On December 6, 2020 BeiGene, Ltd. (NASDAQ: BGNE; HKEX: 06160), a commercial-stage biotechnology company focused on developing and commercializing innovative medicines worldwide, reported clinical data on its BTK inhibitor BRUKINSA (zanubrutinib) at the 62nd American Society for Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (Press release, BeiGene, DEC 6, 2020, View Source [SID1234572237]). These data included an oral presentation on the initial results of the Phase 2 MAGNOLIA trial in patients with relapsed/refractory (R/R) marginal zone lymphoma (MZL) and a poster with follow-up results from Arm C of the Phase 3 SEQUOIA trial in treatment-naïve (TN) patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) with del(17p).

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"BRUKINSA received accelerated approval from the U.S. FDA last year for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy, and we’ve since provided additional clinical data on its efficacy and safety across multiple B-cell malignancies. Initial results from the MAGNOLIA trial showed a high response rate, including complete responses, in patients with relapsed/refractory MZL. Activity was seen in patients with high-risk factors, supporting BRUKINSA’s robust clinical activity and tolerability," said Jane Huang, M.D., Chief Medical Officer, Hematology at BeiGene. "Additionally, the extended follow-up time in Arm C of the SEQUOIA trial allowed us to further evaluate longer-term responses in previously untreated patients with CLL/SLL with del(17p), and we were excited to observe more complete responses and an adverse event profile consistent with the initial results presented at last year’s ASH (Free ASH Whitepaper) meeting. The encouraging data presented today support our ongoing global regulatory plans for BRUKINSA as a potentially best-in-class BTK inhibitor."

For more information on BeiGene’s clinical program and company updates, please visit BeiGene’s virtual booth at this year’s ASH (Free ASH Whitepaper) Annual Meeting at View Source

Initial Results of the Phase 2 MAGNOLIA Trial in R/R MZL

Oral Presentation; Abstract 339

Initial results from the single-arm, open-label, multicenter, Phase 2 MAGNOLIA trial (NCT03846427) demonstrated that BRUKINSA was highly active and generally well-tolerated in patients with R/R MZL. A total of 68 patients with extranodal, splenic, or nodal subtypes who received at least one prior line of CD20-directed regimen were enrolled in the trial, with identified high-risk features including an elderly population with a median age of 70 years, heavily pre-treated population with a median of two prior lines of therapy, more than 30 percent with refractory disease, and nearly 40 percent with nodal MZL.

"As demonstrated by an ORR of 74.2 percent and a clinical benefit rate of nearly 90 percent in the initial results of the MAGNOLIA trial, zanubrutinib’s strong anti-tumor activity could potentially benefit patients with R/R MZL, a disease with limited tolerable and effective therapeutic strategies," commented Stephen Opat, FRACP, FRCPA, MBBS, Director of Clinical Hematology at Monash Health and Head of Department of Hematology at Monash University. "We were particularly excited to see that responses were generally consistent among patients with high-risk features and that zanubrutinib was generally well-tolerated."

At the data cutoff on August 14, 2020, 66 patients were evaluable for efficacy. With a median follow-up time of 10.7 months, results included:

Across all subtypes in the trial, the investigator-assessed overall response rate (ORR), defined as partial response or better, was 74.2% (95% CI: 62.0, 84.2), including 16 (24.2%) complete responses (CRs) and 33 (50.0%) partial responses (PRs);
Responses were generally consistent across all subgroups, including the following high-risk subgroups:
In patients who were 75 and older (n=18), the ORR was 88.9% (95% CI: 65.3, 98.6);
In patients who received at least three lines of prior therapy (n=17), the ORR was 64.7% (95% CI: 38.3, 85.8);
In patients with refractory disease (n=21), the ORR was 71.0% (95% CI: 47.8, 88.7);
In patients with nodal MZL (n=25), the ORR was 84.0% (95% CI: 63.9, 95.5);
The median follow-up time for progression free survival (PFS) was 9.13 months, and the PFS rate at six months and nine months was 80.0% and 67.0%, respectively;
79.0% of the patients maintained response at six months and overall survival (OS) rate at 12 months was 94.0%
95.6% of patients experienced at least one treatment-emergent adverse event (TEAE) of any grade, with the most common (≥10.0%) being diarrhea (20.6%), contusion (19.1%), constipation (13.2%), neutropenia (13.2%), pyrexia (11.8%), upper respiratory tract infection (11.8%), thrombocytopenia (10.3%), and nausea (10.3%);
38.2% of patients experienced at least one Grade ≥3 TEAE, with the most common (in at least two patients) being neutropenia (10.3%), diarrhea (2.9%), pyrexia (2.9%), thrombocytopenia (2.9%), anemia (2.9%), and pneumonia (2.9%);
32.4% of patients experienced at least one serious TEAE; and
Two patients discontinued treatment due to TEAEs, both considered unrelated to zanubrutinib, including one patient with pre-existing cardiovascular disease who experienced a fatal TEAE of myocardial infarction.
Follow-up Results from Arm C of the Phase 3 SEQUOIA Trial in TN Patients with CLL/SLL with del(17p)

Abstract 1306

Follow-up results from the non-randomized Arm C in the randomized, open-label, global Phase 3 SEQUOIA trial of zanubrutinib as a monotherapy (NCT03336333) exhibited a high ORR and a sustained PFS in patients with TN CLL/SLL whose tumor exhibited the deletion of chromosome 17p13.1 [del(17p)]. Compared to the initial results presented at the 2019 ASH (Free ASH Whitepaper) meeting, with a longer median follow-up time of 21.9 months compared to 10 months, CR rate increased to 6.4% from 1.9%. Zanubrutinib’s tolerability profile was generally consistent with previous reports of zanubrutinib treatment in patients with various B-cell malignancies.

"BTK inhibitors have demonstrated positive outcomes in CLL or SLL patients with del(17p), who usually respond poorly to standard chemoimmunotherapy, even in the frontline setting," said Jennifer R. Brown, M.D., Ph.D., Director of the Dana Farber Cancer Institute CLL Center and Professor of Medicine at Harvard Medical School. "With a median follow-up time of close to two years, we were able to observe a high progression-free survival rate of 90.6 percent at 18 months, an overall response rate of 94.5 percent, and a consistent tolerability profile for zanubrutinib."

At the data cutoff on August 10, 2020, all 109 patients enrolled in Arm C were evaluable for efficacy. With a median follow-up time of 21.9 months, results included:

At 18 months, the PFS rate and OS rate were 90.6% (95% CI: 83.3, 94.9) and 95.4% (95% CI: 89.3, 98.1), respectively;
At 18 months, the PFS rate among patients with unfavorable characteristics such as unmutated IGHV and complex karyotype status was 88.0% (95% CI: 78, 94) and 94.0% (95% CI: 77, 98), respectively;
The investigator-assessed ORR was 94.5% (95% CI: 88.4, 98.0), including six (5.5%) CRs, one (0.9%) CR with incomplete bone marrow recovery, one (0.9%) nodular PR, 94 (86.2%) PRs, and one (0.9%) PR with lymphocytosis;
93.1% (95% CI: 86, 97) and 87.7% (95% CI: 78, 93) of the patients maintained response at 12 months and 18 months, respectively;
The most common (≥10.0%) adverse events (AEs) of any grade included contusion (20.2%), upper respiratory tract infection (19.3%), diarrhea (17.4%), nausea (14.7%), back pain (13.8%), constipation (13.8%), rash (13.8%), cough (12.8%), neutropenia (11.9%), arthralgia (11.0%), and pneumonia (10.1%);
52.3% of patients experienced at least one Grade ≥3 AE, with the most common (in ≥2.0% of patients) being neutropenia/decreased neutrophil count (15.6%), pneumonia (4.6%), fall (2.8%), and hypertension (2.8%);
38.5% of the patients experienced at least one serious AE; and
Five (4.6%) patients discontinued treatment due to AE, including two (1.8%) patients who experienced a fatal AE, one being pneumonia leading to sepsis and death, which was considered related to zanubrutinib, and the other being renal failure in the context of disease progression, which was considered unrelated to zanubrutinib.
About BRUKINSA (zanubrutinib)

BRUKINSA (zanubrutinib) is a small molecule inhibitor of Bruton’s tyrosine kinase (BTK), discovered by BeiGene scientists, that is currently being evaluated globally in a broad pivotal clinical program as a monotherapy and in combination with other therapies to treat various B-cell malignancies.

BRUKINSA was approved by the U.S. FDA in November 2019 to treat adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. This indication was approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

BRUKINSA was approved in China in June 2020 for the treatment of MCL in adult patients who have received at least one prior therapy and the treatment of CLL/SLL in adult patients who have received at least one prior therapy. A supplemental new drug application (sNDA) of BRUKINSA in patients with relapsed/refractory Waldenström’s macroglobulinemia (WM) has been accepted by the Center for Drug Evaluation (CDE) of the NMPA and is currently under priority review.

A marketing authorization application (MAA) for BRUKINSA for the treatment of patients with WM who have received at least one prior therapy or as first-line treatment for patients unsuitable for chemo-immunotherapy has been accepted by the European Medicines Agency (EMA).

In addition, multiple regulatory filings of BRUKINSA have been accepted in other countries and are currently under review.

BRUKINSA is not approved outside of the United States and China.

IMPORTANT U.S. SAFETY INFORMATION FOR BRUKINSA (ZANUBRUTINIB)

Warnings and Precautions

Hemorrhage

Fatal and serious hemorrhagic events have occurred in patients with hematological malignancies treated with BRUKINSA monotherapy. Grade 3 or higher bleeding events including intracranial and gastrointestinal hemorrhage, hematuria and hemothorax have been reported in 2% of patients treated with BRUKINSA monotherapy. Bleeding events of any grade, including purpura and petechiae, occurred in 50% of patients treated with BRUKINSA monotherapy.

Bleeding events have occurred in patients with and without concomitant antiplatelet or anticoagulation therapy. Co-administration of BRUKINSA with antiplatelet or anticoagulant medications may further increase the risk of hemorrhage.

Monitor for signs and symptoms of bleeding. Discontinue BRUKINSA if intracranial hemorrhage of any grade occurs. Consider the benefit-risk of withholding BRUKINSA for 3-7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.

Infections

Fatal and serious infections (including bacterial, viral, or fungal) and opportunistic infections have occurred in patients with hematological malignancies treated with BRUKINSA monotherapy. Grade 3 or higher infections occurred in 23% of patients treated with BRUKINSA monotherapy. The most common Grade 3 or higher infection was pneumonia. Infections due to hepatitis B virus (HBV) reactivation have occurred.

Consider prophylaxis for herpes simplex virus, pneumocystis jiroveci pneumonia and other infections according to standard of care in patients who are at increased risk for infections. Monitor and evaluate patients for fever or other signs and symptoms of infection and treat appropriately.

Cytopenias

Grade 3 or 4 cytopenias, including neutropenia (27%), thrombocytopenia (10%), and anemia (8%) based on laboratory measurements, were reported in patients treated with BRUKINSA monotherapy.

Monitor complete blood counts during treatment and treat using growth factor or transfusions, as needed.

Second Primary Malignancies

Second primary malignancies, including non-skin carcinoma, have occurred in 9% of patients treated with BRUKINSA monotherapy. The most frequent second primary malignancy was skin cancer (basal cell carcinoma and squamous cell carcinoma of skin), reported in 6% of patients. Advise patients to use sun protection.

Cardiac Arrhythmias

Atrial fibrillation and atrial flutter have occurred in 2% of patients treated with BRUKINSA monotherapy. Patients with cardiac risk factors, hypertension, and acute infections may be at increased risk. Grade 3 or higher events were reported in 0.6% of patients treated with BRUKINSA monotherapy. Monitor signs and symptoms for atrial fibrillation and atrial flutter and manage as appropriate.

Embryo-Fetal Toxicity

Based on findings in animals, BRUKINSA can cause fetal harm when administered to a pregnant woman. Administration of zanubrutinib to pregnant rats during the period of organogenesis caused embryo-fetal toxicity, including malformations at exposures that were 5 times higher than those reported in patients at the recommended dose of 160 mg twice daily. Advise women to avoid becoming pregnant while taking BRUKINSA and for at least 1 week after the last dose. Advise men to avoid fathering a child during treatment and for at least 1 week after the last dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

Adverse Reactions

The most common adverse reactions in > 10% of patients who received BRUKINSA were neutrophil count decreased (53%), platelet count decreased (39%), upper respiratory tract infection (38%), white blood cell count decreased (30%), hemoglobin decreased (29%), rash (25%), bruising (23%), diarrhea (20%), cough (20%), musculoskeletal pain (19%), pneumonia (18%), urinary tract infection (13%), hematuria (12%), fatigue (11%), constipation (11%), and hemorrhage (10%). The most frequent serious adverse reactions were pneumonia (11%) and hemorrhage (5%).

Of the 118 patients with MCL treated with BRUKINSA, 8 (7%) patients discontinued treatment due to adverse reactions in the trials. The most frequent adverse reaction leading to treatment discontinuation was pneumonia (3.4%). One (0.8%) patient experienced an adverse reaction leading to dose reduction (hepatitis B).

Drug Interactions

CYP3A Inhibitors: When BRUKINSA is co-administered with a strong CYP3A inhibitor, reduce BRUKINSA dose to 80 mg once daily. For co-administration with a moderate CYP3A inhibitor, reduce BRUKINSA dose to 80 mg twice daily.

CYP3A Inducers: Avoid co-administration with moderate or strong CYP3A inducers.

Specific Populations

Hepatic Impairment: The recommended dose of BRUKINSA for patients with severe hepatic impairment is 80 mg orally twice daily.

INDICATION

BRUKINSA is a kinase inhibitor indicated for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.

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

On December 6, 2020 Cardiff Oncology, Inc. (Nasdaq: CRDF), a clinical-stage biotechnology company developing drugs to treat cancers with the greatest medical need for new treatment options, including KRAS-mutated colorectal cancer, castration-resistant prostate cancer and leukemia, reported the presentation of updated data from its Phase 1b/2 study in relapsed/refractory acute myeloid leukemia (AML) (Press release, Cardiff Oncology, DEC 6, 2020, View Source [SID1234572236]). The data were presented as a virtual oral poster presentation at the 62nd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting.

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The presentation highlighted the safety, tolerability and anti-leukemic activity of onvansertib in combination with decitabine in patients with difficult-to-treat relapsed/refractory AML. Nine of 45 (20%) patients achieved a complete remission with or without hematologic count recovery (CR/CRi – 5 in Phase 1b and 4 in Phase 2); 55% of responders had a mutation in a splicing factor. Two patients proceeded to transplant following CR and four patients remain on treatment with duration of response of 9, 10, 17 and 20 months, respectively. Together with data demonstrating the safety and tolerability of the combination therapy, these findings highlight onvansertib’s potential to address critical unmet needs in hematologic malignancies.

"The data generated from this ongoing trial are encouraging, particularly considering the very poor prognosis of the relapsed/refractory AML patient population, in whom the median overall survival is generally only a few months," said Dr. Mark Erlander, chief executive officer of Cardiff Oncology. "We believe the over-representation of the splicing factor mutations in patients who achieved a complete response is worthy of further exploration as it may provide a means for identifying patients upfront who have the greatest likelihood of responding to treatment with onvansertib."

Key data and conclusions from the ASH (Free ASH Whitepaper) presentation include:

9 of 45 (20%) evaluated patients achieved CR/CRi (5 in Phase 1b and 4 in Phase 2)
55% of responders had a mutation in a splicing factor
As of the data cutoff, 2 patients proceeded to transplant following CR and 3 patients had ongoing responses
4 patients have achieved a durable response (≥9 months)
Decreases in mutant ctDNA within the first treatment cycle appear to be highly correlated with clinical response; 7 of 7 (100%) patients with CR/CRi showed a decrease in mutant ctDNA after one cycle of treatment, while only 2 of 15 (13%) non-responders showed a similar decrease
Data indicate that onvansertib in combination with decitabine is a safe and well-tolerated treatment regimen
The poster presentation from the 62nd Annual ASH (Free ASH Whitepaper) meeting is available on the "Scientific Presentations" section of the Cardiff Oncology website at View Source

About the Phase 1b/2 Trial of Onvansertib in Relapsed/Refractory AML

Cardiff Oncology’s ongoing Phase 1b/2 trial (NCT03303339) evaluating onvansertib in combination with decitabine in AML patients who are either treatment naïve and not candidates for induction therapy or who have relapsed or refractory disease after treatment with one prior regimen. Patients receive onvansertib, administered orally, on days 1 through 5 of each 21-28-day cycle in combination with decitabine. The primary efficacy endpoint of objective response (CR + CRi) is assessed in patients who complete at least 1 cycle of treatment.

On December 6, 2020 Oncopeptides AB (publ) (Nasdaq Stockholm: ONCO), a pharmaceutical company focused on the development of targeted therapies for difficult-to-treat hematological diseases reported updated efficacy and safety data from the ongoing phase 2 ANCHOR combination study, following an oral presentation at the 62nd American Society of Hematology (ASH) (Free ASH Whitepaper) virtual annual meeting (Press release, Oncopeptides, DEC 6, 2020, View Source [SID1234572230]). The data showed that a triplet regimen with melflufen (INN melphalan flufenamide) plus dexamethasone in combination with daratumumab or bortezomib in heavily pretreated patients with relapsed refractory multiple myeloma, demonstrated encouraging activity, was well tolerated and had a similar safety profile as when used as a doublet regimen with only melflufen plus dexamethasone. The severe treatment related adverse events reported were primarily hematologic and were clinically manageable with dose reduction.

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The primary objective of the phase 2 ANCHOR study is overall response rate, and a secondary objective is progression free survival. The data represents an analysis of both treatment arms, with a cut-off date of October 19, 2020. The overall response rate for melflufen plus dexamethasone was 73% in combination with daratumumab and 62% in combination with bortezomib. The median progression free survival was 12.9 months when combined with daratumumab. The recommended dose of melflufen for future studies with daratumumab shall be 30 mg. Since the bortezomib arm of ANCHOR still is recruiting, progression free survival has not been reported and the recommended phase 2 dose is yet to be determined. The recruitment is expected to be completed in 2021.

"The ANCHOR data are very promising: both combinations are well tolerated and demonstrated encouraging activity. The data support further development of melflufen in triplet regimens", says Klaas Bakker, MD, PhD, Chief Medical Officer, Oncopeptides AB. "This provides a clear rational for our larger randomized phase 3 LIGHTHOUSE study, which compares melflufen and dexamethasone with subcutaneous daratumumab vs. subcutaneous daratumumab alone. We are preparing study start in close dialogue with relevant authorities and expect to enroll the first patient during the first quarter of 2021".

ANCHOR is a phase 1/2 open label multicenter study evaluating the safety and efficacy of melflufen plus dexamethasone in combination with either daratumumab or bortezomib in patients with relapsed refractory multiple myeloma, who have undergone 1-4 prior lines of therapy. The patients are refractory to an immunomodulatory drug and/or a proteasome inhibitor. They have not received any prior anti-CD38 monoclonal antibody therapy.

The presentation is posted on our website. A link to the presentation can be found here.

For more information, please contact:

The information was submitted for publication on December 6, 2020 at 22:40 (CET).

About melflufen
Melflufen (INN melphalan flufenamide) is a first in class peptide-drug conjugate (PDC) that targets aminopeptidases and rapidly releases alkylating agents into tumor cells. Melflufen is rapidly taken up by myeloma cells due to its high lipophilicity and is immediately hydrolyzed by peptidases to release an entrapped hydrophilic alkylator payload. Aminopeptidases are overexpressed in tumor cells and are even more pronounced in advanced cancers and tumors with a high mutational burden. In vitro, melflufen is 50-fold more potent in myeloma cells than the alkylator payload itself due to the increased intracellular alkylator concentration. Melflufen displays cytotoxic activity against myeloma cell lines resistant to other treatments, including alkylators, and has also demonstrated inhibition of DNA repair induction and angiogenesis in preclinical studies. In the pivotal phase 2 HORIZON study melflufen plus dexamethasone demonstrated encouraging efficacy and a clinically manageable safety profile in heavily pretreated patients with relapsed refractory multiple myeloma, with primarily hematologic Adverse Events (AE) and a low incidence of non-hematologic AEs.

On December 6, 2020 AstraZeneca reported that Long-term follow-up results from the positive ACE-LY-004 Phase II trial showed patients with relapsed or refractory mantle cell lymphoma (MCL) treated with Calquence (acalabrutinib) remained progression free for a median of 22 months, with median overall survival not yet reached at three years of follow-up (Press release, AstraZeneca, DEC 6, 2020, View Source [SID1234572229]). The safety and tolerability profile remained consistent.1 These results were presented at the 62nd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition on 6 December 2020.

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MCL is typically an aggressive, rare form of non-Hodgkin lymphoma (NHL) that accounts for nearly 6% of all NHL cases and is mostly found in males during their early sixties.2,3

At a median follow up of 38.1 months (range: 0.3-59.5), 55 patients (44%) either remained on treatment (24 patients) or continued to be followed for survival (31 patients). The safety profile remained largely unchanged from the last analysis at 26 months, with only 14 patients (11%) having discontinued treatment due to adverse events (AE).1

Michael L. Wang, MD, Professor, Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, and principal investigator of the ACE-LY-004 Phase II trial, said: "Mantle cell lymphoma is an aggressive, difficult-to-treat blood cancer that is typically diagnosed at an advanced stage and often becomes resistant to treatment. This data shows that patients treated with acalabrutinib experienced deep responses over time, while the safety profile remained largely the same, including low rates of Grade 3/4 events, cardiac events and bleeding events, which are important in this patient population."

José Baselga, Executive Vice President, Oncology R&D, said: "These results add to the mounting evidence that Calquence can provide sustained responses in patients over more than three years. Calquence is an important chemo-free treatment option for relapsed or refractory mantle cell lymphoma and is rapidly being embraced across the clinical and patient community."

Summary of efficacy results1

Median follow up of 38.1 months (range: 0.3-59.5)

Efficacy measure

Result (N=124; 95% CI)

ORR (investigator-assessed PR or better per Lugano classification), %

81 (74, 88)

CR, %

48 (39, 57)

Median DOR, months

28.6 (17.5, 39.1)

Estimated DOR rate at 36 months, %

41.9 (31.7, 51.8)

Median PFS, months

22.0 (16.6, 33.3)

Estimated PFS rate at 36 months, %

37.2 (28.2, 46.1)

CI, confidence interval; ORR, overall response rate; PR, partial response; CR, complete response; DOR, duration of response; PFS, progression-free survival; DOR was measured in the 101 subjects who achieved a CR or PR

Figure. Progression-free survival1

graph
CR, complete response; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease

Additionally, an exploratory analysis of 30 patients meeting the criteria for minimal residual disease (MRD) evaluation showed six patients (20%) achieved a complete response and undetectable MRD (uMRD) and maintained uMRD at last assessment.1

AEs in the trial remained largely unchanged with an additional year of follow up. The most frequent AEs of any grade (greater than or equal to 20% of patients) included headache (39%), diarrhoea (37%), fatigue (30%), cough (23%), myalgia (22%) and nausea (22%), and were primarily Grade 1/2. Grade 3/4 AEs included neutropenia (11%), anaemia (10%) and pneumonia (6%).1

Overall, 16 patients (13%) had cardiac AEs (11 with prior cardiac risk factors), with three of the 16 cardiac AEs occurring in the last year of follow up (two were Grade 3/4). Overall, six patients (5%) had Grade 3/4 cardiac AEs. One patient had Grade 3/4 hypertension in the last year (total any grade, n=5 [4%]; total Grade 3/4, n=2 [2%]), and five patients had bleeding AEs in the last year (total any grade, n=46 [37%]). Three patients had Grade 3/4 infections in the last year.1

Initial results from the ACE-LY-004 Phase II trial were presented on 9 December 2017 at the 59th ASH (Free ASH Whitepaper) Annual Meeting and Exposition and served as the basis for the first FDA approval of Calquence in adult patients with MCL who have received at least one prior therapy.4 Calquence is approved for this indication in many other countries. The US MCL indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Mantle cell lymphoma
Mantle cell lymphoma (MCL) is an uncommon type of B-cell non-Hodgkin lymphoma.5 MCL comprises 3% to 6% of non-Hodgkin lymphomas, with an annual incidence of 0.5 per 100,000 population in Western countries; in the US, it was estimated that approximately 3,300 new cases of MCL were diagnosed in 2016.5,6 The median age at diagnosis is 68 years, with MCL occurring more often in men than women. While MCL patients initially respond to treatment, there is a high relapse rate.5

ACE-LY-004
ACE-LY-004 is an open-label, single-arm Phase II clinical trial evaluating Calquence in adult patients with relapsed or refractory MCL.7 Adults with MCL and ECOG PS ≤2 who had relapsed or were refractory to 1-5 prior therapies, had no prior BTK/BCL-2 inhibitor exposure, and did not require warfarin/vitamin K antagonists, received oral Calquence 100mg twice-daily until progressive disease or toxicity. Overall response rate (investigator-assessed partial response or better per Lugano classification), duration of response, progression-free survival, overall survival, and safety were assessed. Minimal residual disease was analysed in formalin-fixed, paraffin-embedded samples and peripheral blood by next-generation sequencing (5×10-6) in patients with available paired samples.1

Calquence
Calquence (acalabrutinib) is a next-generation, selective inhibitor of Bruton’s tyrosine kinase (BTK). Calquence binds covalently to BTK, thereby inhibiting its activity.4,8 In B-cells, BTK signalling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion.4

Calquence is approved for the treatment of chronic lymphocytic leukaemia (CLL) and small lymphocytic lymphoma in the US and is approved for CLL in the EU and several other countries worldwide. Calquence is also approved for the treatment of adult patients with MCL who have received at least one prior therapy in the US and several other countries. Calquence is not currently approved for the treatment of MCL in Europe.

As part of an extensive clinical development programme, AstraZeneca and Acerta Pharma are currently evaluating Calquence in more than 20 company-sponsored clinical trials. Calquence is being developed for the treatment of multiple B-cell blood cancers including CLL, MCL, diffuse large B-cell lymphoma, Waldenström’s macroglobulinaemia, follicular lymphoma, and other haematologic malignancies.

AstraZeneca in haematology
Leveraging its strength in oncology, AstraZeneca has established haematology as one of four key oncology disease areas of focus. The Company’s haematology franchise includes two medicines approved by the US Food and Drug Administration and a robust global development programme for a broad portfolio of potential blood cancer treatments. Acerta Pharma serves as AstraZeneca’s haematology research and development arm. AstraZeneca partners with like-minded science-led companies to advance the discovery and development of therapies to address unmet need.

AstraZeneca in oncology
AstraZeneca has a deep-rooted heritage in oncology and offers a quickly growing portfolio of new medicines that has the potential to transform patients’ lives and the Company’s future. With seven new medicines launched between 2014 and 2020, and a broad pipeline of small molecules and biologics in development, the Company is committed to advance oncology as a key growth driver for AstraZeneca focused on lung, ovarian, breast and blood cancers.

By harnessing the power of six scientific platforms – Immuno-Oncology, Tumour Drivers and Resistance, DNA Damage Response, Antibody Drug Conjugates, Epigenetics, and Cell Therapies – and by championing the development of personalised combinations, AstraZeneca has the vision to redefine cancer treatment and one day eliminate cancer as a cause of death.

On December 6, 2020 MacroGenics, Inc. (NASDAQ: MGNX), a clinical-stage biopharmaceutical company focused on discovering and developing innovative monoclonal antibody-based therapeutics for the treatment of cancer, reported updated results from a single-arm, registrational study of flotetuzumab, an investigational, bispecific CD123 × CD3 DART molecule, in patients with primary induction failure (PIF) and early relapsed (less than six months, or ER6) acute myeloid leukemia (AML) (Press release, MacroGenics, DEC 6, 2020, View Source [SID1234572227]). The data were presented at the 62nd Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) taking place December 5-8, 2020.

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In the open label study of flotetuzumab, 44 AML patients had disease classified as either PIF or ER6. Of these patients, 72.7% (32 of 44) had adverse risk cytogenetics by ELN Risk Stratification (2017). Patients were treated with flotetuzumab at the recommended Phase 2 dose (RP2D) of 500 ng/kg/day by continuous infusion. Data were reported as of the cut-off date of November 10, 2020. The study is currently ongoing, with a total of up to 200 patients planned for enrollment for registrational purposes.

The median time to achieve a response to flotetuzumab was one cycle (range of 1-3 cycles). Responses, including complete remission (CR), CRh (CR with partial hematological recovery) and CRi (CR with incomplete hematological improvement) per a modified International Working Group (IWG) Response Criteria for AML, are summarized in the table below.

PIF/ER (n=44) PIF (n=27) ER6 (n=17)
CR/CRh 25.0% (11) 33.3% (9) 11.8% (2)
CR/CRh/Cri 31.8% (14) 37.0% (10) 23.5% (4)
HSCT 57.1% (8/14) 70.0% (7/10) 25.0% (1/4)
Median Duration of Response 8.13 mos.
(n=14) 15.2 mos.
(n=10) 2.4 mos.
(n=4)
As shown in the table, over 50% of responders (8 of 14) successfully received allogeneic hematopoietic stem cell transplantation (HSCT) as consolidation therapy with durable remission (median not reached). Also, among those PIF/ER6 patients who achieved remission (CR, CRh or CRi), the median duration of response was 8.13 months, with a median overall survival of 10.7 months. Within the PIF/ER6 population, five of ten patients with TP53MUT AML achieved CR/CRh/CRi responses, three of whom went on to receive HSCT. More detailed flotetuzumab clinical data in the TP53MUT AML population is available via a separate poster presentation at ASH (Free ASH Whitepaper) (see "TP53 Abnormalities Correlate with Immune Infiltration and Associate with Response to Flotetuzumab Immunotherapy in Acute Myeloid Leukemia", Session 617).

The most common treatment-related adverse event (TRAE) was infusion-related reaction/cytokine release syndrome (IRR/CRS), which occurred in all patients. However, most CRS events observed were of short duration and mild to moderate (Grade 1 or 2) in severity, with only a single Grade 3 event reported.

"For the approximately 50% of AML patients who fail primary induction therapy or relapse within six months of an initial response, there is no standard of care among the available treatment regimens. Historically, these patients have CR/CRh rates to subsequent interventions in the range of only 5-12% with a median overall survival of approximately 3.5 months. A remission rate of 32% with good duration and a manageable safety profile observed to date in the ongoing registrational study of flotetuzumab in this extremely challenging patient population is very encouraging," said Ibrahim Aldoss, M.D., Assistant Professor of Hematology/HCT at City of Hope Comprehensive Cancer Center.

In addition to the above data provided in an oral presentation, five additional presentations related to flotetuzumab and AML have or will be presented at ASH (Free ASH Whitepaper).

"We are very encouraged by the updated results from this study, and continue to enroll patients in this single arm, registrational trial," said Scott Koenig, M.D., Ph.D., President and CEO of MacroGenics. "Especially encouraging is the duration of response we’ve seen to date in this otherwise fragile population of patients for whom no approved therapies exist."

About Acute Myeloid Leukemia

AML is a hematological malignancy characterized by differentiation arrest and uncontrolled clonal proliferation of neoplastic precursors that prevent normal bone marrow hematopoiesis. Nearly 20,000 new cases of AML are diagnosed in the U.S. each year, with a median age of 69 years at diagnosis. Approximately 40-50% of newly diagnosed patients fail to achieve a complete remission with intensive induction therapy (primary induction failure, or PIF) or experience disease recurrence after a short remission duration (<6 months; early relapsed, or ER6). A very small number of these patients are expected to respond to salvage therapy. Although new targeted agents have been approved for the treatment of frontline or relapsed/refractory AML in recent years, approximately 50% of patients have no known targetable mutations.

About Flotetuzumab

Flotetuzumab (previously known as MGD006) is a clinical-stage bispecific, investigational DART molecule that recognizes both CD123 and CD3. CD123, the interleukin-3 receptor alpha chain, has been reported to be over-expressed on malignant cells in AML and other hematologic malignancies. The primary mechanism of action of flotetuzumab is believed to be its ability to redirect T lymphocytes to kill CD123-expressing cells. To achieve this, the DART molecule combines a portion of an antibody recognizing CD3, an activating molecule expressed by T cells, with an arm that recognizes CD123 on the target cells. MacroGenics is conducting a single-arm, registration-enabling clinical study to evaluate flotetuzumab in up to 200 patients with PIF/ER AML, with complete remission (CR) and CR with partial hematological recovery (CRh) as the primary endpoint. The study will be conducted as a continuation of the ongoing Phase 1/2 study (NCT02152956). The FDA has granted orphan drug designation to flotetuzumab for the treatment of AML. MacroGenics retains global development and commercialization rights to flotetuzumab.