On December 11, 2021 Sanofi reported that Sarclisa (isatuximab) trial is first Phase 3 study to meet primary endpoint of minimal residual disease negativity in transplant-eligible patients with newly diagnosed multiple myeloma (Press release, Sanofi, DEC 11, 2021, View Source [SID1234596806])

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Sarclisa combination therapy is first to demonstrate superiority to standard of care lenalidomide, bortezomib and dexamethasone (RVd) in a Phase 3 trial
50.1% of patients achieved undetectable levels of disease after 18 weeks of induction treatment with Sarclisa-RVd
GMMG will share the results as an oral presentation, and as part of the press program, at ASH (Free ASH Whitepaper) 2021

December 11, 2021

The Phase 3 HD7 trial, conducted by the German-Speaking Myeloma Multicenter Group (GMMG), met the primary endpoint, the rate of minimal residual disease (MRD) negativity after induction therapy and before transplant in patients with newly diagnosed multiple myeloma (MM) treated with Sarclisa (isatuximab) in combination with lenalidomide, bortezomib and dexamethasone (RVd). This is the first Phase 3 trial to evaluate MRD negativity at the end of induction as a primary endpoint, and to demonstrate statistically significant improvement in rates of MRD negativity in this patient population by adding an anti-CD38 monoclonal antibody to RVd. MRD negativity is an important clinical endpoint associated with better patient outcomes, which is meaningful for MM where most patients relapse.1

"It is unprecedented for half of patients to achieve MRD negativity this early in treatment with this regimen," said Hartmut Goldschmidt, M.D., President of GMMG, Professor of Medicine at the Heidelberg University Hospital (UKHD), Germany and principal investigator of the study. "We know that achieving deeper responses earlier in treatment may translate to longer periods of progression free survival and are excited about these results."

After an induction phase of 18 weeks, the rate of MRD negativity for patients receiving Sarclisa combination therapy (n=331) was 50.1% versus 35.6% for those who received RVd (n=329) (odds ratio [OR]=1.83; 95% confidence interval [CI]: 1.34-2.51; p<0.001). The safety and tolerability of Sarclisa observed in this trial was consistent with the observed safety profile of Sarclisa in other clinical trials, with no new safety signals observed. Rates of all adverse events observed were 63.6% for the Sarclisa combination versus 61.3% for RVd and serious adverse effects and discontinuations were similar in both study arms (34.8% versus 36.3%, respectively). However, the number of deaths were higher in the RVd arm (1.2% versus 2.4%) during the induction period. The trial is ongoing, following the second randomization to evaluate progression free survival (PFS) for Sarclisa and lenalidomide combination as maintenance therapy.

"The results of this trial reinforce our belief in Sarclisa’s potential to become the anti-CD38 of choice," said Peter C. Adamson, Global Development Head, Oncology at Sanofi. "To observe such a high proportion of patients who have MRD negative disease following a relatively brief induction period is highly encouraging. We look forward to our continued collaborative efforts with GMMG to deliver a potential treatment option to transplant-eligible patients with newly diagnosed multiple myeloma."

MRD negativity is defined as the absence of myeloma cells in the bone marrow after treatment, as measured by diagnostic techniques that must have a sensitivity of at least 1 in 100,000 cells.2 This assessment is the most sensitive tool to measure the depth of response to treatment in patients with MM.3

This GMMG initiated clinical trial was conducted in close collaboration with Sanofi based on jointly defined research. Sanofi provided financial support to GMMG for this study.

The use of Sarclisa in combination with RVd is investigational and has not been evaluated by any regulatory authority.

About the trial

The pivotal, randomized, open-label, multicenter, Phase 3 GMMG-HD7 trial is a two-part study that enrolled 662 patients with newly diagnosed, transplant-eligible MM across 67 sites in Germany. In the first part of the study, all participants were equally randomized to receive three 42-day cycles of RVd in both arms of the trial, while Sarclisa was added to only one trial arm. During the trial, Sarclisa was administered through an intravenous infusion at a dose of 10 mg/kg once weekly for the first four weeks of cycle one, then every other week for the rest of the induction period.

MRD negativity was assessed by next-generation flow cytometry (cut off 1×10-5) after induction. An odds ratio was used to measure this endpoint to determine the association between adding Sarclisa to standard of care and participants achieving MRD negativity.

The primary endpoints are MRD negativity after induction treatment for the first part of the study, and PFS following the second randomization after transplant for part two of the study, in which Sarclisa is added to lenalidomide maintenance. Secondary endpoints include rates of complete response after induction, overall survival after maintenance therapy and safety.

About Sarclisa

Sarclisa is a monoclonal antibody that targets a specific epitope on the CD38 receptor on MM cells. It is designed to work through multiple mechanisms of action including programmed tumor cell death (apoptosis) and immunomodulatory activity. CD38 is highly and uniformly expressed on the surface of MM cells, making it a potential target for antibody-based therapeutics such as Sarclisa.

Based on the Phase 3 ICARIA-MM study, Sarclisa is approved in a number of countries in combination with pomalidomide and dexamethasone for the treatment of patients with relapsed refractory MM (RRMM) who have received ≥2 prior therapies, including lenalidomide and a proteasome inhibitor. Based on the Phase 3 IKEMA study, Sarclisa is also approved in combination with carfilzomib and dexamethasone in the U.S. for the treatment of patients with RRMM who have received 1–3 prior lines of therapy and in the European Union for patients with MM who have received at least 1 prior therapy. In the U.S., the generic name for Sarclisa is isatuximab-irfc, with irfc as the suffix designated in accordance with Nonproprietary Naming of Biological Products Guidance for Industry issued by the U.S. Food and Drug Administration (FDA).

Sarclisa continues to be evaluated in multiple ongoing Phase 3 clinical trials in combination with current standard treatments across the MM treatment continuum. It is also under investigation for the treatment of other hematologic malignancies and solid tumors. The safety and efficacy of these additional uses have not been reviewed by any regulatory authority worldwide.

For more information on Sarclisa clinical trials, please visit www.clinicaltrials.gov.

About multiple myeloma

MM is the second most common hematologic malignancy,4 with more than 130,000 new diagnoses of MM worldwide yearly.5 Despite available treatments, MM remains an incurable malignancy and is associated with significant patient burden. Since MM does not have a cure, most patients will relapse. Relapsed MM is the term for when the cancer returns after treatment or a period of remission. Refractory MM refers to when the cancer does not respond or no longer responds to therapy.

About the German-Speaking Myeloma Multicenter Group (GMMG)

GMMG is the largest study group focusing on MM in Germany, with headquarters based in Heidelberg. Within the last 20 years, the GMMG study group has performed numerous trials including five randomized, multicenter Phase 3 clinical trials with 4,000 patients enrolled from about 90 participating and co-treating centers throughout Germany. The overall goal of GMMG is to generate improved therapies for myeloma patients through the development and testing of novel and personalized, genome- and signaling-driven treatment strategies.

On December 11, 2021 Bristol Myers Squibb (NYSE: BMY) reported the first disclosure of results from a prespecified interim analysis of the pivotal TRANSFORM study, a global, randomized, multicenter, Phase 3 study evaluating Breyanzi (lisocabtagene maraleucel; liso-cel), a CD19-directed chimeric antigen receptor (CAR) T cell therapy, as a second-line treatment in adults with relapsed or refractory large B-cell lymphoma (LBCL) compared to the standard of care consisting of salvage chemotherapy followed by high-dose chemotherapy plus autologous hematopoietic stem cell transplant (HSCT) (Press release, Bristol-Myers Squibb, DEC 11, 2021, View Source [SID1234596805]). Results show, at a median follow up of 6.2 months, Breyanzi significantly improved event-free survival (EFS) compared to standard of care, the study’s primary endpoint, with a median EFS of 10.1 months (95% CI: 6.1-NR) for Breyanzi and 2.3 months (95% CI: 2.2-4.3) for standard of care (HR: 0.349; p<0.0001), representing a 65% reduction in risk of EFS events with Breyanzi. The data will be presented in an oral session during the 63rd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition (Abstract #91) and has been selected for inclusion in the ASH (Free ASH Whitepaper) Annual Meeting Press Program.

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"For more than 20 years, salvage chemotherapy followed by high-dose chemotherapy and stem cell transplant have been the mainstay of care for patients with second-line relapsed or refractory LBCL, but only a small portion of patients experience long-term benefit with this approach," said Manali Kamdar, M.D., lead investigator and Associate Professor, Clinical Director of Lymphoma Services, Division of Hematology, Hematologic Malignancies and Stem Cell Transplantation, University of Colorado Cancer Center. "With liso-cel outperforming the current standard of care for patients with hard-to-treat disease in the TRANSFORM study, these results may pave the way for a practice-changing treatment approach where patients whose disease relapses or is refractory to frontline therapy can be treated with a personalized CAR T cell therapy to increase the potential for improved outcomes."

In the TRANSFORM study, 184 patients with primary refractory LBCL or relapsed disease within ≤12 months after first-line therapy who were eligible for autologous HSCT were randomized to receive Breyanzi (n=92) or salvage chemotherapy followed by high-dose chemotherapy and autologous HSCT (n=92), which is considered the current standard of care for these patients. In the trial, which allowed for crossover, 50 patients switched from the standard of care arm to receive Breyanzi following failure to achieve a response by nine weeks post-randomization (after three cycles of salvage chemotherapy) or after disease progression at any time.

The majority of patients (86%) treated with Breyanzi achieved a complete or partial response, with 66% of patients achieving a complete response. In comparison, less than half (48%) of patients who received the standard of care achieved a response, and only 39% of these patients achieved a complete response (p<0.0001). Median progression-free survival was significantly longer with Breyanzi compared to standard of care (14.8 months vs. 5.7 months [HR: 0.406; p=0.0001]). Although overall survival data were not yet mature, the prespecified interim analysis showed a trend favoring Breyanzi compared with the standard of care (HR: 0.509, 95% CI: 0.258-1.004, p=0.0257).

Breyanzi exhibited a manageable safety profile with very low rates of severe cytokine release syndrome (CRS) and neurologic events, and no new safety signals were observedin this second-line setting. In the trial, no Grade 4/5 CRS or neurologic events were reported. Any-grade CRS was reported in 49% of patients, with Grade 3 CRS reported in only one patient. Any-grade neurologic events were reported in 12% of patients treated with Breyanzi, with Grade 3 neurologic events reported in four patients (4%).

Results from the long-term follow-up of treatment with Breyanzi in the TRANSCEND NHL 001 study, the largest pivotal trial in third-line plus relapsed or refractory LBCL, reinforcing durable remissions demonstrated with Breyanzi, will also be presented at the meeting during a poster presentation on Sunday, December 12 (Abstract #2840).

"Breyanzi, a differentiated CD-19 directed CAR T cell therapy,has the potential to transform the treatment paradigm for relapsed or refractory LBCL across lines of therapy, with a proven significant clinical benefit and a consistent safety profile in the TRANSFORM and TRANSCEND NHL 001 trials presented at this year’s ASH (Free ASH Whitepaper) Annual Meeting," said Anne Kerber, senior vice president, Cell Therapy Development, Bristol Myers Squibb. "We designed a patient-centric clinical trial program for Breyanzi with the strategic intent to improve outcomes for patients with some of the most aggressive blood cancers, aligned with our commitment to advancing a leading cell therapy portfolio for patients in need."

Breyanzi is approved by the U.S. Food and Drug Administration for the treatment of adult patients with relapsed or refractory LBCL after two or more lines of systemic therapy, 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. Breyanzi is not indicated for the treatment of patients with primary central nervous system lymphoma. The U.S. Prescribing Information for Breyanzi has a BOXED WARNING for the risks 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 use of Breyanzi in primary refractory or relapsed LBCL is investigational and not approved in any geography.

About TRANSFORM

TRANSFORM (NCT03575351) is a pivotal, global, randomized, multicenter Phase 3 trial evaluating Breyanzi compared to current standard of care regimens in adults with high-risk, transplant-eligible, relapsed and refractory large B-cell lymphoma (LBCL). All enrolled patients have LBCL and were relapsed or refractory within ≤12 months from CD20 antibody and anthracycline containing first-line therapy. Patients were randomized to receive Breyanzi or standard of care salvage therapy, including rituximab plus dexamethasone, high-dose cytarabine, and cisplatin (R-DHAP), rituximab plus ifosfamide, carboplatin and etoposide (R-ICE), or rituximab plus gemcitabine, dexamethasone and cisplatin (R-GDP) per the investigators’ choice before proceeding to high-dose chemotherapy and hematopoietic stem cell transplant. The primary endpoint of the study is event-free survival, defined as time from randomization to death from any cause, progressive disease, failure to achieve complete response or partial response, or start of new antineoplastic therapy due to efficacy concerns, whichever occurs first. Complete response rate is a key secondary endpoint. Other efficacy endpoints include progression-free survival, overall survival, overall response rate and duration of response.

About TRANSCEND NHL 001

TRANSCEND NHL 001 is an open-label, multicenter, pivotal Phase 1 study to determine the safety, pharmacokinetics, and antitumor activity of Breyanzi in patients with relapsed/refractory B-cell non-Hodgkin lymphoma, including diffuse large B-cell lymphoma, high-grade B-cell lymphoma, primary mediastinal B-cell lymphoma, follicular lymphoma Grade 3B and mantle cell lymphoma. The primary outcome measures were treatment-related adverse events, dose-limiting toxicities and objective response rate. Secondary outcome measures included complete response rate, duration of response and progression-free survival.

About Breyanzi

Breyanzi is a CD-19 directed chimeric antigen receptor (CAR) T cell therapy with a defined composition and 4-1BB costimulatory domain. Breyanzi is administered as a defined composition to reduce variability of the CD8 and CD4 component dose. The 4-1BB signaling domain enhances the expansion and persistence of the CAR T cells. Breyanzi is approved by the U.S. Food and Drug Administration for the treatment of adult patients with relapsed or refractory LBCL after two or more lines of systemic therapy, 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. Breyanzi is not indicated for the treatment of patients with primary central nervous system lymphoma.

Breyanzi is also approved in Japan for third-line plus relapsed and refractory LBCL, and Marketing Authorization Applications for Breyanzi for this indicationare currently under review in the European Union, Switzerland and Canada. Bristol Myers Squibb’s clinical development program for Breyanzi includes clinical studies in earlier lines of treatment for patients with relapsed or refractory LBCL and other types of lymphoma. For more information, visit clinicaltrials.gov.

Important Safety Information

BOXED WARNING: CYTOKINE RELEASE SYNDROME and NEUROLOGIC TOXICITIES

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.
BREYANZI is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the BREYANZI REMS.
Cytokine Release Syndrome (CRS)

CRS, including fatal or life-threatening reactions, occurred following treatment with BREYANZI. CRS occurred in 46% (122/268) of patients receiving BREYANZI, including ≥ Grade 3 (Lee grading system) CRS in 4% (11/268) of patients. One patient had fatal CRS and 2 had ongoing CRS at time of death. The median time to onset was 5 days (range: 1 to 15 days). CRS resolved in 119 of 122 patients (98%) with a median duration of 5 days (range: 1 to 17 days). Median duration of CRS was 5 days (range 1 to 30 days) in all patients, including those who died or had CRS ongoing at time of death.

Among patients with CRS, the most common manifestations of CRS include fever (93%), hypotension (49%), tachycardia (39%), chills (28%), and hypoxia (21%). 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. Sixty-one of 268 (23%) patients received tocilizumab and/or a corticosteroid for CRS after infusion of BREYANZI. Twenty-seven (10%) patients received tocilizumab only, 25 (9%) received tocilizumab and a corticosteroid, and 9 (3%) received corticosteroids only.

Neurologic Toxicities

Neurologic toxicities that were fatal or life-threatening, occurred following treatment with BREYANZI. CAR T cell-associated neurologic toxicities occurred in 35% (95/268) of patients receiving BREYANZI, including ≥ Grade 3 in 12% (31/268) of patients. Three patients had fatal neurologic toxicity and 7 had ongoing neurologic toxicity at time of death. The median time to onset of the first event was 8 days (range: 1 to 46 days). The onset of all neurologic events occurred within the first 8 weeks following BREYANZI infusion. Neurologic toxicities resolved in 81 of 95 patients (85%) with a median duration of 12 days (range: 1 to 87 days). Three of four patients with ongoing neurologic toxicity at data cutoff had tremor and one subject had encephalopathy. Median duration of neurologic toxicity was 15 days (range: 1 to 785 days) in all patients, including those with ongoing neurologic events at the time of death or at data cutoff.

Seventy-eight (78) of 95 (82%) patients with neurologic toxicity experienced CRS. Neurologic toxicity overlapped with CRS in 57 patients. The onset of neurologic toxicity was after onset of CRS in 30 patients, before CRS onset in 13 patients, same day as CRS onset in 7 patients, and same day as CRS resolution in 7 patients.

Neurologic toxicity resolved in three patients before the onset of CRS. Eighteen patients experienced neurologic toxicity after resolution of CRS.

The most common neurologic toxicities included encephalopathy (24%), tremor (14%), aphasia (9%), delirium (7%), headache (7%), dizziness (6%), and ataxia (6%). Serious events including cerebral edema and seizures occurred with BREYANZI. Fatal and serious cases of leukoencephalopathy, some attributable to fludarabine, have occurred in patients treated with BREYANZI.

CRS and Neurologic Toxicities Monitoring

Monitor patients daily at a certified healthcare facility during the first week following infusion, for signs and symptoms of CRS and neurologic toxicities. Monitor patients for signs and symptoms of CRS and neurologic toxicities for at least 4 weeks after infusion; evaluate and treat promptly. Counsel patients to seek immediate medical attention should signs or symptoms of CRS or neurologic toxicity occur at any time. At the first sign of CRS, institute treatment with supportive care, tocilizumab or tocilizumab and corticosteroids as indicated.

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.
Certified healthcare facilities must ensure that healthcare providers who prescribe, dispense, or administer BREYANZI are trained on the management of CRS and neurologic toxicities.
Further information is available at www.BreyanziREMS.com or contact Bristol Myers Squibb at 1-888-423-5436.

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. Infections (all grades) occurred in 45% (121/268) of patients. Grade 3 or higher infections occurred in 19% of patients. Grade 3 or higher infections with an unspecified pathogen occurred in 16% of patients, bacterial infections occurred in 5%, and viral and fungal infections occurred in 1.5% and 0.4% of patients, respectively. Monitor patients for signs and symptoms of infection before and after BREYANZI administration and treat appropriately. Administer prophylactic antimicrobials according to standard institutional guidelines.

Febrile neutropenia has been observed in 9% (24/268) of patients after BREYANZI infusion and 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.

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. Ten of the 11 patients in the TRANSCEND study with a prior history of HBV were treated with concurrent antiviral suppressive therapy to prevent HBV reactivation during and after treatment with BREYANZI. Perform screening for HBV, HCV, and HIV in accordance with clinical guidelines before collection of cells for manufacturing.

Prolonged Cytopenias

Patients may exhibit cytopenias not resolved for several weeks following lymphodepleting chemotherapy and BREYANZI infusion. Grade 3 or higher cytopenias persisted at Day 29 following BREYANZI infusion in 31% (84/268) of patients, and included thrombocytopenia (26%), neutropenia (14%), and anemia (3%). Monitor complete blood counts prior to and after BREYANZI administration.

Hypogammaglobulinemia

B-cell aplasia and hypogammaglobulinemia can occur in patients receiving treatment with BREYANZI. The adverse event of hypogammaglobulinemia was reported as an adverse reaction in 14% (37/268) of patients; laboratory IgG levels fell below 500 mg/dL after infusion in 21% (56/268) of patients. Hypogammaglobulinemia, either as an adverse reaction or laboratory IgG level below 500 mg/dL after infusion, was reported in 32% (85/268) 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. 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 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, during this initial period.

Adverse Reactions

Serious adverse reactions occurred in 46% of patients. The most common nonlaboratory, serious adverse reactions (> 2%) were CRS, encephalopathy, sepsis, febrile neutropenia, aphasia, pneumonia, fever, hypotension, dizziness, and delirium. Fatal adverse reactions occurred in 4% of patients.

The most common nonlaboratory adverse reactions of any grade (≥ 20%) were fatigue, CRS, musculoskeletal pain, nausea, headache, encephalopathy, infections (pathogen unspecified), decreased appetite, diarrhea, hypotension, tachycardia, dizziness, cough, constipation, abdominal pain, vomiting, and edema.

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 scientific expertise, cutting-edge capabilities and discovery platforms enable the company to look at 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. Because as a leader in cancer care, Bristol Myers Squibb is working to empower all people with cancer to have a better future.

Learn more about the science behind cell therapy and ongoing research at Bristol Myers Squibb here.

On December 11, 2021 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported that new pivotal data on its CD20xCD3 T-cell engaging bispecific antibody, mosunetuzumab, will be presented for the first time at the 63rd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition from 11-14 December 2021 (Press release, Hoffmann-La Roche, DEC 11, 2021, View Source [SID1234596804]).

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Emerging data continue to show the promising benefit-risk profile of mosunetuzumab in relapsed or refractory (R/R) follicular lymphoma (FL), a slow-growing, or indolent, form of non-Hodgkin lymphoma (NHL). Pivotal results from the phase I/II GO29781 study demonstrated that mosunetuzumab induces durable complete responses lasting at least 18 months in heavily pretreated patients with R/R FL who have received two or more prior therapies, with a 60.0% complete response (CR) rate and a median progression-free survival of 17.9 months (95% CI: 10.1-not evaluable). Median duration of response was 22.8 months among responders (95% CI: 9.7-not evaluable). The most common adverse event (AE) was cytokine release syndrome (CRS), which was generally low grade (mainly Grade 1-2).1

"Despite initial successful treatment, many people with follicular lymphoma often experience relapse. Mosunetuzumab could potentially become a highly efficacious treatment option that can be administered without the need for cell collection or genetic engineering," said Levi Garraway, M.D., Ph.D., Roche’s Chief Medical Officer and Head of Global Product Development. "With mosunetuzumab, we also aim to offer a therapy that can be administered in the outpatient setting to people with this devastating blood cancer."

Roche recently submitted the initial marketing authorisation application for mosunetuzumab to the European Medicines Agency, with the hope to bring this drug as soon as possible to people with NHL. Genentech plans to submit the new data to the U.S. Food and Drug Administration in the near future for approval consideration. If approved, mosunetuzumab has the potential to be a first-in-class CD20xCD3 T-cell engaging bispecific antibody in NHL.

Additionally, as part of Roche’s broad pipeline of haematology immunotherapies and application of novel combinations, key data for the bispecific antibodies mosunetuzumab, glofitamab and cevostamab are being presented, including:

Initial results from the phase Ib CO41942 study of mosunetuzumab in combination with lenalidomide in people with R/R FL who have received at least one prior line of therapy demonstrated encouraging preliminary efficacy and a tolerable safety profile.2
Data from the phase Ib/II GO40516 study evaluating mosunetuzumab in combination with Polivy (polatuzumab vedotin) showed promising efficacy and favourable safety in heavily pretreated patients with aggressive R/R NHL with an objective response rate (ORR) of 65.0% and a CR rate of 48.3%. CRS occurred in 18% of patients, and all events occurred in Cycle 1 and were Grade 1-2.3
A phase I/Ib NP30179 dose-escalation study evaluating glofitamab as a monotherapy and in combination with Gazyva/Gazyvaro (obinutuzumab) following pretreatment with Gazyva/Gazyvaro in patients with R/R B-cell NHL showed promising activity in both R/R FL and R/R mantle cell lymphoma (MCL), an uncommon but aggressive form of lymphoma with poor prognosis for those who progress.4
Preliminary results in heavily pretreated patients with R/R FL showed high response rates across all treatment groups, including high-risk subgroups, with an ORR of 81.0% for the glofitamab monotherapy group and an ORR of 100% for the glofitamab plus Gazyva/Gazyvaro combination therapy group.5 For patients with R/R MCL, treated with glofitamab monotherapy following Gazyva/Gazyvaro pretreatment, the ORR was 81.0%.6 Across both studies, the most common AE was CRS, with the majority of events being low grade (Grade 1-2).5,6
Results of the phase Ib/II NP39488 study of glofitamab in combination with Polivy demonstrated encouraging preliminary efficacy and a tolerable safety profile in people with difficult-to-treat R/R diffuse large B-cell lymphoma. With a median follow up of 3.2 months (95% CI: 1.4-3.5), an ORR of 73.0% was observed with a 51.5% CR rate, with patients showing durable responses at ≥6 months. No Grade 3 or higher CRS events were observed, and the safety profile of the combination was consistent with that of the individual medicines.7
Data from the phase I GO39775 dose-escalation and expansion study investigating cevostamab in heavily pretreated patients with R/R multiple myeloma (MM) showed the first-of-its kind FcRH5xCD3 bispecific antibody induced clinically meaningful, target dose-dependent increases in ORR without an increase in the rate of CRS, with an ORR of 54.5% in the 160 mg dose group. Results from double step-up dosing suggest this approach could help mitigate CRS and potentially improve the safety profile compared to single step-up dosing.8
Our investigational cancer immunotherapies, mosunetuzumab and glofitamab, are T-cell engaging bispecific antibodies designed to engage with CD3 on the T cell and CD20 on the tumour cell, bringing them close in proximity and enabling the T cell to eliminate the tumour cell. Although these bispecific antibodies have similar modes of action, they differ in their structure and clinical profiles. Cevostamab, another investigational T-cell engaging bispecific antibody, is designed to target FcRH5 on myeloma cells and CD3 on T cells and is currently being evaluated in people living with R/R MM.

Roche’s broad and comprehensive clinical development programme will continue to evaluate mosunetuzumab, glofitamab and cevostamab as monotherapies and in combination with other established and/or novel therapies for malignant haematological conditions with the goal of providing treatment solutions tailored to the patient journey for each disease.

Keep up to date with ASH (Free ASH Whitepaper) 2021 news and updates by using the hashtag #ASH21 and follow Roche on Twitter via @Roche and on LinkedIn.

About Roche’s investigational CD20xCD3 bispecifics in haematology
Roche is currently developing two T-cell engaging bispecific antibodies, mosunetuzumab and glofitamab, designed to target CD20 on the surface of B cells and CD3 on the surface of T cells. This dual targeting activates and redirects a patient’s existing T cells to engage and eliminate target B cells by releasing cytotoxic proteins into the B cells. Mosunetuzumab and glofitamab differ in their structures, and both are being developed by Roche as part of our ongoing strategy to explore multiple bispecific formats in order to identify those that maximise potential clinical benefits for patients. Mosunetuzumab has a structure similar to that of a natural human antibody in that it has two ‘Fab’ regions but is different from naturally-occurring antibodies in that one ‘Fab’ region targets CD20 and the other ‘Fab’ region targets CD3. Glofitamab is based on a novel structural format that we call ‘2:1,’ which refers to the structure of the antibody. It is engineered to have two ‘Fab’ regions that bind to CD20 and one ‘Fab’ region that binds to CD3. The clinical development programmes for mosunetuzumab and glofitamab include ongoing investigations of these molecules as monotherapies and in combination with other medicines for the treatment of people with CD20-positive B cell (non-Hodgkin lymphomas), including diffuse large B-cell lymphoma and follicular lymphoma .

About cevostamab (FcRH5xCD3 bispecific antibody)
Cevostamab (BFCR4350A) is an FcRH5xCD3 T-cell engaging bispecific antibody designed to target FcRH5 on myeloma cells and CD3 on T cells. FcRH5 is a unique and differentiated target, expressed on nearly all myeloma cells. Cevostamab has a structure similar to that of a natural human antibody in that it has two ‘Fab’ regions, but is different from naturally-occurring antibodies in that one ‘Fab’ region targets FcRH5 and the other ‘Fab’ region targets CD3. This dual targeting activates and re-directs a patient’s existing T cells to engage and eliminate target FcRH5-expressing myeloma cells by releasing cytotoxic proteins into the myeloma cells.

About the GO29781 study
The GO29781 study [NCT02500407] is a phase I/II, multicentre, open-label, dose-escalation study evaluating the safety and pharmacokinetics of mosunetuzumab in people with relapsed or refractory B-cell non-Hodgkin lymphoma. Outcome measures include complete response rate (best response) by independent review facility (primary endpoint), objective response rate, duration of response, progression-free survival, safety and tolerability (secondary endpoints).

About Roche in haematology
Roche has been developing medicines for people with malignant and non-malignant blood diseases for over 20 years; our experience and knowledge in this therapeutic area runs deep. Today, we are investing more than ever in our effort to bring innovative treatment options to patients across a wide range of haematologic diseases. Our approved medicines include MabThera/Rituxan (rituximab), Gazyva/Gazyvaro (obinutuzumab), Polivy (polatuzumab vedotin), Venclexta/Venclyxto (venetoclax) in collaboration with AbbVie, and Hemlibra (emicizumab). Our pipeline of investigational haematology medicines includes T-cell engaging bispecific antibodies, glofitamab and mosunetuzumab, targeting both CD20 and CD3, and cevostamab, targeting both FcRH5 and CD3; Tecentriq (atezolizumab), a monoclonal antibody designed to bind with PD-L1; and crovalimab, an anti-C5 antibody engineered to optimise complement inhibition. Our scientific expertise, combined with the breadth of our portfolio and pipeline, also provides a unique opportunity to develop combination regimens that aim to improve the lives of patients even further.

On December 10, 2021 APIM Therapeutics (APIM), a clinical stage biotech company focusing on the development of novel peptide therapeutics targeting PCNA (Proliferating Cell Nuclear Antigen), reported that a Phase II Investigator Initiated Study (IIS) of ATX-101 will begin enrolling patients with sarcoma at Columbia University Irving Medical Center (Press release, APIM Therapeutics, DEC 10, 2021, View Source,c3468947 [SID1234605479]).

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The clinical study (ClinicalTrials.gov Identifier: NCT05116683) will investigate ATX-101, the lead compound of APIM’s development program, as single agent therapy for patients with leiomyosarcoma and liposarcoma who have received at least one prior treatment. An IND has been granted by the FDA and the local IRB approved the study.

Sarcoma is a rare malignant tumor that originates from connective tissue. Lipo- and leiomyosarcoma are the most frequently observed soft tissue sarcomas. About 12,750 new cases of soft tissue sarcoma are diagnosed in the US every year. Late-stage disease has a poor prognosis with a 5-year survival rate below 20%.

"Sarcoma is a disease with a very high medical need, and new treatments are needed to fight this cancer," said Matthew Ingham, MD, assistant professor of medicine in Hematology & Oncology at Columbia and Principal Investigator of the study. "We are interested in exploring the potential of inhibiting PCNA activity in cancer cells as a potential new therapy for sarcoma patients."

Columbia’s Division of Hematology & Oncology, led by Gary Schwartz, MD, professor of oncology at Columbia, is a leader in translational and clinical research on sarcoma. "ATX-101 has shown encouraging pre-clinical data published in peer reviewed journals," said Dr. Schwartz. "We have been able to confirm these data in our lab. Our study will help us determine if this therapeutic approach has clinical benefit for sarcoma patients."

APIM supports the study financially and provides the investigational drug ATX-101. "APIM is happy to support this IIS. Data from our Phase I study indicate a favorable safety profile of ATX-101, including anticancer activity. This sarcoma study is a valuable complement to our own clinical development program investigating ATX-101 in combination with chemotherapy for patients with ovarian cancer," explained Dr. Jens-Peter Marschner, CMO of APIM.

"Our work with distinguished sarcoma specialists at Columbia University Irving Medical Center is an important step for APIM Therapeutics and indicates that our first in class approach is of academic interest," said Dr. Kostas Alevizopoulos, CEO of APIM. "With this IIS and its translational investigations, additional data will be collected that advance our understanding of complex PCNA-dependent activities in cancer and their inhibition by ATX-101."

About ATX-101

ATX-101 is a first-in-class, cell penetrating peptide featuring a novel PCNA-interacting motif (AlkB homolog 2 PCNA Interacting Motif or APIM). In preclinical experiments, it was shown that APIM-containing proteins bind to PCNA and mediate processes of escape mechanisms and survival of cancer cells. ATX-101 competitively inhibits interaction of PCNA with APIM-containing protein complexes resulting in cancer cell death and altered cellular signaling. These properties translate in anticancer effects of ATX-101 as demonstrated in several preclinical models in vitro and in vivo.

On December 10, 2021 Agendia, Inc., a world leader in precision oncology for breast cancer, reported that it will present a spotlight poster at the 2021 San Antonio Breast Cancer Symposium (SABCS 2021) which confirms the utility of BluePrint in guiding neoadjuvant treatment decisions (Press release, Agendia, DEC 10, 2021, View Source [SID1234597140]).

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The spotlight presentation, resulting from a research collaboration between Agendia and the Netherlands Cancer Institute and titled Effect of pertuzumab plus neoadjuvant trastuzumab-based chemotherapy in early-stage HER2-positive breast cancer according to BluePrint molecularly defined breast cancer subtypes [PD15-07], evaluates the BluePrint 80-gene molecular subtyping test for predicting response to neoadjuvant trastuzumab-based chemotherapy with or without pertuzumab in a large nationwide cohort of patients from the TRAIN2 study (NCT01996267) and the Netherlands Cancer Registry.

Results showed that BluePrint reclassified 15% of the IHC/FISH HER-2+ patients in this study to a different molecular subtype. These reclassified patients typically do not respond as expected to HER2-targeted therapies, indicating a potential role for genomics in treatment planning for HER2+ patients. The data also support the pronounced benefit of adding pertuzumab to neoadjuvant trastuzumab-based chemotherapy in patients with the BluePrint-defined HER2-subtype, with other subtypes having a less pronounced benefit from pertuzumab. These new findings reinforce the heterogeneity of pathologically HER2+ breast cancer and provide support for the results of a prior translational analysis of the APHINITY trial, which also showed that BluePrint may identify subgroups of HER2+ patients with differing degrees of benefit from the addition of pertuzumab based on gene expression.

"In addition to these results reclassifying 15% of patients in this cohort, the data confirm the genomic heterogeneity of clinically HER2+ patients, and suggest that genomic information could help make more precise decisions following diagnosis," said William Audeh, MD, Chief Medical Officer at Agendia. "HER2 is an extremely complex histological subtype of breast cancer. The results presented in this spotlight poster show again the incredible diversity of this subtype, and the importance of looking at these tumors at a genomic level in order to adjust treatment appropriately even before surgery."

In addition, Agendia shared updates and study results from the 30,000-patient breast cancer genome project, the FLEX study:

[OT2-07-01] The FLEX real-world data platform explores new gene expression profiles and investigator-initiated protocols in early stage breast cancer shares data from some of the 38 investigator-initiated sub-studies approved within the FLEX Registry, the real-world, large-scale, prospective, observational breast cancer study (NCT03053193) intended to enable the discovery of novel genomic profiles to improve precision in the management of breast cancer. With purposefully-wide inclusion criteria, and more than 9,000 patients enrolled towards the 30,000-patient goal, the registry aims to enable researchers to investigate the differences and trends between breast cancer subgroups and allow focus on smaller, more diverse patient populations, which have traditionally been challenging to recruit in sufficient numbers for clinical trials.
[P5-07-05] Deciphering the inferior prognosis of young women with estrogen receptor-positive early-stage breast cancer through full transcriptome analysis: a FLEX database sub-study aims to better understand the biological basis for the disparity in outcomes between older and younger women with early-stage breast cancer by identifying genes that distinguish tumors in these two groups. Data demonstrated that there were relatively few gene expression changes identified by age, and that few transcriptional differences were observed between tumors from women aged 40-54 and women older than 55. These results suggest that observed chemotherapy benefit represents differences in host biology rather than intrinsic tumor biology. Additionally, these findings indicate that age is potentially a more relevant cutoff than menopausal status when observing genes to aid in treatment decisions, reinforcing the need for genomic testing to be available to all women with early stage breast cancer regardless of menopausal status.
[P2-08-06] Defining transcriptomic profiles of breast cancer with early lymph node metastases: a FLEX database sub-study provides a foundation for understanding the mechanisms that promote lymph node (LN) metastasis, with data indicating more biological differences between MammaPrint risk and BluePrint subtype than by pathological stage. Early LN metastasis often precedes systemic metastasis and corresponds with a 20% decrease in 10-year survival compared to patients without LN metastasis,1 underscoring the importance of understanding biologic pathways involved in early LN metastasis to identify promising drug targets for early-stage breast cancer treatment.
"The robust variety and value of the data being collected by the FLEX project cannot be overstated," said Cynthia X Ma, MD, PhD, oncologist and FLEX national principal investigator at Washington University School of Medicine in St. Louis. "In the data presented at SABCS 2021 alone, we see insights that can be turned into clinical actions immediately. Especially interesting is the representation of extreme MammaPrint risk groups, with over 1,100 Ultra Low Risk and over 1,200 High Risk 2 patients enrolled in the study. The insights from these analyses will guide physicians supporting the entire breast cancer community in hard-to-treat cases they may see in their practice today. This project could be one of the most impactful, inclusive studies in breast cancer research to date, and the constant learnings from it allow us to better understand biologic drivers of breast cancer and ultimately result in more personalized, precise treatment plans."

Agendia will present six posters that were accepted to SABCS 2021, highlighting Agendia’s mission to help guide the diagnosis and personalized treatment of breast cancer for all patients throughout their treatment journey.