On August 19, 2024 Astellas Pharma Inc. (TSE:4503, President and CEO: Naoki Okamura, "Astellas") reported that the Center for Drug Evaluation (CDE) of China’s National Medical Products Administration (NMPA) has approved PADCEV (enfortumab vedotin) for the treatment of adult patients with locally advanced or metastatic urothelial cancer (la/mUC) after prior treatment with platinum-containing chemotherapy and programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitors (Press release, Astellas, AUG 19, 2024, View Source [SID1234645977]).

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

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

                  Schedule Your 30 min Free Demo!

Urothelial cancer is a debilitating and often aggressive cancer that affects both the lower urinary tract (bladder and urethra) and upper urinary tract (ureter and renal pelvis).3,4,5 Over 92,000 people were diagnosed with bladder cancer in China in 2022, and approximately 41,000 deaths were reported as a result of the disease.6 Survival rates are particularly poor with locally advanced or metastatic urothelial cancer, driving the urgent need for new therapies that extend patients’ lives.

Professor Guo Jun, Principal Investigator, EV-203 trial and Director of the Department of Melanoma and Urological Oncology, Beijing Cancer Hospital, China
"On August 13, 2024, the NMPA officially approved the use of enfortumab vedotin for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma (la/mUC) after prior treatment with platinum-containing chemotherapy and PD-1/PD-L1 inhibitors. This approval, based on a global Phase 3 registration study as well as a bridging study in Chinese patients, is a milestone event where patients will now have access to this new antibody-drug conjugate (ADC) treatment in China."

Professor Dingwei Ye, Academic Leader, Department of Urology and Principal Expert, Urological Oncology MDT Management, Fudan University-Affiliated Cancer Hospital, China
"Enfortumab vedotin will benefit patients in our country, bringing a new treatment to those with locally advanced or metastatic urothelial carcinoma (la/mUC) who have previously received platinum-containing chemotherapy and PD-1/PD-L1 inhibitors."

Professor Zhisong He, Deputy Director, Institute of Urology, Peking University First Hospital, China
"Enfortumab vedotin is an ADC that is directed against Nectin-4. The approval of the EV-203 indication expands doctors’ treatment choices."

Ahsan Arozullah, M.D., M.P.H., Senior Vice President, Head of Oncology Development, Astellas
"We remain committed to driving scientific progress that leads to meaningful changes in the course of cancer across the globe. The approval of enfortumab vedotin by the CDE provides patients in China with another treatment option for locally advanced or metastatic urothelial cancer, providing hope of better outcomes for those affected by this condition."

The CDE’s approval of enfortumab vedotin is supported by data from the global EV-301 and China EV-203 trials. EV-203 serves as a bridging trial to EV-301, a Phase 3 randomized trial that has supported global registrations of enfortumab vedotin. EV-203 (NCT04995419) is a single-arm, open-label, multicenter Phase 2 trial of enfortumab vedotin in Chinese patients with la/mUC who previously received a PD-1/PD-L1 inhibitor and platinum-based chemotherapy.1 Results showed that EV-203 met its primary endpoint, demonstrating statistical significance in ORR for patients treated with enfortumab vedotin alone compared to historical controls (37.5% [n/N=15/40; 95% CI: 22.7–54.2]), as confirmed by the independent review committee.1 The efficacy and pharmacokinetic data from the trial are consistent with global data, with safety findings demonstrating that the majority of treatment related adverse events were grade 1–2.1

Astellas has already reflected the impact from the approval for enfortumab vedotin in China in its financial forecast for the current fiscal year ending March 31, 2025.

For more information, please see the press release "Astellas and Seagen Announce China’s National Medical Products Administration Accepts Biologics License Application for Enfortumab Vedotin in Certain Patients with Locally Advanced or Metastatic Urothelial Cancer" issued on March 9, 2023: View Source

About EV-203
The China EV-203 trial is a Phase 2, multicenter, single-arm bridging trial designed to evaluate the efficacy, safety, and pharmacokinetic performance of enfortumab vedotin as a treatment for patients in China. The trial enrolled a total of 40 patients with la/mUC who previously received a PD-1/PD-L1 inhibitor and platinum-based chemotherapy.1

The trial met the primary endpoint of confirmed objective response rate (ORR) by independent review committee, achieved by 37.5% of patients who received treatment with enfortumab vedotin (n/N=15/40, 95% CI: 22.7-54.2). Complete response was achieved in 1 (2.5%) patient and partial response in 14 (35.0%) patients.1

No new safety signals were identified during the trial. Most treatment-related adverse events reported with enfortumab vedotin were grade 1–2. Two patients discontinued treatment with enfortumab vedotin due to experiencing treatment-related adverse events (acute coronary syndrome and hyperglycemia/rash).1

For more information on the EV-203 trial (NCT04995419) go to View Source

About EV-301
The global EV-301 trial (NCT03474107) is a multicenter, open-label, randomized Phase 3 trial designed to evaluate enfortumab vedotin versus physician’s choice of chemotherapy (docetaxel, paclitaxel or vinflunine) in 608 patients with locally advanced or metastatic urothelial cancer who were previously treated with a PD-1/PD-L1 inhibitor and platinum-containing therapies.2 The primary endpoint was overall survival and secondary endpoints included progression-free survival, overall response rate, duration of response and disease control rate, as well as assessment of safety/tolerability and quality-of-life parameters.

Results from EV-301 showed that median overall survival was longer in the enfortumab vedotin group than in the chemotherapy group (12.88 vs. 8.97 months respectively; HR= 0.70; 95% CI: 0.56-0.89; p=0.001).2 Progression-free survival was also longer in the enfortumab vedotin group than in the chemotherapy group (5.55 vs. 3.71 months respectively; HR=0.62; 95% CI: 0.51-0.75; P<0.001).2 The incidence of treatment-related adverse events was similar in the two groups (93.9% in the enfortumab vedotin group and 91.8% in the chemotherapy group). The incidence of events of grade 3 or higher was also similar in the two groups (51.4% and 49.8%, respectively).2 Results were published in the New England Journal of Medicine.

For more information on the EV-301 trial (NCT03474107) go to View Source

About Bladder and Urothelial Cancer
Urothelial cancer, or bladder cancer, begins in the urothelial cells, which line the urethra, bladder, ureters, renal pelvis, and some other organs.5 Urothelial cancer accounts for 90% of all bladder cancers and can also be found in the renal pelvis, ureter, and urethra.7,8 If bladder cancer has spread to surrounding organs or muscles, it is called locally advanced disease.9 If the cancer has spread to other parts of the body, it is called metastatic disease.10 Approximately 12% of cases are locally advanced or metastatic urothelial cancer at diagnosis.11

In China, the incidence rate of bladder cancer in 2022 ranked 11th among all cancers, with over 92,000 new cases diagnosed that year.6 The five year prevalence of bladder cancer in China is estimated to be 2.5/100,000 cases, or 276,102 cases.6 Continuous treatment and surveillance makes bladder cancer one of the most expensive cancer types over the lifetime of a patient, and the costliest cancer when compared to other malignancies.12

About PADCEV (enfortumab vedotin)
PADCEV (enfortumab vedotin) is a first-in-class antibody-drug conjugate (ADC) that is directed against Nectin-4, a protein located on the surface of cells and highly expressed in bladder cancer.13,14 Nonclinical data suggest the anticancer activity of enfortumab vedotin is due to its binding to Nectin-4-expressing cells, followed by the internalization and release of the anti-tumor agent monomethyl auristatin E (MMAE) into the cell, which result in the cell not reproducing (cell cycle arrest) and in programmed cell death (apoptosis).13

Ongoing Investigational Trials
EV-302 (NCT04223856) is an open-label, randomized, controlled Phase 3 trial, evaluating enfortumab vedotin in combination with pembrolizumab versus platinum-containing chemotherapy in patients with previously untreated locally advanced or metastatic urothelial cancer (la/mUC) who were eligible for cisplatin- or carboplatin-containing chemotherapy regardless of PD-L1 status.

EV-103 (NCT03288545) is an ongoing, multi-cohort, open-label, multicenter Phase 1b/2 trial investigating enfortumab vedotin alone or in combination with pembrolizumab and/or chemotherapy in first- or second-line settings in patients with la/mUC and in patients with muscle-invasive bladder cancer (MIBC).

EV-104 (NCT05014139) is a Phase 1 trial exploring enfortumab vedotin in patients with non-muscle invasive bladder cancer (NMIBC). The trial will be conducted in two parts, assessing dose escalation and dose expansion with enfortumab vedotin when administered intravesically as a monotherapy.

Enfortumab vedotin in combination with pembrolizumab is being investigated in an extensive program in multiple stages of urothelial cancer, including two Phase 3 clinical trials in MIBC in EV-304 (NCT04700124, also known as KEYNOTE-B15) and EV-303 (NCT03924895, also known as KEYNOTE-905).

EV-202 (NCT04225117) is an ongoing, multi-cohort, open-label, multicenter Phase 2 trial investigating enfortumab vedotin alone in patients with previously treated advanced solid tumors. This trial also has a cohort that is investigating enfortumab vedotin in combination with pembrolizumab in patients with previously untreated recurrent/ metastatic head and neck squamous cell carcinoma.

On August 19, 2024 U.S. Food and Drug Administration ("FDA") reported to have lifted the partial clinical hold that was placed on MediLink Therapeutics’ (Suzhou) Co., Ltd. ("MediLink") Phase I trial evaluating BNT326/YL202 (NCT05653752), which was announced on June 17, 2024 (Press release, BioNTech, AUG 19, 2024, View Source [SID1234645978]). The complete response including data analysis, updated investigator brochure and informed consent for patients, and amended clinical trial protocol meets the FDA’s requirements by incorporating additional risk mitigation measures. BNT326/YL202 is a Human Epidermal Growth Factor Receptor 3 ("HER3")-targeting antibody-drug conjugate ("ADC") candidate that is being developed in collaboration between BioNTech SE ("BioNTech") and MediLink. The trial recruitment will be re-initiated. Clinical development will focus on dose levels no higher than 3 mg/kg, where the safety profile was manageable and encouraging clinical activity was observed.

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

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

                  Schedule Your 30 min Free Demo!

The study sponsor MediLink had observed a dose level-dependent trend of treatment-related adverse events ("TRAEs") of BNT326/YL202, in particular neutrophil count decrease ("neutropenia") and an increasing rate of mucositis events. These events are common TRAEs of established chemotherapies and increase a person’s risk for developing serious infections.[1], [2] Neutropenia is usually managed by dose reduction, dose interruption, and/or administration of primary prophylaxis, such as recombinant granulocyte colony-stimulating factors ("G-CSFs") in appropriate patients based on individualized febrile neutropenia risk assessment of the patient and of the chemotherapy regimen.

Based on emerging safety data from the ongoing trial evaluating BNT326/YL202, the companies swiftly and proactively took precautionary measures, including not enrolling additional patients in dose cohorts higher than 3 mg/kg, and reducing dose levels for participants already enrolled at higher dose levels in the trial. In parallel, MediLink has notified the FDA and worked with BioNTech on analyzing the emerging data and implementing further risk mitigation measures. These include updates to the investigator brochure, the informed consent for patients, and the clinical trial protocol with amended guidance on dose delay, reduction and modification, and prophylactic medications addressing TRAEs.

BioNTech and MediLink are committed to patient safety and will continue to develop BNT326/YL202 in solid tumors with high unmet medical need.

On August 19, 2024 Scorpion Therapeutics, Inc. ("Scorpion"), a pioneering clinical-stage oncology company dedicated to transforming the lives of cancer patients by redefining the frontier of precision oncology, reported that it was selected to present initial, first-in-human clinical results from the Phase 1/2 study of STX-478, a mutant-selective PI3Kα inhibitor, in advanced solid tumor patients in a Proffered Paper late-breaking session at the European Society for Medical Oncology ("ESMO") Congress 2024, taking place September 13 – 17, 2024 in Barcelona, Spain (Press release, Scorpion Therapeutics, AUG 19, 2024, View Source [SID1234645996]).

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

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

                  Schedule Your 30 min Free Demo!

"The presentation of first-in-human clinical data for our lead candidate, STX-478, marks an important milestone for patients living with advanced solid tumors driven by PI3Kα mutations, especially HR+/HER2- breast cancer, and for Scorpion as we work to broaden the reach and impact of precision oncology for patients with high unmet medical need," said Mark Chao, M.D., Ph.D., Chief Medical Officer of Scorpion. "While PI3Kα has been one of the highest profile targets in cancer for years, current treatment options suffer from toxicity limitations and subpar efficacy due to a lack of mutant selectivity. These initial data will provide early insight into how STX-478’s differentiated profile translates to potentially superior outcomes in PI3Kα-mutated cancers, and we look forward to presenting initial assessments of safety, pharmacokinetic and pharmacodynamic data and preliminary efficacy data at the ESMO (Free ESMO Whitepaper) 2024 Congress."

Details of the Proffered Paper presentation are as follows:

Title: First-in-human Results of STX-478, a Mutant-selective PI3Kα Inhibitor, in Advanced Solid Tumor Patients
Presentation Number: LBA27
Session Name: Proffered paper session 2: Developmental therapeutics (ID 156)
Session Date & Time: Sunday, September 15, 2024, at 14:45 CEST – 16:15 CEST (8:45 a.m. – 10:15 a.m. ET)
Presentation Time: 14:55 CEST – 15:05 CEST (8:55 a.m. – 9:05 a.m. ET)
Location: Salamanca Auditorium – Hall 5
Presenter: Alberto J. Montero, M.D. (University Hospitals Cleveland, OH, USA)

According to ESMO (Free ESMO Whitepaper), the late-breaking abstract will be published via the ESMO (Free ESMO Whitepaper) website at 00:05 CEST on September 15 (6:05 p.m. ET on September 14). Data presented at the conference will be available to view in the "Publications & Presentations" section of the Scorpion website (View Source) following the ESMO (Free ESMO Whitepaper) 2024 Congress.

About STX-478

STX-478 was designed to improve outcomes in patients harboring PI3Kα mutations, one of the most prevalent drivers of cancer, occurring in over 166,000 patients per year with breast, gynecological and other solid tumors in the United States alone. In preclinical models, STX-478 demonstrated robust activity across a range of PI3Kα mutations while sparing wild-type PI3Kα inhibition in normal tissues; previous generations of non-selective PI3Kα inhibitors have limited patient benefit due to these on-target toxicities. Scorpion’s Phase 1/2 clinical trial is a multi-center, global, open-label study designed to evaluate the safety and tolerability of STX-478 in multiple ascending doses for patients with locally advanced or metastatic HR+/HER2- breast cancer and other solid tumors driven by PI3Kα mutations. The program entered the clinic in 2023 and has rapidly advanced, now in multiple expansion cohorts across a range of solid tumors and in breast cancer as monotherapy and in combinations with fulvestrant and CDK4/6 inhibitors. To learn more about the first-in-human trial of STX-478, please visit this page.

On August 19, 2024 Bristol Myers Squibb (NYSE: BMY) reported that the European Medicines Agency (EMA) has validated its Type II variation application to expand the indication for Breyanzi (lisocabtagene maraleucel; liso-cel), a CD19-directed chimeric antigen receptor (CAR) T cell therapy, to include the treatment of adult patients with relapsed or refractory follicular lymphoma (FL) who have received two or more prior lines of systemic therapy (Press release, Bristol-Myers Squibb, AUG 19, 2024, View Source [SID1234645979]). Validation of the application confirms the submission is complete and allows the scientific review to begin under the EMA’s centralized review procedure.

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

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

                  Schedule Your 30 min Free Demo!

"Follicular lymphoma impacts a significant number of people, and those with relapsed or refractory disease tend to experience shorter responses with each new line of therapy," said Anne Kerber, senior vice president, head of Late Clinical Development, Hematology, Oncology and Cell Therapy (HOCT), Bristol Myers Squibb. " Breyanzi represents a differentiated CAR T cell therapy, and we look forward to working with the European Medicines Agency to bring this important treatment option to patients with relapsed or refractory follicular lymphoma with the goal of improving outcomes and providing lasting remission."

The application is supported by data from the Phase 2 TRANSCEND FL study, the largest clinical trial to date to evaluate a CAR T cell therapy in patients with relapsed or refractory indolent non-Hodgkin lymphoma (NHL), including FL. The study enrolled adults with relapsed or refractory FL treated with Breyanzi in the high-risk second-line and third-line plus setting. In the study, Breyanzi demonstrated a high overall response rate, the study’s primary endpoint, with responses being deep and durable. The safety of Breyanzi in FL is consistent with the well-established and manageable safety profile of Breyanzi observed across clinical trials.

Follicular lymphoma is the second most common form of NHL, accounting for 20 to 30 percent of all NHL cases. FL has historically been considered an incurable disease with patients frequently relapsing following front-line therapy and prognosis worsening after each subsequent relapse. Despite advances in treatment, there remains an unmet need for additional options that offer treatment-free intervals with durable, complete responses.

Breyanzi is currently approved in the European Union for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), high grade B-cell lymphoma (HGBCL), primary mediastinal large B-cell lymphoma (PMBCL) and FL grade 3B (FL3B), who relapsed within 12 months from completion of, or are refractory to, first-line chemoimmunotherapy, and for the treatment of adult patients with relapsed or refractory DLBCL, PMBCL, and FL3B after two or more lines of systemic therapy.

A supplemental New Drug Application for Breyanzi for the treatment of relapsed or refractory follicular lymphoma after one prior line of systemic therapy in patients with high-risk FL and after two or more lines of systemic therapy has also been approved by Japan’s Ministry of Health, Labour and Welfare based on results of the TRANSCEND FL study, making it the first CAR T approved in the second-line setting anywhere and the third approval for Breyanzi in Japan.

About TRANSCEND FL

TRANSCEND FL (NCT04245839) is an open-label, global, multicenter, Phase 2, single-arm study to determine the efficacy and safety of Breyanzi in adult patients with relapsed or refractory indolent B-cell non-Hodgkin lymphoma, including follicular lymphoma. The primary outcome measure is overall response rate, including best overall response of complete response or partial response as determined by an Independent Review Committee. Secondary outcome measures include complete response rate, duration of response, progression-free survival, and safety.

About Breyanzi

Breyanzi is a CD19-directed CAR T cell therapy with a 4-1BB costimulatory domain, which enhances the expansion and persistence of the CAR T cells. Breyanzi is made from a patient’s own T cells, which are collected and genetically reengineered to become CAR T cells that are then delivered via infusion as a one-time treatment.

Breyanzi is approved in the U.S. for the treatment of relapsed or refractory large B-cell lymphoma (LBCL) after at least one prior line of therapy, has received accelerated approval for the treatment of relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma after at least two prior lines of therapy and relapsed or refractory follicular lymphoma in the third-line plus setting, and is approved for the treatment of relapsed or refractory mantle cell lymphoma (MCL) in the third-line plus setting. Breyanzi is also approved in Japan, the European Union (EU), and Switzerland for the second-line treatment of relapsed or refractory LBCL; in Japan, the EU, Switzerland, the UK and Canada for relapsed and refractory LBCL after two or more lines of systemic therapy; and in Japan for the treatment of relapsed or refractory patients with high-risk follicular lymphoma after one prior line of systemic therapy and in patients after two or more lines of systemic therapy.

Bristol Myers Squibb’s clinical development program for Breyanzi includes clinical studies in other types of lymphoma. For more information, visit clinicaltrials.gov .

Full European Summary of Product Characteristics for Breyanzi is available from the EMA website at www.ema.europa.eu .

U.S. FDA-Approved Indications

BREYANZI is a CD19-directed genetically modified autologous T cell immunotherapy indicated for the treatment of:

adult patients with large B-cell lymphoma (LBCL), including diffuse large B-cell lymphoma (DLBCL) not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B, who have:
refractory disease to first-line chemoimmunotherapy or relapse within 12 months of first-line chemoimmunotherapy; or
refractory disease to first-line chemoimmunotherapy or relapse after first-line chemoimmunotherapy and are not eligible for hematopoietic stem cell transplantation (HSCT) due to comorbidities or age; or
relapsed or refractory disease after two or more lines of systemic therapy.
Limitations of Use : BREYANZI is not indicated for the treatment of patients with primary central nervous system lymphoma.

adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who have received at least 2 prior lines of therapy, including a Bruton tyrosine kinase (BTK) inhibitor and a B-cell lymphoma 2 (BCL-2) inhibitor. This indication is approved under accelerated approval based on response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).
adult patients with relapsed or refractory follicular lymphoma (FL) who have received 2 or more prior lines of systemic therapy. This indication is approved under accelerated approval based on response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).
adult patients with relapsed or refractory mantle cell lymphoma (MCL) who have received at least 2 prior lines of systemic therapy, including a Bruton tyrosine kinase (BTK) inhibitor.
U.S. Important Safety Information

WARNING: CYTOKINE RELEASE SYNDROME, NEUROLOGIC TOXICITIES, AND SECONDARY HEMATOLOGICAL MALIGNANCIES

Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients receiving BREYANZI. Do not administer BREYANZI to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab with or without corticosteroids.
Neurologic toxicities, including fatal or life-threatening reactions, occurred in patients receiving BREYANZI, including concurrently with CRS, after CRS resolution, or in the absence of CRS. Monitor for neurologic events after treatment with BREYANZI. Provide supportive care and/or corticosteroids as needed.
T cell malignancies have occurred following treatment of hematologic malignancies with BCMA- and CD19-directed genetically modified autologous T cell immunotherapies, including BREYANZI.
BREYANZI is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the BREYANZI REMS.
Cytokine Release Syndrome

Cytokine release syndrome (CRS), including fatal or life-threatening reactions, occurred following treatment with BREYANZI. In clinical trials of BREYANZI, which enrolled a total of 702 patients with non-Hodgkin lymphoma (NHL), CRS occurred in 54% of patients, including ≥ Grade 3 CRS in 3.2% of patients. The median time to onset was 5 days (range: 1 to 63 days). CRS resolved in 98% of patients with a median duration of 5 days (range: 1 to 37 days). One patient had fatal CRS and 5 patients had ongoing CRS at the time of death. The most common manifestations of CRS (≥10%) were fever, hypotension, tachycardia, chills, hypoxia, and headache.

Serious events that may be associated with CRS include cardiac arrhythmias (including atrial fibrillation and ventricular tachycardia), cardiac arrest, cardiac failure, diffuse alveolar damage, renal insufficiency, capillary leak syndrome, hypotension, hypoxia, and hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS).

Ensure that 2 doses of tocilizumab are available prior to infusion of BREYANZI.

Neurologic Toxicities

Neurologic toxicities that were fatal or life-threatening, including immune effector cell-associated neurotoxicity syndrome (ICANS), occurred following treatment with BREYANZI. Serious events including cerebral edema and seizures occurred with BREYANZI. Fatal and serious cases of leukoencephalopathy, some attributable to fludarabine, also occurred.

In clinical trials of BREYANZI, CAR T cell-associated neurologic toxicities occurred in 31% of patients, including ≥ Grade 3 cases in 10% of patients. The median time to onset of neurotoxicity was 8 days (range: 1 to 63 days). Neurologic toxicities resolved in 88% of patients with a median duration of 7 days (range: 1 to 119 days). Of patients developing neurotoxicity, 82% also developed CRS.

The most common neurologic toxicities (≥5%) included encephalopathy, tremor, aphasia, headache, dizziness, and delirium.

CRS and Neurologic Toxicities Monitoring

Monitor patients daily for at least 7 days following BREYANZI infusion at a REMS-certified healthcare facility for signs and symptoms of CRS and neurologic toxicities and assess for other causes of neurological symptoms. Monitor patients for signs and symptoms of CRS and neurologic toxicities for at least 4 weeks after infusion and treat promptly. At the first sign of CRS, institute treatment with supportive care, tocilizumab, or tocilizumab and corticosteroids as indicated. Manage neurologic toxicity with supportive care and/or corticosteroid as needed. Counsel patients to seek immediate medical attention should signs or symptoms of CRS or neurologic toxicity occur at any time.

BREYANZI REMS

Because of the risk of CRS and neurologic toxicities, BREYANZI is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the BREYANZI REMS. The required components of the BREYANZI REMS are:

Healthcare facilities that dispense and administer BREYANZI must be enrolled and comply with the REMS requirements.
Certified healthcare facilities must have on-site, immediate access to tocilizumab.
Ensure that a minimum of 2 doses of tocilizumab are available for each patient for infusion within 2 hours after BREYANZI infusion, if needed for treatment of CRS.
Further information is available at www.BreyanziREMS.com , or contact Bristol Myers Squibb at 1-866-340-7332.

Hypersensitivity Reactions

Allergic reactions may occur with the infusion of BREYANZI. Serious hypersensitivity reactions, including anaphylaxis, may be due to dimethyl sulfoxide (DMSO).

Serious Infections

Severe infections, including life-threatening or fatal infections, have occurred in patients after BREYANZI infusion. In clinical trials of BREYANZI, infections of any grade occurred in 34% of patients, with Grade 3 or higher infections occurring in 12% of all patients. Grade 3 or higher infections with an unspecified pathogen occurred in 7%, bacterial infections in 3.7%, viral infections in 2%, and fungal infections in 0.7% of patients. One patient who received 4 prior lines of therapy developed a fatal case of John Cunningham (JC) virus progressive multifocal leukoencephalopathy 4 months after treatment with BREYANZI. One patient who received 3 prior lines of therapy developed a fatal case of cryptococcal meningoencephalitis 35 days after treatment with BREYANZI.

Febrile neutropenia developed after BREYANZI infusion in 8% of patients. Febrile neutropenia may be concurrent with CRS. In the event of febrile neutropenia, evaluate for infection and manage with broad-spectrum antibiotics, fluids, and other supportive care as medically indicated.

Monitor patients for signs and symptoms of infection before and after BREYANZI administration and treat appropriately. Administer prophylactic antimicrobials according to standard institutional guidelines. Avoid administration of BREYANZI in patients with clinically significant, active systemic infections.

Viral reactivation: Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients treated with drugs directed against B cells. In clinical trials of BREYANZI, 35 of 38 patients with a prior history of HBV were treated with concurrent antiviral suppressive therapy.

Perform screening for HBV, HCV, and HIV in accordance with clinical guidelines before collection of cells for manufacturing. In patients with prior history of HBV, consider concurrent antiviral suppressive therapy to prevent HBV reactivation per standard guidelines.

Prolonged Cytopenias

Patients may exhibit cytopenias not resolved for several weeks following lymphodepleting chemotherapy and BREYANZI infusion. In clinical trials of BREYANZI, Grade 3 or higher cytopenias persisted at Day 29 following BREYANZI infusion in 35% of patients, and included thrombocytopenia in 25%, neutropenia in 22%, and anemia in 6% of patients. Monitor complete blood counts prior to and after BREYANZI administration.

Hypogammaglobulinemia

B-cell aplasia and hypogammaglobulinemia can occur in patients receiving BREYANZI. In clinical trials of BREYANZI, hypogammaglobulinemia was reported as an adverse reaction in 10% of patients. Hypogammaglobulinemia, either as an adverse reaction or laboratory IgG level below 500 mg/dL after infusion, was reported in 30% of patients. Monitor immunoglobulin levels after treatment with BREYANZI and manage using infection precautions, antibiotic prophylaxis, and immunoglobulin replacement as clinically indicated.

Live vaccines: The safety of immunization with live viral vaccines during or following BREYANZI treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during BREYANZI treatment, and until immune recovery following treatment with BREYANZI.

Secondary Malignancies

Patients treated with BREYANZI may develop secondary malignancies. T cell malignancies have occurred following treatment of hematologic malignancies with BCMA- and CD19-directed genetically modified autologous T cell immunotherapies, including BREYANZI. Mature T cell malignancies, including CAR-positive tumors, may present as soon as weeks following infusion, and may include fatal outcomes. Monitor lifelong for secondary malignancies. In the event that a secondary malignancy occurs, contact Bristol Myers Squibb at 1-888-805-4555 for reporting and to obtain instructions on collection of patient samples for testing.

Effects on Ability to Drive and Use Machines

Due to the potential for neurologic events, including altered mental status or seizures, patients receiving BREYANZI are at risk for developing altered or decreased consciousness or impaired coordination in the 8 weeks following BREYANZI administration. Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, for at least 8 weeks.

Immune Effector Cell-Associated Hemophagocytic Lymphohistiocytosis-Like Syndrome (IEC-HS)

Immune Effector Cell-Associated Hemophagocytic Lymphohistiocytosis-Like Syndrome (IEC-HS), including fatal or life-threatening reactions, occurred following treatment with BREYANZI. Three of 89 (3%) safety evaluable patients with R/R CLL/SLL developed IEC-HS. Time to onset of IEC-HS ranged from 7 to 18 days. Two of the 3 patients developed IEC-HS in the setting of ongoing CRS and 1 in the setting of ongoing neurotoxicity. IEC-HS was fatal in 2 of 3 patients. One patient had fatal IEC-HS and one had ongoing IEC-HS at time of death. IEC-HS is a life-threatening condition with a high mortality rate if not recognized and treated early. Treatment of IEC-HS should be administered per current practice guidelines.

Adverse Reactions

The most common adverse reaction(s) (incidence ≥30%) in:

LBCL are fever, cytokine release syndrome, fatigue, musculoskeletal pain, and nausea. The most common Grade 3-4 laboratory abnormalities include lymphocyte count decrease, neutrophil count decrease, platelet count decrease, and hemoglobin decrease.
CLL/SLL are cytokine release syndrome, encephalopathy, fatigue, musculoskeletal pain, nausea, edema, and diarrhea. The most common Grade 3-4 laboratory abnormalities include neutrophil count decrease, white blood cell decrease, hemoglobin decrease, platelet count decrease, and lymphocyte count decrease.
FL is cytokine release syndrome. The most common Grade 3-4 laboratory abnormalities include lymphocyte count decrease, neutrophil count decrease, and white blood cell decrease.
MCL are cytokine release syndrome, fatigue, musculoskeletal pain, and encephalopathy. The most common Grade 3-4 laboratory abnormalities include neutrophil count decrease, white blood cell decrease, and platelet count decrease.
Please see full Prescribing Information , including Boxed WARNINGS and Medication Guide .

Bristol Myers Squibb: Creating a Better Future for People with Cancer

Bristol Myers Squibb is inspired by a single vision—transforming patients’ lives through science. The goal of the company’s cancer research is to deliver medicines that offer each patient a better, healthier life and to make cure a possibility. Building on a legacy across a broad range of cancers that have changed survival expectations for many, Bristol Myers Squibb researchers are exploring new frontiers in personalized medicine, and through innovative digital platforms, are turning data into insights that sharpen their focus. Deep understanding of causal human biology, cutting-edge capabilities and differentiated research platforms uniquely position the company to approach cancer from every angle.

Cancer can have a relentless grasp on many parts of a patient’s life, and Bristol Myers Squibb is committed to taking actions to address all aspects of care, from diagnosis to survivorship. As a leader in cancer care, Bristol Myers Squibb is working to empower all people with cancer to have a better future.

On August 19, 2024 MOMA Therapeutics, a clinical-stage biopharmaceutical company discovering and developing a new generation of precision therapeutics, reported that the first patient has been dosed in its Phase 1 clinical trial to assess the safety and tolerability of MOMA-313, a novel, highly potent and selective oral polymerase theta helicase inhibitor (Press release, MOMA Therapeutics, AUG 19, 2024, View Source [SID1234645997]).

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

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

                  Schedule Your 30 min Free Demo!

MOMA-313 is initially being developed in combination with a PARP inhibitor for patients with solid tumors harboring alterations in certain DNA repair genes, including subgroups of prostate cancer, pancreatic cancer and breast cancer.

In parallel, MOMA announced the selection of a development candidate for its second lead program, MOMA-341, an oral potent and selective covalent Werner helicase inhibitor for treatment of cancers with microsatellite instability. An IND application filing with the FDA is anticipated in the first quarter of 2025.

"We are excited to be progressing two molecules with best-in-class potential toward the benefit of cancer patients in need in such close proximity," said Asit Parikh, M.D., Ph.D., chief executive officer of MOMA. "The advance into clinical development for a company founded as an idea on paper a few years back is humbling. This progress serves as a testament to the excellence and unwavering commitment of the entire MOMA team."

"Advancing two highly potent and selective drug candidates derived from our proprietary KNOMATIC platform toward the clinic is a unique privilege," added Peter Hammerman, M.D., Ph.D., chief scientific officer of MOMA. "The goal with each candidate is to translate groundbreaking science into life-altering medicine."

About MOMA-313 and the Phase 1 Trial

MOMA-313 is a potent and selective oral polymerase theta (Polθ) helicase inhibitor. Polθ is involved in the repair of DNA double-strand breaks that arise during DNA replication. The Phase 1 trial (NCT06545942) is a multi-center, open-label study designed to evaluate the safety and tolerability of MOMA-313 as monotherapy and in combination with the PARP inhibitor olaparib for patients where a PARP inhibitor would be expected to provide benefit. Response to PARP inhibitors can be short-lived due to primary and acquired resistance. Pre-clinical studies suggest that combining a PARP inhibitor with a Polθ inhibitor could afford unique mechanistic potential to deepen and prolong that response.

About MOMA-341

MOMA is developing MOMA-341 as an oral, potent and selective covalent inhibitor of Werner helicase with a novel chemical scaffold as monotherapy and in combination with chemotherapy and immunotherapy in tumors with microsatellite instability (e.g., colorectal, gastric, endometrial cancers).

About the KNOMATIC platform

The KNOMATIC platform integrates deep structural insights, advanced hit-finding technologies, and computation-enabled lead optimization to accelerate discovery of novel therapeutics targeting families of highly dynamic proteins, such as ATPases and GTPases. MOMA-313 and MOMA-341 were discovered and developed through the application of the KNOMATIC platform.