On December 6, 2020 The Janssen Pharmaceutical Companies of Johnson & Johnson reported results from pooled analyses of long-term follow-up from multiple clinical trials evaluating the use of IMBRUVICA (ibrutinib) monotherapy and in combination as first-line treatment for patients with chronic lymphocytic leukaemia (CLL) with high-risk features (Press release, Janssen Pharmaceuticals, DEC 6, 2020, View Source [SID1234572253]). The data were presented at the 2020 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting. Results from an integrated analysis of two clinical trials with up to 79 months of follow-up (Abstract #2220)1 demonstrated similar progression-free survival (PFS) and overall response rates (ORR) with ibrutinib in patients with or without high-risk genomic features, and further showed significant PFS and ORR benefits with ibrutinib compared with chlorambucil-based therapy regardless of genomic risk features.1

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In addition, data with a median follow-up of more than four years were presented from a pooled analysis of 89 patients with high-risk CLL bearing TP53 aberrations from four clinical trials showing that first-line treatment with ibrutinib resulted in sustained efficacy, including PFS, suggesting that ibrutinib has meaningfully improved the poor prognosis in this high-risk population (Abstract #2219).2

"These large integrated data sets with follow-up up to six years, in addition to other data presented at the meeting in similar populations, contribute to the accumulating evidence supporting the clinically meaningful, long-term treatment benefit of ibrutinib as first-line therapy for patients with CLL," said Craig Tendler, M.D., Vice President, Late Development and Global Medical Affairs, Oncology, Janssen Research & Development, LLC. "Ibrutinib is an approved standard of care in first-line treatment of CLL, and the data presented at the ASH (Free ASH Whitepaper) Annual Meeting further demonstrate the durability of responses in CLL patients with traditional high-risk features."

Two additional studies will be presented in the oral sessions showing real-world treatment patterns or outcomes in patients with CLL treated outside of a clinical trial setting. The first study is a U.S. retrospective analysis describing treatment patterns and time to next treatment (TTNT) in patients with high-risk CLL treated with first-line ibrutinib or chemoimmunotherapy (CIT) (Abstract #372).3 In this U.S. retrospective study, the largest of its kind to date, patients with high-risk CLL treated with single-agent ibrutinib had significantly longer TTNT compared with patients treated with first-line CIT.3 In the second oral presentation, results from the U.S. informCLL registry (Abstract #547) highlighted infrequent prognostic biomarker testing rates prior to initiating CLL therapy, and limited use of such information to guide optimal treatment selection for many patients with high-risk CLL, suggesting an opportunity for additional education of healthcare providers.4

Integrated Analysis of the Phase 3 RESONATE-2 and iLLUMINATE Trials Evaluated Outcomes of First-Line Ibrutinib in Patients with CLL and High-Risk Genomic Features with up to 6.5 Years Follow-up (Abstract #2220)1
Data were presented from a pooled analysis of two Phase 3 studies (RESONATE-2 and iLLUMINATE) with up to 79 months of follow-up evaluating ibrutinib-based therapy in first-line treatment of CLL patients with various high-risk genomic features.1

Key Study Findings:

In patients treated with ibrutinib-based therapy, PFS was comparable between patients with, versus without, specified high-risk genomic features, including del(17p)/TP53 mutated/BIRC3 mutated, the highest risk category.1
At 42 months, PFS rates were significantly higher across all high-risk genomic subgroups in previously untreated patients treated with ibrutinib-based treatment (63 to 82 percent) compared with those receiving chlorambucil-based treatment (6 to 34 percent) with or without obinutuzumab, regardless of mutation.1
At a median duration of ibrutinib treatment of 35.7-43.8 months across high-risk subgroups, there were no meaningful differences in the rates of treatment-emergent adverse events (AEs) of any Grade, or Grade 3 or greater AEs compared to those of the overall population.1
"Certain genomic abnormalities and mutations are predictors of inferior outcomes with chemoimmunotherapy in patients with CLL," said Jan A. Burger,* M.D., Ph.D., Professor, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, and principal study investigator. "Chemoimmunotherapy remains common in real-world practice despite evidence that shows small molecule inhibitor therapies like ibrutinib have demonstrated improved outcomes in high-risk patients compared to chemoimmunotherapy."

"Since its first European approval in 2014, ibrutinib has redefined treatment paradigms for CLL, and these study results offer further evidence of the benefits and tolerability ibrutinib offers to CLL patients," adds Dr Catherine Taylor, Vice President, Medical Affairs Therapeutic Area Strategy, Europe, Middle East and Africa (EMEA), Janssen-Cilag Ltd., Middle East. "For high-risk CLL patients, the treatment landscape has advanced dramatically, with ibrutinib continuing to play a major role in defining what it means to live with genetic variations of this disease, which have historically poor outcomes."

Large, Pooled, Multi-Study Dataset Assessed Long-Term Benefit of First-Line Ibrutinib-Based Treatment in Patients with TP53 Aberrations with up to Four Years Follow-up (Abstract #2219)2
Data were presented from a pooled analysis of four clinical studies evaluating the long-term efficacy and safety of first-line ibrutinib-based therapy in CLL patients with TP53 aberrations present.2 The four studies were: RESONATE2; iLLUMINATE; the E1912 study designed and conducted by the ECOG-ACRIN Cancer Research Group (ECOG-ACRIN) and sponsored by the National Cancer Institute (NCI), part of the National Institutes of Health (NIH); and the 1122e study sponsored by the National Heart, Lung, and Blood Institute (NHLBI).2

Key Study Findings:

With a median follow-up of 50 months, median PFS was not reached (95% CI: 67 months to not estimable).2 At 48 months, the PFS rate was 79 percent and the OS rate was 88 percent among high-risk patients treated with ibrutinib monotherapy.2
Additionally, 46 percent of patients with TP53 aberrations remained on ibrutinib treatment and 39 percent had a complete response.2
No new safety signals were identified in this analysis and in general the rates of Grade ≥3 AEs of clinical interest declined after the first year of ibrutinib treatment.2
Clinical Outcomes Among Real-World Patients with CLL Initiating First-Line Ibrutinib or Chemoimmunotherapy Stratified by Risk Status: Results From a U.S. Retrospective Chart Review Study (Abstract #372)3
Data were presented as an oral presentation from a large real-world study comparing clinical outcomes (TTNT) in high-risk and non-high-risk patients with CLL receiving ibrutinib compared to CIT in the first-line setting.3

Key Study Findings:

Data presented showed that high-risk patients receiving ibrutinib significantly prolonged TTNT compared to those receiving CIT.3
Ibrutinib also provided sustained clinical benefit regardless of risk status, which is consistent with clinical trial results.5,6,7
This study highlighted the need for cytogenetic/molecular testing before CIT treatment, consistent with clinical treatment guidelines.8,9
Real-World Prognostic Biomarker Testing, Treatment Patterns, And Dosing Among Patients With CLL From the informCLL Prospective Observational Registry (Abstract #547)
An oral presentation on Monday, December 7, will feature results from the informCLL real-world prospective observational registry assessing treatment patterns in the era of novel agents.4

Key Study Findings:

The most common index treatment was ibrutinib; the majority of patients treated with ibrutinib remained on therapy at two-year follow-up; and CIT was also used for one-third of patients.4
Data also demonstrated that prognostic biomarker testing rates were poor, especially for the biomarkers TP53 and IGHV.4
Data from informCLL also indicate a ‘knowledge gap’ in terms of prognostic marker testing, interpretation and selection of optimal therapies for patients with high-risk disease.4
*Jan A. Burger is a principal study investigator and was not compensated for any media work

#ENDS#

About Ibrutinib
Ibrutinib is a once-daily, first-in-class Bruton’s tyrosine kinase (BTK) inhibitor that is administered orally, and is jointly developed and commercialised by Janssen Biotech, Inc. and Pharmacyclics LLC, an AbbVie company.10 Ibrutinib blocks the BTK protein; the BTK protein sends important signals that tell B cells to mature and produce antibodies. BTK signalling is needed by specific cancer cells to multiply and spread.11 By blocking BTK, ibrutinib may help move abnormal B cells out of their nourishing environments in the lymph nodes, bone marrow, and other organs.12

Indications for which ibrutinib is approved in Europe include:10

Chronic lymphocytic leukaemia (CLL): As a single agent or in combination with rituximab or obinutuzumab for the treatment of adult patients with previously untreated CLL, and as a single agent or in combination with bendamustine and rituximab (BR) for the treatment of adult patients with CLL who have received at least one prior therapy
Mantle cell lymphoma (MCL): As a single agent for the treatment of adult patients with relapsed or refractory MCL
Waldenström’s macroglobulinemia (WM): As a single agent for the treatment of adult patients who have received at least one prior therapy or in first-line treatment for patients unsuitable for chemo-immunotherapy, and in combination with rituximab for the treatment of adult patients
Ibrutinib is approved in more than 100 countries for at least one indication, and to date, has been used to treat more than 200,000 patients worldwide.13

For a full list of side effects and information on dosage and administration, contraindications and other precautions when using ibrutinib please refer to the Summary of Product Characteristics for further information.

About Chronic Lymphocytic Leukaemia
Chronic lymphocytic leukaemia (CLL) is typically a slow-growing blood cancer of the white blood cells.14 The overall incidence of CLL in Europe is approximately 4.92 cases per 100,000 persons per year and is about 1.5 times more common in men than in women.15 CLL is predominantly a disease of the elderly, with a median age of 72 years at diagnosis.16

The disease eventually progresses in the majority of patients, and they are faced with fewer treatment options with each relapse. Patients are often prescribed multiple lines of therapy as they relapse or become resistant to treatments.

On December 6, 2020 IMV Inc. (Nasdaq:IMV; TSX:IMV) ("IMV" or the "Company"), a clinical-stage biopharmaceutical company pioneering a novel class of cancer immunotherapies and vaccines against infectious diseases, today announces that durable clinical benefits induced by combination treatment of IMV’s T cell therapy with Merck’s Keytruda (pembrolizumab) in subjects with PD-L1 positive recurrent/refractory Diffuse Large B Cell Lymphoma (r/r DLBCL) have been presented at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (Press release, IMV, DEC 6, 2020, View Source [SID1234572252]).

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"Compared to currently approved therapies, this combination has demonstrated a promising duration of response with limited adverse events in this difficult-to-treat patient population," said Dr. Neil Berinstein, principal investigator of the SPiReL study and hematologist at Sunnybrook Health Sciences Center. "The improved clinical response in this subset of patients with PD-L1 expression is an exciting scientific finding. The baseline PD-L1 expression is a potential predictor of response to this treatment combination which may not be attributed to the activity of pembrolizumab alone1 and is more likely caused by the complementary mechanisms of action of these two immunotherapies."

"These are exciting early data and the potential synergistic action of these two immunotherapies paves the way for a new treatment paradigm with combination therapeutics," said Dr. Joanne Schindler, Chief Medical Officer at IMV. "We are also evaluating this combination therapy with Merck in other solid tumor indications and we look forward to exploring further the potential of what we have seen in the SPiReL study."

In his presentation during the annual ASH (Free ASH Whitepaper) meeting, Dr. Neil Berinstein describes the results from the SPiReL study:

In the PD-L1+ population (n=7), subjects
Have significantly higher median Progression Free Survival (PFS) of 230 days, compared to the PD-L1 negative subjects (70 days) with a p-value of 0.007, suggestive of a strong predictive biomarker for this treatment combination,
Demonstrated an objective response in six subjects, including three subjects who have completed one-year of study treatment,
Demonstrated an ORR and a DCR at both 85.7%.
Peripheral blood was assessed for survivin-specific ELISpot responses in 15 subjects with available samples. All 3 subjects with a CR, and 3 of 4 subjects with a PR had positive ELISpot responses while only 1 subject with SD and 1 subject with PD demonstrated survivin-specific ELISpot response, suggestive of an association between the clinical responses with the mechanism of action of DPX-Survivac.
Treatment was well tolerated. The majority of treatment-related adverse events were grade 1 and 2 severity. A majority of these were injection site reactions associated with the subcutaneous administration of DPX-Survivac.
The poster presentation by Dr. Berinstein is available under the Scientific Publications & Posters section on IMV’s website and is also available on the ASH (Free ASH Whitepaper) meeting platform.

Biomarkers associated with clinical response were also discussed in a poster presentation at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 35th Anniversary Annual Meeting, and during a webcast hosted by IMV on November 12, 2020.

About DPX-Survivac

DPX-Survivac is the lead candidate in IMV’s new class of immunotherapy that generates targeted and sustained cancer cell killing capabilities in vivo. Treatments with the DPX-Survivac T cell therapy have demonstrated a favorable safety profile across all clinical studies.

IMV’s T cell therapy, DPX-Survivac, consists of survivin-based peptides formulated in IMV’s proprietary delivery platform (DPX). IMV’s lead compound is designed to generate a sustained cytotoxic T cell response against cancer cells presenting survivin peptides on their surface.

Survivin, recognized by the National Cancer Institute (NCI) as a promising tumor-associated antigen, is broadly over-expressed in most cancer types, and plays an essential role in antagonizing cell death, supporting tumor-associated angiogenesis, and promoting resistance to chemotherapies. IMV has identified over 20 cancer indications in which survivin can be targeted by DPX-Survivac.

DPX-Survivac has received Fast Track designation from the U.S. Food and Drug Administration (FDA) as maintenance therapy in advanced ovarian cancer, as well as Orphan Drug designation status from the U.S. FDA and the European Medicines Agency (EMA) in the ovarian cancer indication.

About the SPiReL Study

"SPiReL" is a Phase 2 non-randomized, open label, efficacy, and safety study of a novel immunotherapy combination with DPX-Survivac and pembrolizumab. Intermittent low dose cyclophosphamide is given as an immune modulator. Subjects with r/r incurable DLBCL and survivin expression are eligible for participation. The primary outcome is to document the objective response rate using modified Cheson criteria for the combination treatment. Secondary objectives include safety, duration of response and time to next treatment. Exploratory endpoints include T cell response, tumor immune cell infiltration, and biomarker analysis. To date, 24 subjects have been enrolled.

On December 6, 2020 Gilead Sciences, Inc. (Nasdaq: GILD) reported updated results from the magrolimab Phase 1b trial. Magrolimab is an investigational, potential first-in-class, anti-CD47 monoclonal antibody being studied in previously untreated acute myeloid leukemia (AML) patients who are ineligible for intensive chemotherapy, including patients with TP53-mutant AML (Press release, Gilead Sciences, DEC 6, 2020, View Source [SID1234572238]). The study continues to demonstrate high response rates with magrolimab in combination with azacitidine, with an overall response rate of 63% (n=27/43) among the total patient population and 69% (n=20/29) in TP53-mutant patients. The data were presented at the 62nd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition (Abstract #330).

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"In this ongoing study, treatment with magrolimab and azacitidine continues to achieve promising, durable responses in patients with AML who are ineligible for first-line chemotherapy," said David Sallman, MD, H. Lee Moffitt Cancer Center and Research Institute, an investigator for the clinical trial. "These findings are especially encouraging for patients with TP53 mutations, which are associated with poor outcomes and limited response to existing treatment options."

In the study, 64 patients were treated with magrolimab plus azacitidine, including 47 patients with the TP53 mutation, a treatment-refractory and poor-prognosis population. As of November 2020, 63% (n=27/43) of patients evaluable for efficacy achieved an objective response per European LeukemiaNet 2017 criteria, 42% (n=18/43) achieved a complete remission (CR), and 12% (n=5/43) achieved a CR with an incomplete count recovery (CRi). The median duration of response (DOR) was 9.6 months (range: 0.03+ to 18.7 months) and the median time to response was 1.95 months (range: 0.95 to 5.6 months).

For patients with the TP53 mutation, 69% (n=20/29) achieved a response, 45% (n=13/29) achieved a CR and 14% (n=4/29) achieved a CRi. The median DOR was 7.6 months (range: 0.03+ to 15.1+ months) and the minimum residual disease (MRD) negativity in patients with a CR/CRi was 29% (n=5/17).

Preliminary median overall survival (OS) for TP53-wild-type patients (n=16) was 18.9 months (95% CI: 4.34, NE) and for TP53-mutant patients (n=47) was 12.9 months (95% CI: 8.21, 17.28). The median follow-up for TP53-wild-type and TP53-mutant patients was 12.5 months and 4.7 months, respectively. Additional patients and longer follow-up in a comparative trial are needed to further characterize the survival benefit.

Treatment-related adverse events observed with over 15% incidence included anemia, fatigue, blood bilirubin increased, infusion related reaction, neutropenia, thrombocytopenia and ALT increase. Most patients were cytopenic at baseline, and no significant increased cytopenias, infections or immune-related adverse events (AEs) were observed in the study. Thirty-day all-cause mortality was 4.7% (n=3/64), and 60-day mortality was 7.8% (n=5/64). Treatment discontinuation due to drug-related AE occurred in 4.7% of all patients.

"We continue to be encouraged by the response rates seen in this study and are rapidly advancing the development of magrolimab based on its potential to help address significant unmet medical needs," said Daejin Abidoye, Senior Vice President, Head of Oncology, Gilead Sciences.

Magrolimab is investigational and not approved anywhere globally. Its efficacy and safety have not been established.

About Acute Myeloid Leukemia (AML)

AML is a type of cancer that starts in the bone marrow and can quickly move to the blood and other parts of the body. including the lymph nodes, spleen and central nervous system. AML most often develops from cells that would turn into red blood cells, neutrophils, and platelets but can also evolve from other blood disorders such as myelodysplastic syndromes. Approximately 20,000 Americans will be diagnosed with AML each year.

About the Study

The Phase 1b trial, funded in part by the California Institute of Regenerative Medicine (CIRM), is designed to evaluate the safety, tolerability and efficacy of magrolimab combined with azacitidine in untreated patients with AML who are ineligible for induction chemotherapy. All patients in the trial received a magrolimab 1 mg/kg priming dose, coupled with intrapatient dose escalation, to mitigate on-target anemia. Patients were then treated with full doses of azacitidine and a magrolimab maintenance dose of 30 mg/kg once weekly or every two weeks. Based on pharmacokinetics and CD47 receptor occupancy data in the bone marrow from the ongoing trial, dosing every two weeks has been selected to optimize patient convenience.

About Magrolimab

Magrolimab is a potential, first-in-class investigational monoclonal antibody against CD47 and a macrophage checkpoint inhibitor that is designed to interfere with recognition of CD47 by the SIRPα receptor on macrophages, thus blocking the "don’t eat me" signal used by cancer cells to avoid being ingested by macrophages. Magrolimab is being developed in several hematologic cancers, including myelodysplastic syndrome (MDS), as well as solid tumor malignancies.

The U.S. Food and Drug Administration (FDA) recently assigned Breakthrough Designation to magrolimab, in combination with azacitidine, for the treatment of adult patients with newly-diagnosed MDS including intermediate-, high-, or very high-risk tumor types. Magrolimab also received PRIME Designation for treatment of MDS from the European Medicines Agency (EMA). In addition, magrolimab received Fast Track Designation by the FDA for the treatment of MDS, AML, diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma; and has been granted Orphan Drug Designation by the FDA and EMA for MDS and AML.

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.