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 Bristol Myers Squibb (NYSE: BMY) reported updated results from the primary analysis of the Phase 3 COMMANDS trial, comparing Reblozyl(luspatercept-aamt) versus epoetin alfa for the treatment of anemia in erythropoiesis stimulating agent (ESA)-naïve patients with lower-risk myelodysplastic syndromes (MDS) (Oral Presentation #193) who may require red blood cell (RBC) transfusions (Press release, Bristol-Myers Squibb, DEC 9, 2023, View Source [SID1234638321]). These data are being presented in an oral presentation at the 2023 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting, from December 9-12.

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"These data from the COMMANDS trial, including additional patients and longer follow-up from the data shown at ASCO (Free ASCO Whitepaper), confirm the positive outcome of the interim analysis with superior efficacy and durability compared to ESAs and exemplify how Reblozyl may impact the treatment of anemia related to MDS," said Guillermo Garcia-Manero, M.D., lead investigator and Chief of the Section of Myelodysplastic Syndromes at The University of Texas MD Anderson Cancer Center. "Further, beyond the intent-to-treat population, the analysis confirms that Reblozyl demonstrated clinical benefit across subgroups."

Results from COMMANDS are under review with the European Commission and served as the basis of a priority review approval by the United States Food and Drug Administration in August 2023 for Reblozyl as a treatment for anemia in ESA-naïve adult patients with very low- to intermediate-risk MDS who may require regular RBC transfusions. Reblozyl is being developed and commercialized through a global collaboration with Merck as of November 2021.

COMMANDS Primary Results
At the time of the primary analysis (March 31, 2023), 363 patients were randomized 1:1 to Reblozyl and epoetin alfa. Results from the primary analysis of the intent to treat (ITT) population showed:

60.4% (n=110) of patients receiving Reblozyl vs. 34.8% (n=63) of patients receiving epoetin alfa achieved the primary endpoint of RBC-TI of at least 12 weeks with concurrent mean hemoglobin (Hb) increase of at least 1.5 g/dL within the first 24 weeks (p<0.0001).
Erythroid response (HI-E) increase of at least 8 weeks was achieved by 74.2% (n=135) of Reblozyl patients vs. 53% (n=96) of epoetin alfa patients (p<0.0001).
RBC transfusion independence (RBC-TI) of at least 12 weeks was achieved by 68.1% (n=124) of Reblozyl patients vs. 48.6% (n=88) of epoetin alfa patients (p<0.0001).
Duration of response was 126.6 weeks (99-NE) for Reblozyl in patients who achieved TI for at least 12 weeks (achieved weeks 1-24) compared to 89.7 weeks (61.9-123.9) for epoetin alfa (Hazard Ratio [HR]: 0.586; 95% Confidence Interval [CI]: 0.380-0.904, p=0.0147).
"As patients with lower-risk MDS often receive limited benefit from current standard therapies, including ESAs, these confirmatory data further show how Reblozyl has the potential to create a paradigm shift in the treatment of anemia associated with this disease," said Anne Kerber, senior vice president, Head of Late Clinical Development, Hematology, Oncology, Cell Therapy (HOCT), Bristol Myers Squibb.

Safety results were consistent with previous MDS studies, and progression to acute myeloid leukemia and total deaths were similar between arms of the study. The most common treatment-emergent adverse events in at least 10% of patients were diarrhea, fatigue, COVID-19, hypertension, dyspnea, nausea, peripheral edema, asthenia, dizziness, anemia, back pain and headache. Rates of reported fatigue and asthenia were shown to decrease over time.

In addition to the overall benefit observed in the ITT population, sub-analyses confirmed similar or greater RBC-TI of Reblozyl compared to epoetin alfa regardless of mutational profile, IPSS-M status, ring sideroblast status, transfusion burden and serum erythropoietin (sEPO) level. Duration of RBC-TI favored Reblozyl across all subgroups, including ring sideroblast status.

Finally, three posters will be presented highlighting additional analyses of the COMMANDS study and the mechanism of Reblozyl.

Reblozyl showed favorability over epoetin alfa in various mutational background observed in lower-risk MDS in an analysis of response by mutational burden (Poster Presentation #4591).
An analysis of clonal-hematopoiesis related mutations (Poster Presentation #3214) showed that 85% of patients in the COMMANDS study had at least one CHIP-related mutation. Further, Reblozyl was associated with the downregulation of inflammatory gene signatures and upregulation of anti-inflammatory pathways.
In another analysis (Poster Presentation #1845), Reblozyl was associated with modulation of inflammation and restoration of effective erythropoiesis in bone marrow samples from the COMMANDS study, reinforcing its role in the expansion and maturation of early and late-stage erythroid precursors.
About COMMANDS
COMMANDS (NCT03682536) is a Phase 3, open-label, randomized study evaluating the efficacy and safety of Reblozyl versus epoetin alfa for the treatment of anemia due to very low-, low- or intermediate-risk (IPSS-R) myelodysplastic syndrome (MDS) in patients who are red blood cell (RBC) transfusion dependent and were erythropoiesis stimulating agent (ESA)-naïve.

The primary endpoint evaluated in this study is RBC transfusion independence (RBC-TI) for 12 weeks with a mean hemoglobin (Hb) increase ≥1.5 g/dL. Key secondary endpoints include erythroid response (HI-E) of at least 8 weeks during weeks 1-24 of the study, RBC-TI ≥12 weeks and RBC-TI for 24 weeks. Eligible patients were ≥18 years old with lower-risk MDS who require transfusions. Patients were randomized 1:1 to receive subcutaneous Reblozyl (starting dose 1.0 mg/kg, titration up to 1.75 mg/kg) once every 3 weeks or epoetin alfa (starting dose 450 IU/kg, titration up to 1050 IU/kg) weekly for ≥24 weeks. The majority of study participants (>90%) were outside of the United States and a non-U.S.-licensed epoetin alfa product was used in the control arm for such patients.

About MDS
Myelodysplastic syndromes (MDS) are a group of closely related blood cancers characterized by ineffective production of healthy red blood cells (RBC), white blood cells and platelets, which can lead to anemia and frequent or severe infections. People with MDS who develop anemia often require blood transfusions to increase the number of healthy RBCs in circulation. Frequent transfusions are associated with an increased risk of iron overload, transfusion reactions and infections.Patients who become RBC transfusion-dependent have a significantly shorter overall survival than those who are not dependent on transfusions, partially due to iron overload or to more severe bone marrow disease than in non-transfusion dependent patients.

About Reblozyl(luspatercept-aamt)
REBLOZYL (luspatercept-aamt), a first-in-class therapeutic option, promotes late-stage red blood cell maturation in animal models. REBLOZYL is being developed and commercialized through a global collaboration and North American co-promotion with Merck following Merck’s acquisition of Acceleron Pharma, Inc. in November 2021. REBLOZYL is indicated in the U.S. for the treatment of:

anemia in adult patients with beta thalassemia who require regular red blood cell (RBC) transfusions.
anemia without previous erythropoiesis stimulating agent use (ESA-naïve) in adult patients with very low- to intermediate-risk myelodysplastic syndromes (MDS) who may require regular red blood cell (RBC) transfusions.
anemia failing an erythropoiesis stimulating agent and requiring 2 or more red blood cell (RBC) units over 8 weeks in adult patients with very low- to intermediate-risk myelodysplastic syndrome with ring sideroblasts (MDS-RS) or with myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T).
REBLOZYL is not indicated for use as a substitute for RBC transfusions in patients who require immediate correction of anemia. In the U.S., REBLOZYL is not indicated for use in patients with non-transfusion-dependent beta thalassemia.

U.S. Important Safety Information
WARNINGS AND PRECAUTIONS

Thrombosis/Thromboembolism
In adult patients with beta thalassemia, thromboembolic events (TEE) were reported in 8/223 (3.6%) of REBLOZYL-treated patients. TEEs included deep vein thrombosis, pulmonary embolus, portal vein thrombosis, and ischemic stroke. Patients with known risk factors for thromboembolism (splenectomy or concomitant use of hormone replacement therapy) may be at further increased risk of thromboembolic conditions. Consider thromboprophylaxis in patients at increased risk of TEE. Monitor patients for signs and symptoms of thromboembolic events and institute treatment promptly.

Hypertension
Hypertension was reported in 11.4% (63/554) of REBLOZYL-treated patients. Across clinical studies, the incidence of Grade 3 to 4 hypertension ranged from 2% to 9.6%. In patients with beta thalassemia with normal baseline blood pressure, 13 (6.2%) patients developed systolic blood pressure (SBP) ≥130 mm Hg and 33 (16.6%) patients developed diastolic blood pressure (DBP) ≥80 mm Hg. In ESA-refractory or -intolerant adult patients with MDS with normal baseline blood pressure, 26 (30%) patients developed SBP ≥130 mm Hg and 23 (16%) patients developed DBP ≥80 mm Hg. In ESA-naïve adult patients with MDS with normal baseline blood pressure, 23 (36%) patients developed SBP ≥140 mm Hg and 11 (6%) patients developed DBP ≥80 mm Hg. Monitor blood pressure prior to each administration. Manage new or exacerbations of preexisting hypertension using anti-hypertensive agents.

Extramedullary Hematopoietic (EMH) Masses
In adult patients with transfusion-dependent beta thalassemia, EMH masses were observed in 3.2% of REBLOZYL-treated patients, with spinal cord compression symptoms due to EMH masses occurring in 1.9% of patients (BELIEVE and REBLOZYL long-term follow-up study).

In a study of adult patients with non-transfusion-dependent beta thalassemia, a higher incidence of EMH masses was observed in 6.3% of REBLOZYL-treated patients vs. 2% of placebo-treated patients in the double-blind phase of the study, with spinal cord compression due to EMH masses occurring in 1 patient with a prior history of EMH. REBLOZYL is not indicated for use in patients with non-transfusion-dependent beta thalassemia.

Possible risk factors for the development of EMH masses in patients with beta thalassemia include history of EMH masses, splenectomy, splenomegaly, hepatomegaly, or low baseline hemoglobin (<8.5 g/dL). Signs and symptoms may vary depending on the anatomical location. Monitor patients with beta thalassemia at initiation and during treatment for symptoms and signs or complications resulting from the EMH masses and treat according to clinical guidelines. Discontinue treatment with REBLOZYL in case of serious complications due to EMH masses. Avoid use of REBLOZYL in patients requiring treatment to control the growth of EMH masses.

Embryo-Fetal Toxicity
REBLOZYL may cause fetal harm when administered to a pregnant woman. REBLOZYL caused increased post-implantation loss, decreased litter size, and an increased incidence of skeletal variations in pregnant rat and rabbit studies. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for at least 3 months after the final dose.

ADVERSE REACTIONS

Beta-Thalassemia
Serious adverse reactions occurred in 3.6% of patients on REBLOZYL. Serious adverse reactions occurring in 1% of patients included cerebrovascular accident and deep vein thrombosis. A fatal adverse reaction occurred in 1 patient treated with REBLOZYL who died due to an unconfirmed case of acute myeloid leukemia (AML).

Most common adverse reactions (at least 10% for REBLOZYL and 1% more than placebo) were headache (26% vs 24%), bone pain (20% vs 8%), arthralgia (19% vs 12%), fatigue (14% vs 13%), cough (14% vs 11%), abdominal pain (14% vs 12%), diarrhea (12% vs 10%) and dizziness (11% vs 5%).

ESA-naïve adult patients with Myelodysplastic Syndromes
Grade ≥3 (≥2%) adverse reactions included hypertension and dyspnea.

The most common (≥10%) all-grade adverse reactions included diarrhea, fatigue, hypertension, peripheral edema, nausea, and dyspnea.

ESA-refractory or -intolerant adult patients with Myelodysplastic Syndromes
Grade ≥3 (≥2%) adverse reactions included fatigue, hypertension, syncope and musculoskeletal pain. A fatal adverse reaction occurred in 5 (2.1%) patients.

The most common (≥10%) adverse reactions included fatigue, musculoskeletal pain, dizziness, diarrhea, nausea, hypersensitivity reactions, hypertension, headache, upper respiratory tract infection, bronchitis, and urinary tract infection.

LACTATION
It is not known whether REBLOZYL is excreted into human milk or absorbed systemically after ingestion by a nursing infant. REBLOZYL was detected in milk of lactating rats. When a drug is present in animal milk, it is likely that the drug will be present in human milk. Because many drugs are excreted in human milk, and because of the unknown effects of REBLOZYL in infants, a decision should be made whether to discontinue nursing or to discontinue treatment. Because of the potential for serious adverse reactions in the breastfed child, breastfeeding is not recommended during treatment and for 3 months after the last dose.

DRUG ABUSE POTENTIAL
Abuse: Abuse of REBLOZYL may be seen in athletes for the effects on erythropoiesis. Misuse of drugs that increase erythropoiesis, such as REBLOZYL, by healthy persons may lead to polycythemia, which may be associated with life-threatening cardiovascular complications.

Please see accompanying U.S. Full Prescribing Information for REBLOZYL.

On December 9, 2023 Corvus Pharmaceuticals, Inc. (NASDAQ: CRVS), a clinical-stage biopharmaceutical company, reported new interim data from its Phase 1/1b clinical trial of soquelitinib in patients with relapsed PTCL (Press release, Corvus Pharmaceuticals, DEC 9, 2023, View Source [SID1234638322]). Soquelitinib demonstrated durable anti-tumor activity, evidenced by progression free survival, duration of response and overall survival rates that exceed current standard of care therapies for patients with relapsed PTCL. The data continues to support the advancement of soquelitinib into a Phase 3 registrational clinical trial in PTCL.

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"We have continued to enroll patients in the soquelitinib Phase 1/1b clinical trial to further confirm the eligibility requirements and design for our planned Phase 3 clinical trial," said Richard A. Miller, M.D., co-founder, president and chief executive officer of Corvus. "As anticipated, the additional patient data confirm that the number of prior therapies and immunocompetence are important patient eligibility requirements, with an optimum range of ≥1 to ≤3 prior therapies. The data also demonstrated anti-tumor activity, and in particular, durable responses, both of which continue to guide our plans to conduct a registration Phase 3 trial in relapsed peripheral T cell lymphoma. Overall, we are eager to initiate the Phase 3 clinical trial given the limited efficacy and challenging safety profile for the currently approved treatment options. If approved, soquelitinib would be the first approved agent for treatment of relapsed PTCL based on a randomized trial."

New Soquelitinib Interim Data from the Phase 1/1b Clinical Trial
Updated interim data as of November 27, 2023 (data shown below in Figures 1-3): A total of 36 patients were enrolled in the Phase 1/1b trial at the optimum 200 mg two-times a day dose, including 21 evaluable patients who would be eligible in the planned registrational Phase 3 clinical trial based on ≥1 and ≤3 prior therapies (eligible patient population) and 11 evaluable in the corresponding ineligible population based on ˃3 prior therapies (ineligible patient population). In the Phase 1/1b clinical trial, the median number of prior therapies was 2 for the eligible patient population and 6 for the ineligible patient population. The rationale for enrolling these patient populations and the stratification analysis was to confirm the eligibility requirements planned for our Phase 3 clinical trial.

For the eligible patient population, objective responses (complete response, CR plus partial response, PR) were seen in 7 of 21 patients with disease control (CR, PR and stable disease) in 12 of 21 patients. The stable disease group included 5 patients who achieved tumor reductions that did not meet the criteria for a PR, with two of these patients continuing on therapy.
For the eligible patient population, the median duration of response (DOR) for the seven patients with objective response by Lugano criteria was 14.5+ months (ranged from 6.9-25.2 months); three of these patients continued on therapy.
A total of five patients in the eligible patient population remained on therapy, including one patient with a CR at 21+ months, two patients with a PR at 3+ and 8+ months, and 2 with stable disease at 3+ and 5+ months.
Kaplan Meier estimated median progression free survival was 6 months for the eligible patient population.
Kaplan Meier estimated overall survival at 2 years was 77% for all 36 patients.
One additional eligible patient, not shown here, was treated at a higher dose and achieved a PR. While in PR, this patient went on to receive a bone marrow transplant and achieved a CR, which has continued as of the data cutoff without any further therapy for 2+ years.
For the ineligible patient population, no objective responses were seen in 11 evaluable patients.

Molecular Studies on Patient Tumors Support Soquelitinib’s Novel Mechanism of Action
Additional new interim data from the Phase 1/1b clinical trial of soquelitinib will be presented today Ning Ding, Ph.D. from Peking University Cancer Hospital & Institute in Beijing, China, in a poster session (abstract #1442) at the 65th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition, which is taking place in-person and virtually from December 9-12, 2023. The poster reports on the evaluation of blood samples and tumor biopsies from eight patients who participated in the trial, taken at baseline and during treatment (one patient was sampled during stable disease and again during response, and therefore was counted twice as reflected in the data below). The results support soquelitinib’s novel mechanism of action, and demonstrated increases in cytotoxic killer T cells and reductions in markers of T cell exhaustion:

Responding patients (N=2) showed a sustained increase in CD4+ Th1 cells in the blood and an increase in CD8+ TEMRA cells (T effector memory cells). TEMRA cells are T cells that have responded to an antigen and are able to mediate effector functions, such as the destruction of tumor cells.
Patients with stable disease (N=4) showed increases in these cell populations that were transient.
Patients who progress (N=3) showed no increase in these cells.
Single cell RNA sequencing of tumor biopsies showed soquelitinib treatment increased expression of cytolytic effector molecules and led to a reduction of T cell exhaustion markers.
Dr. Miller added, "We are pleased to see that the molecular studies presented at ASH (Free ASH Whitepaper) illustrate the importance of host immune system function and soquelitinib’s novel mechanism of action that acts by inducing a host anti-tumor immune response."

The ASH (Free ASH Whitepaper) poster is available to ASH (Free ASH Whitepaper) attendees in the poster hall and via the virtual event platform, and is also available on the Publications and Presentations page of the Corvus website.

On December 9, 2023 Eisai (Headquarters: Tokyo, CEO: Haruo Naito) and Merck & Co., Inc., Rahway, NJ, USA (known as MSD outside of the United States and Canada) reported that the Phase 3 LEAP-001 trial evaluating LENVIMA, the orally available multiple receptor tyrosine kinase inhibitor discovered by Eisai, plus KEYTRUDA, the anti-PD-1 therapy from Merck & Co., Inc., Rahway, NJ, USA, did not meet its dual primary endpoints of overall survival (OS) and progression-free survival (PFS) for the first-line treatment of patients with advanced or recurrent endometrial carcinoma whose disease is mismatch repair proficient (pMMR)/not microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) /MSI-H (Press release, Eisai, DEC 9, 2023, View Source [SID1234638323]).

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At the final analysis, KEYTRUDA plus LENVIMA did not improve OS or PFS sufficiently to meet the study’s prespecified statistical criteria in the first-line treatment of certain patients with advanced or recurrent endometrial carcinoma versus a standard of care, platinum-based chemotherapy doublet (carboplatin plus paclitaxel). The safety profile of LENVIMA plus KEYTRUDA was consistent with that observed in previously reported studies evaluating the combination. A full evaluation of the data from this study is ongoing. The companies will work with investigators to share the results with the scientific community.

"We remain confident in the proven benefit of KEYTRUDA plus LENVIMA for the treatment of appropriate patients with certain types of previously-treated advanced endometrial carcinoma based on results from the KEYNOTE-775/Study 309 trial and will continue to research the KEYTRUDA plus LENVIMA combination in patients with other types of difficult-to-treat cancers," said Dr. Gregory Lubiniecki, Vice President, Global Clinical Development, Merck & Co., Inc., Rahway, NJ, USA Research Laboratories. "We are disappointed that the LEAP-001 trial did not-2-reach its primary endpoints, as we had hoped to bring another potential treatment option to patients when first diagnosed with certain types of advanced or recurrent endometrial carcinoma."

"Results from the LEAP-001 trial underscore the challenges of treating patients with advanced or recurrent endometrial carcinoma in the first-line setting," said Dr. Corina Dutcus, Senior Vice President, Oncology Global Clinical Development Lead at Eisai Inc. "We remain optimistic about clinical development program for LENVIMA plus KEYTRUDA and are proud that the combination has become a standard of care option for patients with certain types of advanced or recurrent endometrial carcinoma whose disease has progressed following prior systemic therapy, and will continue our efforts to contribute to these patients. We are grateful to the patients, their loved ones, and the investigators whose participation is what makes scientific advancement possible."

LENVIMA plus KEYTRUDA is approved in the U.S., the EU, Japan and other countries for the treatment of certain types of advanced endometrial carcinoma following prior systemic therapy in any setting and advanced renal cell carcinoma (RCC). Lenvatinib is marketed as KISPLYX for advanced RCC in the EU. Eisai and Merck & Co., Inc., Rahway, NJ, USA are studying the LENVIMA plus KEYTRUDA combination through the LEAP (LEnvatinib And Pembrolizumab) clinical program in various tumor types, including but not limited to hepatocellular carcinoma, RCC, head and neck cancer, gastric cancer and esophageal cancer, across multiple clinical trials. Results from the LEAP-001 trial do not affect the current approved indications for the KEYTRUDA plus LENVIMA combination or other ongoing trials from the LEAP clinical program.

About LEAP-001

LEAP-001 is a randomized, open-label Phase 3 trial (ClinicalTrials.gov, NCT03884101) evaluating LENVIMA plus KEYTRUDA versus carboplatin plus paclitaxel for the first-line treatment of advanced or recurrent endometrial carcinoma. The dual primary endpoints are PFS, as assessed by blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, and OS. The secondary endpoints include objective response rate, as assessed by BICR per RECIST v1.1, quality of life measures, and safety. The study enrolled an estimated 842 patients who were randomized 1:1 to receive:  LENVIMA (20 mg orally once daily) plus KEYTRUDA (200 mg intravenously [IV] on Day 1 of each three-week cycle); or Paclitaxel (175 mg/m2 IV on Day 1 of each three-week cycle) plus carboplatin (IV infusion at a total dose of area-under-the-curve 6 [per Calvert’s formula] given on Day 1 of each three-week cycle).

About Endometrial Carcinoma

Endometrial carcinoma begins in the inner lining of the uterus, which is known as the endometrium and is the most common type of cancer in the uterus. Worldwide, it was estimated there were more than 417,000 new cases of uterine body cancer diagnosed and more than 97,000 deaths from the disease in 2020 (these estimates include both endometrial carcinomas and uterine sarcomas, more than 90% of uterine body cancers occur in the endometrium, so the actual numbers for endometrial carcinoma cases and deaths may be slightly lower than these estimates). In Japan, there were more than 17,000 new cases of uterine body cancer and more than 3,000 deaths from the disease in 2020.5 In the U.S., it is estimated there will be approximately 66,000 new cases of uterine body cancer diagnosed and approximately 13,000 deaths from the disease in 2023. In Europe, it is estimated there were more than 130,000 new cases of uterine body cancer and more than 29,000 deaths in 2020.3 The five-year relative survival rate for metastatic endometrial carcinoma (stage IV) is estimated to be approximately 20%.

About LENVIMA (lenvatinib) Capsules

LENVIMA, discovered and developed by Eisai, is an orally available multiple receptor tyrosine kinase inhibitor that inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). LENVIMA inhibits other kinases that have been implicated in pathogenic angiogenesis, tumor growth, and cancer progression in addition to their normal cellular functions, including fibroblast growth factor (FGF) receptors FGFR1-4, the platelet derived growth factor receptor alpha (PDGFRα), KIT, and RET. In syngeneic mouse tumor models, LENVIMA decreased tumor-associated macrophages, increased activated cytotoxic T cells, and demonstrated greater antitumor activity in combination with an anti-PD-1 monoclonal antibody compared to either treatment alone. LENVIMA has been approved for the indications below.

Thyroid cancer

 Indication as monotherapy (Approved in over 80 countries including Japan, the United States, China, and countries in Europe and Asia) Japan: Unresectable thyroid cancer The United States: The treatment of patients with locally recurrent or metastatic, progressive, radioiodine-refractory differentiated thyroid cancer (DTC) Europe: The treatment of adult patients with progressive, locally advanced or metastatic, differentiated (papillary/follicular/Hürthle cell) thyroid carcinoma (DTC), refractory to radioactive iodine (RAI)

Hepatocellular carcinoma  Indication as monotherapy (Approved in over 80 countries including Japan, the United States, China, and countries in Europe and Asia) Japan: Unresectable hepatocellular carcinoma The United States: The first-line treatment of patients with unresectable hepatocellular carcinoma (HCC) Europe: The treatment of adult patients with advanced or unresectable hepatocellular carcinoma (HCC) who have received no prior systemic therapy Thymic carcinoma  Indication as monotherapy (Approved in Japan) Japan: Unresectable thymic carcinoma

Renal cell carcinoma (In Europe, the agent was launched under the brand name Kisplyx)  Indication in combination with everolimus (Approved in over 65 countries including the United States, and countries in Europe and Asia) The United States: The treatment of adult patients with advanced renal cell carcinoma (RCC) following one prior anti-angiogenic therapy Europe: The treatment of adult patients with advanced renal cell carcinoma following one prior vascular endothelial growth factor (VEGF) targeted therapy  Indication in combination with KEYTRUDA (generic name: pembrolizumab) (Approved in over 45 countries including Japan, the United States, and countries in Europe and Asia) Japan: Radically unresectable or metastatic renal cell carcinoma The United States: The first-line treatment of adult patients with advanced renal cell carcinoma Europe: The first-line treatment of adult patients with advanced renal cell carcinoma Endometrial carcinoma  Indication in combination with KEYTRUDA (Approved [including conditional approval] in over 50 countries including Japan, the United States, and countries in Europe and Asia) Japan: Unresectable, advanced or recurrent endometrial carcinoma that progressed after cancer chemotherapy The United States: The treatment of patients with advanced endometrial carcinoma (EC) that is not microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation Europe: The treatment of adult patients with advanced or recurrent endometrial carcinoma (EC) who have disease progression on or following prior treatment with a platinum-containing therapy in any setting and are not candidates for curative surgery

About KEYTRUDA (pembrolizumab) Injection, 100mg

KEYTRUDA is an anti-programmed death receptor-1 (PD-1) therapy that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells. Merck & Co., Inc., Rahway, NJ, USA has the industry’s largest immuno-oncology clinical research program. There are currently more than 1,600 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient’s likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

On December 9, 2023 Aptose Biosciences Inc. ("Aptose" or the "Company") (NASDAQ: APTO, TSX: APS), a clinical-stage precision oncology company developing highly differentiated targeted agents to treat hematologic malignancies, reported that a growing body of clinical data for Aptose’s lead compound tuspetinib (TUS), demonstrates significant benefit as a single agent and in combination with venetoclax (VEN) in patients with relapsed or refractory acute myeloid leukemia (R/R AML) in the ongoing APTIVATE Phase 1/2 study (Press release, Aptose Biosciences, DEC 9, 2023, View Source [SID1234638339]). Data were presented in an oral presentation today at the 65th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition by lead investigator Naval G. Daver, M.D., Professor, Director Leukemia Research Alliance Program, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX.

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Tuspetinib is a once-daily, oral, precision targeted kinase inhibitor that suppresses select kinases that drive the proliferation of AML. These key kinase targets include the SYK, FLT3, JAK1/2, mutant forms of KIT, RSK2, and the TAK1-TAB1 kinases operative in AML, while avoiding non-therapeutic kinase targets to promote safety.

Dr. Daver reported data from more than 100 relapsed/refractory patients from multiple international clinical sites, who had failed prior therapy and then were treated with tuspetinib (TUS) as a single agent or tuspetinib in combination with venetoclax (TUS/VEN). TUS and TUS/VEN delivered multiple composite complete remissions (CRcs) in this very ill AML population, while maintaining a favorable safety profile across all treated patients.

"Tuspetinib is clearly an active and surprisingly well tolerated agent in one of the most challenging and heterogeneous disease settings in oncology – relapsed and refractory AML," said Dr. Daver. "Tuspetinib has demonstrated broad activity, including activity in patients with FLT3 wild-type AML (accounting for more than 70% of the AML population), FLT3 mutated AML, NPM1 mutated AML, as well as in patients with mutations historically associated with resistance to targeted therapy. Most notably, TUS targets VEN resistance mechanisms, enabling TUS/VEN uniquely to treat the very ill prior-VEN AML population, including both FLT3 mutant and FLT3 wildtype disease. From a broader perspective, the growing body of antileukemic activity, and continued favorable safety profile, support advancement of tuspetinib in a TUS/VEN/HMA triplet for the treatment of frontline newly diagnosed AML patients."

Dr. Daver also pointed out that while patients on the TUS/VEN therapy are early in their treatment cycles, most achieving a response remained on treatment and that responses have begun to mature as dosing continues.

Highlights of Dr. Daver’s ASH (Free ASH Whitepaper) oral presentation:

TUS as Single Agent

As a single agent at therapeutic doses of 80-160 mg in 68 evaluable patients, TUS was more active in VEN-naïve patients, with an overall CRc rate of 29% (8/28)
This included a 42% CRc rate (5/12) in FLT3-mutated patients
And a 19% CRc rate (3/16) in FLT3-unmutated, or wildtype, AML patients
Responses and blood counts improved with continuous dosing
Many bridged to an allogeneic stem cell transplant (HSCT)
Durability was observed when HSCT was not performed
80 mg was selected as the recommended phase 2 dose
Tuspetinib showed a favorable safety profile with only mild adverse events (AEs) and no dose-limiting toxicities (DLTs) up to 160 mg per day, and no drug discontinuations from drug related toxicity
TUS/VEN Combination Therapy

In the TUS/VEN doublet study, 49 patients were dosed with 80 mg of tuspetinib and 200 mg of venetoclax, with 36 evaluable (and 13 patients too early to assess)
Patients were heavily exposed to Prior-VEN and Prior-FLT3 inhibitor treatment
TUS/VEN was active in both VEN-naïve and prior Prior-VEN relapsed/refractory patients
TUS demonstrated composite complete remission (CRc) rates:
Among all evaluable patients, TUS/VEN demonstrated a CRc rate of 25% (9/36); 43% (3/7) in VEN-naïve patients, and 21% (6/29) in Prior-VEN patients.
Among FLT3 wildtype patients, TUS/VEN demonstrated an overall CRc rate of 20% (5/25); 33% (2/6) in VEN-naïve patients, and 16% (3/19) in Prior-VEN patients
Among FLT3 mutant patients, TUS/VEN demonstrated an overall CRc rate of 36% (4/11); a complete response in a VEN-naïve patient (1/1); a 30% (3/10) in Prior-VEN patients; and 44% (4/9) in patients treated prior with a FLT3 inhibitor
Key findings:
TUS/VEN is a well tolerated combination therapy
TUS/VEN is active across broad populations of R/R AML
TUS/VEN is active in FLT3 wildtype, representing ~70% of AML patients
TUS/VEN retains activity in the difficult-to-treat Prior-VEN AML population
"The wealth of data we have generated – and continue to generate – on tuspetinib points to a highly active, well-differentiated drug for AML populations that are in need of options beyond currently available therapies," said Rafael Bejar, M.D., Ph.D., Chief Medical Officer at Aptose. "Brisk patient enrollment in our APTIVATE trial has led to a fast-growing database that includes many more patients at various stages of treatment. We look forward to reporting our next set of data in the first quarter of 2024."

The slides from Dr. Daver’s presentation are available on Aptose’s website here.