10.8 months; HR: 0.85 [95% CI: 0.63-1.14]) and HER2-low groups (median OS: 15.4 vs. 11.5 months; HR: 0.75 [95% CI: 0.57-0.97]).

"With these longer-term results in pre-treated HR+/HER2- metastatic breast cancer, Trodelvy has demonstrated proven survival benefit for patients who have had few options until now," said Bill Grossman, MD, PhD, Senior Vice President, Therapeutic Area Head, Gilead Oncology. "We believe Trodelvy has the potential to transform outcomes for women across many different types of breast cancers. The survival benefit demonstrated for patients with pre-treated metastatic HR+/HER2- and metastatic triple-negative breast cancer are just the beginning of our clinical development journey. Our ambition is to extend this benefit to more patients, earlier in their treatment journey, where the potential impact is greatest."

In TROPiCS-02, the most common grade ≥3 treatment emergent adverse events were neutropenia (52%), diarrhea (10%) and fatigue (6%) in the Trodelvy arm, and neutropenia (39%), thrombocytopenia (4%), fatigue (4%) and dyspnea (4%) for those treated with TPC. No new safety signals were identified. No patients treated with Trodelvy in TROPiCS-02 experienced interstitial lung disease (ILD). Trodelvy has a well-characterized safety profile consistent with that in previous studies. In the TROPiCS-02 study, the discontinuation rate due to adverse reactions was 6% for Trodelvy and 4% for patients on single-agent chemotherapy.

Trodelvy was approved in February 2023 by the U.S. Food and Drug Administration for the treatment of adult patients with unresectable locally advanced or metastatic HR+/HER2- breast cancer who have received endocrine-based therapy and at least two additional systemic therapies in the metastatic setting. The European Medicines Agency has also validated a Type II Variation Marketing Authorization Application for Trodelvy in HR+/HER2- metastatic breast cancer.

Trodelvy is also recommended as a Category 1, preferred treatment for metastatic HR+/HER2- breast cancer by the National Comprehensive Cancer Network (NCCN) as defined in the Clinical Practice Guidelines in Oncology (NCCN Guidelines).i

Trodelvy has a Boxed Warning for severe or life-threatening neutropenia and severe diarrhea; please see below for additional Important Safety Information.

About HR+/HER2- Breast Cancer

Hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer is the most common type of breast cancer and accounts for approximately 70% of all new cases. Almost one in three cases of early-stage breast cancer eventually become metastatic, and among patients with HR+/HER2- metastatic disease, the five-year relative survival rate is 34%. As patients with HR+/HER2- metastatic breast cancer become resistant to endocrine-based therapy, their primary treatment option is limited to single-agent chemotherapy. In this setting, it is common to receive multiple lines of chemotherapy regimens over the course of treatment, and the prognosis remains poor.

About the TROPiCS-02 Study

The TROPiCS-02 study is a global, multicenter, open-label, Phase 3 study, randomized 1:1 to evaluate Trodelvy versus physicians’ choice of chemotherapy (eribulin, capecitabine, gemcitabine, or vinorelbine) in 543 patients with HR+/HER2- metastatic breast cancer who were previously treated with endocrine therapy, CDK4/6 inhibitor and two to four lines of chemotherapy for metastatic disease. The primary endpoint is progression-free survival per Response Evaluation Criteria in Solid Tumors (RECIST 1.1) as assessed by blinded independent central review (BICR) for participants treated with Trodelvy compared to those treated with chemotherapy. Secondary endpoints include overall survival, overall response rate, clinical benefit rate and duration of response, as well as assessment of safety and tolerability and quality of life measures. In the study, HER2 negativity was defined per American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) and the College of American Pathologists (CAP) criteria as immunohistochemistry (IHC) score of 0, IHC 1+ or IHC 2+ with a negative in-situ hybridization (ISH) test. More information about TROPiCS-02 is available at View Source

About Trodelvy

Trodelvy (sacituzumab govitecan-hziy) is a first-in-class Trop-2 directed antibody-drug conjugate. Trop-2 is a cell surface antigen highly expressed in multiple tumor types, including in more than 90% of breast and bladder cancers. Trodelvy is intentionally designed with a proprietary hydrolyzable linker attached to SN-38, a topoisomerase I inhibitor payload. This unique combination delivers potent activity to both Trop-2 expressing cells and the microenvironment.

Trodelvy is approved in more than 40 countries, with multiple additional regulatory reviews underway worldwide, for the treatment of adult patients with unresectable locally advanced or metastatic triple-negative breast cancer (TNBC) who have received two or more prior systemic therapies, at least one of them for metastatic disease.

Trodelvy is also approved in the U.S. to treat certain patients with pre-treated HR+/HER2- metastatic breast cancer and has an accelerated approval for treatment of certain patients with second-line metastatic urothelial cancer; see below for full indication statements.

Trodelvy is also being developed for potential investigational use in other TNBC, HR+/HER2- and metastatic UC populations, as well as a range of tumor types where Trop-2 is highly expressed, including metastatic non-small cell lung cancer (NSCLC), metastatic small cell lung cancer (SCLC), head and neck cancer, and endometrial cancer.

U.S. Indications for Trodelvy

In the United States, Trodelvy is 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.
Locally advanced or metastatic urothelial cancer (mUC) who have previously received a platinum-containing chemotherapy and either programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
U.S. Important Safety Information for Trodelvy

BOXED WARNING: NEUTROPENIA AND DIARRHEA

Severe or life-threatening neutropenia may occur. Withhold Trodelvy for absolute neutrophil count below 1500/mm3 or neutropenic fever. Monitor blood cell counts periodically during treatment. Consider G-CSF for secondary prophylaxis. Initiate anti-infective treatment in patients with febrile neutropenia without delay.
Severe diarrhea may occur. 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.
CONTRAINDICATIONS

Severe hypersensitivity reaction to Trodelvy.
WARNINGS AND PRECAUTIONS

Neutropenia: Severe, life-threatening, or fatal neutropenia can occur 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%. Withhold Trodelvy for absolute neutrophil count below 1500/mm3 on Day 1 of any cycle or neutrophil count below 1000/mm3 on Day 8 of any cycle. Withhold Trodelvy for neutropenic fever. Administer G-CSF as clinically indicated or indicated in Table 1 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 (e.g., fluid and electrolyte substitution) may also be employed as clinically indicated. Patients who exhibit an excessive cholinergic response to treatment can receive appropriate premedication (e.g., atropine) for subsequent treatments.

Hypersensitivity and Infusion-Related Reactions: Serious hypersensitivity reactions including life-threatening anaphylactic reactions have occurred with Trodelvy. 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: 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 (e.g., 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.

ADVERSE REACTIONS

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 (SAR) (>1%) were neutropenia (7%), diarrhea (4%), and pneumonia (3%). SAR were reported in 27% of patients, and 5% 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 (SAR) (>1%) were diarrhea (5%), febrile neutropenia (4%), neutropenia (3%), abdominal pain, colitis, neutropenic colitis, pneumonia, and vomiting (each 2%). SAR 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.

In the TROPHY study (locally advanced or metastatic urothelial cancer), the most common adverse reactions (incidence ≥25%) were diarrhea, fatigue, nausea, any infection, alopecia, decreased appetite, constipation, vomiting, rash, and abdominal pain. The most frequent serious adverse reactions (SAR) (≥5%) were infection (18%), neutropenia (12%, including febrile neutropenia in 10%), acute kidney injury (6%), urinary tract infection (6%), and sepsis or bacteremia (5%). SAR were reported in 44% of patients, and 10% discontinued due to adverse reactions. The most common Grade 3-4 lab abnormalities (incidence ≥25%) in the TROPHY study were reduced neutrophils, leukocytes, and lymphocytes.

DRUG INTERACTIONS

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.

On June 5, 2023 Gilead Sciences, Inc. (Nasdaq: GILD) reported longer-term overall survival (OS) results from the Phase 3 TROPiCS-02 study evaluating Trodelvy (sacituzumab govitecan-hziy) versus comparator chemotherapy (physicians’ choice of chemotherapy, TPC) in patients with HR+/HER2- (IHC0, IHC1+, IHC2+/ISH-) metastatic breast cancer who received endocrine-based therapies and at least two chemotherapies (Press release, Gilead Sciences, JUN 5, 2023, View Source;Metastatic-Breast-Cancer [SID1234632493]). In this exploratory analysis, Trodelvy demonstrated a clinically meaningful improvement in median OS benefit compared to TPC (median OS: 14.5 months vs. 11.2 months; hazard ratio (HR): 0.79; [95% CI: 0.65-0.95]; nominal p=0.0133). These findings will be shared as an oral presentation at the 2023 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (Abstract #1003). This abstract has also been selected to be included in the 2023 Best of ASCO (Free ASCO Whitepaper) program, which will be held this summer following the ASCO (Free ASCO Whitepaper) Annual Meeting.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

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"These longer-term results show the durable overall survival benefit of sacituzumab govitecan over traditional chemotherapy in pre-treated HR+/HER2- metastatic breast cancer," said Sara Tolaney, MD, MPH, Chief of the Division of Breast Oncology at the Dana-Farber Cancer Institute, and Associate Professor of Medicine, Harvard Medical School. "At this stage of disease, sequential chemotherapy is common, and benefits may become smaller with subsequent lines of therapy. The potential for a novel agent that may allow patients to live longer is especially meaningful."

Progression-free survival (PFS) rates for Trodelvy vs. TPC were consistently higher at landmark milestones of 6, 12 and 18 months (45.6% vs. 29.4%, 21.7% vs. 8.4% and 14.4 vs. 4.7%, respectively). Similarly, OS rates for Trodelvy vs. TPC were consistently higher at landmark milestones of 12, 18, and 24 months (60.9% vs. 47.1%, 39.2% vs. 31.7%, and 25.7% vs. 21.1%, respectively). Ninety-two percent of patients in TROPiCS-02 were also eligible for evaluation of OS by HER2 status, as measured by immunohistochemistry (HER2 IHC0, n=217; HER2-low, n=283). Patients treated with Trodelvy demonstrated improved OS versus TPC in both the HER2 IHC0 (median OS: 13.6 months vs. 10.8 months; HR: 0.85 [95% CI: 0.63-1.14]) and HER2-low groups (median OS: 15.4 vs. 11.5 months; HR: 0.75 [95% CI: 0.57-0.97]).

"With these longer-term results in pre-treated HR+/HER2- metastatic breast cancer, Trodelvy has demonstrated proven survival benefit for patients who have had few options until now," said Bill Grossman, MD, PhD, Senior Vice President, Therapeutic Area Head, Gilead Oncology. "We believe Trodelvy has the potential to transform outcomes for women across many different types of breast cancers. The survival benefit demonstrated for patients with pre-treated metastatic HR+/HER2- and metastatic triple-negative breast cancer are just the beginning of our clinical development journey. Our ambition is to extend this benefit to more patients, earlier in their treatment journey, where the potential impact is greatest."

In TROPiCS-02, the most common grade ≥3 treatment emergent adverse events were neutropenia (52%), diarrhea (10%) and fatigue (6%) in the Trodelvy arm, and neutropenia (39%), thrombocytopenia (4%), fatigue (4%) and dyspnea (4%) for those treated with TPC. No new safety signals were identified. No patients treated with Trodelvy in TROPiCS-02 experienced interstitial lung disease (ILD). Trodelvy has a well-characterized safety profile consistent with that in previous studies. In the TROPiCS-02 study, the discontinuation rate due to adverse reactions was 6% for Trodelvy and 4% for patients on single-agent chemotherapy.

Trodelvy was approved in February 2023 by the U.S. Food and Drug Administration for the treatment of adult patients with unresectable locally advanced or metastatic HR+/HER2- breast cancer who have received endocrine-based therapy and at least two additional systemic therapies in the metastatic setting. The European Medicines Agency has also validated a Type II Variation Marketing Authorization Application for Trodelvy in HR+/HER2- metastatic breast cancer.

Trodelvy is also recommended as a Category 1, preferred treatment for metastatic HR+/HER2- breast cancer by the National Comprehensive Cancer Network (NCCN) as defined in the Clinical Practice Guidelines in Oncology (NCCN Guidelines).i

Trodelvy has a Boxed Warning for severe or life-threatening neutropenia and severe diarrhea; please see below for additional Important Safety Information.

About HR+/HER2- Breast Cancer

Hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer is the most common type of breast cancer and accounts for approximately 70% of all new cases. Almost one in three cases of early-stage breast cancer eventually become metastatic, and among patients with HR+/HER2- metastatic disease, the five-year relative survival rate is 34%. As patients with HR+/HER2- metastatic breast cancer become resistant to endocrine-based therapy, their primary treatment option is limited to single-agent chemotherapy. In this setting, it is common to receive multiple lines of chemotherapy regimens over the course of treatment, and the prognosis remains poor.

About the TROPiCS-02 Study

The TROPiCS-02 study is a global, multicenter, open-label, Phase 3 study, randomized 1:1 to evaluate Trodelvy versus physicians’ choice of chemotherapy (eribulin, capecitabine, gemcitabine, or vinorelbine) in 543 patients with HR+/HER2- metastatic breast cancer who were previously treated with endocrine therapy, CDK4/6 inhibitor and two to four lines of chemotherapy for metastatic disease. The primary endpoint is progression-free survival per Response Evaluation Criteria in Solid Tumors (RECIST 1.1) as assessed by blinded independent central review (BICR) for participants treated with Trodelvy compared to those treated with chemotherapy. Secondary endpoints include overall survival, overall response rate, clinical benefit rate and duration of response, as well as assessment of safety and tolerability and quality of life measures. In the study, HER2 negativity was defined per American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) and the College of American Pathologists (CAP) criteria as immunohistochemistry (IHC) score of 0, IHC 1+ or IHC 2+ with a negative in-situ hybridization (ISH) test. More information about TROPiCS-02 is available at View Source

About Trodelvy

Trodelvy (sacituzumab govitecan-hziy) is a first-in-class Trop-2 directed antibody-drug conjugate. Trop-2 is a cell surface antigen highly expressed in multiple tumor types, including in more than 90% of breast and bladder cancers. Trodelvy is intentionally designed with a proprietary hydrolyzable linker attached to SN-38, a topoisomerase I inhibitor payload. This unique combination delivers potent activity to both Trop-2 expressing cells and the microenvironment.

Trodelvy is approved in more than 40 countries, with multiple additional regulatory reviews underway worldwide, for the treatment of adult patients with unresectable locally advanced or metastatic triple-negative breast cancer (TNBC) who have received two or more prior systemic therapies, at least one of them for metastatic disease.

Trodelvy is also approved in the U.S. to treat certain patients with pre-treated HR+/HER2- metastatic breast cancer and has an accelerated approval for treatment of certain patients with second-line metastatic urothelial cancer; see below for full indication statements.

Trodelvy is also being developed for potential investigational use in other TNBC, HR+/HER2- and metastatic UC populations, as well as a range of tumor types where Trop-2 is highly expressed, including metastatic non-small cell lung cancer (NSCLC), metastatic small cell lung cancer (SCLC), head and neck cancer, and endometrial cancer.

U.S. Indications for Trodelvy

In the United States, Trodelvy is 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.
Locally advanced or metastatic urothelial cancer (mUC) who have previously received a platinum-containing chemotherapy and either programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
U.S. Important Safety Information for Trodelvy

BOXED WARNING: NEUTROPENIA AND DIARRHEA

Severe or life-threatening neutropenia may occur. Withhold Trodelvy for absolute neutrophil count below 1500/mm3 or neutropenic fever. Monitor blood cell counts periodically during treatment. Consider G-CSF for secondary prophylaxis. Initiate anti-infective treatment in patients with febrile neutropenia without delay.
Severe diarrhea may occur. 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.
CONTRAINDICATIONS

Severe hypersensitivity reaction to Trodelvy.
WARNINGS AND PRECAUTIONS

Neutropenia: Severe, life-threatening, or fatal neutropenia can occur 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%. Withhold Trodelvy for absolute neutrophil count below 1500/mm3 on Day 1 of any cycle or neutrophil count below 1000/mm3 on Day 8 of any cycle. Withhold Trodelvy for neutropenic fever. Administer G-CSF as clinically indicated or indicated in Table 1 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 (e.g., fluid and electrolyte substitution) may also be employed as clinically indicated. Patients who exhibit an excessive cholinergic response to treatment can receive appropriate premedication (e.g., atropine) for subsequent treatments.

Hypersensitivity and Infusion-Related Reactions: Serious hypersensitivity reactions including life-threatening anaphylactic reactions have occurred with Trodelvy. 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: 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 (e.g., 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.

ADVERSE REACTIONS

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 (SAR) (>1%) were neutropenia (7%), diarrhea (4%), and pneumonia (3%). SAR were reported in 27% of patients, and 5% 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 (SAR) (>1%) were diarrhea (5%), febrile neutropenia (4%), neutropenia (3%), abdominal pain, colitis, neutropenic colitis, pneumonia, and vomiting (each 2%). SAR 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.

In the TROPHY study (locally advanced or metastatic urothelial cancer), the most common adverse reactions (incidence ≥25%) were diarrhea, fatigue, nausea, any infection, alopecia, decreased appetite, constipation, vomiting, rash, and abdominal pain. The most frequent serious adverse reactions (SAR) (≥5%) were infection (18%), neutropenia (12%, including febrile neutropenia in 10%), acute kidney injury (6%), urinary tract infection (6%), and sepsis or bacteremia (5%). SAR were reported in 44% of patients, and 10% discontinued due to adverse reactions. The most common Grade 3-4 lab abnormalities (incidence ≥25%) in the TROPHY study were reduced neutrophils, leukocytes, and lymphocytes.

DRUG INTERACTIONS

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.

On June 5, 2023 Gilead Sciences, Inc. (Nasdaq: GILD) reported longer-term overall survival (OS) results from the Phase 3 TROPiCS-02 study evaluating Trodelvy (sacituzumab govitecan-hziy) versus comparator chemotherapy (physicians’ choice of chemotherapy, TPC) in patients with HR+/HER2- (IHC0, IHC1+, IHC2+/ISH-) metastatic breast cancer who received endocrine-based therapies and at least two chemotherapies (Press release, Gilead Sciences, JUN 5, 2023, View Source;Metastatic-Breast-Cancer [SID1234632493]). In this exploratory analysis, Trodelvy demonstrated a clinically meaningful improvement in median OS benefit compared to TPC (median OS: 14.5 months vs. 11.2 months; hazard ratio (HR): 0.79; [95% CI: 0.65-0.95]; nominal p=0.0133). These findings will be shared as an oral presentation at the 2023 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (Abstract #1003). This abstract has also been selected to be included in the 2023 Best of ASCO (Free ASCO Whitepaper) program, which will be held this summer following the ASCO (Free ASCO Whitepaper) Annual Meeting.

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"These longer-term results show the durable overall survival benefit of sacituzumab govitecan over traditional chemotherapy in pre-treated HR+/HER2- metastatic breast cancer," said Sara Tolaney, MD, MPH, Chief of the Division of Breast Oncology at the Dana-Farber Cancer Institute, and Associate Professor of Medicine, Harvard Medical School. "At this stage of disease, sequential chemotherapy is common, and benefits may become smaller with subsequent lines of therapy. The potential for a novel agent that may allow patients to live longer is especially meaningful."

Progression-free survival (PFS) rates for Trodelvy vs. TPC were consistently higher at landmark milestones of 6, 12 and 18 months (45.6% vs. 29.4%, 21.7% vs. 8.4% and 14.4 vs. 4.7%, respectively). Similarly, OS rates for Trodelvy vs. TPC were consistently higher at landmark milestones of 12, 18, and 24 months (60.9% vs. 47.1%, 39.2% vs. 31.7%, and 25.7% vs. 21.1%, respectively). Ninety-two percent of patients in TROPiCS-02 were also eligible for evaluation of OS by HER2 status, as measured by immunohistochemistry (HER2 IHC0, n=217; HER2-low, n=283). Patients treated with Trodelvy demonstrated improved OS versus TPC in both the HER2 IHC0 (median OS: 13.6 months vs. 10.8 months; HR: 0.85 [95% CI: 0.63-1.14]) and HER2-low groups (median OS: 15.4 vs. 11.5 months; HR: 0.75 [95% CI: 0.57-0.97]).

"With these longer-term results in pre-treated HR+/HER2- metastatic breast cancer, Trodelvy has demonstrated proven survival benefit for patients who have had few options until now," said Bill Grossman, MD, PhD, Senior Vice President, Therapeutic Area Head, Gilead Oncology. "We believe Trodelvy has the potential to transform outcomes for women across many different types of breast cancers. The survival benefit demonstrated for patients with pre-treated metastatic HR+/HER2- and metastatic triple-negative breast cancer are just the beginning of our clinical development journey. Our ambition is to extend this benefit to more patients, earlier in their treatment journey, where the potential impact is greatest."

In TROPiCS-02, the most common grade ≥3 treatment emergent adverse events were neutropenia (52%), diarrhea (10%) and fatigue (6%) in the Trodelvy arm, and neutropenia (39%), thrombocytopenia (4%), fatigue (4%) and dyspnea (4%) for those treated with TPC. No new safety signals were identified. No patients treated with Trodelvy in TROPiCS-02 experienced interstitial lung disease (ILD). Trodelvy has a well-characterized safety profile consistent with that in previous studies. In the TROPiCS-02 study, the discontinuation rate due to adverse reactions was 6% for Trodelvy and 4% for patients on single-agent chemotherapy.

Trodelvy was approved in February 2023 by the U.S. Food and Drug Administration for the treatment of adult patients with unresectable locally advanced or metastatic HR+/HER2- breast cancer who have received endocrine-based therapy and at least two additional systemic therapies in the metastatic setting. The European Medicines Agency has also validated a Type II Variation Marketing Authorization Application for Trodelvy in HR+/HER2- metastatic breast cancer.

Trodelvy is also recommended as a Category 1, preferred treatment for metastatic HR+/HER2- breast cancer by the National Comprehensive Cancer Network (NCCN) as defined in the Clinical Practice Guidelines in Oncology (NCCN Guidelines).i

Trodelvy has a Boxed Warning for severe or life-threatening neutropenia and severe diarrhea; please see below for additional Important Safety Information.

About HR+/HER2- Breast Cancer

Hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer is the most common type of breast cancer and accounts for approximately 70% of all new cases. Almost one in three cases of early-stage breast cancer eventually become metastatic, and among patients with HR+/HER2- metastatic disease, the five-year relative survival rate is 34%. As patients with HR+/HER2- metastatic breast cancer become resistant to endocrine-based therapy, their primary treatment option is limited to single-agent chemotherapy. In this setting, it is common to receive multiple lines of chemotherapy regimens over the course of treatment, and the prognosis remains poor.

About the TROPiCS-02 Study

The TROPiCS-02 study is a global, multicenter, open-label, Phase 3 study, randomized 1:1 to evaluate Trodelvy versus physicians’ choice of chemotherapy (eribulin, capecitabine, gemcitabine, or vinorelbine) in 543 patients with HR+/HER2- metastatic breast cancer who were previously treated with endocrine therapy, CDK4/6 inhibitor and two to four lines of chemotherapy for metastatic disease. The primary endpoint is progression-free survival per Response Evaluation Criteria in Solid Tumors (RECIST 1.1) as assessed by blinded independent central review (BICR) for participants treated with Trodelvy compared to those treated with chemotherapy. Secondary endpoints include overall survival, overall response rate, clinical benefit rate and duration of response, as well as assessment of safety and tolerability and quality of life measures. In the study, HER2 negativity was defined per American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) and the College of American Pathologists (CAP) criteria as immunohistochemistry (IHC) score of 0, IHC 1+ or IHC 2+ with a negative in-situ hybridization (ISH) test. More information about TROPiCS-02 is available at View Source

About Trodelvy

Trodelvy (sacituzumab govitecan-hziy) is a first-in-class Trop-2 directed antibody-drug conjugate. Trop-2 is a cell surface antigen highly expressed in multiple tumor types, including in more than 90% of breast and bladder cancers. Trodelvy is intentionally designed with a proprietary hydrolyzable linker attached to SN-38, a topoisomerase I inhibitor payload. This unique combination delivers potent activity to both Trop-2 expressing cells and the microenvironment.

Trodelvy is approved in more than 40 countries, with multiple additional regulatory reviews underway worldwide, for the treatment of adult patients with unresectable locally advanced or metastatic triple-negative breast cancer (TNBC) who have received two or more prior systemic therapies, at least one of them for metastatic disease.

Trodelvy is also approved in the U.S. to treat certain patients with pre-treated HR+/HER2- metastatic breast cancer and has an accelerated approval for treatment of certain patients with second-line metastatic urothelial cancer; see below for full indication statements.

Trodelvy is also being developed for potential investigational use in other TNBC, HR+/HER2- and metastatic UC populations, as well as a range of tumor types where Trop-2 is highly expressed, including metastatic non-small cell lung cancer (NSCLC), metastatic small cell lung cancer (SCLC), head and neck cancer, and endometrial cancer.

U.S. Indications for Trodelvy

In the United States, Trodelvy is 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.
Locally advanced or metastatic urothelial cancer (mUC) who have previously received a platinum-containing chemotherapy and either programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
U.S. Important Safety Information for Trodelvy

BOXED WARNING: NEUTROPENIA AND DIARRHEA

Severe or life-threatening neutropenia may occur. Withhold Trodelvy for absolute neutrophil count below 1500/mm3 or neutropenic fever. Monitor blood cell counts periodically during treatment. Consider G-CSF for secondary prophylaxis. Initiate anti-infective treatment in patients with febrile neutropenia without delay.
Severe diarrhea may occur. 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.
CONTRAINDICATIONS

Severe hypersensitivity reaction to Trodelvy.
WARNINGS AND PRECAUTIONS

Neutropenia: Severe, life-threatening, or fatal neutropenia can occur 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%. Withhold Trodelvy for absolute neutrophil count below 1500/mm3 on Day 1 of any cycle or neutrophil count below 1000/mm3 on Day 8 of any cycle. Withhold Trodelvy for neutropenic fever. Administer G-CSF as clinically indicated or indicated in Table 1 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 (e.g., fluid and electrolyte substitution) may also be employed as clinically indicated. Patients who exhibit an excessive cholinergic response to treatment can receive appropriate premedication (e.g., atropine) for subsequent treatments.

Hypersensitivity and Infusion-Related Reactions: Serious hypersensitivity reactions including life-threatening anaphylactic reactions have occurred with Trodelvy. 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: 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 (e.g., 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.

ADVERSE REACTIONS

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 (SAR) (>1%) were neutropenia (7%), diarrhea (4%), and pneumonia (3%). SAR were reported in 27% of patients, and 5% 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 (SAR) (>1%) were diarrhea (5%), febrile neutropenia (4%), neutropenia (3%), abdominal pain, colitis, neutropenic colitis, pneumonia, and vomiting (each 2%). SAR 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.

In the TROPHY study (locally advanced or metastatic urothelial cancer), the most common adverse reactions (incidence ≥25%) were diarrhea, fatigue, nausea, any infection, alopecia, decreased appetite, constipation, vomiting, rash, and abdominal pain. The most frequent serious adverse reactions (SAR) (≥5%) were infection (18%), neutropenia (12%, including febrile neutropenia in 10%), acute kidney injury (6%), urinary tract infection (6%), and sepsis or bacteremia (5%). SAR were reported in 44% of patients, and 10% discontinued due to adverse reactions. The most common Grade 3-4 lab abnormalities (incidence ≥25%) in the TROPHY study were reduced neutrophils, leukocytes, and lymphocytes.

DRUG INTERACTIONS

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.