On December 10, 2023 bluebird bio inc. (NASDAQ: BLUE) reported that data for gene therapy program in transfusion-dependent (TDT) beta-thalassemia were presented at the 65th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition (Press release, bluebird bio, DEC 10, 2023, View Source [SID1234638368]). Updated follow-up data showed sustained treatment effect, reduced iron management burden and improved quality of life measures in patients with beta-thalassemia who require regular red blood cell transfusions following treatment with betibeglogene autotemcel (beti-cel) (FDA approved and marketed in the U.S. as ZYNTEGLO).

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"Long-term results presented at ASH (Free ASH Whitepaper) 2023 showed durable transfusion independence and a continued positive safety profile in patients with beta-thalassemia treated with our beti-cel gene therapy through up to nine years of follow-up," said Richard Colvin, M.D., Ph.D., chief medical officer, bluebird bio. "These data represent the longest follow-up with a gene therapy for patients with beta-thalassemia requiring regular transfusions and continue to show that beti-cel is a potentially curative therapy across ages and genotypes, through the achievement of durable transfusion independence and normal or near-normal hemoglobin levels."

As of January 30, 2023, 63 patients had received beti-cel across four clinical studies with a median follow-up of 5 years (60.1 months; range: 23.8-109.5). These include two Phase 3 studies (N=41) that led to the FDA approval of ZYNTEGLO in August 2022 as the first and only gene therapy for patients with beta-thalassemia who require regular red blood cell transfusions.

Sustained Efficacy and Safety Results, and Improved Quality of Life Measures in Adult and Pediatric Patients With Transfusion-Dependent β-Thalassemia Up to 9 Years Post Treatment With Betibeglogene Autotemcel (beti-cel) (poster #1102)

Among patients in the Phase 3 studies, 90.2% (37/41) achieved transfusion independence (TI). As of the data cutoff date, TI was maintained through last follow-up (up to 6 years) across ages and genotypes. Among patients in the Phase 1/2 studies, 68.2% (15/22) achieved TI, with 14 patients sustaining TI through the last follow-up (up to 9 years). One patient, with human immunodeficiency virus complicated by gastrointestinal infection and bleeding, no longer met protocol-defined TI as a result of a hemoglobin level <9 g/dL at year 6. The patient continued to benefit from beti-cell therapy and was not receiving chronic red blood cells transfusions as of the last follow-up.

Among 12 adult patients and 22 pediatric patients in the Phase 1/2 and Phase 3 studies, health-related quality of life (HRQOL) was assessed at baseline and every 6 months. Clinically meaningful improvements in quality of life assessments, including various quality of life assessments for mental, physical and psychosocial health, were demonstrated in both adult and pediatric patients up to 36 months.

As of the cutoff date, the safety results following beti-cel treatment largely reflected the known side effects of hematopoietic stem cell collection and the busulfan conditioning regimen. Overall, 19% of patients experienced ≥1 beti-cel-related AE. The most common beti-cel-related AEs (occurring in ≥3 patients) were abdominal pain (7.9% of patients) and thrombocytopenia (4.8% of patients). Five patients experienced serious veno-occlusive liver disease; all 5 received defibrotide and recovered. No malignancies, insertional oncogenesis, or vector-derived replication-competent lentivirus were reported.

Improvement in Iron Burden in Patients With Transfusion-Dependent β-Thalassemia (TDT) Treated With Betibeglogene Autotemcel (beti-cel) Gene Therapy: Up to 9 Years of Follow-Up (poster #2480)

Additionally, iron management outcomes were presented from patients with transfusion-dependent beta-thalassemia who completed either a Phase 1/2 or Phase 3 beti-cel parent study and subsequently enrolled in the long-term follow-up study and were followed for up to 9 years. Across all studies, 37/51 patients restarted chelation, and 12 received phlebotomy post-infusion; however, 69% (35/51) were able to stop chelation therapy, demonstrating restoration of iron levels over time and reduced iron management burden in those patients.

About ZYNTEGLO (betibeglogene autotemcel) or beti-cel

ZYNTEGLO is a first-in-class, one-time ex-vivo LVV gene therapy. It is approved for the treatment of beta-thalassemia in adult and pediatric patients who require regular red blood cell transfusions and was launched commercially more than a year ago. ZYNTEGLO works by adding functional copies of a modified form of the beta-globin gene (βA-T87Q-globin gene) into a beta-thalassemia patient’s own hematopoietic (blood) stem cells to enable the production of a modified functional adult hemoglobin (HbAT87Q). Once a patient has the βA-T87Q-globin gene, they have the potential to increase ZYNTEGLO-derived adult hemoglobin (HbAT87Q) and total hemoglobin to normal or near normal levels that can eliminate the need for regular red blood cell (RBC) transfusions.

Indication

ZYNTEGLO is indicated for the treatment of adult and pediatric patients with beta-thalassemia who require regular red blood cell (RBC) transfusions.

Important Safety Information

Delayed Platelet Engraftment

Delayed platelet engraftment has been observed with ZYNTEGLO treatment. Bleeding risk is increased prior to platelet engraftment and may continue after engraftment in patients with prolonged thrombocytopenia; 15% of patients had ≥ Grade 3 decreased platelets on or after Day 100.

Patients should be made aware of the risk of bleeding until platelet recovery has been achieved. Monitor patients for thrombocytopenia and bleeding according to standard guidelines. Conduct frequent platelet counts until platelet engraftment and platelet recovery are achieved. Perform blood cell count determination and other appropriate testing whenever clinical symptoms suggestive of bleeding arise.

Risk of Neutrophil Engraftment Failure

There is a potential risk of neutrophil engraftment failure after treatment with ZYNTEGLO. Neutrophil engraftment failure is defined as failure to achieve three consecutive absolute neutrophil counts (ANC) ≥ 500 cells/microliter obtained on different days by Day 43 after infusion of ZYNTEGLO. Monitor neutrophil counts until engraftment has been achieved. If neutrophil engraftment failure occurs in a patient treated with ZYNTEGLO, provide rescue treatment with the back-up collection of CD34+ cells.

Risk of Insertional Oncogenesis

There is a potential risk of LVV mediated insertional oncogenesis after treatment with ZYNTEGLO.

Patients treated with ZYNTEGLO may develop hematologic malignancies and should be monitored lifelong. Monitor for hematologic malignancies with a complete blood count (with differential) at Month 6 and Month 12 and then at least annually for at least 15 years after treatment with ZYNTEGLO, and integration site analysis at Months 6, 12, and as warranted.

In the event that a malignancy occurs, contact bluebird bio at 1 833-999-6378 for reporting and to obtain instructions on collection of samples for testing.

Hypersensitivity Reactions

Allergic reactions may occur with the infusion of ZYNTEGLO. The dimethyl sulfoxide (DMSO) in ZYNTEGLO may cause hypersensitivity reactions, including anaphylaxis.

Anti-retroviral and Hydroxyurea Use

Patients should not take prophylactic HIV anti-retroviral medications or hydroxyurea for at least one month prior to mobilization, or for the expected duration for elimination of the medications, and until all cycles of apheresis are completed. If a patient requires anti-retrovirals for HIV prophylaxis, then confirm a negative test for HIV before beginning mobilization and apheresis of CD34+ cells.

Interference with Serology Testing

Patients who have received ZYNTEGLO are likely to test positive by polymerase chain reaction (PCR) assays for HIV due to integrated BB305 LVV proviral DNA, resulting in a false-positive test for HIV. Therefore, patients who have received ZYNTEGLO should not be screened for HIV infection using a PCR-based assay.

Adverse Reactions

The most common non-laboratory adverse reactions (≥20%) were mucositis, febrile neutropenia, vomiting, pyrexia, alopecia, epistaxis, abdominal pain, musculoskeletal pain, cough, headache, diarrhea, rash, constipation, nausea, decreased appetite, pigmentation disorder, and pruritus. The most common Grade 3 or 4 laboratory abnormalities (>50%) include neutropenia, thrombocytopenia, leukopenia, anemia, and lymphopenia.

Drug Interactions

Drug-drug interactions between iron chelators and the myeloablative conditioning agent must be considered. Iron chelators should be discontinued at least 7 days prior to initiation of conditioning. The prescribing information for the iron chelator(s) and the myeloablative conditioning agent should be consulted for the recommendations regarding co-administration with CYP3A substrates.

Some iron chelators are myelosuppressive. After ZYNTEGLO infusion, avoid use of these iron chelators for 6 months. If iron chelation is needed, consider administration of non-myelosuppressive iron chelators. Phlebotomy can be used in lieu of iron chelation, when appropriate.

Pregnancy/Lactation

Advise patients of the risks associated with conditioning agents, including on pregnancy and fertility.

ZYNTEGLO should not be administered to women who are pregnant, and pregnancy after ZYNTEGLO infusion should be discussed with the treating physician.

ZYNTEGLO is not recommended for women who are breastfeeding, and breastfeeding after ZYNTEGLO infusion should be discussed with the treating physician.

Females and Males of Reproductive Potential

A negative serum pregnancy test must be confirmed prior to the start of mobilization and re-confirmed prior to conditioning procedures and before ZYNTEGLO administration.

Women of childbearing potential and men capable of fathering a child should use an effective method of contraception (intra uterine device or combination of hormonal and barrier contraception) from start of mobilization through at least 6 months after administration of ZYNTEGLO.

Advise patients of the option to cryopreserve semen or ova before treatment if appropriate.

Please see full Prescribing Information for ZYNTEGLO.

On December 9, 2023 TScan Therapeutics, Inc. (Nasdaq: TCRX), a clinical-stage biopharmaceutical company focused on the development of T cell receptor (TCR)-engineered T cell therapies (TCR-T) for the treatment of patients with cancer, reported a poster presentation at the 65th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition (Press release, TScan Therapeutics, DEC 9, 2023, View Source [SID1234638438]). The poster highlights initial data from the Phase 1 multi-arm clinical trial evaluating TSC-100 and TSC-101, which are designed to treat residual disease and prevent relapse following hematopoietic cell transplantation (HCT) in patients with acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), or acute lymphocytic leukemia (ALL) (NCT05473910).

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"We are excited to present initial clinical data in our heme program, with six patients in our treatment arms and four patients in our control arm. Complete donor chimerism and MRD negativity, two favorable indicators of treatment success, were achieved and maintained in all six treated patients, four of whom have been on the study for over six months. In contrast, these indicators were not achieved in any of the four control-arm patients. In addition, one of the control-arm patients relapsed at six months, and two other control-arm patients required clinical intervention due to worsening chimerism, a sign of potential future relapse," said Debora Barton, M.D., Chief Medical Officer. "We have now enrolled and dosed patients up to the third and final dose level with no DLTs observed to date and no safety signals thus far, indicating that the third dose level will likely be the recommended Phase 2 dose. After establishing the recommended Phase 2 dose, we plan to open expansion cohorts at that dose to further characterize safety and evaluate translational and efficacy endpoints. There are currently 10 active clinical sites, and additional sites are in the process of being activated to participate in these expansion cohorts."

"Hematopoietic cell transplantation is currently the best treatment option for many patients suffering from AML, MDS, and ALL, as approximately 60% of patients are cured by this procedure," said Gavin MacBeath, Ph.D., Chief Executive Officer. "Unfortunately, for patients who relapse following transplantation, the prognosis is very poor. We have designed TSC-100 and TSC-101 to address this unmet need and increase the success rate of transplantation. We are very encouraged by these early data as they indicate that our therapies are working as designed. The translational data show that our cell therapies are eliminating all residual patient-derived malignant, pre-malignant, and benign cells, which are the cells that drive relapse. We are grateful to all the patients and their families who are participating in this trial and look forward to sharing more data in 2024 as the study continues to enroll."

The Phase 1 trial is a multi-arm dose escalation study evaluating TSC-100, TSC-101, or HCT alone in patients with AML, ALL or MDS undergoing haploidentical allogeneic HCT with reduced intensity conditioning. Patients enrolled in Dose Level 1 receive a single dose of either TSC-100 or TSC-101 approximately 21 days post-transplant. Patients enrolled in Dose Level 2 receive the same dose of TSC-100 or TSC-101 approximately 21 days post-transplant, followed by a second dose administered 40 days after the initial dose. For patients in Dose Level 3, the second dose is escalated four-fold. Primary endpoints include safety and dose-finding, and secondary and exploratory endpoints include relapse rates versus standard-of-care as well as qualitative biological readouts, including MRD and donor chimerism. MRD specifically measures malignant cells, to identify any residual disease present in a patient, and donor chimerism measures a combination of malignant, pre-malignant and normal cells, measuring any remaining patient-derived hematopoietic cells.

Key Poster Highlights:

TSC-100 treatment arm (N=3 T-ALL, AML, AML)

•
3/3 patients treated with TSC-100 achieved complete donor chimerism and MRD negativity.

TSC-101 treatment arm (N=3 TP53 mutated MDS, AML, B-ALL)

•
3/3 patients treated with TSC-101 achieved complete donor chimerism and MRD negativity, including a TP53-mutated MDS patient who remained with no detectable disease for over seven months post-HCT.

•
One patient with AML was MRD-positive following HCT and converted to MRD-negative following treatment with TSC-101.

Four control arm patients (MDS, MDS, TP53-mutated MDS, AML) have been enrolled and received standard of care HCT alone:

•
One TP53-mutated MDS control-arm patient evolved with MRD positivity and worsening mixed chimerism, finally experiencing disease relapse approximately six months after transplantation.

•
Two MDS control-arm patients developed worsening mixed chimerism that prompted early withdrawal of immunosuppression, which was complicated by grade 1 or grade 3 skin graft-vs-host disease.

•
0/4 of the control-arm patients achieved and maintained complete donor chimerism.

Higher sensitivity assays used to detect the activity of T cells:

•
Donor chimerism detected by high-sensitivity next-generation sequencing assay (AlloHeme) with limit of detection 0.13%.

•
MRD detected by next-generation sequencing with limit of detection of 0.05-0.1%.

A copy of the poster can be accessed on the "Publications" section of the Company’s website at www.tscan.com.

Virtual KOL Event

The Company will host a virtual KOL event featuring Monzr M. Al Malki, M.D., on Monday, December 11, 2023, at 8:00 a.m. ET to discuss the data presented at ASH (Free ASH Whitepaper). Dr. Al Malki is an Associate Professor in the Department of Hematology & Hematopoietic Cell Transplantation and Director of the Unrelated Donor Bone Marrow Transplant and Haploidentical Transplant Programs at City of Hope. Details for attending the live event can be found here.

On December 9, 2023 Blueprint Medicines Corporation (Nasdaq: BPMC) reported data showcasing its commitment to advance the scientific understanding and treatment of systemic mastocytosis (SM) at the 65th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition being held December 9-12 in San Diego (Press release, Blueprint Medicines, DEC 9, 2023, View Source [SID1234638351]). Data that will be presented include results from the HARBOR Part 1 trial of elenestinib in indolent systemic mastocytosis (ISM) and analyses of real-world data highlighting the burden of and urgency to treat ISM.

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"Blueprint Medicines has transformed the standard of care for advanced and indolent systemic mastocytosis with AYVAKIT (avapritinib), and its proven and compelling clinical profile is redefining what well-controlled disease means for patients living with SM," said Becker Hewes, M.D., Chief Medical Officer at Blueprint Medicines. "Building on the success of AYVAKIT and the clinical expertise amassed during its development, we are strategically advancing our investigational next-generation KIT D816V inhibitor, elenestinib, to expand and extend Blueprint Medicines’ SM franchise leadership over the long term."

HARBOR Part 1 trial data in patients with ISM showed elenestinib was well-tolerated and clinically active at all dose levels tested, supporting further development. In patients treated with elenestinib, most adverse events (AEs) were Grade 1 or 2, and there were no discontinuations due to AEs. Elenestinib showed clinically meaningful symptom improvements as assessed by the validated Indolent Systemic Mastocytosis Symptom Assessment Form Total Symptom Score (ISM-SAF TSS), and rapid and profound reductions across multiple measures of mast cell burden.

At ASH (Free ASH Whitepaper), new data on the burden of disease highlight the urgency to treat patients with ISM. A real-world analysis of U.S. health claims data showed patients with ISM had lower survival compared to a matched population cohort (p<0.0001), and a model-based analysis assessed that the lifetime risk of progression from ISM to advanced SM was approximately 20 percent. In addition, a data presentation reports on a diagnostic tool to aid in the identification of patients with SM, which was developed based on a real-world analysis at The Quality Cancer Care Alliance (QCCA).

In total, Blueprint Medicines’ presence at ASH (Free ASH Whitepaper) builds on over a decade of innovative research in the field of SM, and reflects the company’s ongoing leadership in transforming care for patients living with the disease.

ASH abstracts are listed below:

Oral Presentations

Presentation Title: Decreased Survival Among Patients with Indolent Systemic Mastocytosis: A Population-Level Retrospective Cohort Analysis Using Healthcare Claims Dataset
Session Title: 634. Myeloproliferative Syndromes: Clinical and Epidemiological: Rare Myeloproliferative Neoplasms: Unveiling Promising Pathways and Novel Therapies
Session Date & Time: Today, December 9 from 9:30 – 11:00 a.m. PT (12:30 – 2:00 p.m. ET)
Presentation Date & Time: Today, December 9 at 10:00 a.m. PT (1:00 p.m. ET)
Abstract Number: 75
Location: San Diego Convention Center, Ballroom 20AB

Presentation Title: Elenestinib, an Investigational, Next Generation KIT D816V Inhibitor, Reduces Mast Cell Burden, Improves Symptoms, and Has a Favorable Safety Profile in Patients with Indolent Systemic Mastocytosis: Analysis of the HARBOR Trial
Session Title: 634. Myeloproliferative Syndromes: Clinical and Epidemiological: Rare Myeloproliferative Neoplasms: Unveiling Promising Pathways and Novel Therapies
Session Date & Time: Today, December 9 from 9:30 – 11:00 a.m. PT (12:30 – 2:00 p.m. ET)
Presentation Date & Time: Today, December 9 at 10:15 a.m. PT (1:15 p.m. ET)
Abstract Number: 76
Location: San Diego Convention Center, Ballroom 20AB

Poster Presentation

Presentation Title: Development and Validation of a Diagnostic Tool for the Timely Diagnosis of Patients with Systemic Mastocytosis
Session Title: 906. Outcomes Research—Myeloid Malignancies: Poster II
Session Date & Time: Sunday, December 10 from 6:00 – 8:00 p.m. PT (9:00 – 11:00 p.m. ET)
Abstract Number: 3800
Location: San Diego Convention Center, Halls G-H

Publication-Only Abstract

Title: A Model of Cumulative Risk of Disease Progression Among Patients with Indolent Systemic Mastocytosis
Abstract Number: 6406

Copies of Blueprint Medicines data presentations from the ASH (Free ASH Whitepaper) annual meeting will be available in the "Science—Publications and Presentations" section of the company’s website at www.BlueprintMedicines.com.

About AYVAKIT (avapritinib)

AYVAKIT (avapritinib) is a precision therapy approved by the U.S. Food and Drug Administration (FDA) for the treatment of three indications: adults with ISM, adults with advanced SM, including aggressive SM (ASM), SM with an associated hematological neoplasm (SM-AHN) and mast cell leukemia (MCL), and adults with unresectable or metastatic gastrointestinal stromal tumor (GIST) harboring a PDGFRA exon 18 mutation, including PDGFRA D842V mutations. For more information, visit AYVAKIT.com. This medicine is approved by the European Commission (AYVAKYT) for the treatment of adults with ASM, SM-AHN or MCL, after at least one systemic therapy, and adults with unresectable or metastatic GIST harboring the PDGFRA D842V mutation. Please click here to see the full U.S. Prescribing Information for AYVAKIT, and click here to see the European Summary of Product Characteristics for AYVAKYT.

In November 2023, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) issued a positive opinion recommending the approval of AYVAKYT for the treatment of adult patients with ISM with moderate to severe symptoms inadequately controlled on symptomatic treatment.

To learn about ongoing or planned clinical trials, contact Blueprint Medicines at [email protected] or 1-888-BLU-PRNT (1-888-258-7768). Additional information is available at blueprintclinicaltrials.com or clinicaltrials.gov.

Important Safety Information

Intracranial Hemorrhage—Serious intracranial hemorrhage (ICH) may occur with AYVAKIT treatment; fatal events occurred in <1% of patients. Overall, ICH (eg, subdural hematoma, ICH, and cerebral hemorrhage) occurred in 2.9% of 749 patients who received AYVAKIT in clinical trials. In Advanced SM patients who received AYVAKIT at 200 mg daily, ICH occurred in 2 of 75 patients (2.7%) who had platelet counts ≥50 x 109/L prior to initiation of therapy and in 3 of 80 patients (3.8%) regardless of platelet counts. In ISM patients, no events of ICH occurred in the 246 patients who received any dose of AYVAKIT in the PIONEER study.

Monitor patients closely for risk factors of ICH, which may include history of vascular aneurysm, ICH or cerebrovascular accident within the prior year, concomitant use of anticoagulant drugs, or thrombocytopenia.

Symptoms of ICH may include headache, nausea, vomiting, vision changes, or altered mental status. Advise patients to seek immediate medical attention for signs or symptoms of ICH.

Permanently discontinue AYVAKIT if ICH of any grade occurs. In Advanced SM patients, a platelet count must be performed prior to initiating therapy. AYVAKIT is not recommended in Advanced SM patients with platelet counts <50 x 109/L. Following treatment initiation, platelet counts must be performed every 2 weeks for the first 8 weeks. After 8 weeks of treatment, monitor platelet counts every 2 weeks or as clinically indicated based on platelet counts. Manage platelet counts of <50 x 109/L by treatment interruption or dose reduction.

Cognitive Effects—Cognitive adverse reactions can occur in patients receiving AYVAKIT and occurred in 33% of 995 patients overall in patients who received AYVAKIT in clinical trials including: 28% of 148 Advanced SM patients (3% were Grade ≥3), and 7.8% of patients with ISM who received AYVAKIT + best supportive care (BSC) versus 7.0% of patients who received placebo + BSC (<1% were Grade 3). Depending on the severity and indication, withhold AYVAKIT and then resume at same dose or at a reduced dose upon improvement, or permanently discontinue.

Photosensitivity—AYVAKIT may cause photosensitivity reactions. In all patients treated with AYVAKIT in clinical trials (n=1049), photosensitivity reactions occurred in 2.5% of patients. Advise patients to limit direct ultraviolet exposure during treatment with AYVAKIT and for one week after discontinuation of treatment.

Embryo-Fetal Toxicity—AYVAKIT can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females and males of reproductive potential to use an effective method of contraception during treatment with AYVAKIT and for 6 weeks after the final dose of AYVAKIT. Advise women not to breastfeed during treatment with AYVAKIT and for 2 weeks after the final dose.

Adverse Reactions—The most common adverse reactions (≥20%) in patients with Advanced SM were edema, diarrhea, nausea, and fatigue/asthenia.

The most common adverse reactions (≥10%) in patients with ISM were eye edema, dizziness, peripheral edema, and flushing.

Drug Interactions—Avoid coadministration of AYVAKIT with strong or moderate CYP3A inhibitors. If coadministration with a moderate CYP3A inhibitor cannot be avoided in patients with Advanced SM, reduce dose of AYVAKIT. Avoid coadministration of AYVAKIT with strong or moderate CYP3A inducers.

To report suspected adverse reactions, contact Blueprint Medicines Corporation at 1-888-258-7768 or FDA at 1-800-FDA-1088 or View Source

Please click here to see the full Prescribing Information for AYVAKIT.

On December 9, 2023 The Menarini Group ("Menarini"), a leading international pharmaceutical and diagnostics company, and Stemline Therapeutics, Inc. ("Stemline"), a wholly-owned subsidiary of the Menarini Group, focused on bringing transformational oncology treatments to cancer patients, reported results from a new post hoc analysis of the pivotal EMERALD clinical study that demonstrated a clinically meaningful improvement in progression-free survival (PFS) across all relevant subgroups (Press release, Menarini, DEC 9, 2023, View Source;metastatic-breast-cancer-mbc-with-esr1-mutations-at-sa-302010206.html [SID1234638346]). The data show favorable PFS for single-agent ORSERDU (elacestrant) compared to standard-of-care (SOC) for patients with ER+, HER2- advanced or metastatic breast cancer (mBC) with tumors that are endocrine sensitive and which harbor ESR1 mutations, when prior treatment duration with CDK4/6 inhibitors was at least 12 months. This data is being presented at the 2023 San Antonio Breast Cancer Symposium (SABCS), December 5-9, 2023.

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EMERALD is a Phase 3 registrational trial that demonstrated statistically significant PFS with ORSERDU versus SOC endocrine monotherapy (fulvestrant, letrozole, anastrozole, exemestane). Based on these results, the FDA approved ORSERDU on January 27, 2023, for the treatment of postmenopausal women or adult men with ER+, HER2-, ESR1 mutated advanced or metastatic breast cancer with disease progression following at least one line of endocrine therapy. ESR1 mutations are present in up to 40% of ER+, HER2- advanced or mBC. They are a known driver of resistance to standard endocrine therapy, and until now, the tumors that harbor these mutations have been more difficult to treat.

Importantly, a prior post hoc subgroup analysis of the EMERALD PFS results, which was presented at SABCS 2022, demonstrated that the duration of prior CDK4/6 inhibitor treatment was positively associated with longer PFS on ORSERDU but not with SOC. For patients with ESR1 mutations who were treated with CDK4/6 inhibitors for at least 12 months prior to randomization on EMERALD, ORSERDU achieved a median PFS of 8.6 months versus 1.9 months on SOC, with a 59% reduction in the risk of progression or death (HR=0.41 95% CI: 0.26-0.63). [1]

In this updated analysis, Menarini Stemline evaluated the benefit of single-agent ORSERDU in highly prevalent clinical and key biomarker subgroups, including patients who had bone, liver and/or lung metastases; those with common concomitant PIK3CA or TP53 mutations; or those with HER2-low expression.

"These updated findings further reinforce that monotherapy ORSERDU is a promising second-line treatment option for ER+, HER2- patients with metastatic breast cancer whose tumors harbor ESR1 mutations," said Virginia Kaklamani, MD, DSc, breast medical oncologist and professor of medicine, UT Health San Antonio, MD Anderson Cancer Center. "We’ve seen consistent improvements versus standard of care in progression-free survival across many important subgroups with monotherapy elacestrant for patients whose prior treatment duration with CDK 4/6 was at least 12 months. We’ve observed these results not just for bone metastases, but also for liver and/or lung metastases, and in patients with common co-mutations such as PIK3CA and TP53, and in patients with HER2-low expression."

ORSERDU demonstrated clinically meaningful improvement in PFS, compared to SOC endocrine monotherapy (fulvestrant, letrozole, anastrozole, exemestane), across these subgroups. ORSERDU showed significantly greater PFS when prior treatment duration with CDK4/6 inhibitors was at least 12 months, indicating that when ESR1 mutated tumors remain endocrine sensitive, the ER pathway could be a key driver of disease, regardless of the metastatic site, concomitant PIK3CA or TP53 mutations, or HER2-low expression. The full abstract can be viewed here.

"The data presented here at SABCS 2023 build on our body of knowledge on ORSERDU and its potential as a single agent therapy targeting ESR1 mutated tumors," said Elcin Barker Ergun, CEO of the Menarini Group. "At Menarini Stemline our goal is to provide transformational treatments to help extend and improve the lives of people living with cancer. We are proud to offer a much-needed endocrine option for a multitude of appropriate metastatic breast cancer patients, and one that also has a manageable safety profile."

Safety data were consistent with previously reported results. The most common adverse reactions with ORSERDU were musculoskeletal pain, nausea, triglycerides increased, cholesterol increased, vomiting, fatigue, dyspepsia, diarrhea, calcium decreased, back pain, creatinine increased, arthralgia, sodium decreased, constipation, headache, hot flush, abdominal pain, anemia, potassium decreased, and alanine aminotransferase increased. Important Safety Information for ORSERDU is provided below.

See here for details of the Menarini Group/Stemline Therapeutics’ full range of presentations at SABCS 2023.

About the EMERALD Phase 3 Study (NCT03778931)
The EMERALD Phase 3 trial is a randomized, open label, active-controlled study evaluating elacestrant as second- or third-line monotherapy in ER+, HER2- advanced/mBC patients. The study enrolled 478 patients who had received prior treatment with one or two lines of endocrine therapy, including a CDK4/6 inhibitor. Patients in the study were randomized to receive either elacestrant or the investigator’s choice of an approved hormonal agent. The primary endpoints of the study were progression-free survival (PFS) in the overall patient population and in patients with estrogen receptor 1 gene (ESR1) mutations. In the group of patients whose tumors had ESR1-mutations, elacestrant achieved a median PFS of 3.8 months vs 1.9 months on the SOC, and reduced the risk of progression or death by 45% (PFS HR=0.55, 95% CI: 0.39, 0.77) vs SOC.

About ORSERDU (elacestrant)
U.S. Indication: ORSERDU (elacestrant), 345 mg tablets, is indicated for the treatment of postmenopausal women or adult men with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative, ESR1-mutated advanced or metastatic breast cancer with disease progression following at least one line of endocrine therapy.

Full prescribing information for the U.S. can be found at www.orserdu.com.

Important Safety Information
Warning and Precautions

Dyslipidemia: Hypercholesterolemia and hypertriglyceridemia occurred in patients taking ORSERDU at an incidence of 30% and 27%, respectively. The incidence of Grade 3 and 4 hypercholesterolemia and hypertriglyceridemia were 0.9% and 2.2%, respectively. Monitor lipid profile prior to starting and periodically while taking ORSERDU.
Embryo-Fetal Toxicity: Based on findings in animals and its mechanism of action, ORSERDU can cause fetal harm when administered to a pregnant woman. 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 ORSERDU and for 1 week after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ORSERDU and for 1 week after the final dose.

Adverse Reactions

Serious adverse reactions occurred in 12% of patients who received ORSERDU. Serious adverse reactions in >1% of patients who received ORSERDU were musculoskeletal pain (1.7%) and nausea (1.3%). Fatal adverse reactions occurred in 1.7% of patients who received ORSERDU, including cardiac arrest, septic shock, diverticulitis, and unknown cause (one patient each).
The most common adverse reactions (>10%), including laboratory abnormalities, of ORSERDU were musculoskeletal pain (41%), nausea (35%), increased cholesterol (30%), increased AST (29%), increased triglycerides (27%), fatigue (26%), decreased hemoglobin (26%), vomiting (19%), increased ALT (17%), decreased sodium (16%), increased creatinine (16%), decreased appetite(15%), diarrhea(13%), headache (12%), constipation (12%), abdominal pain (11%), hot flush (11%), and dyspepsia (10%).

Drug interactions

Concomitant use with CYP3A4 Inducers and/or inhibitors: Avoid concomitant use of strong or moderate CYP3A4 inhibitors with ORSERDU. Avoid concomitant use of strong or moderate CYP3A4 inducers with ORSERDU.

Use in specific populations

Lactation: Advise lactating women to not breastfeed during treatment with ORSERDU and for 1 week after the last dose.
Hepatic Impairment: Avoid use of ORSERDU in patients with severe hepatic impairment (Child-Pugh C). Reduce the dose of ORSERDU in patients with moderate hepatic impairment (Child-Pugh B).
The safety and effectiveness of ORSERDU in pediatric patients have not been established.

To report SUSPECTED ADVERSE REACTIONS, contact Stemline Therapeutics, Inc. at 1-877-332-7961 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

About The Elacestrant Clinical Development Program
Elacestrant is also being investigated in several clinical trials in metastatic breast cancer disease, alone or in combination with other therapies. ELEVATE (NCT05563220) is a phase 1b/2 clinical trial that will evaluate the safety and efficacy of elacestrant combined with alpelisib, everolimus, palbociclib, abemaciclib, and ribociclib. ELECTRA (NCT05386108) is an open-label phase 1b/2, multicenter study evaluating elacestrant in combination with abemaciclib in patients with ER+, HER2- breast cancer. The phase 2 portion evaluates this treatment regimen in this patient population with brain metastases. ELCIN (NCT05596409) is a phase 2 trial evaluating the efficacy of elacestrant in patients with estrogen receptor positive (ER+)/human epidermal growth factor receptor-2 negative (HER2-) advanced/metastatic breast cancer who received one or two prior hormonal therapies and no prior cyclin-dependent kinase targeting enzymes CDK4 and CDK6 inhibitor (CDK4/6i) in the metastatic setting. Elacestrant is also being evaluated in early breast cancer disease.

On December 9, 2023 Jazz Pharmaceuticals plc (Nasdaq: JAZZ) reported updated data from the Phase 2a trial of investigational zanidatamab, a HER2-targeted bispecific antibody, in combination with palbociclib, a CDK4/6 inhibitor, and fulvestrant, a selective estrogen receptor antagonist, in patients with HER2-positive (HER2+)/HR-positive (HR+) metastatic breast cancer (mBC) as part of a late-breaking oral presentation at the 2023 San Antonio Breast Cancer Symposium (SABCS) (Press release, Jazz Pharmaceuticals, DEC 9, 2023, View Source [SID1234638344]).

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Data from 51 patients with heavily pretreated HER2+/HR+ mBC (median of 4 prior regimens in the metastatic setting) who were treated with zanidatamab plus palbociclib and fulvestrant demonstrated a progression-free survival at six months (PFS6) of 67% (n=34) [95% confidence interval: 52, 79]. Secondary endpoint findings included a median progression-free survival (mPFS) of 12 months [95% CI: 8, 15] and a confirmed objective response rate (cORR) of 35% [95% CI: 21, 50] with a median duration of response (DOR) of 15 months. The combination regimen was well tolerated with a manageable safety profile.

"Metastatic breast cancer is a particularly aggressive and devastating disease, and patients whose cancer has progressed despite numerous therapeutic interventions are in dire need of additional treatment options – particularly chemotherapy-free options," 1,2 said Santiago Escrivá-de-Romani, MD, Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron University Hospital, and primary trial investigator. "Targeting both the HER2 and hormone receptor pathways can be a promising approach for applicable patients, and the durable responses seen in this study signal the potential for this combination to fill a persistent and much needed treatment gap among these patients."3

"The late-breaking data presented at SABCS for zanidatamab in combination with palbociclib and fulvestrant in HER2+/HR+ metastatic breast cancer as a chemotherapy-free treatment option in heavily pretreated patients provide yet another example of the promise this HER2-targeted bispecific antibody holds in the treatment of HER2-expressing cancers where significant unmet needs exist," said Rob Iannone, M.D., M.S.C.E., executive vice president, global head of research and development of Jazz Pharmaceuticals. "We are encouraged by the meaningful clinical benefit seen in this trial, and we look forward to continuing to advance our broader clinical development program for zanidatamab in breast cancer and other HER2-expressing solid tumors, with the goal of addressing some of the greatest unmet needs in cancer with HER2 expression."

Trial Results

Results of the Phase 2a trial (NCT04224272) presented at SABCS indicate that zanidatamab in combination with palbociclib and fulvestrant, demonstrated meaningful PFS outcomes with a well tolerated safety profile in patients with heavily pretreated HER2+/HR+ mBC.

The single-arm trial evaluated zanidatamab plus palbociclib and fulvestrant in 51 patients with HER2+/HR+ unresectable, locally advanced or metastatic breast cancer who had received prior treatment with at least trastuzumab, pertuzumab, and T-DM1, and no prior treatment with a CDK4/6 inhibitor. Patients treated with the combination regimen received a median of four prior systemic regimens in the metastatic setting (range, 1-12).

Recommended doses of the zanidatamab plus palbociclib and fulvestrant combination therapy were determined in Part 1 of the study. The primary endpoint of Part 2 was PFS6. Other endpoints included mPFS, cORR per RECIST v1.1, DCR and DOR.

At the time of data cutoff (August 3, 2023), treatment with zanidatamab in combination with palbociclib and fulvestrant resulted in a PFS6 of 67% (n=34) and mPFS of 12 months [95% CI: 8, 15]. Median duration of follow-up was 16 months (range, 2-32). Patients treated with the combination regimen achieved a cORR of 35% and DCR of 91%.

Efficacy

All pts (N=51)

PFS6, n (%)

(95% CI)

34 (67)

(52-79)

Median PFS, mo

(95% CI)

12

(8-15)

cORR, n (%)

(95% CI)

16 (35)

(21-50)

Confirmed best overall response (cBOR), n (%)

Complete Response

Partial response

SD

PD

3 (6)

13 (28)

26 (56)

4 (9)

DCR, n (%)

(95% CI)

42 (91)

(79-98)

Median DOR, mo

(95% CI)

15

(12-25)

Zanidatamab plus palbociclib and fulvestrant was well tolerated with a manageable safety profile. One serious treatment-related AE (transaminases increased) was reported (which resolved). No treatment-related deaths were reported. The most common treatment-related AEs (>20% of patients) were diarrhea, neutrophil count decrease/neutropenia, nausea, stomatitis, anemia, vomiting and asthenia. One patient discontinued the combination treatment due to an AE; three patients discontinued palbociclib due to an AE.

The abstract is available to conference registrants on the SABCS conference website here. (Abstract Number LBO1-04).

Additional data being presented at SABCS for zanidatamab include a spotlight poster presentation highlighting positive results of an investigator-sponsored Phase 1 trial evaluating neoadjuvant single-agent zanidatamab in patients with stage 1 node-negative HER2+ breast cancer (Abstract Number PS09-03).

About Zanidatamab
Zanidatamab is an investigational bispecific antibody that can simultaneously bind two non-overlapping epitopes of HER2, known as biparatopic binding. This unique design and increased binding results in multiple mechanisms of action, including dual HER2 signal blockade, removal of HER2 protein from the cell surface, and immune-mediated cytotoxicity leading to encouraging antitumor activity in patients. Zanidatamab is being developed in multiple clinical trials as a targeted treatment option for patients with solid tumors that express HER2. Zanidatamab is being developed by Jazz and BeiGene, Ltd. (BeiGene) under license agreements from Zymeworks, which first developed the molecule.

The U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy designation for zanidatamab development in patients with previously treated HER2 gene-amplified biliary tract cancers (BTC), and two Fast Track designations for zanidatamab: one as a single agent for refractory BTC and one in combination with standard of care chemotherapy for first-line gastroesophageal adenocarcinoma (GEA). Additionally, zanidatamab has received Orphan Drug designations from FDA for the treatment of BTC and GEA, as well as Orphan Drug designation from the European Medicines Agency for the treatment of BTC and gastric cancer. Zanidatamab was also granted Breakthrough Therapy designation from the Center for Drug Evaluation (CDE) in China.

In this Phase 2a trial, zanidatamab is being explored in combination with palbociclib under a clinical trial and supply agreement with Pfizer Inc.