On December 8, 2024 Genmab (Nasdaq: GMAB) reported results from the Phase 1b/2 EPCORE CLL-1 clinical trial evaluating epcoritamab (Abstract #883), a T-cell engaging bispecific antibody administered subcutaneously, demonstrated an overall response rate (ORR) of 61 percent and a complete response (CR) rate of 39 percent in difficult-to-treat adult patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) treated with epcoritamab monotherapy (Press release, Genmab, DEC 8, 2024, View Source [SID1234648866]). These results, from the monotherapy expansion (EXP) cohort (n=23) of the trial, along with the first safety data from the optimization (OPT) cohort, were presented at the 66th Annual Meeting and Exposition of the American Society of Hematology (ASH) (Free ASH Whitepaper), during the ASH (Free ASH Whitepaper) Annual Meeting Press Program. The data will be presented during an oral session on December 9, 2024.

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In the EXP cohort, the median time to response was two (2.0) months and the median time to CR was 5.6 months. Among all patients in the cohort, median progression-free survival (PFS) was 12.8 months and median overall survival (OS) was not reached (median follow-up was 22.8 months). An estimated 65 percent of patients were alive at 15 months. Among 12 responders evaluable for minimal residual disease (MRD) by next-generation sequencing in peripheral blood, nine patients (75 percent) had undetectable MRD.

The most frequent non-hematologic treatment-emergent adverse events (TEAEs) in the EXP cohort were cytokine release syndrome (CRS; 96 percent), diarrhea (48 percent), peripheral edema (48 percent), fatigue (43 percent), and injection-site reaction (43 percent). Cytopenias were common (anemia, 65 percent; thrombocytopenia, 65 percent; neutropenia, 48 percent); however, most patients had baseline anemia and thrombocytopenia, suggesting that these events were largely disease-related. Three cases of immune effector cell-associated neurotoxicity syndrome (ICANS) were reported (one Grade 1; two Grade 2), and there was one clinical tumor lysis syndrome (CTLS) case (Grade 2). These cases did not lead to treatment discontinuation. Four fatal TEAEs occurred – two cases of pneumonia, one case of sepsis and one case of squamous cell carcinoma of the skin.

The EXP cohort followed a 2-step step-up dose regimen, and CRS was manageable and primarily low grade (9 percent Grade 1, 70 percent Grade 2, 17 percent Grade 3). In the first data from the separate OPT cohort, which followed a 3-step step-up dose regimen, CRS severity was substantially reduced with only low-grade events (71 percent Grade 1, 12 percent Grade 2). In both cohorts, CRS events primarily occurred following the first full dose, and none led to treatment discontinuation. No ICANS or CTLS cases were reported in the OPT cohort.

"These EPCORE CLL-1 data are encouraging, especially as the majority of patients were heavily pre-treated with at least four lines of therapy," said Alexey Danilov, MD, PhD, Marianne and Gerhard Pinkus, Professor and Director of Early Clinical Therapeutics and Associate Director of the Toni Stephenson Lymphoma Center, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope. "Despite progress in treating chronic lymphocytic leukemia, there remains a tremendous need for additional therapeutic options for high-risk patients whose disease has progressed following standard chemoimmunotherapy and targeted therapies."

Additional data from the EXP cohort showed high response rates in patients with high-risk factors treated with epcoritamab, including TP53 aberrations, IGHV-unmutated disease and double-exposed disease – prognostic markers that are associated with disease progression and decreased survival.i,ii,iii In patients with TP53 aberrations (n=15), the ORR was 67 percent with a CR of 33 percent. Among patients with IGHV-unmutated disease (n=16), the ORR was 63 percent, and the CR was 44 percent. In double-refractory patients, the ORR was 53 percent, and the CR was 37 percent.

All patients in the trial had prior chemoimmunotherapy, and most patients had previously received targeted therapies such as BTK and BCL2 inhibitors (double-exposed) and had high-risk disease characteristics.

"Chronic lymphocytic leukemia is incurable, and patients often need a variety of treatments throughout their lifetime, especially if their disease has high-risk prognostic factors, has relapsed or has become refractory to the current standard-of-care, including targeted therapies," said Dr. Judith Klimovsky, Executive Vice President & Chief Development Officer, Genmab. "These early data show the potential therapeutic applicability of epcoritamab in relapsed or refractory chronic lymphocytic leukemia, and further reinforce the potential of epcoritamab as a core therapy for the treatment of B-cell malignancies."

Use of epcoritamab in CLL is not approved in the U.S. or in the EU or in any other territory. The safety and efficacy of epcoritamab for use in CLL have not been established.

About Chronic Lymphocytic Leukemia (CLL)
Chronic lymphocytic leukemia (CLL) is the most prevalent type of leukemia, affecting over 200,000 people in the United States alone.iv Chronic lymphocytic leukemia can be classified as either slow growing (indolent) or fast growing (aggressive).v CLL is incurable, and many patients will likely relapse and progress on frontline therapies.vi Most patients will experience consecutive episodes of disease progression and will require several lines of treatment in their lifetime.vii,viii

About the EPCORE CLL-1 Trial
EPCORE CLL-1 is a Phase 1b/2, open-label, multi-center trial to evaluate the safety and preliminary efficacy of epcoritamab as a monotherapy and in combination with standard of care agents in patients with difficult-to-treat relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL), R/R small lymphocytic lymphoma (SLL) and Richter’s Syndrome (RS). The trial consists of two parts: a dose-escalation phase (Phase 1b) and an expansion phase (Phase 2). Patients with RS are only included in the expansion phase. The primary objective of Phase 1b is to determine the recommended Phase 2 dose and the maximum tolerated dose as well as establish the safety profile of epcoritamab monotherapy and epcoritamab plus venetoclax in participants with R/R CLL. The purpose of Phase 2 is to assess and evaluate the preliminary efficacy, safety and tolerability profiles of epcoritamab monotherapy and epcoritamab plus venetoclax for patients with R/R CLL and SLL. Additionally, epcoritamab monotherapy and combination therapy will be evaluated in patients with RS to assess their efficacy, safety and tolerability profiles. More information on this trial can be found at View Source (NCT: 04623541).

About Epcoritamab
Epcoritamab is an 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.ix

Epcoritamab (approved under the brand name EPKINLY in the U.S. and Japan, and TEPKINLY in the EU) has received regulatory approval in certain lymphoma indications in several territories. Epcoritamab is being co-developed by Genmab and AbbVie as part of the companies’ oncology collaboration. The companies will share commercial responsibilities in the U.S. and Japan, with AbbVie responsible for further global commercialization. Both companies will pursue additional international regulatory approvals for the investigational R/R FL indication and additional approvals for the R/R DLBCL indication.

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 five ongoing Phase 3, open-label, randomized trials including a trial evaluating epcoritamab as a monotherapy in patients with R/R DLBCL compared to investigator’s choice chemotherapy (NCT04628494), a trial evaluating epcoritamab in combination with R-CHOP in adult patients with newly diagnosed DLBCL (NCT05578976), a trial evaluating epcoritamab in combination with rituximab and lenalidomide (R2) in patients with R/R FL (NCT05409066), a trial evaluating epcoritamab in combination with rituximab and lenalidomide (R2) compared to chemoimmunotherapy in patients with previously untreated FL (NCT06191744), and a trial evaluating epcoritamab in combination with lenalidomide compared to chemotherapy infusion in patients with R/R DLBCL (NCT06508658). The safety and efficacy of epcoritamab has not been established for these investigational uses. Please visit www.clinicaltrials.gov for more information.

On December 08, 2024 AstraZeneca reported the positive results from the AMPLIFY Phase III trial showed CALQUENCE (acalabrutinib) in combination with venetoclax demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared to standard-of-care chemoimmunotherapy in previously untreated adult patients with chronic lymphocytic leukemia (CLL) (Press release, AstraZeneca, DEC 8, 2024, View Source [SID1234648886]).

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These results will be presented at the American Society of Hematology (ASH) (Free ASH Whitepaper) 2024 Annual Meeting in San Diego, CA.

At a median follow up of 41 months, results showed CALQUENCE plus venetoclax reduced the risk of disease progression or death by 35% compared to standard-of-care chemoimmunotherapy (hazard ratio [HR] 0.65; 95% confidence interval [CI] 0.49-0.87; p=0.0038). CALQUENCE plus venetoclax with obinutuzumab demonstrated a 58% reduction in the risk of disease progression or death compared to standard-of-care chemoimmunotherapy (HR 0.42; 95% CI 0.30-0.59; p<0.0001). Median PFS was not reached for either experimental arm versus median PFS of 47.6 months for chemoimmunotherapy.

Interim overall survival (OS) data demonstrated a favorable trend which was nominally statistically significant for CALQUENCE plus venetoclax (HR 0.33; 95% CI 0.18-0.56; p<0.0001), however the OS data were immature at the time of this analysis and the trial will continue to assess OS as a key secondary endpoint.

Jennifer R. Brown, MD, PhD, Director of the CLL Center of the Division of Hematologic Malignancies, Dana-Farber Cancer Institute, and the Worthington and Margaret Collette Professor of Medicine at Harvard Medical School, and principal investigator of the trial, said: "Chronic lymphocytic leukemia is considered an incurable cancer and patients live with the disease and the long-term effects of their treatments for many years. The AMPLIFY results show the promise of a new all-oral fixed-duration therapy approach which would allow patients to take breaks from treatment, reducing the risk of long-term adverse events and drug resistance."

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: "Based on these impressive data from the AMPLIFY trial, CALQUENCE is the only second-generation BTK inhibitor to demonstrate efficacy in the front-line treatment of patients with chronic lymphocytic leukemia as both a treat-to-progression and a fixed-duration approach. This advance is an important development for patients and their physicians who seek new options and more flexibility in managing this disease in the long term."

Both investigational arms demonstrated durable responses, with estimated 36-month PFS rates of 76.5% for CALQUENCE plus venetoclax and 83.1% with the addition of obinutuzumab compared to 66.5% for chemoimmunotherapy. Patients also demonstrated a robust response in both investigational arms with an overall response rate (ORR) of 92.8% for CALQUENCE plus venetoclax and 92.7% with the addition of obinutuzumab, compared to 75.2% for chemoimmunotherapy.

Summary of Results: AMPLIFY

CALQUENCE plus venetoclax

CALQUENCE plus venetoclax and obinutuzumab

Control arm

Patient population (n)

291

286

290

Median PFS

(months)

NR

NR

47.6

PFS HR vs. control

(95% CI)

0.65

p=0.0038

0.42

p<0.0001

Reference

36-month PFS rate

76.5%

83.1%

66.5%

ORR (95% CI)

92.8% (89.4-95.4)

p<0.0001

92.7% (89.2-95.3)

p<0.0001

75.2% (70.0-79.9)

OS HR vs. control (95% CI)

0.33 (0.18-0.56)

p<0.0001

0.76 (0.49-1.18)

p=0.2224

Reference

NR=Not reached

Control arm = Investigator’s choice of fludarabine-cyclophosphamide-rituximab or bendamustine-rituximab

The safety and tolerability of CALQUENCE was consistent with its known safety profile, and no new safety signals were identified. Grade 3 or higher adverse events (AEs) occurred in 53.6% of patients treated with CALQUENCE plus venetoclax, 69.4% of patients treated with CALQUENCE plus venetoclax with obinutuzumab and 60.6% for patients treated with standard-of-care chemoimmunotherapy. The most common Grade 3 or higher AE was neutropenia across all arms, seen in 26.8%, 35.2% and 32.4% of patients respectively. There were over twice as many COVID-19 related deaths in the CALQUENCE plus venetoclax with obinutuzumab arm compared with the CALQUENCE plus venetoclax arm.

Notably, low rates of tumor lysis syndrome (TLS) were observed in both CALQUENCE arms with events of any grade seen in 0.3% of patients treated with CALQUENCE plus venetoclax and 0.4% with the addition of obinutuzumab, compared to 3.1% for patients treated with chemoimmunotherapy. No cases of clinical TLS were observed across CALQUENCE treatment arms.

CALQUENCE has been used to treat more than 85,000 patients worldwide1 and is approved for the treatment of CLL and small lymphocytic lymphoma (SLL) in the US and Japan, approved for CLL in the EU and many other countries worldwide and approved in China for relapsed or refractory CLL and SLL.

INDICATION AND USAGE

CALQUENCE is a Bruton tyrosine kinase (BTK) inhibitor indicated for the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

IMPORTANT SAFETY INFORMATION ABOUT CALQUENCE (acalabrutinib) tablets

Serious and Opportunistic Infections

Fatal and serious infections, including opportunistic infections, have occurred in patients with hematologic malignancies treated with CALQUENCE.

Serious or Grade 3 or higher infections (bacterial, viral, or fungal) occurred in 19% of 1029 patients exposed to CALQUENCE in clinical trials, most often due to respiratory tract infections (11% of all patients, including pneumonia in 6%). These infections predominantly occurred in the absence of Grade 3 or 4 neutropenia, with neutropenic infection reported in 1.9% of all patients. Opportunistic infections in recipients of CALQUENCE have included, but are not limited to, hepatitis B virus reactivation, fungal pneumonia, Pneumocystis jirovecii pneumonia, Epstein-Barr virus reactivation, cytomegalovirus, and progressive multifocal leukoencephalopathy (PML). Consider prophylaxis in patients who are at increased risk for opportunistic infections. Monitor patients for signs and symptoms of infection and treat promptly.

Hemorrhage

Fatal and serious hemorrhagic events have occurred in patients with hematologic malignancies treated with CALQUENCE. Major hemorrhage (serious or Grade 3 or higher bleeding or any central nervous system bleeding) occurred in 3.0% of patients, with fatal hemorrhage occurring in 0.1% of 1029 patients exposed to CALQUENCE in clinical trials. Bleeding events of any grade, excluding bruising and petechiae, occurred in 22% of patients.

Use of antithrombotic agents concomitantly with CALQUENCE may further increase the risk of hemorrhage. In clinical trials, major hemorrhage occurred in 2.7% of patients taking CALQUENCE without antithrombotic agents and 3.6% of patients taking CALQUENCE with antithrombotic agents. Consider the risks and benefits of antithrombotic agents when co-administered with CALQUENCE. Monitor patients for signs of bleeding.

Consider the benefit-risk of withholding CALQUENCE for 3-7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.

Cytopenias

Grade 3 or 4 cytopenias, including neutropenia (23%), anemia (8%), thrombocytopenia (7%), and lymphopenia (7%), developed in patients with hematologic malignancies treated with CALQUENCE. Grade 4 neutropenia developed in 12% of patients. Monitor complete blood counts regularly during treatment. Interrupt treatment, reduce the dose, or discontinue treatment as warranted.

Second Primary Malignancies

Second primary malignancies, including skin cancers and other solid tumors, occurred in 12% of 1029 patients exposed to CALQUENCE in clinical trials. The most frequent second primary malignancy was skin cancer, reported in 6% of patients. Monitor patients for skin cancers and advise protection from sun exposure.

Cardiac Arrhythmias

Serious cardiac arrhythmias have occurred in patients treated with CALQUENCE. Grade 3 atrial fibrillation or flutter occurred in 1.1% of 1029 patients treated with CALQUENCE, with all grades of atrial fibrillation or flutter reported in 4.1% of all patients. Grade 3 or higher ventricular arrhythmia events were reported in 0.9% of patients. The risk may be increased in patients with cardiac risk factors, hypertension, previous arrhythmias, and acute infection. Monitor for symptoms of arrhythmia (eg, palpitations, dizziness, syncope, dyspnea) and manage as appropriate.

Hepatotoxicity, Including Drug-Induced Liver Injury

Hepatotoxicity, including severe, life-threatening, and potentially fatal cases of drug-induced liver injury (DILI), has occurred in patients treated with Bruton tyrosine kinase inhibitors, including CALQUENCE.

Evaluate bilirubin and transaminases at baseline and throughout treatment with CALQUENCE. For patients who develop abnormal liver tests after CALQUENCE, monitor more frequently for liver test abnormalities and clinical signs and symptoms of hepatic toxicity. If DILI is suspected, withhold CALQUENCE. Upon confirmation of DILI, discontinue CALQUENCE.

ADVERSE REACTIONS

The most common adverse reactions (≥30%) of any grade in patients with CLL were anemia,* neutropenia,* thrombocytopenia,* headache, upper respiratory tract infection, and diarrhea.

*Treatment-emergent decreases (all grades) of hemoglobin, platelets, and neutrophils were based on laboratory measurements and adverse reactions.

In patients with previously untreated CLL exposed to CALQUENCE, fatal adverse reactions that occurred in the absence of disease progression and with onset within 30 days of the last study treatment were reported in 2% for each treatment arm, most often from infection. Serious adverse reactions were reported in 39% of patients in the CALQUENCE plus obinutuzumab arm and 32% in the CALQUENCE monotherapy arm, most often due to events of pneumonia (7% and 2.8%, respectively).

Adverse reactions led to CALQUENCE dose reduction in 7% and 4% of patients in the CALQUENCE plus obinutuzumab arm (N=178) and CALQUENCE monotherapy arm (N=179), respectively. Adverse events led to discontinuation in 11% and 10% of patients, respectively. Increases in creatinine to 1.5 to 3 times the upper limit of normal (ULN) occurred in 3.9% and 2.8% of patients in the CALQUENCE combination arm and monotherapy arm, respectively.

In patients with relapsed/refractory CLL exposed to CALQUENCE, serious adverse reactions occurred in 29% of patients. Serious adverse reactions in >5% of patients who received CALQUENCE included lower respiratory tract infection (6%). Fatal adverse reactions within 30 days of the last dose of CALQUENCE occurred in 2.6% of patients, including from second primary malignancies and infection.

Adverse reactions led to CALQUENCE dose reduction in 3.9% of patients (N=154), dose interruptions in 34% of patients, most often due to respiratory tract infections followed by neutropenia, and discontinuation in 10% of patients, most frequently due to second primary malignancies followed by infection. Increases in creatinine to 1.5 to 3 times ULN occurred in 1.3% of patients who received CALQUENCE.

DRUG INTERACTIONS

Strong CYP3A Inhibitors: Avoid co-administration of CALQUENCE with a strong CYP3A inhibitor. If these inhibitors will be used short-term, interrupt CALQUENCE. After discontinuation of strong CYP3A inhibitor for at least 24 hours, resume previous dosage of CALQUENCE.

Moderate CYP3A Inhibitors: Reduce the dosage of CALQUENCE to 100 mg once daily when co-administered with a moderate CYP3A inhibitor.

Strong CYP3A Inducers: Avoid co-administration of CALQUENCE with a strong CYP3A inducer. If co-administration is unavoidable, increase the dosage of CALQUENCE to 200 mg approximately every 12 hours.

SPECIFIC POPULATIONS

Based on findings in animals, CALQUENCE may cause fetal harm and dystocia when administered to a pregnant woman. There are no available data in pregnant women to inform the drug-associated risk. Advise pregnant women of the potential risk to a fetus.

Pregnancy testing is recommended for females of reproductive potential prior to initiating CALQUENCE therapy. Advise female patients of reproductive potential to use effective contraception during treatment with CALQUENCE and for 1 week following the last dose of CALQUENCE.

It is not known if CALQUENCE is present in human milk. Advise lactating women not to breastfeed while taking CALQUENCE and for 2 weeks after the last dose.

Avoid use of CALQUENCE in patients with severe hepatic impairment (Child-Pugh class C). No dosage adjustment of CALQUENCE is recommended in patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment.

Please see full Prescribing Information, including Patient Information.

Notes

Chronic Lymphocytic Leukemia (CLL)

CLL is the most prevalent type of leukemia in adults, with over 100,000 new cases globally in 2019.2 Although some people with CLL may not experience any symptoms at diagnosis, others may experience symptoms, such as weakness, fatigue, weight loss, chills, fever, night sweats, swollen lymph nodes and abdominal pain.3 In CLL, there is an accumulation of abnormal lymphocytes within the blood, bone marrow and lymph nodes. As the number of abnormal cells increases, there is less room within the marrow for the production of normal white blood cells, red blood cells and platelets.4 This could result in infection, anemia and bleeding. B-cell receptor signaling through BTK is one of the essential growth pathways for CLL.

AMPLIFY

AMPLIFY is a randomized, global, multi-center, open-label Phase III trial evaluating the efficacy and safety of CALQUENCE in combination with venetoclax with and without obinutuzumab compared to investigator’s choice of chemoimmunotherapy (fludarabine-cyclophosphamide-rituximab or bendamustine-rituximab) in adult patients with previously untreated CLL without del(17p) or TP53 mutation.5 Patients were randomized 1:1:1 to receive either CALQUENCE plus venetoclax, CALQUENCE plus venetoclax with obinutuzumab for a fixed duration or standard-of-care chemoimmunotherapy.5 Both the CALQUENCE containing arms were administered for a fixed duration of 14 cycles (each 28 days), and the standard-of-care chemoimmunotherapy was for 6 cycles.5

The primary endpoint is PFS in the CALQUENCE and venetoclax arm as assessed by an Independent Review Committee and PFS in the CALQUENCE plus venetoclax with obinutuzumab is a key secondary endpoint. Other key secondary endpoints include OS and undetectable measurable residual disease.5 The trial includes 27 countries across North and South America, Europe, Asia and Oceania.5

The AMPLIFY trial enrolled patients from 2019 to 2021, continuing through the COVID-19 pandemic.5 Patients with blood cancer remain at a disproportionately high risk of severe outcomes from COVID-19, including hospitalization and death compared to the general population.6

CALQUENCE

CALQUENCE (acalabrutinib) is a second-generation, selective inhibitor of Bruton’s tyrosine kinase (BTK). CALQUENCE binds covalently to BTK, thereby inhibiting its activity.7 In B-cells, BTK signaling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis and adhesion.

CALQUENCE is also approved in the US, China and several other countries for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. CALQUENCE is not currently approved for the treatment of MCL in Japan or the EU.

As part of an extensive clinical development program, CALQUENCE is currently being evaluated as a single treatment and in combination with standard-of-care chemoimmunotherapy for patients with multiple B-cell blood cancers, including CLL, MCL and diffuse large B-cell lymphoma.

On December 8, 2024 Merck (NYSE: MRK), known as MSD outside of the United States and Canada, reported the first presentation of data from the Phase 2 waveLINE-007 trial evaluating zilovertamab vedotin, Merck’s investigational antibody drug conjugate (ADC) that targets receptor tyrosine kinase-like orphan receptor 1 (ROR1), in combination with cyclophosphamide, doxorubicin and prednisone plus rituximab (R-CHP) for the treatment of patients with previously untreated diffuse large B-cell lymphoma (DLBCL) (Press release, Merck & Co, DEC 8, 2024, View Source [SID1234648868]). At a pre-planned analysis, zilovertamab vedotin in combination with R-CHP achieved a 100% (n=15) complete response (CR) rate in patients treated with zilovertamab vedotin at 1.75 mg/kg. Based on the data, the study has established 1.75 mg/kg as the recommended Phase 3 dose of zilovertamab vedotin. These data are being presented for the first time today in an oral presentation (Abstract #578) at the 66th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition.

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"There is a need for additional first-line treatment options to help patients with diffuse large B-cell lymphoma, since, unfortunately, approximately 40% still experience relapsed or refractory disease after initial treatment with the current standard of care," said Dr. Muhit Ozcan, the study’s principal investigator, Ankara University School of Medicine. "These data from the Phase 2 waveLINE-007 trial are promising and support further research in the first-line setting in a larger patient population to help address this significant unmet need for patients."

"We are pleased to see these early positive results from the Phase 2 waveLINE-007 trial, in which zilovertamab vedotin demonstrated a highly promising response rate and a manageable safety profile in combination with standard of care," said Dr. Gregory Lubiniecki, vice president, oncology clinical research, Merck Research Laboratories. "We look forward to advancing our research of this investigational ROR1-directed antibody drug conjugate, which we believe has strong potential in multiple hematologic malignancies."

As announced, data from more than 20 abstracts are being presented from across a broad range of hematologic malignancies from Merck’s hematology pipeline, which includes a diverse range of investigational assets with novel modalities, at the 66th ASH (Free ASH Whitepaper) Annual Meeting and Exposition.

Study design and additional data from waveLINE-007

WaveLINE-007 is a non-randomized, open-label Phase 2 trial (ClinicalTrials.gov, NCT05406401) evaluating zilovertamab vedotin (MK-2140) in combination with R-CHP in patients with previously untreated DLBCL. The primary endpoints are safety (number of patients with dose limiting toxicity, adverse events and discontinuation due to adverse events) and CR rate based on investigator review per Lugano Response Criteria. Secondary endpoints include objective response rate (ORR) and duration of response (DOR) per Lugano Response Criteria. As of data cut-off, 36 patients were enrolled in the study to receive zilovertamab vedotin plus R-CHP intravenously on day 1 of each 21-day cycle (Q3W) for up to eight cycles. The treatment arms of the study included:

1.75 mg/kg (n=15); all 15 patients in this arm completed the trial (none discontinued)
2.0 mg/kg (n=15); 14 patients in this arm completed treatment and one patient discontinued after cycle 1 due to physician decision and was entered to safety follow-up, or
2.25 mg/kg (n=6); 5 patients in this arm completed treatment and one patient discontinued due to physician decision
The efficacy results showed a CR was achieved in combination with R-CHP in 100% (n=15) of patients receiving the 1.75 mg/kg dose of zilovertamab vedotin (CI: 95%, 78.2-100.0), 93.3% (n=14) of patients receiving the 2.0 mg/kg dose (CI: 95%, 68.1-99.8) and 100% (n=6) of patients receiving the 2.25 mg/kg dose (CI: 95%, 54.1-100.0). The total CR rate at the end of treatment was 97.2% (CI: 95%, 85.5-99.9). The median follow-up for all patients was 17.6 months (range, 7.1-24.6). The ORR was 100% (CI: 95%, 78.2-100.0) for patients receiving the 1.75 mg/kg dose, 93.3% (CI: 95%, 68.1-99.8) for patients receiving the 2.0 mg/kg dose, and 100% (CI: 95%, 54.1-100.0) for patients receiving the 2.25 mg/kg dose, all in combination with R-CHP. The median DOR has not been reached for all patients, and the total 12-month DOR was 93.5%. Based on the data, the recommended zilovertamab vedotin dose was determined to be 1.75 mg/kg.

Serious treatment-related adverse events (TRAEs) occurred in 11% (n=4) of all patients (1.75 mg/kg [n=1], 2.0 mg/kg [n=1], 2.25 mg/kg [n=2]). Grade 3-4 TRAEs occurred in 58% (n=21) of all patients. The most common of these events were neutropenia, nausea, anemia and diarrhea.

About diffuse large B-cell lymphoma

Lymphoma is cancer beginning in the lymphatic system – the network of organs, vessels and tissues that protects the body from infection. There are many subtypes of lymphoma, which are often categorized into two main types – Hodgkin lymphoma and non-Hodgkin lymphoma (NHL). DLBCL, the most common form of NHL, is derived from white blood cells that grow rapidly and uncontrollably, enlarging the lymph nodes and often migrating to other parts of the body. DLBCL accounts for approximately 25-30% of all non-Hodgkin lymphomas worldwide. In the U.S., it is estimated that approximately 25,000 patients are diagnosed with DLBCL each year. The five-year relative survival rate for DLBCL is 60-70%.

About zilovertamab vedotin (MK-2140)

Zilovertamab vedotin is an investigational ADC that targets ROR1. ROR1 is a transmembrane protein that is overexpressed in multiple hematologic malignancies. Merck is committed to research with zilovertamab vedotin across B-cell malignancies and is establishing a robust program of clinical trials under the name waveLINE. The waveLINE program includes a Phase 2/3 study in patients with relapsed or refractory DLBCL (waveLINE-003, NCT05139017) and a Phase 3 study in treatment naïve patients with DLBCL (waveLINE-010, NCT06717347).

On December 8, 2024 Novartis reported positive, longer-term results from the pivotal Phase III ASC4FIRST trial with Scemblix (asciminib) showing superior major molecular response (MMR) rates at week 961. The study compared the MMR rate of Scemblix to investigator-selected standard-of-care (SoC) tyrosine kinase inhibitors (TKIs) (imatinib, nilotinib, dasatinib and bosutinib) and to imatinib alone in adult patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase (Ph+ CML-CP) at the week 96 evaluation, the study’s key secondary endpoints (Press release, Novartis, DEC 8, 2024, View Source [SID1234648869]). The longer-term results showed an increasing difference in Scemblix MMR rate vs. SoC, vs. imatinib and vs. 2G TKIs (nilotinib, dasatinib and bosutinib)1. Results were presented at the 66th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition (ASH) (Free ASH Whitepaper)1.

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"These 96-week results are very encouraging for clinicians who aspire to obtain a balance of efficacy and tolerability profiles to help newly diagnosed adult CML patients achieve and maintain treatment goals," said Jorge Cortes, M.D., Director, Georgia Cancer Center. "The sustained superior efficacy, deeper and more durable responses, and favorable safety and tolerability profile compared to standard of care TKIs continue to support the promise of Scemblix as a potentially practice-changing treatment option."

The median follow-up was 2.2 years for Scemblix and investigator-selected SoC TKIs1. Over 22% more patients treated with once-daily Scemblix achieved MMR at week 96 vs. all investigator-selected SoC TKIs, and nearly 30% more patients achieved MMR at week 96 vs. imatinib alone1. The Scemblix MMR rate was 15.1% (95% CI: 2.3, 28.0; not crossing zero) higher vs. 2G TKIs (72% vs. 56.9%)1. Patients treated with Scemblix also achieved deeper rates of molecular responses (MR4 and MR4.5) compared with investigator-selected SoC TKIs1.

Overalla
Scemblix (n=201)
vs. IS SoC TKIs
(n=204) Imatinib stratumb
Scemblix (n=101)
vs. imatinib (n=102) 2G TKI stratumc
Scemblix (n=100)
vs. 2G TKIs
(n=102)
Key secondary endpoints MMR rates
at week 96 74.1% vs. 52% 76.2% vs. 47.1%
Secondary endpointsd MMR rates
at week 96 72% vs. 56.9%
MR4
at week 96 48.8% vs. 27.5% 52.5% vs. 23.5% 45% vs. 31.4%
MR4.5
at week 96 30.9% vs. 17.7% 35.6% vs. 11.8% 26% vs. 23.5%
a All patients receiving Scemblix (n=201) or investigator-selected SoC TKIs (n=204). Treatment difference after adjusting for pre-randomization selected TKI and EUTOS long-term survival (ELTS) risk groups at baseline.
b The 203 patients within the pre-randomization-selected imatinib stratum were randomized to receive either Scemblix (n=101) or imatinib (n=102). Treatment difference after adjusting for ELTS risk groups at baseline.
c The 202 patients within the pre-randomization selected 2G TKIs stratum were randomized to receive either Scemblix (n=100) or 2G TKIs (n=102: nilotinib, 48%; dasatinib, 41%; bosutinib, 11%).
d Secondary endpoints were not powered for statistical significance.
The safety profile of Scemblix at 96-weeks was consistent with the 4-year follow-up of the Phase III ASCEMBL trial, with no new safety concerns observed to date1,2,4. Fewer grade ≥3 AEs and dose adjustments to manage AEs were reported for Scemblix, and discontinuation due to AEs was more than 50% lower for Scemblix vs. both imatinib and 2G TKIs1. The most frequent AEs (≥15%) were diarrhea, headache, fatigue, musculoskeletal pain, and rash1.

Week 96 Scemblix
n=200 Imatinib
n=99 2G TKIs
n=102
Grade ≥ AEsa 44.5% 49.5% 59.8%
Discontinuation due to AEsa 5.5% 13.1% 12.7%
AEs leading to dose adjustments/interruptionsa 33% 41.4% 57.8%
aIn patients who experienced ≥1 adverse event.
Novartis also presented today at ASH (Free ASH Whitepaper) interim data from the Phase II ASC2ESCALATE dose-escalation study in both the second line (2L) and newly diagnosed Ph+ CML-CP settings5. In the analysis of 2L patients at week 24 (n=28) Scemblix demonstrated MMR rates of 42.9% and deep molecular responses (MR4 25% and MR4.5 10.7%), with a consistent safety and tolerability profile5. The most common AEs (>15%) were nausea, hypertension, and vomiting5.

"Novartis’ decades-long work in CML and deep relationships within the community have informed our Scemblix clinical trial program of over 10 years, the centerpiece of our continuing drive to address ongoing unmet medical needs for people with CML," said Jeff Legos, Executive Vice President, Global Head of Oncology Development, Novartis. "These latest findings reinforce the differentiated efficacy, safety and tolerability profile of Scemblix in newly diagnosed and previously treated adult CML patients."

Scemblix was recently granted accelerated approval in the US to treat newly diagnosed adults with Ph+ CML-CP, which together with its approval in previously treated adult patients with Ph+ CML-CP expands the population of Scemblix-eligible patients by four-fold 2. In addition, the National Comprehensive Cancer Network (NCCN) updated its Clinical Practice Guidelines in Oncology (NCCN Guidelines) for the treatment of CML, recommending asciminib as a category 1 – preferred treatment for newly diagnosed Ph+ CML-CP and across all risk categories3.

About the ASC4FIRST Phase III Clinical Trial
ASC4FIRST (NCT04971226) is a Phase III, head-to-head, multi-center, open-label, randomized study of oral Scemblix 80 mg QD vs. IS first- or second-generation TKIs (imatinib, nilotinib, dasatinib or bosutinib) in 405 adult patients with newly diagnosed Ph+ CML-CP2,6. The trial met both primary endpoints with Scemblix demonstrating superior MMR rates at week 48 vs. investigator-selected SoC TKIs (imatinib, nilotinib, dasatinib and bosutinib) (67.7% vs. 49.0%) and imatinib alone (69.3% vs. 40.2%) as well as the secondary, non-powered endpoint for the 2G TKI stratum of (66% vs 57.8%)1,6. The study remains ongoing with further efficacy and safety readouts planned.

About the ASC2ESCALATE Phase II Study
ASC2ESCALATE (NCT05384587) is a Phase II, multicenter, single-arm, dose-escalation study of oral Scemblix 80 mg QD in both the second line (2L) and newly diagnosed (1L) Ph+ CML-CP settings in the US 5,7. While Scemblix is already approved across lines of therapy, this is the first prospective trial to assess asciminib in the 2L setting and a dose-escalation strategy of asciminib as 2L and 1L treatment for patients with CML-CP not meeting molecular milestones 5. The proportion of patients achieving MMR at 12 months in the 2L setting will be measured as the primary endpoint 5. The study remains ongoing and has completed enrollment with 196 patients (100 patients in 2L, 96 patients in 1L)5.

About Scemblix (asciminib)
Scemblix is the first CML treatment that works by Specifically Targeting the ABL Myristoyl Pocket (referred to as a STAMP inhibitor in scientific literature)4,8,9. Other currently approved CML treatments are TKIs that target the ATP-binding site (ATP-competitive)9.

In the US, Scemblix was granted accelerated approval to treat newly diagnosed adults with Ph+ CML-CP and is also approved for previously treated adult patients with Ph+ CML-CP. Outside the US, it is approved in more than 75 countries, including the EU, to treat those who have previously been treated with two or more TKIs with Ph+ CML-CP2,10,11. In some countries, including the US, Scemblix is also approved in patients with Ph+ CML-CP with the T315I mutation2,3,10.

Scemblix is being studied across multiple treatment lines for Ph+ CML-CP, both as a monotherapy and in combination2,4,6,8,10,12-24.

Patient Access and Support
Novartis, with its 20+ year history in CML, is committed to continuing to address areas of unmet patient need and reducing barriers to patient access and affordability that prevent patients from benefiting from innovation. Novartis Patient Support is available to help guide eligible patients through the various aspects of getting started on treatment including help understanding insurance coverage and identifying potential financial assistance options. Patients or providers can call 866-433-8000 or visit support.scemblix.com to learn more.

On December 7, 2024 Beam Therapeutics Inc. (Nasdaq: BEAM), a biotechnology company developing precision genetic medicines through base editing, reported new safety and efficacy data from its BEACON Phase 1/2 clinical trial of BEAM-101 in patients with sickle cell disease (SCD) with severe vaso-occlusive crises (VOCs) (Press release, Beam Therapeutics, DEC 7, 2024, View Source [SID1234648891]). The data were featured today in the press program for the 66th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition in San Diego and will be presented in an oral session on Sunday, Dec. 8, 2024, at 10 a.m. PT.

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

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

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Consistent with Beam’s previously announced data, updated data from seven patients treated with investigational base-editing therapy BEAM-101 demonstrated robust and durable increases in fetal hemoglobin (HbF) and reductions in sickle hemoglobin (HbS), rapid neutrophil and platelet engraftment, and normalized or improved markers of hemolysis. No VOCs were reported post-engraftment. A summary of the results from the ongoing clinical study is provided below.

"These initial data from the BEACON trial are very encouraging and highlight the potential of BEAM-101 to deliver meaningful clinical benefits to patients with severe sickle cell disease," said Matthew M. Heeney, M.D., associate chief of hematology at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center. "The data from the first seven patients demonstrate the ability for BEAM-101 to dramatically modify the hemoglobin profile to express a majority of protective fetal hemoglobin. All patients mobilized efficiently and had rapid engraftment with a low number of neutropenic days. I look forward to the continued maturation of the data to provide further insights into the long-term benefits of BEAM-101 for people living with sickle cell disease."

"It’s an honor to share the initial results from BEACON with the hematology community at the ASH (Free ASH Whitepaper) Annual Meeting, where there is broad recognition of the significant burden that sickle cell disease places on patients and their families," said John Evans, chief executive officer of Beam. "We believe these early data for BEAM-101 are a testament to the potential of our base-editing technology to provide a differentiated option for sickle cell patients, having demonstrated a robust increase in fetal hemoglobin of >60%, a decrease in hemoglobin S to <40% and resolution of anemia in all patients. Additionally, the data from our ESCAPE nongenotoxic conditioning program – to be presented on Sunday – highlight our commitment to expanding access to treatment by decreasing the burden and complications patients potentially face when undergoing transplantation. We look forward to continuing to rapidly advance both programs for patients with sickle cell disease."

To date, more than 35 patients have cleared screening and enrolled in the BEACON Phase 1/2 clinical trial, and of these, 11 patients have been dosed with BEAM-101. As of an Oct. 28, 2024, data cut-off, a total of seven patients with severe SCD were treated with BEAM-101 and included in the safety and efficacy analysis with follow up ranging from 1 to 11 months.

Key highlights include the following:

•
Rapid and Sustained Increases in Protective Fetal Hemoglobin (HbF): All patients achieved endogenous HbF levels exceeding 60% and reduction in corresponding sickle hemoglobin (HbS) below 40% that was durable. A pancellular distribution of HbF was observed after the elimination of transfused blood.

•
Robust and Sustained Total Hemoglobin (Hb) Levels: Total hemoglobin levels increased rapidly with resolution of anemia in patients after elimination of the transfused blood.

•
Efficient Cell Collection and Rapid Engraftment: All patients achieved the minimum target cell dose in either 1 or 2 cycles of mobilization (average: 1.4). The mean time to neutrophil engraftment was 17.1 days (range: 15–21), with a low mean duration of neutropenia (6.3 days). The mean time to platelet engraftment was 19.1 days (range: 11–34).

•
Normalization of Hemolysis Markers: Key markers of hemolysis, including indirect bilirubin, haptoglobin, lactate dehydrogenase and reticulocytes, normalized or improved in all patients following BEAM-101 treatment.

•
Safety Profile Consistent with Busulfan and Autologous Hematopoietic Stem Cell Transplantation (HSCT): The safety profile of BEAM-101 was consistent with busulfan conditioning and autologous HSCT. The most common treatment-emergent adverse events (TEAEs) were consistent with busulfan conditioning, including febrile neutropenia, stomatitis and anemia. One patient died four months after BEAM-101 infusion due to respiratory failure that was determined by the investigator to be likely related to busulfan conditioning and deemed unrelated to BEAM-101. No VOCs were reported post-engraftment.

ASH Investor Event Information

Beam will host a live and webcast investor event on Dec. 8, 2024, at 8:00 p.m. PT in San Diego to review the key presentations from this year’s ASH (Free ASH Whitepaper) meeting. The event will be webcast live and can be accessed under "Events & Presentations" in the Investors section of the company’s website at www.beamtx.com. The archived webcast will be available on the company’s website beginning approximately two hours after the event.

About BEAM-101

BEAM-101 is an investigational genetically modified cell therapy for the treatment of severe sickle cell disease (SCD). The one-time therapy consists of autologous CD34+ hematopoietic stem and progenitor cells (HSPCs) that have been base-edited in the promotor regions of the HBG1/2 genes and are administered via a hematopoietic stem cell transplant procedure. The BEAM-101 edit is designed to inhibit the transcriptional repressor BCL11A from binding to the promoter without disrupting BCL11A expression, leading to increased production of non-sickling and anti-sickling fetal hemoglobin (HbF) and thus mimicking the effects of naturally occurring variants seen in hereditary persistence of fetal hemoglobin. HbF is the predominant hemoglobin variant during development and early life. The safety and efficacy of BEAM-101 is being evaluated in the ongoing BEACON Phase 1/2 study, an open-label, single-arm, multicenter trial in adult patients with SCD with severe vaso-occlusive crises (VOCs).