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.

On December 9, 2023 AbbVie (NYSE: ABBV) and Genmab A/S (Nasdaq: GMAB) reported that adult patients with relapsed/refractory (R/R) follicular lymphoma (FL) previously treated with two or more prior therapies experienced strong and durable responses with high overall response (ORR) and complete response (CR) rates when treated with epcoritamab (DuoBody CD3xCD20), an investigational, subcutaneously administered T-cell engaging bispecific antibody (Press release, AbbVie, DEC 9, 2023, View Source [SID1234638343]). More than half of patients who responded to treatment in the study remained responsive to treatment at the time of data analysis (i.e., median duration of response was not reached). Data from the dose-expansion cohort of the Phase 1/2 EPCORE NHL-1 clinical trial are being shared during a poster presentation on Saturday, December 9 at 5:30 PM PT at the ASH (Free ASH Whitepaper) congress in San Diego, California. Updated data from this study include an optimized, step-up dosing schedule showing reduced incidence and severity of cytokine release syndrome (CRS), a notable side effect from immune-engaging cancer treatments.

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"Despite treatment advances for patients with follicular lymphoma whose disease has unfortunately progressed, treating relapsed or refractory follicular lymphoma remains highly challenging, particularly as a third-line treatment," said Catherine Thieblemont, M.D., Ph.D., head of the hemato-oncology department, Paris University, Hôpital Saint-Louis Assistance-Publique-Hopitaux de Paris (APHP) in Paris. "The patients in this trial represent a historically difficult-to-treat patient population. The data presented today are especially notable because they demonstrated high overall and complete response rates for this investigational therapy and a preview for its potential as a treatment option."

"Further developing epcoritamab as a core therapy to help treat more patients with B-cell malignancies, including follicular lymphoma, is an important goal we share with our partner Genmab," said Mariana Cota Stirner, M.D., Ph.D., vice president, therapeutic area head for hematology, AbbVie. "These data at this year’s ASH (Free ASH Whitepaper) further build our confidence in epcoritamab’s treatment potential as well as development for earlier patient treatment."

Results from this cohort of 128 adult patients show the following:

At a median follow-up of 17.4 months, ORR, the study’s primary endpoint, was 82%, with a CR rate of 63%; the median time to response and CR were 1.4 months and 1.5 months, respectively.
Among prespecified high-risk subgroups such as patients refractory to prior treatments (double refractory (70%), or refractory to last prior treatment (69%), among others), ORR and CR rates were generally consistent with the overall study population.
Median duration of response and duration of CR were not yet reached.
An estimated 85% and 74% of patients who experienced a CR remained responsive to treatment at 12 and 18 months, respectively.
Additional study data can be found here: (abstract #1655).
No new safety signals were detected. The most common treatment-emergent AE (TEAE) was CRS with 67% occurrence (40% Grade 1, 25% Grade 2, 2% Grade 3). Following an optimized step-up dose regimen in a separate cohort to reduce the risk and severity of CRS, 24 out of 50 patients (48%) experienced grade 1-2 CRS (40% Grade 1, 8% Grade 2, 0% Grade 3). As well, no cases of Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) were reported. This data may support investigating optimized step-up dose in an outpatient setting. Additional common TEAEs (>20%) were injection-site reaction (57%), COVID-19 (40%), fatigue (30%), neutropenia (29%), diarrhea (27%) and pyrexia (25%). TEAEs leading to treatment discontinuation occurred in 19% of patients, and death related to TEAEs occurred in 13 patients (10%).

AbbVie and Genmab recently announced that the U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy Designation (BTD) to epcoritamab for the treatment of adult patients with R/R FL after two or more therapies. Additionally, the European Medicines Agency (EMA) has validated a Type II application for epcoritamab in the same indication. If approved, R/R FL would become the second conditionally approved indication for epcoritamab in the European Union. More information is available here.

About the Phase 1/2 EPCORE NHL-1 Trial
EPCORE NHL-1 is an open-label, multi-center safety and preliminary efficacy trial of epcoritamab that consists of three parts: a Phase 1 first-in-human, dose escalation part; a Phase 2a expansion part; and a Phase 2a dose optimization part. The trial was designed to evaluate subcutaneous epcoritamab in adult patients with relapsed, progressive or refractory CD20+ mature B-cell non-Hodgkin’s lymphoma (NHL), including follicular lymphoma (FL). In the Phase 2a expansion part, additional patients are being enrolled to further explore the safety and efficacy of epcoritamab in three cohorts of patients with different types of relapsed or refractory (R/R) B-cell NHLs who have limited therapeutic options. The dose optimization part evaluates the potential for alternative step-up dosing regimens to help further minimize Grade 2 cytokine release syndrome (CRS) and mitigate Grade ≥3 CRS. The application for BTD included additional data from this cohort of patients. The primary endpoint of the expansion part was overall response rate as assessed by an independent review committee. Secondary efficacy endpoints included duration of response, complete response rate, duration of complete response, progression-free survival, and time to response as determined by the Lugano criteria. Overall survival, time to next therapy, and rate of minimal residual disease negativity were also evaluated as secondary efficacy endpoints.

About Follicular Lymphoma (FL)
FL is typically an indolent (or slow growing) form of non-Hodgkin’s lymphoma (NHL) that arises from B-lymphocytes.1 FL is the second most common form of NHL, accounting for 20-30% of all NHL cases, and represents 10-20% of all lymphomas in the western world.1,2,3 Although FL is typically considered an indolent (or slow-growing) lymphoma, it remains incurable with conventional therapy4,5 and patients who achieve remission often experience relapse.6

About Epcoritamab
Epcoritamab is an investigational IgG1-bispecific antibody created using Genmab’s proprietary DuoBody technology and administered subcutaneously. Genmab’s DuoBody-CD3 technology is designed to direct cytotoxic T cells selectively to elicit an immune response toward target cell types. Epcoritamab is designed to simultaneously bind to CD3 on T cells and CD20 on B cells and induces T-cell-mediated killing of CD20+ cells.7

Epcoritamab (approved under the brand name EPKINLY in the United States and TEPKINLY in the European Union) has received regulatory approval in adults with certain types of large B-cell lymphoma (LBCL), including diffuse large B-cell lymphoma (DLBCL), globally. EPKINLY is approved under the FDA’s Accelerated Approval program based on response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. Use of epcoritamab in FL is not approved in the U.S. or in the EU. AbbVie will continue to pursue regulatory submissions for epcoritamab across international markets.

Genmab and AbbVie continue to evaluate the use of epcoritamab as a monotherapy, and in combination, across lines of therapy in a range of hematologic malignancies. This includes three ongoing Phase 3, open-label, randomized trials including a trial evaluating epcoritamab as a monotherapy in patients with R/R DLBCL (NCT: 04628494) compared to investigator’s choice chemotherapy, a Phase 3 trial evaluating epcoritamab in combination with R-CHOP in adult patients with newly diagnosed DLBCL (NCT: 05578976), and a Phase 3 clinical trial evaluating epcoritamab in combination with rituximab and lenalidomide (R2) in patients with R/R FL (NCT: 05409066). Epcoritamab is not approved to treat patients with newly diagnosed DLBCL or with FL. The safety and efficacy of epcoritamab has not been established for these investigational uses. Please visit clinicaltrials.gov for more information.

EPKINLY (epcoritamab-bysp) U.S. USE and IMPORTANT SAFETY INFORMATION

USE

EPKINLY is a prescription medicine used to treat adults with certain types of diffuse large B-cell lymphoma (DLBCL) and high-grade B-cell lymphoma that has come back (relapsed) or that did not respond to previous treatment (refractory), and who have received 2 or more treatments for their cancer.

EPKINLY is approved based on patient response data. A study is ongoing to confirm the clinical benefit of EPKINLY. It is not known if EPKINLY is safe and effective in children.

IMPORTANT SAFETY INFORMATION

Important Warnings—EPKINLY can cause serious side effects, including:

Cytokine Release Syndrome (CRS). CRS is common during treatment with EPKINLY and can be serious or life-threatening. Tell your healthcare provider or get medical help right away if you develop symptoms of CRS, including fever of 100.4°F (38°C) or higher, dizziness or lightheadedness, trouble breathing, chills, fast heartbeat, feeling anxious, headache, confusion, shaking (tremors), or problems with balance and movement, such as trouble walking.

Due to the risk of CRS, you will receive EPKINLY on a "step-up" dosing schedule. The step-up dosing schedule is when you receive smaller "step-up" doses of EPKINLY on day 1 and day 8 of your first cycle of treatment (cycle 1). You will receive your first full dose of EPKINLY on day 15 of cycle 1. If your dose of EPKINLY is delayed for any reason, you may need to repeat the step-up dosing schedule. Before each dose in cycle 1, you will receive medicines to help reduce your risk of CRS. Your healthcare provider will decide if you need to receive medicine to help reduce your risk of CRS with future cycles.

Neurologic problems. EPKINLY can cause serious neurologic problems that can be life-threatening and lead to death. Neurologic problems may happen days or weeks after you receive EPKINLY. Your healthcare provider may refer you to a healthcare provider who specializes in neurologic problems. Tell your healthcare provider right away if you develop any symptoms of neurologic problems, including trouble speaking or writing, confusion and disorientation, drowsiness, tiredness or lack of energy, muscle weakness, shaking (tremors), seizures, or memory loss.
Due to the risk of CRS and neurologic problems, you should be hospitalized for 24 hours after receiving your first full dose of EPKINLY on day 15 of cycle 1. Your healthcare provider will monitor you for symptoms of CRS and neurologic problems during treatment with EPKINLY, as well as other side effects, and treat you if needed. Your healthcare provider may temporarily stop or completely stop your treatment with EPKINLY if you develop CRS, neurologic problems, or any other side effects that are severe.

Do not drive or use heavy or potentially dangerous machinery if you develop dizziness, confusion, tremors, drowsiness, or any other symptoms that impair consciousness until your symptoms go away. These may be symptoms of CRS or neurologic problems.

EPKINLY can also cause other serious side effects, including:

Infections. EPKINLY can cause serious infections that may lead to death. Your healthcare provider will check you for symptoms of infection before and during treatment. Tell your healthcare provider right away if you develop any symptoms of infection during treatment, including fever of 100.4°F (38°C) or higher, cough, chest pain, tiredness, shortness of breath, painful rash, sore throat, pain during urination, or feeling weak or generally unwell.
Low blood cell counts. Low blood cell counts are common during treatment with EPKINLY and can be serious or severe. Your healthcare provider will check your blood cell counts during treatment. EPKINLY may cause low blood cell counts, including low white blood cell counts (neutropenia), which can increase your risk for infection; low red blood cell counts (anemia), which can cause tiredness and shortness of breath; and low platelet counts (thrombocytopenia), which can cause bruising or bleeding problems.
Your healthcare provider may temporarily stop or completely stop treatment with EPKINLY if you develop certain side effects.

Before you receive EPKINLY, tell your healthcare provider about all of your medical conditions, including if you:

have an infection.
are pregnant or plan to become pregnant. EPKINLY may harm your unborn baby. Females who are able to become pregnant: Your healthcare provider should do a pregnancy test before you start treatment with EPKINLY. You should use effective birth control (contraception) during treatment and for 4 months after your last dose of EPKINLY. Tell your healthcare provider if you become pregnant or think that you may be pregnant during treatment with EPKINLY.
are breastfeeding or plan to breastfeed. It is not known if EPKINLY passes into your breast milk. Do not breastfeed during treatment with EPKINLY and for 4 months after your last dose of EPKINLY.
Tell your healthcare provider about all of the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

The most common side effects of EPKINLY include CRS, tiredness, muscle and bone pain, injection site reactions, fever, stomach-area (abdominal) pain, nausea, and diarrhea.
These are not all the possible side effects of EPKINLY. Call your doctor for medical advice about side effects.

You are encouraged to report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch or to Genmab US, Inc. at 1-855-4GENMAB (1-855-443-6622).

Please see the Full Prescribing Information and Medication Guide, including Important Warnings.

On December 9, 2023 Servier, a leader in oncology committed to bringing the promise of tomorrow to the patients we serve,reported that it will be presenting new data in acute myeloid leukemia (AML) at the 65th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition (Press release, Servier, DEC 9, 2023, View Source [SID1234638342]). These data provide a compelling and in-depth look into the treatment patterns and clinical outcomes observed in real-world settings, offering valuable insights for informed decision-making in patient care.

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"During our initial five years in the oncology space, Servier has more than doubled its portfolio and launched several new indications for TIBSOVO in IDH1-mutant cancers, including frontline AML, myelodysplastic syndromes (MDS) and previously treated cholangiocarcinoma (CCA) – many of these indications serving as a best-in-class treatment option," said Arjun Prasad," Head of Commercial, Servier Pharmaceuticals. "As the leader driving the science behind targeted mutant IDH inhibition, we strive to maximize the benefits of molecular testing to improve patient outcomes and continue to focus on areas of unmet need where patients could benefit from personalized medicine, from our multiple approvals across hematology and solid tumors to ongoing research in difficult to treat and rare cancers such as chondrosarcoma."

More information on testing for IDH mutations in cancer can be found at IDHlearnmore.com.

Data being presented at ASH (Free ASH Whitepaper) include real-world evidence analysis in patients with newly diagnosed AML (intensive chemotherapy induction ineligible (ICIE) and a susceptible IDH1 mutation comparing Tibsovo in combination with hypomethylating agents (HMA) versus venetoclax in combination with hypomethylating agents. In the analysis of 238 patients, Tibsovo+HMA elicited a higher complete response (CR) rate versus venetoclax+HMA at 42.9% vs. 26.7% (p=0.007). 6-month event-free survival also favored Tibsovo+HMA at 56.0% vs. 39.6% (p=0.044), as well as 11.5% of patients on Tibsovo+HMA achieving bridge to transplant versus 5.0% on a venetoclax+HMA regimen (p=0.066). Median time from diagnosis to start of treatment was 14 versus 20 days for Tibsovo+HMA vs venetoclax+HMA. Treatment discontinuation was 37% for both regimens and toxicity incidence was similar, with the exception of higher febrile neutropenia (FN) rates for venetoclax+HMA versus Tibsovo+HMA (7.9% vs. 1.6%; p=0.009). Patients receiving Tibsovo+HMA had a 61% lower relative risk of unscheduled acute care use in the first 12 weeks (42.9% versus 70.3% for venetoclax+HMA; p<0.001). Venetoclax schedule intensity was also captured, with only 22.8% receiving the full FDA-labeled 28 days of venetoclax during the 28-day cycles; 44.6% did not receive >11 days of venetoclax per cycle. The full analysis will be presented on Monday, December 11 at 4:30 p.m. PST.

"At Servier, we bring the patient voice into everything we do, and our commitment to patients extends far beyond approval," emphasized Becky Martin, PhD, Chief of Medical, Servier Pharmaceuticals. "As a privately held company, we have the ability to invest in the long-term in ways that help to create better understandings on the real-world impact our medicines have on the lives of patients. We’re proud to once again present real-world evidence at ASH (Free ASH Whitepaper), offering the broader oncology community insights into treatment patterns that can help in the development of the best possible treatment regimen for each individual patient."

Additional data being presented at ASH (Free ASH Whitepaper) includes molecular measurable residual disease (MRD) in ICIE patients with newly diagnosed mIDH1 AML treated with Tibsovo+azacitidine, further bolstering the clinical profile of Tibsovo in the front-line setting, as well as real-world analyses examining treatment patterns in both ALL and AML.