On September 16, 2021 Bayer reported that Data from three subset analyses and one matching-adjusted indirect comparison (MAIC) model for Vitrakvi (larotrectinib) showcase its consistent noteworthy clinical profile and add to its existing safety data for patients with solid tumors harboring an NTRK gene fusion (also known as TRK fusion cancer) (Press release, Bayer, SEP 16, 2021, View Source [SID1234587836]). These analyses add to the body of evidence for the compound, which has the largest dataset and longest follow-up of any TRK inhibitor. These results are being presented at the ESMO (Free ESMO Whitepaper) Congress 2021, to be held between September 16-21, 2021.

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Vitrakvi is approved for the treatment of adult and pediatric patients with solid tumors that have an NTRK gene fusion without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity, and have no satisfactory alternative treatments or that have progressed following treatment. Patients should be selected for therapy based on a Food and Drug Administration (FDA)-approved test. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.1

"As we continue to see ongoing analyses of larotrectinib across a wide range of solid tumors and ages, its consistent results in NTRK fusion-positive cancers support its efficacy and safety in adults and children." said Alexander Drilon, M.D., Chief of Early Drug Development Service at Memorial Sloan Kettering Cancer Center.* "These data reinforce the importance of early comprehensive genomic testing to uncover actionable oncogenic drivers, including NTRK gene fusions, to help identify patients who are most likely to benefit from a targeted treatment approach."

"The U.S. FDA approval of Vitrakvi nearly three years ago represented a paradigm shift in how we treat cancer, by inhibiting the oncogenic driver that is causing a solid tumor to grow and spread rather than the location where it originates," said Scott Z. Fields, M.D., Senior Vice President and Head of Oncology Development at Bayer’s Pharmaceutical Division. "The long-term data for Vitrakvi continue to support consistent responses and similar safety profile seen with the addition of new patients and with longer follow-up. These findings reinforce the importance of precision oncology medicines as a meaningful advancement in cancer care."

Larotrectinib efficacy and safety in adult patients with tropomyosin receptor kinase (TRK) fusion cancer (Abstract 535P)2

In an updated subgroup analysis with longer follow-up (data cut-off July 20, 2020) in 130 evaluable patients out of 140 total adult patients with non-central nervous system (CNS) TRK fusion cancer across 20 different tumor types, Vitrakvi continued to show efficacy. Among evaluable patients, the overall response rate (ORR) was 67% (95% CI 58–75) per investigator assessment, including 12% complete responses and 55% partial responses. Among the evaluable patients with CNS metastases (n=15), ORR was 73% (95% CI 45–92). Among all patients, the median duration of response (DoR) was 49.3 months (95% CI 26.3–NE) at a median follow-up of 23.2 months.

Grade 3–4 treatment related adverse events (TRAEs) occurred in 17 patients (12%) and no new safety signals were identified. Data were pooled from three clinical trials (NCT02122913, NCT02637687, NCT02576431).

Larotrectinib in non-CNS TRK fusion cancer patients: outcomes by prior therapy and performance status (Abstract 534P)3

In a post-hoc subgroup analysis with adult and pediatric patients (n=218; data cut-off July 20, 2020), patients were evaluated based on treatment history and baseline performance status. A total of 218 patients were evaluated based on performance status as defined by Eastern Cooperative Oncology Group (ECOG PS) or equivalent Lansky/Karnofsky performance status for pediatric patients. Out of the 218 evaluable patients, 216 patients were assessed based on prior line of systemic therapy, as two patients were excluded from analysis due to data entry ambiguity. Investigator-assessed treatment response rates were highest in patients who had no previous systemic treatment (ORR=81%; 95% CI 69–91; n=58) or with a baseline ECOG PS of 0 (ORR=85%; 95% CI 77–91; n=114); however, while patients in each group showed responses from Vitrakvi across prior line of systemic therapy and baseline ECOG PS, there were differences. In patients who received Vitrakvi following one line of systemic therapy (n=59), the ORR was 73% (95% CI 60–84). In patients who received two lines of systemic therapy (n=42), the ORR was 69% (95% CI 53–82), and in patients who received three or more lines of systemic therapy (n=57) the ORR was 75% (95% CI 62–86). In patients with an ECOG PS of 1 (n=78), the ORR was 66% (95% CI 54–77), followed by 61% (95% CI 39–80; n=23) with an ECOG PS of 2, and 33% (95% CI 1–91; n=3) with an ECOG PS of 3. Across all patients, ORR was 75% (95% CI 68–81) and median DoR was 49.3 months (95% CI 27.3–NE). Data were pooled from three clinical trials (NCT02122913, NCT02637687, NCT02576431).

Incidence of fractures in TRK fusion cancer patients treated with larotrectinib (Abstract 536P)4

In a pooled analysis of 331 patients (n=214 adult, 117 pediatric) with solid and CNS tumors treated with Vitrakvi, the incidence of fractures, which can be an event of concern in oncology patients, was analyzed. Fractures were mainly Grade 1 or 2 (n=12 adult fractures, n=8 pediatric fractures) and were associated with trauma (fall) or were tumor-related. Treatment-emergent fractures of all grades were reported in 7% (n=15) of adults and 7.7% (n=9) of children. No fractures were considered to be treatment-related by Investigator. Data were pooled from three clinical trials (NCT02122913, NCT02637687, NCT02576431).

Matching-adjusted indirect comparison for treatment of NTRK fusion cancer with larotrectinib versus entrectinib (Abstract 104P)5

A MAIC of data from clinical trials with Vitrakvi (data cut-off July 2020) and entrectinib (data cut-off October 2018) analyzed the efficacy endpoints overall survival (OS), progression-free survival (PFS), ORRs including complete responses and DoR as well as safety observed in these trials, matching patients based on available common baseline characteristics (gender, age, race, ECOG score, select tumor types, metastatic disease, NTRK gene, CNS metastases, number of prior lines of therapy). Although cross-trial comparisons are subject to limitations, MAIC is an alternative method for comparative data when a head-to-head randomized control trial (RCT) is not available and/or possible, such as in the case of TRK fusion cancer in part due to the rarity of the disease.6 The analysis provides further, more granular information between the efficacy and safety outcomes between the clinical trials with these treatments. Data were pooled from three Vitrakvi clinical trials (NCT02122913, NCT02637687, NCT02576431) and three entrectinib studies (ALKA-372-001, STARTRK-1 and STARTRK-2).

About Vitrakvi (larotrectinib)

Vitrakvi (larotrectinib) is indicated for the treatment of adult and pediatric patients with solid tumors that have a neurotrophic receptor tyrosine kinase (NTRK) gene fusion without a known acquired resistance mutation, are metastatic or where surgical resection will likely result in severe morbidity, and have no satisfactory alternative treatments or that have progressed following treatment.

Select patients for therapy based on an FDA-approved test.

This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Important Safety Information for Vitrakvi (larotrectinib)

Central Nervous System Effects: Central nervous system (CNS) adverse reactions occurred in patients receiving VITRAKVI, including dizziness, cognitive impairment, mood disorders, and sleep disturbances.

In patients who received VITRAKVI, all grades CNS effects including cognitive impairment, mood disorders, dizziness and sleep disorders were observed in 42% with Grades 3-4 in 3.9% of patients.

Cognitive impairment occurred in 11% of patients. The median time to onset of cognitive impairment was 5.6 months (range: 2 days to 41 months). Cognitive impairment occurring in ≥ 1% of patients included memory impairment (3.6%), confusional state (2.9%), disturbance in attention (2.9%), delirium (2.2%), cognitive disorders (1.4%), and Grade 3 cognitive adverse reactions occurred in 2.5% of patients. Among the 30 patients with cognitive impairment, 7% required a dose modification and 20% required dose interruption.

Mood disorders occurred in 14% of patients. The median time to onset of mood disorders was 3.9 months (range: 1 day to 40.5 months). Mood disorders occurring in ≥1% of patients included anxiety (5%), depression (3.9%), agitation (2.9%), and irritability (2.9%). Grade 3 mood disorders occurred in 0.4% of patients.

Dizziness occurred in 27% of patients, and Grade 3 dizziness occurred in 1.1% of patients. Among the 74 patients who experienced dizziness, 5% of patients required a dose modification and 5% required dose interruption.

Sleep disturbances occurred in 10% of patients. Sleep disturbances included insomnia (7%), somnolence (2.5%), and sleep disorder (0.4%). There were no Grade 3-4 sleep disturbances. Among the 28 patients who experienced sleep disturbances, 1 patient each (3.6%) required a dose modification or dose interruption.

Advise patients and caretakers of these risks with VITRAKVI. Advise patients not to drive or operate hazardous machinery if they are experiencing neurologic adverse reactions. Withhold or permanently discontinue VITRAKVI based on the severity. If withheld, modify the VITRAKVI dosage when resumed.

Skeletal Fractures: Among 187 adult patients who received VITRAKVI across clinical trials, fractures were reported in 7% and among 92 pediatric patients, fractures were reported in 9% (N=279; 8%). Median time to fracture was 11.6 months (range 0.9 to 45.8 months) in patients followed per fracture. Fractures of the femur, hip or acetabulum were reported in 4 patients (3 adult, 1 pediatric). Most fractures were associated with minimal or moderate trauma. Some fractures were associated with radiologic abnormalities suggestive of local tumor involvement. VITRAKVI treatment was interrupted due to fracture in 1.4% patients.

Promptly evaluate patients with signs or symptoms of potential fracture (e.g., pain, changes in mobility, deformity). There are no data on the effects of VITRAKVI on healing of known fractures or risk of future fractures.

Hepatotoxicity: In patients who received VITRAKVI, increased AST of any grade occurred in 52% of patients and increased ALT of any grade occurred in 45%. Grade 3-4 increased AST or ALT occurred in 3.1% and 2.5% of patients, respectively. The median time to onset of increased AST was 2.1 months (range: 1 day to 4.3 years). The median time to onset of increased ALT was 2.3 months (range: 1 day to 4.2 years). Increased AST and ALT leading to dose modifications occurred in 1.4% and 2.2% of patients, respectively. Increased AST or ALT led to permanent discontinuation in 3 (1.1%) patients.

Monitor liver tests, including ALT and AST, every 2 weeks during the first month of treatment, then monthly thereafter, and as clinically indicated. Withhold or permanently discontinue VITRAKVI based on the severity. If withheld, modify the VITRAKVI dosage when resumed.

Embryo-Fetal Toxicity: VITRAKVI can cause fetal harm when administered to a pregnant woman. VITRAKVI resulted in malformations in rats and rabbits at maternal exposures that were approximately 11- and 0.7-times, respectively, those observed at the clinical dose of 100 mg twice daily. Advise women of the potential risk to a fetus. Advise females of reproductive potential to use an effective method of contraception during treatment and for 1 week after the final dose of VITRAKVI.

Most Common Adverse Reactions (≥20%): The most common adverse reactions (≥20%), including laboratory abnormalities, were: increased AST (52%), increased ALT (45%), anemia (42%), musculoskeletal pain (42%), fatigue (36%), hypoalbuminemia (36%), neutropenia (36%), increased alkaline phosphatase (34%), cough (32%), leukopenia (28%), constipation (27%), diarrhea (27%), dizziness (27%), hypocalcemia (25%), nausea (25%), vomiting (25%), pyrexia (24%), lymphopenia (22%) and abdominal pain (21%).

Drug Interactions: Avoid coadministration of VITRAKVI with strong CYP3A4 inhibitors (including grapefruit or grapefruit juice), strong CYP3A4 inducers (including St. John’s wort), or sensitive CYP3A4 substrates. If coadministration of strong CYP3A4 inhibitors or inducers cannot be avoided, modify the VITRAKVI dose as recommended. If coadministration of sensitive CYP3A4 substrates cannot be avoided, monitor patients for increased adverse reactions of these drugs.

Lactation: Advise women not to breastfeed during treatment with VITRAKVI and for 1 week after the final dose.

Please see the full Prescribing Information for VITRAKVI (larotrectinib).

About TRK Fusion Cancer

TRK fusion cancer occurs when an NTRK gene fuses with another unrelated gene, producing a chimeric TRK protein. The altered protein, or TRK fusion protein, becomes constitutively active or overexpressed, triggering a signaling cascade. These TRK fusion proteins are oncogenic drivers promoting cell growth and survival, leading to TRK fusion cancer. TRK fusion cancer is not limited to certain types of tissues and can occur in any part of the body. TRK fusion cancer occurs in various adult and pediatric solid tumors with varying frequency, including lung, thyroid, GI cancers (colon, cholangiocarcinoma, pancreatic and appendiceal), sarcoma, CNS cancers (glioma and glioblastoma), salivary gland cancers (including secretory carcinoma of the salivary gland) and pediatric cancers (infantile fibrosarcoma and other soft tissue sarcomas).1,7

About Oncology at Bayer

Bayer is committed to delivering science for a better life by advancing a portfolio of innovative treatments. The oncology franchise at Bayer includes six marketed products and several other assets in various stages of clinical development. Together, these products reflect the company’s approach to research, which prioritizes targets and pathways with the potential to impact the way that cancer is treated.

On September 16, 2021 Shasqi, a clinical-stage biotechnology company developing precision activated oncology therapeutics with its proprietary Click Activated Protodrugs Against Cancer (CAPAC) platform, reported that interim data from its Phase 1 clinical study of SQ3370 in advanced sarcomas and other solid tumors, as well as additional non-clinical data at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress, being held virtually on September 16-21, 2021 (Press release, Shasqi, SEP 16, 2021, View Source [SID1234587835]).

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The interim Phase 1 clinical data were presented at the developmental therapeutics virtual poster session:

Abstract Title: Early pharmacokinetic data from a Phase I study of SQ3370 (NCT04106492) in patients with advanced solid tumors provides proof-of-concept for the click chemistry-based CAPAC platform
Presentation Number: 547P
Virtual Poster Session Title: Developmental therapeutics
Link to full poster details here.
The non-clinical data were presented at the basic science virtual poster session:

Abstract Title: Click Activated Protodrugs Against Cancer (CAPAC) Platform Enhances the Safety, Pharmacokinetics, and Antitumor Efficacy of Cancer Therapies in vivo
Presentation Number: 9P
Virtual Poster Session Title: Basic science
Link to full poster details here.
"These early data from our Phase 1 study of SQ3370 provide initial validation for our click chemistry-based platform in humans with an encouraging safety profile," said José M. Mejía Oneto, M.D., Ph.D., Founder and CEO of Shasqi. "Cytotoxic agents remain standard of care for many cancers because they are effective at killing tumor cells. Our platform is designed to enhance the therapeutic benefit of these agents while minimizing toxicity. With this early validation of our platform, we can continue to advance SQ3370 and explore the application of our technology beyond chemotherapies to other standard of care cancer therapies with a limited therapeutic window."

"Conventional chemotherapeutics are not tumor-specific and can lead to toxicity. In this study, which administered up to four times the standard dose of doxorubicin, we showed that SQ3370 has the potential to widen the therapeutic window and improve the safety profile when compared to standard doxorubicin or liposomal doxorubicin," said Vivek Subbiah, M.D., Principal Investigator, Associate Professor of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center. "The early signs of clinical activity without dose limiting toxicities in this group of heavily pretreated patients, some of whom have progressed through standard doxorubicin and other chemotherapies, are encouraging. As the study advances, we will further evaluate the safety and efficacy of higher doses of SQ3370."

The interim Phase 1 results of the first-in-human, dose escalation study of SQ3370 in patients with advanced solid tumors that are refractory/relapsed following or otherwise ineligible for standard of care therapy, were presented in poster format at ESMO (Free ESMO Whitepaper) 2021. Key study findings include:

All nine patients received at least one cycle of SQ3370
Eight out of nine patients had metastatic disease
Escalating doses ranged from 0.38x to 4x the molar equivalent of conventional doxorubicin
Nonclinical and clinical pharmacokinetics (PK) data are consistent, demonstrating more than 50 times higher exposure of doxorubicin in tumor versus plasma
No dose-limiting toxicities (DLT’s) have been observed
The most common treatment emergent adverse events reported were nausea, fatigue, constipation and pyrexia
Five out of eight evaluable patients had a best response of stable disease, including patients who progressed on prior doxorubicin or other prior systemic therapies
Maximum tolerated dose has not yet been reached
SQ3370 dose escalation is ongoing
Non-clinical results on the safety, PK, and antitumor efficacy of Click Activated Protodrugs Against Cancer (CAPAC) Platform in animal models were presented in poster format at ESMO (Free ESMO Whitepaper) 2021. Key findings included:

GLP study in canine models showed that the highest non-severely toxic dose (HNSTD) of SQ3370 was 8.95 mg/kg/cycle. Side effects were dose-dependent and reversible with no evidence of cardiotoxicity
Rat PK modeling shows that doxorubicin exposure in the tumor is >300x higher than plasma
SQ3370 murine models showed antitumor efficacy in multiple tumor types both in injected and non-injected lesions (abscopal effect).
CAPAC and SQ3370:

SQ3370 utilizes Shasqi’s proprietary CAPAC platform, a click chemistry-based approach that activates cancer drugs at a tumor with decreased systemic toxicity. The platform is based on the chemical reaction between an attenuated trans-cyclooctene-modified protodrug and a tetrazine-modified biopolymer. The biopolymer is injected into the target tumor lesion, where it precisely activates an intravenously infused protodrug. Unlike traditional targeted therapies, the CAPAC platform is agnostic to tumor characteristics that can vary from patient to patient, such as biomarker expression and enzymatic activity.

On September 16, 2021 Y-mAbs Therapeutics, Inc. ("Y-mAbs", NASDAQ: YMAB), a commercial-stage biopharmaceutical company focused on the development and commercialization of novel, antibody-based therapeutic products for the treatment of cancer, reported the acceptance of two presentations at the International Society of Pediatric Oncology ("SIOP") Virtual Annual Congress held October 21 through October 24, 2021 (Press release, Y-mAbs Therapeutics, SEP 16, 2021, View Source [SID1234587834]).

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DANYELZA (naxitamab-gqgk)

The abstracts include the following oral presentation of DANYELZA, the Company’s approved therapy for the treatment of pediatric patients with relapsed or refractory high-risk neuroblastoma, which is currently also being evaluated for the treatment of osteosarcoma and other GD2-positive tumors:

"Naxitamab treatment of refractory/relapsed high-risk neuroblastoma (R/R HR NB); subgroup analysis of updated efficacy and safety data for the registrational Phase II trial", submitted by SJD Barcelona Children’s Hospital in Barcelona, Spain
Omburtamab

The abstracts also include the following poster presentation of omburtamab, the Company’s lead product candidate, which is currently being evaluated for the treatment of patients with CNS/Leptomeningeal metastasis from neuroblastoma, diffuse intrinsic pontine glioma ("DIPG"), and desmoplastic small round cell tumors ("DSRCT"):

"Outcomes of intraventricular 131-I-8H9 and external beam radiotherapy in patients with medulloblastoma, ependymoma, and pineoblastoma," submitted by Memorial Sloan Kettering Cancer Center ("MSK") in New York
Researchers at MSK developed DANYELZA and omburtamab, which are exclusively licensed by MSK to Y-mAbs. As a result of this licensing arrangement, MSK has institutional financial interests in the compounds.

About DANYELZA (naxitamab-gqgk)

DANYELZA (naxitamab-gqgk) is indicated, in combination with granulocyte-macrophage colony-stimulating factor ("GM-CSF"), for the treatment of pediatric patients 1 year of age and older and adult patients with relapsed or refractory high-risk neuroblastoma in the bone or bone marrow who have demonstrated a partial response, minor response, or stable disease to prior therapy. This indication was approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefits in a confirmatory trial. DANYELZA includes a Boxed Warning for serious infusion-related reactions, such as cardiac arrest and anaphylaxis, and neurotoxicity, such as severe neuropathic pain and transverse myelitis. See full Prescribing Information for complete Boxed Warning and other important safety information.

On September 16, 2021 PharmaCyte Biotech, Inc. (NASDAQ: PMCB), a biotechnology company focused on developing cellular therapies for cancer and diabetes using its signature live-cell encapsulation technology, Cell-in-a-Box, reported the first test results of the biocompatibility studies of its CypCaps clinical trial product candidate (Press release, PharmaCyte Biotech, SEP 16, 2021, View Source [SID1234587833]). These results were from an "In Vitro Complement Activation Study of Empty Cellulose Sulphate Capsules," the same capsules PharmaCyte uses in its treatment for pancreatic cancer.

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PharmaCyte’s Chief Executive Officer, Kenneth L. Waggoner, said, "A number of studies are currently ongoing by independent, third-party CROs on the biocompatibility of our CypCaps pancreatic cancer product candidate and its components. We are pleased to report that we have received the results from the first of these studies showing that, as expected, the capsule material does not activate a major line of the human body’s innate defense – the complement system. This is just one of the biocompatibility studies that are being performed and, in the coming weeks, we expect that the results of other studies will become available."

The complement system consists of multiple proteins, approximately 30 of which are circulating blood proteins that work together to promote immune and inflammatory responses. The complement system’s principal role is to help identify, destroy, and remove foreign pathogens such as bacteria and viruses, as well as damaged cell materials (for example, cells and proteins).

The objective of the ISO 10993-4: 2017 (E) compliant study was to evaluate the complement activation potential of empty cellulose sulphate capsules when mixed with normal human serum complement under in vitro test conditions. The study was performed by a third-party GLP laboratory. That laboratory concluded that empty cellulose sulphate capsules did not activate the complement system under defined experimental conditions based on the results of the study. These results were also supported by statistical comparisons.

To learn more about PharmaCyte’s pancreatic cancer treatment and how it works inside the body to treat locally advanced inoperable pancreatic cancer, we encourage you to watch the company’s documentary video complete with medical animations at: View Source

On September 16, 2021 Gilead Sciences, Inc. (Nasdaq: GILD) reported new data from the Phase 3 ASCENT study evaluating Trodelvy (sacituzumab govitecan-hziy) in patients with relapsed or refractory metastatic triple-negative breast cancer (TNBC) who received two or more prior systemic therapies, at least one of them for metastatic disease (Press release, Gilead Sciences, SEP 16, 2021, View Source [SID1234587831]). In a retrospective subgroup analysis, Trodelvy improved progression-free survival (PFS), overall survival (OS) and objective response rate (ORR) compared with chemotherapy chosen by the patients’ physicians in patients who were not initially diagnosed with TNBC. The results were presented at the European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2021 from September 16-21, 2021 (Poster #258P).

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"In the metastatic stage of breast cancer, it is not uncommon for people to change from one subtype to another," said Javier Cortés, MD, Head of the International Breast Cancer Center (IBCC), Madrid and Barcelona, Spain. "Roughly one-third of patients with TNBC in the ASCENT study were not originally diagnosed with TNBC, and they still experienced a survival benefit with Trodelvy compared with chemotherapy. For treating physicians, this reinforces Trodelvy’s efficacy in more complex patients."

This analysis included 146 chemotherapy-eligible brain metastasis-negative patients with an original breast cancer diagnosis that was not TNBC, of which 70 received Trodelvy and 76 received physician’s choice of chemotherapy. Among these patients, Trodelvy improved median PFS compared with chemotherapy (4.6 months vs. 2.3 months; HR: 0.48; P=0.0004), median OS (12.4 months vs. 6.7 months; HR: 0.44; P<0.0001) and ORR (31% vs. 4%). Outcomes were similar to those of the overall ASCENT trial population.

The safety profile of Trodelvy in this subgroup was consistent with prior reports from the ASCENT study. Key treatment-related grade ≥3 adverse events for Trodelvy compared to chemotherapy were neutropenia (59% vs. 40%), leukopenia (12% vs. 9%), anemia (8% vs. 7%) and diarrhea (7% vs. 0%). There were no treatment-related deaths with Trodelvy. The Trodelvy U.S. Prescribing Information has a BOXED WARNING for severe or life-threatening neutropenia and severe diarrhea; see below for Important Safety Information.

"Trodelvy is already transforming outcomes for patients with second-line or later metastatic TNBC," said Bill Grossman, MD, PhD, Senior Vice President, Oncology Clinical Research, Gilead Sciences. "Gilead is committed to continued research that further defines the clinical profile of Trodelvy. As such, we are pleased that this sub-analysis in patients not initially diagnosed with TNBC demonstrated similarly strong overall survival, progression-free survival and response rates as were observed in the overall ASCENT study population."

About Triple-Negative Breast Cancer

TNBC is the most aggressive type of breast cancer and accounts for approximately 15% of all breast cancers. TNBC is diagnosed more frequently in younger and premenopausal women and is more prevalent in Black and Hispanic women. TNBC cells do not have estrogen and progesterone receptors and have limited HER2. Due to the nature of TNBC, treatment options are extremely limited compared with other breast cancer types. TNBC has a higher chance of recurrence and metastases than other breast cancer types. The average time to metastatic recurrence for TNBC is approximately 2.6 years compared with 5 years for other breast cancers, and the relative five-year survival rate is much lower. Among women with metastatic TNBC, the five-year survival rate is 12%, compared with 28% for those with other types of metastatic breast cancer.

About the ASCENT Study

The ASCENT study is a global, open-label, randomized Phase 3 study that enrolled more than 500 patients across 230 study locations. The study evaluated the efficacy and safety of Trodelvy compared with a single-agent chemotherapy of the physician’s choice in patients with unresectable, locally advanced or metastatic TNBC who had received at least two prior systemic treatments. Patients were randomized to receive either Trodelvy or a chemotherapy chosen by the patients’ treating physicians. The primary endpoint was PFS (as determined by blinded independent central review) in patients without brain metastases. Secondary endpoints included: PFS for full study population or intention-to-treat (ITT) population, OS in both the ITT population and in the subgroup without brain metastasis, independently determined ORR, duration of response, time to onset of response according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1), quality of life and safety. More information about ASCENT is available at View Source

About Trodelvy

Trodelvy (sacituzumab govitecan-hziy) is a first-in-class antibody and topoisomerase inhibitor conjugate directed to the Trop-2 receptor, a protein overexpressed in multiple types of epithelial tumors, including metastatic TNBC and metastatic UC, where high expression is associated with poor survival and relapse. Beyond the approvals of Trodelvy in the United States, it is also approved in Australia, Switzerland, and the UK for adults with metastatic TNBC. Trodelvy is also under regulatory review in the EU and Canada, as well as in Singapore through our partner Everest Medicines. Trodelvy is also being investigated as a potential treatment for hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer and metastatic non-small cell lung cancer. Additional evaluation across multiple solid tumors is also underway.

In the United States, Trodelvy is indicated for the treatment of:

Adult patients with unresectable locally advanced or metastatic TNBC who have received two or more prior systemic therapies, at least one of them for metastatic disease.
Adult patients with locally advanced or metastatic UC who have previously received a platinum-containing chemotherapy and either programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor.
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. Administer atropine, if not contraindicated, for early diarrhea of any severity. At the onset of late 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 61% of patients treated with Trodelvy. Grade 3-4 neutropenia occurred in 47% of patients. Febrile neutropenia occurred in 7%. 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.

Diarrhea: Diarrhea occurred in 65% of all patients treated with Trodelvy. Grade 3-4 diarrhea occurred in 12% of patients. One patient had intestinal perforation following diarrhea. Neutropenic colitis occurred in 0.5% of 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 37% of patients. Grade 3-4 hypersensitivity occurred in 2% of patients. The incidence of hypersensitivity reactions leading to permanent discontinuation of Trodelvy was 0.3%. The incidence of anaphylactic reactions was 0.3%. Pre-infusion medication is recommended. Observe patients closely for hypersensitivity and infusion-related reactions during each infusion and for at least 30 minutes after completion of each infusion. Medication to treat such reactions, as well as emergency equipment, should be available for immediate use. Permanently discontinue Trodelvy for Grade 4 infusion-related reactions.

Nausea and Vomiting: Nausea occurred in 66% of all patients treated with Trodelvy and Grade 3 nausea occurred in 4% of these patients. Vomiting occurred in 39% of patients and Grade 3-4 vomiting occurred in 3% 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 67% in patients homozygous for the UGT1A1*28, 46% in patients heterozygous for the UGT1A1*28 allele and 46% in patients homozygous for the wild-type allele. The incidence of Grade 3-4 anemia was 25% in patients homozygous for the UGT1A1*28 allele, 10% in patients heterozygous for the UGT1A1*28 allele, and 11% 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 ASCENT study (IMMU-132-05), the most common adverse reactions (incidence ≥25%) were fatigue, neutropenia, diarrhea, nausea, alopecia, anemia, 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 TROPHY study (IMMU-132-06), the most common adverse reactions (incidence ≥25%) were diarrhea, fatigue, neutropenia, nausea, any infection, alopecia, anemia, decreased appetite, constipation, vomiting, abdominal pain, and rash. 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 substantially reduced in patients concomitantly receiving UGT1A1 enzyme inducers. Avoid administering UGT1A1 inducers with Trodelvy.

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