On September 16, 2024 GSK plc (LSE/NYSE: GSK) reported that Japan’s Ministry of Health, Labour and Welfare (MHLW) has accepted for review a new drug application (NDA) for Blenrep (belantamab mafodotin) in combination with bortezomib plus dexamethasone (BorDex) or pomalidomide plus dexamethasone (PomDex) as a treatment for relapsed or refractory multiple myeloma (Press release, GlaxoSmithKline, SEP 17, 2024, View Source [SID1234646665]). MHLW also has granted orphan drug designation for Blenrep, which reflects the high unmet medical need and ensures priority NDA review in multiple myeloma.

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This is the third major regulatory filing acceptance for belantamab mafodotin combinations in the treatment of relapsed/refractory multiple myeloma, following marketing authorisation application acceptance2 by the European Medicines Agency (EMA) in July 2024 and by the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK earlier this month.

Hesham Abdullah, Senior Vice President, Global Head Oncology, R&D, GSK, said: "Blenrep combinations show potential based on the results of the DREAMM-7 and DREAMM-8 trials to redefine the treatment of relapsed/refractory multiple myeloma. We are committed to working with health authorities worldwide to advance Blenrep along regulatory pathways so we can bring these additional treatment options to patients as quickly as possible."

Multiple myeloma presents a growing health concern in Japan, where the number of patients diagnosed with multiple myeloma per year has increased continuously over the last five decades.3,4 This underscores the urgent need for more treatment options for patients in Japan, particularly those with progressing disease that has become resistant to the current standard of care.

The application is based on interim results from the DREAMM-7 and DREAMM-8 phase III trials, which both met their primary endpoints, showing statistically significant and clinically meaningful improvements in progression-free survival (PFS) for the belantamab mafodotin combinations compared to standard of care combinations in relapsed or refractory multiple myeloma. A positive overall survival (OS) trend was observed in both trials but was not statistically significant at the time of interim analysis. Follow-up for OS continues. The DREAMM-7 trial is evaluating belantamab mafodotin combined with BorDex versus daratumumab plus BorDex, while the DREAMM-8 trial is evaluating belantamab mafodotin in combination with PomDex versus bortezomib plus PomDex.

Results from both trials also showed clinically meaningful improvements across all other secondary efficacy endpoints, including deeper and more durable responses compared to the respective standard of care combinations. The safety and tolerability profiles of the belantamab mafodotin combinations in DREAMM-7 and DREAMM-8 trials were broadly consistent with the known profiles of the individual agents.

About multiple myeloma
Multiple myeloma is the third most common blood cancer globally and is generally considered treatable but not curable.1,5 There are approximately more than 180,000 new cases of multiple myeloma diagnosed globally each year.6 More than 7,200 new cases of multiple myeloma are diagnosed in Japan each year.1 Research into new therapies is needed as multiple myeloma commonly becomes refractory to available treatments.7

About DREAMM-7
The DREAMM-7 phase III clinical trial is a multicentre, open-label, randomised trial evaluating the efficacy and safety of belantamab mafodotin in combination with BorDex compared to a combination of daratumumab and BorDex in patients with relapsed/refractory multiple myeloma who previously were treated with at least one prior line of multiple myeloma therapy, with documented disease progression during or after their most recent therapy.

A total of 494 participants, including Japanese patients, were randomised at a 1:1 ratio to receive either belantamab mafodotin in combination with BorDex or a combination of daratumumab and BorDex. Belantamab mafodotin was scheduled to be dosed at 2.5mg/kg intravenously every three weeks.

The primary endpoint is PFS as per an independent review committee. The key secondary endpoints include OS, duration of response (DOR), and minimal residual disease (MRD) negativity rate as assessed by next-generation sequencing. Other secondary endpoints include overall response rate (ORR), safety, and patient reported and quality of life outcomes.

Results from DREAMM-7 were first presented8 at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Plenary Series in February 2024, shared in an encore presentation at the 2024 ASCO (Free ASCO Whitepaper) Annual Meeting, and published in the New England Journal of Medicine.

A Japan expansion cohort is set to further evaluate the DREAMM-7 protocol in Japanese patients. Results for Japanese participants will be presented at a future scientific meeting.

About DREAMM-8
The DREAMM-8 phase III clinical trial is a multicentre, open-label, randomised trial evaluating the efficacy and safety of belantamab mafodotin in combination with PomDex compared to a combination of bortezomib and PomDex in patients with relapsed/refractory multiple myeloma previously treated with at least one prior line of multiple myeloma therapy, including a lenalidomide-containing regimen, and who have documented disease progression during or after their most recent therapy. Compared to the patient population studied in the DREAMM-7 trial, patients in DREAMM-8 were more heavily pre-treated in that all had prior exposure to lenalidomide, 75% were refractory to lenalidomide, 25% had prior daratumumab exposure and of those most were daratumumab refractory.

A total of 302 participants, including Japanese patients, were randomised at a 1:1 ratio to receive either belantamab mafodotin plus PomDex, or bortezomib plus PomDex.

The primary endpoint is PFS as per an independent review committee. The key secondary endpoints include OS and MRD negativity rate as assessed by next-generation sequencing. Other secondary endpoints include ORR, DOR, safety, and patient reported and quality of life outcomes.

Results from DREAMM-8 were first presented9 at the 2024 ASCO (Free ASCO Whitepaper) Annual Meeting and published in the New England Journal of Medicine.

A Japan expansion cohort is set to further evaluate the DREAMM-8 protocol in Japanese patients. Results for Japanese participants will be presented at a future scientific meeting.

About Blenrep
Blenrep is an antibody-drug conjugate comprising a humanised B-cell maturation antigen monoclonal antibody conjugated to the cytotoxic agent auristatin F via a non-cleavable linker. The drug linker technology is licensed from Seagen Inc.; the monoclonal antibody is produced using POTELLIGENT Technology licensed from BioWa Inc., a member of the Kyowa Kirin Group.

Blenrep is approved as monotherapy in Hong Kong, Israel and Singapore. Refer to the local Summary of Product Characteristics for a full list of adverse events and complete important safety information.

On September 16, 2024 Eisai (Headquarters: Tokyo, CEO: Haruo Naito) and Merck & Co., Inc., Rahway, NJ, USA (known as MSD outside of the United States and Canada) reported results from the first interim analysis of the Phase 3 LEAP-012 trial evaluating LENVIMA (lenvatinib), the orally available multiple receptor tyrosine kinase inhibitor (TKI) discovered by Eisai, plus KEYTRUDA (pembrolizumab), the anti-PD-1 therapy from Merck & Co., Inc., Rahway, NJ, USA, in combination with transarterial chemoembolization (TACE) compared to TACE alone for the treatment of patients with unresectable, non-metastatic hepatocellular carcinoma (HCC) (Press release, Eisai, SEP 16, 2024, View Source [SID1234646692]). These late-breaking data were presented for the first time on September 14 (Central European Summer Time) during a Presidential Symposium at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2024 (Presentation #LBA3).

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After a median follow-up of 25.6 months (range, 12.6-43.5), LENVIMA plus KEYTRUDA in combination with TACE demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS), reducing the risk of disease progression or death by 34% (HR=0.66 [95% CI, 0.51-0.84]; p=0.0002) compared to TACE alone. Median PFS was 14.6 months (95% CI, 12.6-16.7) for the LENVIMA plus KEYTRUDA-based regimen versus 10.0 months (95% CI, 8.1-12.2) for TACE alone. At this analysis, a trend toward improvement in overall survival (OS), the trial’s other primary endpoint, was observed for the LENVIMA plus KEYTRUDA-based regimen versus TACE alone (HR=0.80 [95% CI, 0.57-1.11]; p=0.0867); the OS data are not mature and did not reach statistical significance at the time of this interim analysis. The trial is continuing, and follow-up of OS is ongoing. The safety profile of the LENVIMA plus KEYTRUDA-based regimen was consistent with that observed in previously reported studies evaluating the combination.

"Hepatocellular carcinoma is one of the leading causes of cancer-related deaths worldwide, highlighting the need for new treatment options,1,2" said Dr. Josep Llovet, Director of the Liver Cancer Program and Professor of Medicine at the Icahn School of Medicine at Mount Sinai. "These findings from the LEAP-012 trial demonstrate the potential of lenvatinib plus pembrolizumab in combination with TACE to extend progression-free survival for patients diagnosed with unresectable, non-metastatic disease."

"Global incidence rates for hepatocellular carcinoma are expected to rise by more than 50 percent over the next two decades and there have been limited advances for patients with unresectable, non-metastatic forms of disease, 3" said Dr. Gregory Lubiniecki, Vice President, Global Clinical Development, MSD Research Laboratories. "These results reflect our commitment to exploring therapeutic options for these patients, including in earlier stages of disease. We’re encouraged by the potential for another treatment option for patients with unresectable non-metastatic hepatocellular carcinoma in addition to the existing monotherapy indications for KEYTRUDA and LENVIMA."

"Transarterial chemoembolization (TACE) has been a standard of care option for patients with unresectable, non-metastatic hepatocellular carcinoma for many years; however, many patients experience disease progression within one year,4,5,6,7" said Dr. Corina Dutcus, Senior Vice President, Oncology Global Clinical Development Lead at Eisai Inc. "Data from the Phase 3 LEAP-012 study demonstrate that the addition of LENVIMA plus KEYTRUDA to TACE may help address the unmet need for therapies that can improve progression-free survival for people with this disease. We are grateful to the patients and investigators for their participation in this study."

Treatment was administered to 237 patients receiving the KEYTRUDA plus LENVIMA-based regimen and 241 patients receiving TACE alone. Treatment-related adverse events (TRAEs) occurred in 98.7% of patients receiving LENVIMA plus KEYTRUDA in combination with TACE versus 84.6% of patients receiving TACE alone and led to the discontinuation of both study drugs in 8.4% versus 1.2% of patients, respectively. Serious adverse events were observed in 33.3% of patients receiving LENVIMA plus KEYTRUDA in combination with TACE versus 12.4% of patients receiving TACE alone. Grade 3 or 4 TRAEs occurred in 71.3% of patients receiving LENVIMA plus KEYTRUDA in combination with TACE versus 31.1% for TACE alone and TRAEs led to death in 1.7% (n=4) versus 0.4% (n=1) of patients, respectively.

LENVIMA monotherapy is approved for the treatment of patients with unresectable HCC in more than 80 countries, including in Japan, the U.S., Europe and China.

KEYTRUDA is approved as a monotherapy for the treatment of patients with HCC secondary to hepatitis B who have received prior systemic therapy other than a PD-1/PD-L1-containing regimen in the U.S. and as a monotherapy for the treatment of patients with HCC who have been previously treated with sorafenib or oxaliplatin-containing chemotherapy in China.

LENVIMA plus KEYTRUDA is approved in the U.S., the EU, Japan and other countries for the treatment of advanced renal cell carcinoma (RCC) and certain types of advanced endometrial carcinoma. Lenvatinib is marketed as KISPLYX for advanced RCC in the EU. Eisai and Merck & Co., Inc., Rahway, NJ, USA are studying the LENVIMA plus KEYTRUDA combination through the LEAP (LEnvatinib And Pembrolizumab) clinical program in various tumor types, including but not limited to HCC, RCC, head and neck cancer, gastric cancer and esophageal cancer across multiple clinical trials.

About LEAP-012

LEAP-012 is a multicenter, randomized, double-blind Phase 3 trial (ClinicalTrials.gov, NCT04246177(New Window)) evaluating LENVIMA plus KEYTRUDA in combination with TACE versus dual placebo plus TACE for the treatment of patients with unresectable, non-metastatic HCC. The primary endpoints are PFS as assessed by blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) following a maximum of five target lesions, and with a requirement that new intrahepatic lesions must meet LI-RADS 5 criteria, and OS. Secondary endpoints include objective response rate, duration of response, disease control rate, and time to progression as assessed by BICR per RECIST v1.1 and Modified Response Evaluation Criteria in Solid Tumors (mRECIST), as well as PFS as assessed by BICR per mRECIST and safety. The study randomized 480 patients 1:1 to receive:

LENVIMA (12 mg [for participants with screening body weight ≥60 kg] or 8 mg [for participants with screening body weight <60 kg] orally once a day) plus KEYTRUDA (400 mg intravenously [IV] every six weeks [Q6W]) in combination with TACE (conducted as a background procedure of chemotherapeutic and embolic agents injected via hepatic artery 2-4 weeks after start of study intervention, and after the first tumor assessment scan and ≥1 month after the first TACE); or IV placebo administered Q6W plus oral placebo administered once a day in combination with TACE.
All study drugs were continued until protocol-specified discontinuation criteria. KEYTRUDA was administered for up to two years (approximately 18 doses). After completing two years of combination therapy, LENVIMA may have been administered as a single agent until protocol-specified discontinuation criteria were met.

About hepatocellular carcinoma

Liver cancer is one of the leading causes of cancer-related deaths worldwide.1 In the U.S., the incidence rates of liver cancer have more than tripled since 1980, and death rates have doubled during that time. 8 Incidence rates are expected to continue to rise in various regions across the world until 2040, including in countries with advanced healthcare systems.3 It is estimated there were more than 865,000 new cases of liver cancer and more than 757,000 deaths from the disease globally in 2022.1 In Japan, it is estimated there were over 41,000 new cases of liver cancer and almost 26,000 deaths from the disease in 2022.9 In the U.S., it is estimated there will be approximately 42,000 patients diagnosed with liver cancer and almost 30,000 patient deaths from the disease in 2024.10 The five-year relative survival rate for liver cancer in the U.S. is 22%, based on SEER data from 2013-2019.11 Hepatocellular carcinoma (HCC) is the most common type of liver cancer, accounting for an estimated 90% of primary liver cancer cases.12

About LENVIMA (lenvatinib) Capsules

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

Thyroid cancer

・Indication as monotherapy

(Approved mainly in Japan, the United States, Europe, China and Asia)

Japan: Unresectable thyroid cancer

The United States: The treatment of patients with locally recurrent or metastatic, progressive, radioiodine-refractory differentiated thyroid cancer (DTC)

Europe: The treatment of adult patients with progressive, locally advanced or metastatic, differentiated (papillary/follicular/Hürthle cell) thyroid carcinoma (DTC), refractory to radioactive iodine (RAI)

Hepatocellular carcinoma

・Indication as monotherapy

(Approved mainly in Japan, the United States, Europe, China and Asia)

Japan: Unresectable hepatocellular carcinoma

The United States: The first-line treatment of patients with unresectable hepatocellular carcinoma (HCC)

Europe: The treatment of adult patients with advanced or unresectable hepatocellular carcinoma (HCC) who have received no prior systemic therapy

Thymic carcinoma

・Indication as monotherapy (Approved in Japan)

Japan: Unresectable thymic carcinoma

Renal cell carcinoma (In Europe, the agent was launched under the brand name Kisplyx)

・Indication in combination with everolimus

(Approved mainly in the United States, Europe and Asia)

The United States: The treatment of adult patients with advanced renal cell carcinoma (RCC) following one prior anti-angiogenic therapy

Europe: The treatment of adult patients with advanced renal cell carcinoma following one prior vascular endothelial growth factor (VEGF) targeted therapy

・Indication in combination with KEYTRUDA (generic name: pembrolizumab)

(Approved mainly in Japan, the United States, Europe and Asia)

Japan: Radically unresectable or metastatic renal cell carcinoma

The United States: The first-line treatment of adult patients with advanced renal cell carcinoma

Europe: The first-line treatment of adult patients with advanced renal cell carcinoma

Endometrial carcinoma

・Indication in combination with KEYTRUDA

(Approved mainly in Japan, the United States, Europe and Asia)

Japan: Unresectable, advanced or recurrent endometrial carcinoma that progressed after cancer chemotherapy

The United States: The treatment of patients with advanced endometrial carcinoma (EC) that is not microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation

Europe: The treatment of adult patients with advanced or recurrent endometrial carcinoma (EC) who have disease progression on or following prior treatment with a platinum-containing therapy in any setting and are not candidates for curative surgery

About KEYTRUDA (pembrolizumab) Injection, 100mg
KEYTRUDA is an anti-programmed death receptor-1 (PD-1) therapy that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

Merck & Co., Inc., Rahway, NJ, USA has the industry’s largest immuno-oncology clinical research program. There are currently more than 1,600 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient’s likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

On September 16, 2024 Personalis, Inc. (Nasdaq: PSNL), a leader in MRD testing, reported findings presented this week at the European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress (ESMO) (Free ESMO Whitepaper) Congress 2024 in Barcelona, Spain (Press release, Personalis, SEP 16, 2024, View Source [SID1234646691]). Personalis’ NeXT Personal assay was designed to detect and monitor residual and recurrent disease (MRD) in cancer patients by detecting very small traces of circulating tumor DNA (ctDNA) in the blood. It was launched to the clinic in late 2023 and is being co-commercialized in partnership with Tempus AI, Inc.

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Two studies were presented at ESMO (Free ESMO Whitepaper) further demonstrating the importance of using ultrasensitive MRD assay to monitor lung cancer patients and patients on immunotherapy.

In the first of these studies, Professor Charles Swanton and his colleagues at Cancer Research UK, University College London and the Francis Crick Institute analyzed over 400 non-small cell lung cancer (NSCLC) patients from their TRACERx lung cancer study, using the NeXT Personal assay. It represents one of the largest and most comprehensive MRD studies in lung cancer performed to date. These new results expand on and further strengthen the ground-breaking results of the initial study presented at last year’s ESMO (Free ESMO Whitepaper) congress.

Strong detection rates for residual lung cancer in the landmark period, the first 120 days after surgery
A high percentage of these landmark detections (42%) occur in the ultrasensitive range (less than 80 ppm) enabled by NeXT Personal
Pre-operative detections predict clinical outcome in lung adenocarcinoma, the most common type of lung cancer
Dynamic monitoring with NeXT Personal through adjuvant therapy can stratify patients for clinical outcome
NeXT Personal demonstrated high sensitivity for detecting early-stage lung cancer recurrence with detection months ahead of imaging and the ability to identify low and high-recurrence risk patients before and after surgery.

In the second abstract, Dr. Rodrigo Toledo at the Vall d’Hebron Institute of Oncology (VHIO) presented data on a large cohort of over 200 late-stage cancer patients on immunotherapy profiled using the NeXT Personal assay, significantly expanding on the initial cohort first presented earlier this year. The study was unique in having a validation set of patients and it demonstrated that patients who had a significant decrease in ctDNA levels in response to immunotherapy had significantly longer overall survival than those who did not.

"The expanded data from the TRACERx and VHIO studies are important for demonstrating the robust performance and clinical importance of our NeXT Personal MRD test," said Richard Chen, Chief Medical Officer and EVP of R&D at Personalis. "There are now 6 studies that have been presented pointing to a critical role of an ultra-sensitive MRD approach for identifying patients at risk for cancer recurrence, monitoring therapy response, and detecting cancer recurrence earlier."

On September 16, 2024 Mauna Kea Technologies (Euronext Growth: ALMKT), inventor of Cellvizio, the multidisciplinary probe and needle-based confocal laser endomicroscopy (p/nCLE) platform, reported the publication in the peer-reviewed Journal of Thoracic Disease of new ground-breaking clinical results demonstrating the efficacy of its needle-based Confocal Laser Endomicroscopy (nCLE) technology for the characterization of peripheral lung cancer and preparation of surgical resection (Press release, Mauna Kea Technologies, SEP 16, 2024, View Source [SID1234646690]).

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This study, conducted by the team of Professor Stéphane Renaud at the University Hospital of Nancy, evaluated the use of Cellvizio’s nCLE platform in combination with Electromagnetic Navigation Bronchoscopy (ENB) to characterize suspicious pulmonary nodules and prepare them for surgical resection when needed. The results highlight the potential of nCLE to rapidly and accurately identify malignant lesions while minimizing the risks associated with traditional diagnostic methods including ionizing radiation.

The study included 30 patients with suspicious pulmonary nodules with a median size of 16 mm. The findings revealed a sensitivity of 96.43% and a specificity of 100% in characterizing malignant lesions, based on previously published nCLE image classification. The median time of contact with the suspicious lesions was just 5 minutes with no major complications reported, demonstrating the technology’s efficiency in clinical practice. Additionally, the use of nCLE also improved the quality and quantity of tissue sampling, thus enabling molecular and genomics analyses, which have become essential tools for the choice and planning of treatments.

Professor Stéphane Renaud, Thoracic Surgeon at University Hospital Nancy and principal investigator of the study, stated: "We are extremely pleased with the results of this study, which brings to light the high diagnostic value of needle-based endomicroscopy in combination with Electromagnetic Navigation Bronchoscopy and its ability to improve our treatment planning and minimize patient risk. With a much-enhanced ability to target our biopsies, we have also been able to obtain essential tissue material for molecular and genomics analyses, which are crucial for guiding immunotherapy strategies. This combination of technologies will certainly play a key role in the fight against lung cancer in the future."

"We are thrilled by these outstanding clinical results, which reinforce the value of our needle-based endomicroscopy platform in advancing the field of lung cancer diagnostics and treatment," commented Sacha Loiseau, Ph.D., Chairman and CEO of Mauna Kea Technologies. "This study confirms that Cellvizio can play a pivotal role not only in enabling real-time, accurate, and minimally invasive diagnosis, but also in helping physicians improve their treatment planning and, in turn, patient outcomes."

On September 16, 2024 Bayer reported results from the investigational pivotal Phase III ARANOTE trial demonstrated that NUBEQA (darolutamide) plus androgen deprivation therapy (ADT) showed a statistically significant and clinically meaningful improvement in radiological progression-free survival (rPFS) compared to placebo plus ADT in patients with metastatic hormone-sensitive prostate cancer (mHSPC) (Press release, Bayer, SEP 16, 2024, View Source [SID1234646689]). The results were presented today as a late-breaking oral presentation at the 2024 European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress in Barcelona, Spain and published simultaneously in The Journal of Clinical Oncology.

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The results were consistent with the established safety profile of NUBEQA, with no new safety signals observed. Rates of serious adverse events were similar between the treatment arms (23.6% for NUBEQA plus ADT compared to 23.5% for placebo plus ADT), while discontinuation due to treatment-emergent adverse events (TEAEs) was 6.1% in patients treated with NUBEQA plus ADT compared to 9% in patients receiving placebo plus ADT.1

NUBEQA is indicated in the U.S. for the treatment of adult patients with mHSPC in combination with docetaxel and for the treatment of adult patients with non-metastatic castration-resistant prostate cancer (nmCRPC).2

The randomized, double-blind, placebo-controlled Phase III ARANOTE trial was designed to assess the efficacy and safety of NUBEQA plus ADT in patients with mHSPC. A total of 669 patients were randomized 2:1 to receive either 600 mg of NUBEQA (N=446) or placebo (N=223) twice daily in addition to ADT.1

"Each diagnosis of metastatic hormone-sensitive prostate cancer is unique, shaped by factors such as age, comorbidities and patient preferences. Each patient therefore requires a tailored treatment approach that thoughtfully addresses these key considerations," said Fred Saad, Professor and Chairman of Surgery and Director of Genitourinary Oncology at the University of Montreal Hospital Center (CHUM), and Principal Investigator of the ARANOTE trial. "With the positive results from ARANOTE, in addition to the ARASENS data, darolutamide has now demonstrated efficacy and safety data both with and without chemotherapy in mHSPC."

"The positive outcomes from the ARANOTE trial provide physicians with additional data that could broaden the use of NUBEQA as a treatment option for more patients with metastatic hormone-sensitive prostate cancer, which accounts for approximately 10% of prostate cancer diagnoses in the United States," said Neal Shore, M.D., FACS, Medical Director, Carolina Urologic Research Center. "These data demonstrate the potential of this therapy to provide significant benefits to patients with mHSPC, regardless of chemotherapy use."

"The ARANOTE trial was designed to investigate NUBEQA plus ADT compared to placebo plus ADT to provide an additional treatment option for patients with metastatic hormone-sensitive prostate cancer," said Christian Rommel, Ph.D., Head of Research and Development at Bayer’s Pharmaceuticals Division. "Supported by our robust clinical development program, our goal is to expand the option of NUBEQA to as many patients as possible."

Bayer plans to submit the data from the ARANOTE trial to the U.S. Food and Drug Administration (FDA) to support the expanded use of NUBEQA in patients with mHSPC.

Detailed Results from ARANOTE1

Results of the rPFS analysis were consistent across prespecified subgroups, including 40% risk reduction (HR 0.60, 95% CI: 0.44-0.80) in patients with high-volume mHSPC and 70% risk reduction (HR 0.30, 95% CI: 0.15-0.60) in patients with low-volume disease. An analysis of immature overall survival data (OS), which measures the time from treatment until death from any cause, showed an HR of 0.81 (95% CI 0.59-1.12) versus placebo plus ADT. The ARANOTE data also suggested clinical benefits across all other secondary endpoints, including delaying the time to castration-resistant prostate cancer (CRPC) (HR 0.40; 95% CI, 0.32-0.51), time to PSA progression (HR 0.31; 95% CI 0.23-0.41), time to pain progression (HR 0.72; 95% CI 0.54-0.96), and time to initiation of subsequent systemic therapy (HR 0.40; 95% CI 0.29-0.56), compared to placebo plus ADT, though not assessed for statistical significance.

Incidence rates for adverse events Grade 3 or higher were similar between the two groups (35.5% and 35.7%, respectively). The incidence of fatigue was lower with NUBEQA plus ADT than with placebo plus ADT (5.6% and 8.1%, respectively).

About the ARANOTE Trial1

The primary endpoint of the ARANOTE trial is rPFS, measured as time from randomization to date of first documented radiological disease progression or death due to any cause, whichever occurs first. Secondary endpoints include overall survival (time to death from any cause), time to first castration-resistant event, time to initiation of subsequent anti-cancer therapy, time to prostate-specific antigen (PSA) progression, PSA undetectable rates, time to pain progression, and safety assessments.

About the ARASENS Trial3

The ARASENS trial (NCT02799602) is the only randomized Phase III, multi-center, double-blind, placebo-controlled trial prospectively designed to compare the use of a second-generation androgen receptor inhibitor (ARi) (NUBEQA) plus androgen deprivation therapy (ADT) and the chemotherapy docetaxel to ADT plus docetaxel in patients with metastatic hormone-sensitive prostate cancer (mHSPC). A total of 1,306 newly diagnosed patients were randomized in a 1:1 ratio to receive 600 mg of NUBEQA twice a day or matching placebo plus ADT and docetaxel.

The primary endpoint of the trial was overall survival (OS). Secondary endpoints included time to castration-resistant prostate cancer (CRPC), time to pain progression, time to first symptomatic skeletal event (SSE), and time to initiation of subsequent anticancer therapy, all measured at 12-week intervals, as well as adverse events (AEs) as a measure of safety and tolerability.

About NUBEQA (darolutamide)2

NUBEQA (darolutamide) is an androgen receptor inhibitor (ARi) with a distinct chemical structure that competitively inhibits androgen binding, AR nuclear translocation, and AR-mediated transcription.

In addition to the ARANOTE trial, darolutamide is being evaluated in a robust clinical development program, which includes studies across various stages of prostate cancer, including in the ARASTEP Phase III trial evaluating darolutamide plus ADT versus ADT alone in HSPC patients with high-risk biochemical recurrence (BCR), no evidence of metastatic disease by conventional imaging, and a positive PSMA PET/CT at baseline, as well as in the Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP) led international Phase III co-operative group DASL-HiCaP (ANZUP1801) trial evaluating NUBEQA as an adjuvant treatment for localized prostate cancer with very high risk of recurrence. Information about these trials can be found at www.clinicaltrials.gov.

NUBEQA is developed jointly by Bayer and Orion Corporation, a globally operating Finnish pharmaceutical company.

INDICATIONS

NUBEQA (darolutamide) is an androgen receptor inhibitor indicated for the treatment of adult patients with:

Non-metastatic castration-resistant prostate cancer (nmCRPC)
Metastatic hormone-sensitive prostate cancer (mHSPC) in combination with docetaxel
IMPORTANT SAFETY INFORMATION

Warnings & Precautions

Ischemic Heart Disease – In a study of patients with nmCRPC (ARAMIS), ischemic heart disease occurred in 3.2% of patients receiving NUBEQA versus 2.5% receiving placebo, including Grade 3-4 events in 1.7% vs. 0.4%, respectively. Ischemic events led to death in 0.3% of patients receiving NUBEQA vs. 0.2% receiving placebo. In a study of patients with mHSPC (ARASENS), ischemic heart disease occurred in 3.2% of patients receiving NUBEQA with docetaxel vs. 2% receiving placebo with docetaxel, including Grade 3-4 events in 1.3% vs. 1.1%, respectively. Ischemic events led to death in 0.3% of patients receiving NUBEQA with docetaxel vs. 0% receiving placebo with docetaxel. Monitor for signs and symptoms of ischemic heart disease. Optimize management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidemia. Discontinue NUBEQA for Grade 3-4 ischemic heart disease.

Seizure – In ARAMIS, Grade 1-2 seizure occurred in 0.2% of patients receiving NUBEQA vs. 0.2% receiving placebo. Seizure occurred 261 and 456 days after initiation of NUBEQA. In ARASENS, seizure occurred in 0.6% of patients receiving NUBEQA with docetaxel, including one Grade 3 event, vs. 0.2% receiving placebo with docetaxel. Seizure occurred 38 to 340 days after initiation of NUBEQA. It is unknown whether antiepileptic medications will prevent seizures with NUBEQA. Advise patients of the risk of developing a seizure while receiving NUBEQA and of engaging in any activity where sudden loss of consciousness could cause harm to themselves or others. Consider discontinuation of NUBEQA in patients who develop a seizure during treatment.

Embryo-Fetal Toxicity – Safety and efficacy of NUBEQA have not been established in females. NUBEQA can cause fetal harm and loss of pregnancy. Advise males with female partners of reproductive potential to use effective contraception during treatment with NUBEQA and for 1 week after the last dose.

Adverse Reactions

In ARAMIS, serious adverse reactions occurred in 25% of patients receiving NUBEQA vs. 20% of patients receiving placebo. Serious adverse reactions in ≥1% of patients who received NUBEQA included urinary retention, pneumonia, and hematuria. Fatal adverse reactions occurred in 3.9% of patients receiving NUBEQA vs. 3.2% of patients receiving placebo. Fatal adverse reactions in patients who received NUBEQA included death (0.4%), cardiac failure (0.3%), cardiac arrest (0.2%), general physical health deterioration (0.2%), and pulmonary embolism (0.2%). The most common adverse reactions (>2% with a ≥2% increase over placebo), including laboratory test abnormalities, were increased AST, decreased neutrophil count, fatigue, increased bilirubin, pain in extremity and rash. Clinically relevant adverse reactions occurring in ≥2% of patients treated with NUBEQA included ischemic heart disease and heart failure.

In ARASENS, serious adverse reactions occurred in 45% of patients receiving NUBEQA with docetaxel vs. 42% of patients receiving placebo with docetaxel. Serious adverse reactions in ≥2% of patients who received NUBEQA with docetaxel included febrile neutropenia (6%), decreased neutrophil count (2.8%), musculoskeletal pain (2.6%), and pneumonia (2.6%). Fatal adverse reactions occurred in 4% of patients receiving NUBEQA with docetaxel vs. 4% of patients receiving placebo with docetaxel. Fatal adverse reactions in patients who received NUBEQA included COVID-19/COVID-19 pneumonia (0.8%), myocardial infarction (0.3%), and sudden death (0.3%). The most common adverse reactions (≥10% with a ≥2% increase over placebo with docetaxel) were constipation, rash, decreased appetite, hemorrhage, increased weight, and hypertension. The most common laboratory test abnormalities (≥30%) were anemia, hyperglycemia, decreased lymphocyte count, decreased neutrophil count, increased AST, increased ALT, and hypocalcemia. Clinically relevant adverse reactions in <10% of patients who received NUBEQA with docetaxel included fractures, ischemic heart disease, seizures, and drug-induced liver injury.

Drug Interactions

Effect of Other Drugs on NUBEQA – Combined P-gp and strong or moderate CYP3A4 inducers decrease NUBEQA exposure, which may decrease NUBEQA activity. Avoid concomitant use.

Combined P-gp and strong CYP3A4 inhibitors increase NUBEQA exposure, which may increase the risk of NUBEQA adverse reactions. Monitor more frequently and modify NUBEQA dose as needed.

Effects of NUBEQA on Other Drugs – NUBEQA inhibits breast cancer resistance protein (BCRP) transporter. Concomitant use increases exposure (AUC) and maximal concentration of BCRP substrates, which may increase the risk of BCRP substrate-related toxicities. Avoid concomitant use where possible. If used together, monitor more frequently for adverse reactions, and consider dose reduction of the BCRP substrate.

NUBEQA inhibits OATP1B1 and OATP1B3 transporters. Concomitant use may increase plasma concentrations of OATP1B1 or OATP1B3 substrates. Monitor more frequently for adverse reactions and consider dose reduction of these substrates.

Review the Prescribing Information of drugs that are BCRP, OATP1B1, and OATP1B3 substrates when used concomitantly with NUBEQA.

For important risk and use information about NUBEQA, please see the full Prescribing Information.

About Metastatic Hormone-Sensitive Prostate Cancer

Prostate cancer is the second most common cancer in men and the fifth most common cause of cancer death in men worldwide.4 In 2020, an estimated 1.4 million men were diagnosed with prostate cancer, including almost 300,000 cases in the U.S., and about 375,000 died from the disease worldwide.5,6

At the time of diagnosis, most men have localized prostate cancer, meaning their cancer is confined to the prostate gland and can be treated with curative surgery or radiotherapy. Upon relapse when the disease will metastasize or spread, androgen deprivation therapy (ADT) is the cornerstone of treatment for this hormone-sensitive disease. Approximately 10% of men will already present with mHSPC when first diagnosed.7,8,9 Men with metastatic hormone-sensitive prostate cancer (mHSPC) will start their treatment with hormone therapy, such as ADT, androgen receptor inhibitor (ARi) plus ADT, or a combination of the chemotherapy docetaxel and ADT. Despite this treatment, most men with mHSPC will eventually progress to castration-resistant prostate cancer (CRPC), a condition with limited survival.