On May 29, 2020 EMD Serono, the biopharmaceutical business of Merck KGaA, Darmstadt, Germany in the US and Canada, reported that updated data from the ongoing, single-arm Phase II VISION study evaluating tepotinib* as a single agent in patients with advanced non-small cell lung cancer (NSCLC) with MET exon 14 (METex14) skipping alterations were published in The New England Journal of Medicine (NEJM) (Press release, EMD Serono, MAY 29, 2020, View Source [SID1234558711]). Results from the primary analysis of data from 99 patients with at least 9 months of follow-up demonstrate consistent response rate and durable anti-tumor activity across lines of treatment in patients assessed by both liquid biopsy (LBx) and tissue biopsy (TBx). Results from the VISION study were also presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) ASCO (Free ASCO Whitepaper)20 Virtual Scientific Program on May 29, including data from the primary analysis (Abstract #9556) and including patient-reported outcomes (PROs) of health-related quality of life (HRQoL) (Abstract #9575). Tepotinib is designed to be a highly selective1 oral MET inhibitor that is administered once daily and is designed to inhibit the oncogenic MET receptor signaling caused by MET (gene) alterations.

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"MET exon 14 skipping is a primary oncogenic driver, but until recently there have been no approved treatment options targeting this genetic alteration in NSCLC," said Paul K. Paik, M.D., primary study investigator, lead author and Clinical Director, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center. "These new findings highlight the importance of routine next-generation sequencing to identify METex14 skipping alterations and demonstrate tepotinib’s durable anti-tumor activity in patients who are typically elderly, and whose cancers are often harder to treat."

This new analysis of data from 99 patients in the fully enrolled Cohort A with at least 9 months of follow-up was published by The New England Journal of Medicine on May 29. Results demonstrate objective response rate (ORR) of 46% (95% CI, 36–57) among patients with METex14 skipping alterations identified by either LBx or TBx as assessed by Independent Review Committee (IRC), and 56% (95% CI, 45–66) as assessed by investigators. The median duration of response (DOR) was 11.1 months (95% CI, 7.2–could not be estimated (NE)) among patients with METex14 skipping alterations identified by either LBx or TBx as assessed by IRC, and 14.0 months (95% CI, 9.7–18.3) as assessed by investigators. Results were consistent across different lines of treatment and in patients assessed by LBx or TBx. Additional endpoints were progression-free survival (PFS) and overall survival (OS).

Patients with brain metastases at baseline (n=11) benefitted similarly from treatment. In these patients, systemic ORR as assessed by independent review was 55% (95% CI, 23–83), with a median DOR of 9.5 months (95% CI, 6.6–NE) and a median PFS of 10.9 months (95% CI, 8.0–NE).

Results also include the first patient-reported quality-of-life outcomes in patients with NSCLC with METex14 skipping alterations. Quality of life was maintained over time of treatment with tepotinib, with symptoms of dyspnea remaining stable and cough symptoms improving. The first longitudinal on-treatment biomarker data from LBx samples were also reported, showing high concordance between molecular circulating free DNA response (defined as METex14 depletion) and clinical response based on measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST).

Out of 152 patients evaluable for safety, treatment-related adverse events (TRAEs) of all grades were reported in 135 patients (89%). Grade 3 TRAEs were reported in 38 patients (25%), and 3 patients (2%) experienced Grade 4 TRAEs. One death was considered by the investigator to be treatment-related and occurred in a 79-year-old patient with respiratory failure and dyspnea, secondary to interstitial lung disease. The most common Grade ≥3 TRAE was peripheral edema, which occurred in 11 patients (7%). Serious TRAEs were reported in 23 patients (15%). Permanent tepotinib discontinuations due to TRAEs were reported in 17 patients (11%), and 50 patients (33%) required a dose reduction due to TRAEs. Peripheral edema was the most common TRAE leading to a dose reduction (25 patients, 16%) or dose interruption (28 patients, 18%); permanent discontinuation was uncommon (7 patients, 5%).

"Designed to have a highly selective mechanism of action, tepotinib has the potential to make a difference in the treatment and lives of people living with non-small cell lung cancer harboring METex14 skipping alterations," said Luciano Rossetti, Global Head of Research & Development for EMD Serono. "Following on the recent approval of tepotinib in Japan as the first therapy for the treatment of advanced NSCLC harboring MET gene alterations, the publication of these data underscores our commitment to advancing scientific understanding and potential therapeutic options for this challenging cancer."

The ongoing Phase II VISION (NCT02864992) clinical trial is a single-arm, open-label, multi-cohort study investigating the safety and efficacy of tepotinib as a single agent in patients with advanced or metastatic NSCLC with METex14 skipping alterations identified by LBx and/or TBx. The use of both LBx and TBx to identify patients for the VISION study is intended to support improved patient selection and is consistent with the company’s focus on patient-centric drug development.

Lung cancer is the most common type of cancer worldwide, with 2 million cases diagnosed annually.2 Alterations of the MET signaling pathway are found in various cancer types, including 3% to 5% of NSCLC cases, and correlate with aggressive tumor behavior and poor clinical prognosis.3-5 Patients with NSCLC harboring METex14 skipping tend to be older than those with NSCLC harboring other alterations.6 In the Phase II VISION study, the patient population is generally characterized as elderly, with a median age of 74.0 years, and as having poor clinical prognosis typical of NSCLC with METex14 skipping alterations.

In March 2020, the Japanese Ministry of Health, Labour and Welfare (MHLW) approved tepotinib for the treatment of patients with unresectable, advanced or recurrent NSCLC with METex14 skipping alterations. In September 2019, the US Food and Drug Administration (FDA) granted Breakthrough Therapy Designation for tepotinib in patients with metastatic NSCLC harboring METex14 skipping alterations who progressed following platinum-based cancer therapy. EMD Serono plans to file tepotinib for regulatory review with the FDA in 2020. Tepotinib is also being investigated in the INSIGHT 2 study (NCT03940703) in combination with the tyrosine kinase inhibitor (TKI) osimertinib in epidermal growth factor receptor (EGFR)-mutated, MET amplified, locally advanced or metastatic NSCLC that has acquired resistance to prior EGFR TKI.

Discovered in-house at Merck KGaA, Darmstadt, Germany, tepotinib is an oral MET inhibitor that is designed to inhibit the oncogenic MET receptor signaling caused by MET (gene) alterations.

*Tepotinib is currently under clinical investigation and not yet approved in any markets outside of Japan.

Dr. Paik has provided compensated advisory services to EMD Serono.

About Non-Small Cell Lung Cancer
With 2 million cases diagnosed annually, lung cancer (including trachea, bronchus and lung) is the most common type of cancer worldwide and the leading cause of cancer-related death, with 1.7 million mortality cases worldwide.2 Alterations of the MET signaling pathway, including MET exon 14 (METex14) skipping alterations and MET amplifications, occur in 3% to 5% of NSCLC cases.3-5

About Tepotinib
Tepotinib is an oral MET inhibitor that is designed to inhibit the oncogenic MET receptor signaling caused by MET (gene) alterations. Discovered in-house at Merck KGaA, Darmstadt, Germany, it has been designed to have a highly selective mechanism of action, with the potential to improve outcomes in aggressive tumors that have a poor prognosis and harbor these specific alterations. Tepotinib is currently under clinical investigation in NSCLC and not yet approved in any markets outside of Japan. Merck KGaA, Darmstadt, Germany, is actively assessing the potential of investigating tepotinib in combination with novel therapies and in other tumor indications.

References

Bladt F, et al. Clin Cancer Res 2013;19:2941-2951.
Bray F, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68(6):394-424. View Source View Source.
Reungwetwattana T, et al. Lung Cancer 2017;103:27-37.
Mo HN, et al. Chronic Dis Transl Med 2017;3(3):148-153.
Lutterbach B, et al. Cancer Res 2007;67:2081-8.
Schrock AB et al. J Thorac Oncol 2016;11(9):1493-1502.
All Merck KGaA, Darmstadt, Germany press releases are distributed by e-mail at the same time they become available on the EMD Group Website. In case you are a resident of the USA or Canada please go to www.emdgroup.com/subscribe to register for your online subscription of this service as our geo-targeting requires new links in the email. You may later change your selection or discontinue this service.

On May 29, 2020 Myovant Sciences (NYSE: MYOV), a healthcare company focused on redefining care for women and for men, reported additional results from its Phase 3 HERO study of once-daily, oral relugolix (120 mg) in men with advanced prostate cancer in an oral presentation at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper)’s ASCO (Free ASCO Whitepaper)20 Virtual Scientific Program and simultaneous publication in the New England Journal of Medicine (NEJM) (Press release, Myovant Sciences, MAY 29, 2020, https://investors.myovant.com/news-releases/news-release-details/myovant-sciences-announces-additional-positive-efficacy-and [SID1234558710]). The data expand on earlier findings from the HERO study, demonstrating the superiority of relugolix to leuprolide acetate across multiple endpoints, and further show that treatment with relugolix was associated with a lower risk of major adverse cardiovascular events compared to leuprolide acetate.

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Relugolix met the primary endpoint and demonstrated superiority to leuprolide acetate across six key secondary endpoints, all with p-values < 0.0001. In the primary endpoint responder analysis, 96.7% of men receiving once-daily, oral relugolix achieved sustained testosterone suppression to castrate levels (< 50 ng/dL) through 48 weeks, compared to 88.8% of men treated with leuprolide acetate.

Detailed secondary endpoint data, presented and published today, showed notable differences in the rapid and profound suppression of testosterone, PSA response, and testosterone recovery after discontinuation of treatment. In the relugolix group, testosterone suppression to less than 50 ng/dL was achieved in 56.0% of men by Day 4 and 98.7% by Day 15, compared to 0.0% by Day 4 and 12.1% by Day 15 for men in the leuprolide acetate group. Additionally, in the relugolix group, profound testosterone suppression to less than 20 ng/dL was achieved in 78.4% of men at Day 15, compared to 1.0% at Day 15 for men in the leuprolide acetate group. A higher proportion of men in the relugolix group achieved a 50% reduction in PSA by Day 15 and confirmed at Day 29 compared to those in the leuprolide acetate group (79.4% vs. 19.8%, respectively). Within 90 days of treatment discontinuation, 54% of men in the relugolix group achieved normal testosterone levels (≥ 280 ng/dL) with a mean testosterone level of 288.4 ng/dL, compared to 3% of men in the leuprolide acetate group with a mean testosterone level of 58.6 ng/dL.

"A faster effect in lowering testosterone for prostate cancer patients can be clinically significant – likewise, a more rapid testosterone recovery after stopping treatment, could potentially improve a patient’s quality of life," said Neal Shore, M.D., medical director of the Carolina Urologic Research Center, HERO program steering committee member, presenter of the ASCO (Free ASCO Whitepaper) data, and lead author on the NEJM paper. "Both of these findings could make a meaningful difference in the treatment journey for men with advanced prostate cancer."

Men in the relugolix group had a 54% lower risk of major adverse cardiovascular events compared to men in the leuprolide acetate group (2.9% vs. 6.2%, respectively). Additionally, in men with a history of these events, the relugolix group had 80% fewer major adverse cardiovascular events reported compared to the leuprolide acetate group (3.6% vs. 17.8%, respectively). More than 90% of men in the HERO study had at least one cardiovascular risk factor, including lifestyle risk factors such as tobacco use and obesity, comorbidities such as diabetes and hypertension, and prior history of a major adverse cardiovascular event.

"Cardiovascular disease is the leading cause of death in men with prostate cancer," said Dr. Shore. "An oral therapeutic option with strong efficacy that also reduces cardiovascular risk compared to that of conventional GnRH agonist therapy would be a critical achievement for men with advanced prostate cancer."

As previously reported, the incidence of adverse events in the HERO study was comparable for relugolix and leuprolide acetate groups (92.9% vs. 93.5%, respectively). The most frequently reported adverse events, reported in at least 10% of men in the relugolix group, were hot flashes, fatigue, constipation, mild to moderate diarrhea, and arthralgia.

"Relugolix has the potential to be an important new treatment option for men with prostate cancer and would represent significant progress in our company’s commitment to redefine care for men," said Lynn Seely, M.D., chief executive officer of Myovant Sciences. "We are grateful to have the opportunity to share these additional data through presentation and publication in such highly-respected venues as the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) and the New England Journal of Medicine. We have already submitted our New Drug Application to the FDA with the goal of bringing this oral, once-daily potential treatment to men with prostate cancer as expeditiously as possible, especially given the current environment with the COVID-19 pandemic and the difficulties and risks men face traveling to hospitals and clinics to receive injections."

Myovant submitted a New Drug Application (NDA) to the FDA for relugolix in April 2020, which, if approved, would be the first and only oral gonadotropin-releasing hormone (GnRH) receptor antagonist treatment for men with advanced prostate cancer.

The ASCO (Free ASCO Whitepaper) presentation (#5602), "HERO phase III trial: Results comparing relugolix, an oral GnRH receptor antagonist, versus leuprolide acetate for advanced prostate cancer," is available for on-demand viewing.

Conference Call
Myovant will hold a conference call to discuss these data on Monday, June 1, 2020 at 8:30 a.m. Eastern Time / 5:30 a.m. Pacific Time. Myovant management will be joined by Neal Shore, M.D. To participate in the live conference call, please dial 1-800-532-3746 for domestic callers and +1-470-495-9166 for international callers. A live webcast of the conference call will also be available on the investor relations page of Myovant’s website at investors.myovant.com and will remain archived on Myovant’s website for at least 30 days.

About the Phase 3 HERO Program in Advanced Prostate Cancer
Myovant’s Phase 3 clinical program for advanced prostate cancer consisted of a randomized, open-label, parallel-group, multinational clinical study designed to evaluate the safety and efficacy of relugolix in men with androgen-sensitive advanced prostate cancer who required at least one year of continuous androgen deprivation therapy. Men enrolled in the study were randomized 2:1 to receive a single loading dose of relugolix 360 mg followed by relugolix 120 mg once daily, or to treatment with leuprolide acetate 3-month depot injection, respectively.

Data from an additional key secondary endpoint, castration resistance-free survival, are expected in the third quarter of 2020.

About Prostate Cancer
Prostate cancer is the second most prevalent form of cancer in men and the second leading cause of death due to cancer in men in the U.S. Cardiovascular mortality is the leading cause of death in men with prostate cancer and accounts for 34% of deaths in men with prostate cancer in the U.S. Approximately three million men in the U.S. are currently living with prostate cancer, and approximately 170,000 men are estimated to be newly diagnosed in 2019. Advanced prostate cancer is prostate cancer that has spread or come back after treatment and may include men with biochemical recurrence (rising PSA in the absence of metastatic disease on imaging), locally advanced disease, or metastatic disease. Treatment for advanced prostate cancer typically involves androgen deprivation therapy, which reduces testosterone to very low levels, commonly referred to as castrate levels. GnRH receptor agonists, such as leuprolide acetate, or slow-release injections are the current standard of care for androgen deprivation therapy. However, GnRH receptor agonists may be associated with mechanism-of-action limitations, including the potentially detrimental initial rise in testosterone levels that can exacerbate clinical symptoms, which is known as clinical or hormonal flare, and delayed testosterone recovery after the drug is discontinued. Approximately 200,000 men are treated with androgen deprivation therapy with a GnRH agonist or antagonist each year.

About Relugolix
Relugolix is a once-daily, oral gonadotropin-releasing hormone (GnRH) receptor antagonist that reduces testicular testosterone production, a hormone known to stimulate the growth of prostate cancer, and ovarian estradiol production, a hormone known to stimulate the growth of uterine fibroids and endometriosis. Myovant is developing relugolix as a monotherapy tablet (120 mg once daily) for men with advanced prostate cancer. Myovant is also developing a relugolix combination tablet (relugolix 40 mg, estradiol 1.0 mg, and norethindrone acetate 0.5 mg) for women with uterine fibroids and for women with endometriosis.

On May 29, 2020 Iovance Biotherapeutics, Inc. (NASDAQ: IOVA), a late-stage biotechnology company developing novel T cell-based cancer immunotherapies, reported long-term interim data from Cohort 2 in the C-144-01 study of lifileucel in advanced melanoma during an oral session at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper)’s (ASCO) (Free ASCO Whitepaper) ASCO (Free ASCO Whitepaper)20 Virtual Scientific Program (Press release, Iovance Biotherapeutics, MAY 29, 2020, View Source [SID1234558709]).

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"We are very pleased to present the long term follow up data for lifileucel in melanoma at the ASCO (Free ASCO Whitepaper) Scientific Program," said Maria Fardis, Ph.D., President and Chief Executive Officer of Iovance Biotherapeutics. "The median duration of response has not been reached at 18.7 months of study follow up supporting potential benefit of the one-time treatment of lifileucel TIL therapy in advanced melanoma patients. The latest data at ASCO (Free ASCO Whitepaper) also demonstrate durable responses with lifileucel across the broad spectrum of our study population, including a wide age range of metastatic melanoma patients who have received prior anti-CTLA-4 and BRAF targeted treatments, and equally in patients with PD-L1 high and low status."

Jason Chesney, MD PhD, Director, James Graham Brown Cancer Center, University of Louisville and C-144-01 study investigator stated, "One of the greatest challenges oncologists face today is the treatment of melanoma patients who have progressed on immune checkpoint and BRAF/MEK inhibitors. The preliminary results of the C-144-01 study demonstrate that autologous tumor infiltrating lymphocytes (TILs; lifileucel) induce durable clinical responses in a significant percentage of this moribund population. Importantly, this new study opens the door for trials of TILs in many other cancer types and in combination with our growing repertoire of immunomodulatory agents."

Updated interim results from Cohort 2 are now available from an oral abstract session titled, "Long-term follow up of lifileucel (LN-144) cryopreserved autologous tumor infiltrating lymphocyte therapy in patients with advanced melanoma progressed on multiple prior therapies." As of the April 23, 2020 data extract for the oral presentation, lifileucel shows a 36.4% overall response rate (2 complete responses and 22 partial responses) and a disease control rate of 80% (n=66). Median duration of response (DOR) was not reached at 18.7 months of median study follow up (2.2 to 26.9+ months).

The Cohort 2 patients had heavily pretreated metastatic melanoma with high baseline disease burden. They have progressed on multiple prior therapies (3.3 mean prior therapies), including anti-PD-1 and BRAF/MEK inhibitors. The adverse event profile was consistent with the underlying advanced disease, lymphodepletion and IL-2 regimens.

Michael Kaplan, President and CEO of the Melanoma Research Alliance, stated, "While the last decade has brought incredible progress in delivering new treatments for melanoma, we know that more than half of patients with advanced melanoma are still in need of additional options. It is particularly exciting to see a new treatment approach, like lifileucel, that can offer hope and real results for some for whom checkpoint immunotherapy alone has yet to prove successful. The Melanoma Research Alliance is excited that Iovance has taken a significant step forward in ensuring more treatment options for patients who once had very few."

The oral abstract session is available on demand in the ASCO (Free ASCO Whitepaper) Meeting Library at View Source Details of the presentation are as follows:

Title: Long-term follow up of lifileucel (LN-144) cryopreserved autologous tumor infiltrating lymphocyte therapy in patients with advanced melanoma progressed on multiple prior therapies
Authors: Amod Sarnaik, et al.
Session Title: Melanoma/Skin Cancers
Session Type: Oral Abstract Session
Abstract Number: 10006
Location: ASCO (Free ASCO Whitepaper)20 Virtual Scientific Program at View Source

On May 29, 2020 BeiGene, Ltd. (NASDAQ: BGNE; HKEX: 06160), a commercial-stage biotechnology company focused on developing and commercializing innovative molecularly-targeted and immuno-oncology drugs for the treatment of cancer, reported follow-up data from the Phase 3 ASPEN trial comparing BRUKINSA (zanubrutinib) to ibrutinib for the treatment of Waldenström’s macroglobulinemia (WM) and long-term follow-up data from a Phase 1/2 study in patients with treatment naïve and relapsed/refractory (R/R) WM, presented at the 2020 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Virtual Scientific Program (Press release, BeiGene, MAY 29, 2020, View Source/news-releases/news-release-details/beigene-presents-updated-head-head-results-phase-3-trial" target="_blank" title="View Source/news-releases/news-release-details/beigene-presents-updated-head-head-results-phase-3-trial" rel="nofollow">View Source [SID1234558708]).

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"The totality of data from the two trials presented at ASCO (Free ASCO Whitepaper) suggests that zanubrutinib may be a preferred treatment option for patients with WM, regardless of whether they have received prior treatment," said Constantine S. Tam, MBBS, M.D., Disease Group Lead for Low Grade Lymphoma and Chronic Lymphocytic Leukemia at the Peter MacCallum Cancer Center, Australia, and a member of the steering committee and principal investigator for the ASPEN trial. "WM can be a devastating disease for patients and their families. We must offer therapies that are both effective in managing WM and well-tolerated to offer the best quality of life. In the ASPEN trial, zanubrutinib demonstrated a more favorable safety profile and was shown to be a more tolerable option for patients than ibrutinib, especially when considering adverse events of particular interest such as atrial fibrillation, hypertension and diarrhea."

While the ASPEN trial did not achieve statistical significance on its primary endpoint of superiority in complete response (CR) and very good partial response (VGPR) rates for zanubrutinib compared to ibrutinib, zanubrutinib demonstrated a numerically higher VGPR rate, as well as clinically meaningful improvements in safety and tolerability compared to ibrutinib. Additional five-month investigator-assessed follow-up data in the overall patient population reinforced the trend toward higher VGPR rates for zanubrutinib and advantages in safety. In a separate presentation of Phase 1/2 long-term follow-up data, rates of VGPR/CR increased with continued zanubrutinib treatment and the therapy was well tolerated.

"These results reinforce that zanubrutinib is a highly effective BTK inhibitor with clinically meaningful improvements in safety and tolerability compared to ibrutinib. Importantly, since WM is typically a disease of older individuals, zanubrutinib appears to have advantages related to cardiovascular safety risks over ibrutinib," said Jane Huang, M.D., Chief Medical Officer, Hematology at BeiGene. "The choice to evaluate zanubrutinib directly against ibrutinib underscores our bold approach to R&D and our commitment to develop better treatments for patients across the globe."

ASPEN Trial Data
Oral Presentation, Abstract #8007

Data presented from the Phase 3 ASPEN trial (NCT03053440) include the 201 patients in the randomized cohort of patients with WM and a MYD88 mutation.

At data cutoff of August 31, 2019, with 19.4 months median follow-up:
The combined CR+VGPR rate as assessed by independent review committee (IRC) for the overall intent-to-treat population was 28.4% in the zanubrutinib arm and 19.2% in the ibrutinib arm (2-sided descriptive p=0.0921);
The combined CR+VGPR rate as assessed by investigators for the overall intent-to-treat population was 28.4% in the zanubrutinib arm and 17.2% in the ibrutinib arm (2-sided descriptive p=0.0437);
Most common grade ≥ 3 adverse events (≥5% in either arm) for zanubrutinib compared to ibrutinib included hypertension (6% vs. 11%), neutropenia (16% vs. 8%), pneumonia (1% vs. 7%), anemia (5% vs. 5%), and thrombocytopenia (5% vs. 3%);
Categories of AEs of interest for BTK inhibitors for zanubrutinib compared to ibrutinib included atrial fibrillation/flutter of any grade (2.0% vs. 15.3%), bleeding of any grade (48.5% vs. 59.2%), major hemorrhage (5.9% vs. 9.2%), diarrhea (20.8% vs. 31.6%), hypertension (10.9% vs. 17.3%); neutropenia (29.7% vs. 13.3%), infection (66.3% vs. 67.3%), and second malignancy (11.9% vs. 11.2%);
Despite higher rates of grade ≥ 3 neutropenia among AEs of interest in the zanubrutinib arm (19.8% vs. 8.2% for ibrutinib), rates of infection were similar in patients taking zanubrutinib and ibrutinib (all grades: 66.3% vs. 67.3%; grade ≥ 3: 17.8% vs. 19.4%); and
In the zanubrutinib arm, four (4.0%) patients discontinued treatment due to AEs and one (1.0%) patient had an adverse event leading to death; in the ibrutinib arm, nine patients (9.2%) discontinued due to AEs and four (4.1%) patients had an adverse event leading to death.
After an additional five-months of follow-up with a data cutoff of January 31, 2020, with 24.2 months median follow-up:
CR+VGPR as assessed by investigator for zanubrutinib was 30.4% compared to 18.2% for ibrutinib (exploratory analysis; 2-sided descriptive p=0.0302);
Categories of AEs of interest for BTK inhibitors for zanubrutinib compared to ibrutinib included atrial fibrillation/flutter of any grade (3.0% vs. 18.4%), bleeding of any grade (50.5% vs. 60.2%), major hemorrhage (5.9% vs. 10.2%), diarrhea (21.8% vs. 32.7%), hypertension (12.9% vs. 20.4%); and neutropenia (31.7% vs. 15.3%);
Despite higher rates of grade ≥ 3 neutropenia in the zanubrutinib arm (22.8% vs. 8.2% for ibrutinib), rates of infection remained similar in patients taking zanubrutinib and ibrutinib (all grade: 69.3% vs. 71.4%; grade ≥ 3: 18.8% vs. 23.5%); and
No additional patients discontinued treatment due to AEs in the zanubrutinib arm, compared to an additional five patients in the ibrutinib arm (4% vs 14.3%). No additional patients had an adverse event leading to death in both arms (1.0% vs. 4.1%).
ASPEN Data from Non-Randomized Cohort, Patients with MYD88 Wild-Type (MYD88wt) WM
Electronic Abstract #20056

Additional data from the ASPEN trial presented in an abstract included 28 patients who were centrally determined at study entry to have the MYD88WT or mutation unknown genotype. These patients were enrolled into a non-randomized cohort assigned to receive zanubrutinib 160mg twice daily (BID).

As of August 31, 2019, the median follow-up was 17.9 months and 17 patients remained on study treatment. Updated results included:

In the 26 centrally confirmed MYD88WT patients, the overall response rate (ORR) assessed by IRC was 80.8%, with a major response rate of 50.0%, including a VGPR rate of 26.9%;

Progression-free survival (PFS) event-free rate at 12 months was 72.4%;

In this cohort of 28 patients with MYD88WT or mutation unknown genotype, the most frequently reported AEs (≥ 20%) were diarrhea, anemia, contusion, pyrexia, and upper respiratory tract infection. Major hemorrhage was reported in 2 patients, and atrial fibrillation was reported in 1 patient. There were no fatal AEs; and

Two patients (7.1%) discontinued zanubrutinib due to adverse events, and 6 patients (14.3%) discontinued due to disease progression.
Phase 1/2 Trial Data
Poster Presentation, Abstract #8051

Data presented from the Phase 1/2 trial (NCT02343120) evaluating zanubrutinib in patients with treatment-naïve or relapsed/refractory WM include:

As of January 29, 2020, with a median follow-up of 35.3 months, 73% remained on treatment;

The ORR was 96% and the VGPR/CR rate was 46%;

The proportion of patients achieving a best response of VGPR or CR increased with treatment duration;

Three-year PFS event-free rate was 80%, and overall survival was 83%;

Reasons for treatment discontinuation included AEs in 13% of patients, disease progression in 10%, and other in 4%;

The most commonly reported AEs (≥ 20%) were upper respiratory tract infection (55%), contusion (33%, all grade 1), cough (23%), and diarrhea (21%);

62.3% of patients (48/77) experienced at least one grade ≥3 AE and five patients experienced AEs leading to death;

AEs of interest included minor bleeding (35%), hypertension (18%), major hemorrhage (5%), and atrial fibrillation/flutter (5%).
Investor Conference Call

The Company will host an investor conference call and webcast on Friday, May 29, 2020 at 8:00 p.m. ET to discuss results presented at the ASCO (Free ASCO Whitepaper) Virtual Scientific Program.

A live webcast of the conference call can be accessed from the investors section of BeiGene’s website at View Source or View Source An archived replay will be available for 90 days following the event.

To learn more about BeiGene’s pipeline and data presented during the ASCO (Free ASCO Whitepaper)2020 Virtual Scientific Program, visit BeiGeneVirtualCongress.com.

About Waldenström’s Macroglobulinemia

WM is a rare lymphoma representing approximately 1% of all non-Hodgkin lymphomas and typically progresses slowly after diagnosis.1 In the United States, approximately 3,000 people are diagnosed with WM each year.1

About the ASPENTrial

The Phase 3 randomized, open-label, multicenter ASPEN clinical trial (NCT03053440) evaluated zanubrutinib versus ibrutinib in patients with relapsed/refractory (R/R) or treatment-naïve (TN) Waldenström’s macroglobulinemia. The primary objective was to establish superiority of zanubrutinib compared to ibrutinib as demonstrated by the proportion of patients achieving complete response (CR) or very good partial response (VGPR). Secondary endpoints included major response rate, duration of response and progression-free survival, and safety, measured by incidence, timing and severity of treatment-emergent adverse events. The pre-specified analysis populations for the trial included the overall population (n=201) and R/R patients (n=164). Exploratory endpoints included quality of life measures.

The study included two cohorts, a randomized cohort (cohort 1) consisting of 201 patients with a MYD88 mutation and a non-randomized cohort (cohort 2) in which 28 patients with MYD88 wild-type (MYD88WT) received zanubrutinib because they have historically responded poorly to ibrutinib therapy.

The randomized cohort 1 enrolled 102 patients (including 83 relapsed or refractory (R/R) patients and 19 treatment-naïve (TN) patients) in the zanubrutinib arm and 99 patients (including 81 R/R patients and 18 TN patients) in the ibrutinib arm. Patients in the zanubrutinib arm were assigned to receive zanubrutinib 160 mg twice daily (BID) and patients in the ibrutinib arm received 420 mg of ibrutinib once daily (QD).

About the Zanubrutinib Clinical Trial Program

Clinical trials of zanubrutinib include:

Fully-enrolled Phase 3 ASPEN clinical trial in patients with Waldenström’s macroglobulinemia (WM) comparing zanubrutinib to ibrutinib (NCT03053440), currently the only approved BTK inhibitor for WM;

Phase 3 SEQUOIA trial comparing zanubrutinib with bendamustine plus rituximab in patients with treatment-naive (TN) chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) (NCT03336333);

Phase 3 ALPINE trial comparing zanubrutinib to ibrutinib in patients with relapsed/refractory (R/R) CLL/SLL (NCT03734016);

Phase 2 trial in combination with GAZYVA (obinutuzumab) in patients with R/R follicular lymphoma (FL) (NCT03332017);

Phase 3 trial comparing zanubrutinib and rituximab to bendamustine and rituximab in patients with untreated MCL (NCT04002297);

Phase 2 MAGNOLIA trial in patients with R/R marginal zone lymphoma (MZL) (NCT03846427);

Phase 2 ROSEWOOD trial (NCT03332017) in China comparing obinutuzumab and zanubrutinib vs obinutuzumab alone in treating patients with R/R FL;

Phase 2 trial (NCT04382586) in the U.S. comparing zanubrutinib plus supportive care to placebo plus supportive care for the treatment of patients with COVID-19 disease and pulmonary distress;

Phase 2 trial (NCT03332173) in China in patients with R/R WM; and

Completed Phase 2 trials in China in patients with R/R MCL (NCT03206970) and R/R CLL/SLL (NCT03206918).
About BRUKINSA (zanubrutinib)

BRUKINSA 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 to treat adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy on November 14, 2019. 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.

New Drug Applications (NDAs) in China for relapsed refractory (R/R) MCL and R/R chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) have been accepted by the China National Medical Products Administration (NMPA) and granted priority review and are pending approval.

BRUKINSA is not approved for use outside the United States. BRUKINSA is not approved for the treatment of Waldenström’s macroglobulinemia.

IMPORTANT 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 May 29, 2020 Affimed N.V. (Nasdaq: AFMD), a clinical-stage immuno-oncology company committed to giving patients back their innate ability to fight cancer, reported details of its AFM13 REDIRECT clinical trial design and rationale at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2020 Annual Meeting, being held in virtual format on May 29-31, 2020 (Press release, Affimed, MAY 29, 2020, View Source [SID1234558707]).

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AFM13 is a first-in-class innate cell engager that induces specific and selective killing of CD30-positive tumor cells by engaging and activating NK cells and macrophages thereby leveraging the power of the innate immune system. As detailed in the poster at ASCO (Free ASCO Whitepaper), REDIRECT is a registration-directed trial with AFM13 as monotherapy in patients with relapsed/refractory peripheral T cell lymphoma or transformed mycosis fungoides. The study is actively recruiting.

"We recognize that we target difficult to treat malignancies and we are committed to advancing AFM13 in the clinic for patients who currently have limited treatment options," said Dr. Andreas Harstrick, Affimed’s Chief Medical Officer. "Having received the U.S. FDA orphan drug designation for AFM13 last month further reinforced our commitment to this area with high unmet medical need and the importance of developing new therapies."

The REDIRECT poster presented at ASCO (Free ASCO Whitepaper) is available online at View Source

About AFM13

AFM13 is a first-in-class tetravalent, bispecific innate cell engager that specifically binds to CD30 on tumor cells and to CD16A on NK cells and macrophages. AFM13 is being developed in peripheral T cell lymphoma (pTCL) and in other CD30-positive lymphomas. AFM13 has shown a favorable safety profile and signs of therapeutic efficacy as a monotherapy in CD30-positive non-Hodgkin lymphoma with cutaneous manifestation. In addition, data from a combination study of AFM13 with Merck’s anti-PD-1 antibody Keytruda (pembrolizumab) in Hodgkin lymphoma (HL) supports proof of principle for the combination of NK cell engagement with checkpoint inhibition. AFM13 has been granted orphan drug designation by the U.S. Food and Drug Administration for HL.