On December 11, 2021 Genentech, a member of the Roche Group (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 & Exposition from December 11-14, 2021 (Press release, Genentech, DEC 11, 2021, View Source [SID1234596847]).

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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’s 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).

"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., 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."

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. Roche recently submitted the initial marketing authorization application for mosunetuzumab to the European Medicines Agency, with the hope to bring this drug as soon as possible to people with NHL.

Additionally, as part of Genentech’s broad pipeline of hematology 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.
Data from the Phase Ib/II GO40516 study evaluating mosunetuzumab in combination with Polivy (polatuzumab vedotin-piiq) showed promising efficacy and favorable 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.
A Phase I/Ib NP30179 dose-escalation study evaluating glofitamab as a monotherapy and in combination with Gazyva (obinutuzumab) following pretreatment with Gazyva 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.
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 combination therapy group. For patients with R/R MCL treated with glofitamab monotherapy following Gazyva pretreatment, the ORR was 81.0%. Across both studies, the most common AE was CRS, with the majority of events being low grade (Grade 1-2).
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.
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.
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 tumor cell, bringing them close in proximity and enabling the T cell to eliminate the tumor 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.

Genentech’s broad and comprehensive clinical development program will continue to evaluate mosunetuzumab, glofitamab and cevostamab as monotherapies and in combination with other established and/or novel therapies for malignant hematological 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 Genentech on Twitter via @Genentech and on LinkedIn.

About Genentech’s Investigational Bispecifics in Hematology

Genentech 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 Genentech as part of our ongoing strategy to explore multiple bispecific formats, to identify those that maximize 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 which 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 programs 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’s lymphomas), including diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL).

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, multicenter, open-label, dose-escalation study evaluating the safety and pharmacokinetics of mosunetuzumab in people with relapsed or refractory B-cell non-Hodgkin’s lymphoma. Outcome measures include complete response rate (best response) by independent review facility (primary endpoint), objective response rate, duration of response, progression-free survival, and safety and tolerability (secondary endpoints).

Polivy U.S. Indication

Polivy is a prescription medicine used with other medicines, bendamustine and a rituximab product, to treat diffuse large B-cell lymphoma in adults who have progressed after at least two prior therapies.

The accelerated approval of Polivy is based on a type of response rate. There are ongoing studies to confirm the clinical benefit of Polivy.

Important Safety Information

Possible serious side effects

Everyone reacts differently to Polivy therapy, so it’s important to know what the side effects are. Some people who have been treated with Polivy have experienced serious to fatal side effects. A patient’s doctor may stop or adjust a patient’s treatment if any serious side effects occur. Patients must contact their healthcare team if there are any signs of these side effects.

Nerve problems in arms and legs: This may happen as early as after the first dose and may worsen with every dose. If a patient already has nerve pain, Polivy may make it worse. The patient’s doctor will monitor for signs and symptoms, such as changes in sense of touch, numbness or tingling in hands or feet, nerve pain, burning sensation, any muscle weakness, or changes to walking patterns
Infusion-related reactions: A patient may experience fever, chills, rash, breathing problems, low blood pressure, or hives within 24 hours of the infusion
Infections: Patients should contact their healthcare team if they experience a fever of 100.4°F or higher, chills, cough, or pain during urination. Also, a patient’s doctor may give medication before giving Polivy, which may prevent some infections, and monitor blood counts throughout treatment with Polivy. Treatment with Polivy can cause severe low blood cell counts
Rare and serious brain infections: A patient’s doctor will monitor the patient closely for signs and symptoms of these types of infections. Patients should contact their doctor if they experience confusion, dizziness or loss of balance, trouble talking or walking, or vision changes
Tumor lysis syndrome: Caused by the fast breakdown of cancer cells. Signs include nausea, vomiting, diarrhea, and lack of energy
Potential harm to liver: Some signs include tiredness, weight loss, pain in the abdomen, dark urine, and yellowing of the skin or the white part of the eyes. Patients may be at higher risk if they already have liver problems or are taking other medication
Side effects seen most often

The most common side effects during treatment were:

Low blood cell counts (platelets, red blood cells, white blood cells)
Nerve problems in arms and legs
Tiredness or lack of energy
Diarrhea
Nausea
Fever
Decreased appetite
Infections
Polivy may not be for everyone. A patient should talk to their doctor if they are:

Pregnant or may be pregnant: Data have shown that Polivy may harm an unborn baby
Planning to become pregnant: Women should avoid getting pregnant while taking Polivy. Women should use effective contraception during treatment and for at least 3 months after their last Polivy treatment. Men taking Polivy should use effective contraception during treatment and for at least 5 months after their last Polivy treatment
Breastfeeding: Women should not breastfeed while taking Polivy and for at least 2 months after the last dose
These may not be all the side effects. Patients should talk to their healthcare provider for more information about the benefits and risks of Polivy treatment.

Report side effects to the FDA at (800) FDA-1088 or View Source Report side effects to Genentech at (888) 835-2555.

Please visit View Source for the full Prescribing Information for additional Important Safety Information.

Gazyva U.S. Indication

Gazyva is a prescription medicine used with the chemotherapy drug, bendamustine, followed by Gazyva alone for follicular lymphoma (FL) in adults who did not respond to a rituximab-containing regimen, or whose FL returned after such treatment.

Important Safety Information

The most important safety information patients should know about Gazyva

Patients must tell their doctor right away about any side effects they experience. Gazyva can cause side effects that can become serious or life-threatening, including:

Hepatitis B Virus (HBV): Hepatitis B can cause liver failure and death. If a patient has a history of hepatitis B infection, Gazyva could cause it to return. Patients should not receive Gazyva if they have active hepatitis B liver disease. The patient’s doctor or healthcare team will need to screen them for hepatitis B before, and monitor the patient for hepatitis during and after treatment with Gazyva. Sometimes this will require treatment for hepatitis B. Symptoms of hepatitis include: worsening of fatigue and yellow discoloration of skin or eyes
Progressive Multifocal Leukoencephalopathy (PML): PML is a rare and serious brain infection caused by a virus. PML can be fatal. If a patient has a weakened immune system, it could put them at risk. The patient’s doctor will watch for symptoms. Symptoms of PML include: confusion, difficulty talking or walking, dizziness or loss of balance, and vision problems
Who should not receive Gazyva:

Patients should NOT receive Gazyva if they have had an allergic reaction (e.g., anaphylaxis or serum sickness) to Gazyva. Patients must contact their healthcare team if they have had an allergic reaction to obinutuzumab or any other ingredients in Gazyva in the past
Additional possible serious side effects of Gazyva:

Patients must tell their healthcare team right away about any side effect they experience. Gazyva can cause side effects that may become severe or life-threatening, including:

Infusion-related reactions (IRRs): These side effects may occur during or within 24 hours of any Gazyva infusion. Some IRRs can be serious, including, but not limited to, severe allergic reactions (anaphylaxis), acute life-threatening breathing problems, or other life-threatening IRRs. If the patient has a reaction, the infusion is either slowed or stopped until their symptoms are resolved. Most patients are able to complete infusions and receive medication again. However, if the IRR is life-threatening, the infusion of Gazyva will be permanently stopped. The patient’s healthcare team will take steps to help lessen any side effects the patient may have to the infusion process. The patient may be given medicines to take before each Gazyva treatment. Symptoms of IRRs may include: fast heartbeat, tiredness, dizziness, headache, redness of the face, nausea, chills, fever, vomiting, diarrhea, rash, high blood pressure, low blood pressure, difficulty breathing, and chest discomfort
Hypersensitivity reactions including serum sickness: Some patients receiving Gazyva may have severe or life-threatening allergic reactions. This reaction may be severe, may happen during or after an infusion, and may affect many areas of the body. If an allergic reaction occurs, the patient’s doctor will stop the infusion and permanently discontinue Gazyva
Tumor lysis syndrome (TLS): Tumor lysis syndrome, including fatal cases, has been reported in patients receiving Gazyva. Gazyva works to break down cancer cells quickly. As cancer cells break apart, their contents are released into the blood. These contents may cause damage to organs and the heart, and may lead to kidney failure requiring the need for dialysis treatment. The patient’s doctor may prescribe medication to help prevent TLS. The patient’s doctor will also conduct regular blood tests to check for TLS. Symptoms of TLS may include nausea, vomiting, diarrhea, and tiredness
Infections: While the patient is taking Gazyva, they may develop infections. Some of these infections may be fatal and severe, so the patient should be sure to talk to their doctor if they think they have an infection. Patients administered Gazyva in combination with chemotherapy, followed by Gazyva alone, are at a high risk of infections during and after treatment. Patients with a history of recurring or chronic infections may be at an increased risk of infection. Patients with an active infection should not be treated with Gazyva. Patients taking Gazyva plus bendamustine may be at higher risk for fatal or severe infections compared to patients taking Gazyva plus CHOP or CVP
Low white blood cell count: When the patient has an abnormally low count of infection-fighting white blood cells, it is called neutropenia. While the patient is taking Gazyva, their doctor will do blood work to check their white blood cell count. Severe and life-threatening neutropenia can develop during or after treatment with Gazyva. Some cases of neutropenia can last for more than one month. If the patient’s white blood cell count is low, their doctor may prescribe medication to help prevent infections
Low platelet count: Platelets help stop bleeding or blood loss. Gazyva may reduce the number of platelets the patient has in their blood; having low platelet count is called thrombocytopenia. This may affect the clotting process. While the patient is taking Gazyva, their doctor will do blood work to check their platelet count. Severe and life-threatening thrombocytopenia can develop during treatment with Gazyva. Fatal bleeding events have occurred in patients treated with Gazyva. If the patient’s platelet count gets too low, their treatment may be delayed or reduced
The most common side effects seen with Gazyva in a study that included relapsed or refractory FL patients were infusion-related reactions, fatigue, low white blood cell counts, cough, upper respiratory tract infection, and joint or muscle pain.

Before receiving Gazyva, patients should talk to their doctor about:

Immunizations: Before receiving Gazyva therapy, the patient should tell their healthcare provider if they have recently received or are scheduled to receive a vaccine. Patients who are treated with Gazyva should not receive live vaccines
Pregnancy: The patient should tell their doctor if they are pregnant, think that they might be pregnant, or plan to become pregnant. Gazyva may harm a patient’s unborn baby. The patient should speak to their healthcare team about using Gazyva while they are pregnant. The patient should talk to their doctor or their child’s doctor about the safety and timing of live virus vaccinations to their infant if they received Gazyva during pregnancy. Women of childbearing potential should use effective contraception while taking Gazyva and for 6 months after their Gazyva treatment
Breastfeeding: Because of the potential risk of serious side reactions in breastfed children, women should not breastfeed while taking Gazyva and for 6 months after their last dose
Patients should tell their doctor about any side effects.

These are not all of the possible side effects of Gazyva. For more information, patients should ask their doctor or pharmacist.

Gazyva is available by prescription only.

Report side effects to the FDA at (800) FDA-1088, or View Source Report side effects to Genentech at (888) 835-2555.

Please visit View Source for the Gazyva full Prescribing Information, including BOXED WARNINGS, for additional Important Safety Information.

About Genentech in Hematology

For more than 20 years, Genentech has been developing medicines with the goal to redefine treatment in hematology. Today, we’re investing more than ever in our effort to bring innovative treatment options to people with diseases of the blood. For more information visit View Source

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 11, 2021 City of Hope reported that data from an investigational Phase 1/2, single arm trial using a bispecific antibody called mosunetuzumab highlights the paradigm-changing potential of a new treatment option for people with follicular lymphoma, a type of blood cancer and the most common indolent form of non-Hodgkin lymphoma (NHL) (Press release, City of Hope, DEC 11, 2021, View Source [SID1234596848]). Patients within the trial achieved high response rates with 80% of patients responding positively to the treatment, and 60% had a complete response, meaning the cancer could not be detected.

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"Our study demonstrated that an antibody based on bispecific T cell engaging technology is proving to work very well with high response rates — and safely — in blood cancer patients who need more effective therapies and with fewer side effects," said Elizabeth Budde, M.D., Ph.D., associate professor, City of Hope Division of Lymphoma, Department of Hematology & Hematopoietic Cell Transplantation, who discussed the results today at an ASH (Free ASH Whitepaper) press briefing. "Mosunetuzumab is a very promising therapy, showing deep and durable responses for patients whose lymphoma has relapsed or is no longer responding to currently available therapies."

Instead of concentrating on a singular target, "bispecific" antibodies are therapeutics that act on two cellular targets simultaneously. In the case of mosunetuzumab, one "arm" targets the CD3 protein on T cells, an immune cell that can help in the fight against cancer if engaged; a second "arm" binds to CD20, a protein commonly found on lymphoma cells.

"The two cell groups are pulled together, with mosunetuzumab serving as a kind of bridge," Budde said. "Being in such close proximity allows the now activated T cells to better recognize and attack the lymphoma cells."

Ninety patients with follicular lymphoma, who ranged in age from 29 to 90 years old, were enrolled in the multicenter international trial. The patients received mosunetuzmab, a Genentech medicine, intravenously every 21 days for a minimum of eight cycles and up to 17 cycles.

The median time to first response was 1.4 months. With a median follow up of 17.8 months, 70% patients with response continued to do well.

Cytokine release syndrome was a side effect in 44% of patients. Most were low grade and occurred during the first cycle. All resolved completely. Other side effects included fatigue and headache. Only two patients discontinued treatment due to mosunetuzumab-related side effects.

Genentech, a member of the Roche Group, plans to submit this 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 the first CD20xCD3 T cell engaging bispecific antibody approved for NHL.

Renee Bentson, 69, of Covina, California, was one of the first participants in the trial at City of Hope. Before she was diagnosed with cancer, Bentson, who was physically active and running seven miles a day, began to notice a rash, chest pain and night sweats. When an unusual fatigue set in and lumps began to appear, first on one side of her torso, then the other and on one arm, Bentson consulted a doctor, who promptly ordered a biopsy.

Bentson was diagnosed with follicular lymphoma, which makes up about 20% of all lymphoma cases. It tends to strike older people, and though it does respond to initial treatment, it is not curable with convention therapy and relapse is frequent. Remission duration tends to get shorter with each subsequent relapse after treatment.

While some patients do well on chemotherapy, Bentson was concerned about the potential side effects. She participated in a series of immunotherapy clinical trials. The cancer would shrink, but not disappear, and later it would recur. With mosunetuzumab, which was her fourth line of treatment, the cancer went into remission in early 2017 and she has been cancer free since then.

"I’m just so grateful that it worked," said Bentson, who experienced few side effects from the treatment.

City of Hope is a leader in blood cancer immunotherapies. The National Cancer Institute-designated comprehensive cancer center has performed more than 17,000 bone marrow/stem cell transplants and is a leader in chimeric antigen receptor (CAR) T therapy, with nearly 800 patients treated with immune effector cells, including CAR T therapy, and nearly 80 open or completed trials.

On December 11, 2021 Jazz Pharmaceuticals plc (Nasdaq: JAZZ) reported initial positive results from a Phase 2/3 trial of intramuscular (IM) administration of Rylaze (asparaginase erwinia chrysanthemi (recombinant)-rywn) in adult and pediatric patients with acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL) who have developed hypersensitivity or silent inactivation to an E. coli-derived asparaginase (Press release, Jazz Pharmaceuticals, DEC 11, 2021, View Source [SID1234596882]). The study was developed and conducted in close collaboration with the Children’s Oncology Group (COG). These initial results will be presented for the first time today at the 63rd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting.

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Three cohorts with unique, IM administration dosing schedules were evaluated in the trial, demonstrating a safety profile consistent with other asparaginases. In Cohort 1c, a dosing regimen of Rylaze administered 25 mg/m2 on Monday and Wednesday and 50 mg/m2 on Friday demonstrated a positive benefit-to-risk profile, showing that Rylaze maintains a clinically meaningful level of nadir serum asparaginase activity (NSAA) ≥0.1 IU/mL at both 48 and 72 hours. Rylaze was approved by the U.S. Food and Drug Administration (FDA) on June 30, 2021 under the Real-Time Oncology Review (RTOR) program for use as a component of a multi-agent chemotherapeutic regimen for the treatment of ALL or LBL in adult and pediatric patients one month and older who have developed hypersensitivity to E. coli-derived asparaginase. Rylaze was approved at the dosing schedule of 25 mg/m2 every 48 hours based on data from Cohort 1a, in conjunction with data produced by a preliminary population pharmacokinetic (PPK) model.

These data will support additional regulatory filings for Rylaze, including a supplemental Biologics Licensing Application (sBLA) in early 2022 for a Monday/Wednesday/Friday (M/W/F) IM dosing schedule that will be reviewed under the FDA RTOR program. These data will also support regulatory submissions in Europe in mid-2022, with potential for approval in 2023.

"Asparaginase is an integral part of ALL therapy that is associated with improvement in survival rates. Following FDA approval earlier this year, Rylaze is already providing patients who have developed hypersensitivity to E. coli-derived asparaginase with a much-needed, effective therapeutic option with reliable supply and consistently high quality," said Rob Iannone, M.D., M.S.C.E., executive vice president, research and development and chief medical officer of Jazz Pharmaceuticals. "Rylaze is proof of Jazz’s ability to take medicines from concept through development, approval and launch, and we look forward to working with the FDA through the sBLA submission with these additional data in early 2022 in support of a label expansion for M/W/F dosing."

"The results from the Phase 2/3 study for Rylaze help to expand our knowledge of its dosing and safety profile, and support Monday/Wednesday/Friday dosing, which is more in line with clinical practice," said primary study investigator Dr. Luke Maese, associate professor at the University of Utah, Primary Children’s Hospital and Huntsman Cancer Institute. "The accelerated development and approval of Rylaze ensured that many patients with LBL and ALL – most of whom are children – who cannot tolerate E. coli-derived asparaginases have a new treatment option that maintains therapeutic levels of asparaginase activity throughout duration of treatment."

Interim Trial Results
Data presented at ASH (Free ASH Whitepaper) 2021 include initial analyses from an ongoing Phase 2/3 open-label, multicenter, dose confirmation and pharmacokinetic (PK) study of Rylaze (also known as JZP458) in patients with ALL/LBL who developed hypersensitivity or silent inactivation to a long-acting E. coli-derived asparaginase. Preliminary data are from Part A of the study, which investigated three Cohorts via IM administration:

Cohort 1a (n=33): studied a dose of 25 mg/m2 Monday/Wednesday/Friday
Cohort 1b (n=53): studied a dose of 37.5 mg/m2 Monday/Wednesday/Friday
Cohort 1c (n=52): studied a dose of 25 mg/m2 on Monday and Wednesday and 50 mg/m2 on Friday
Part B of the Phase 2/3 study remains active to further confirm the dose and schedule of the intravenous (IV) route of administration for Rylaze.

Efficacy Findings
The primary efficacy endpoints of the trial were the proportion of patients with a last 72-hour (from Friday to Monday) NSAA levels of ≥0.1 IU/mL during the first treatment course, in addition to safety and tolerability of Rylaze in patients with ALL/LBL.

The key secondary endpoint included the proportion of patients achieving the last 48-hour NSAA ≥0.1 IU/mL during the first treatment course.

The proportion of patients with observed NSAA levels ≥0.1 IU/mL with a 95% CI during Course 1 from these initial results is as follows (primary and key secondary endpoints):

Cohort 1a

Cohort 1b

Cohort 1c

At 48 hours

97% (CI: 91%, 100%)

98% (CI: 95%, 100%)

96% (CI: 90%, 100%)

At 72 hours

66% (CI: 48%, 83%)

80% (CI: 70%, 91%)

90% (CI:81%, 98%)

Based on a PPK modeling and simulation analysis versus observed data for Cohort 1c, the proportion of patients predicted to achieve NSAA levels ≥0.1 IU/mL with a 95% CI from these initial results is as follows:

Observed

Model Prediction

At 48 hours

96% (CI: 90%, 100%)

93% (CI: 92%, 94%)

At 72 hours

90% (CI:81%, 98%)

91% (CI: 90%, 92%)

The mean serum asparaginase activity (SAA) levels were also determined: mean SAA levels (95% CIs) from the initial data in Cohorts 1a, 1b and 1c at 48 hrs were 0.45 IU/mL (0.37, 0.53), 0.84 IU/mL (0.68, 0.99), and 0.66 IU/mL (0.54, 0.77); and at 72 hrs were 0.15 IU/mL (0.12, 0.19), 0.30IU/mL (0.23, 0.37), and 0.46 IU/mL (0.34, 0.58), respectively. These results reflect the higher dose on Friday from Cohort 1c.

Safety Findings
Grade 3/4 treatment-emergent adverse events (TEAEs), regardless of causality, occurred in 78/137 (57%) patients. There were no treatment-related TEAEs leading to death. The most commonly reported non-hematologic TEAEs (in ≥20% in any cohort) regardless of causality included: vomiting, nausea, fatigue, decreased appetite, pyrexia, abdominal pain, alanine aminotransferase (ALT) increased, febrile neutropenia, back pain, headache, sinus tachycardia, stomatitits, pain in extremity, aspartate aminotransferase (AST) increased and hyperglycemia. Treatment-related TEAEs leading to study drug discontinuation occurred in 6/137 (4%) of patients.

Overall, the safety profile of Rylaze was consistent with the reported safety information for patients with ALL/LBL receiving asparaginase with combination chemotherapy.

Further study analyses (including PK and safety analyses) are ongoing, and full study results will be reported at a later date.

About Rylaze (asparaginase erwinia chrysanthemi (recombinant)-rywn)
Rylaze, also known as JZP458, is approved in the U.S. for use as a component of a multi-agent chemotherapeutic regimen for the treatment of acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL) in adult and pediatric patients one month or older who have developed hypersensitivity to E. coli-derived asparaginase. Rylaze has orphan drug designation for the treatment of ALL/LBL in the United States. Rylaze is a recombinant erwinia asparaginase that uses a novel Pseudomonas fluorescens expression platform. JZP458 was granted Fast Track designation by the U.S. Food and Drug Administration (FDA) in October 2019 for the treatment of this patient population. Rylaze was approved as part of the Real-Time Oncology Review (RTOR) program, an initiative of the FDA’s Oncology Center of Excellence designed for efficient delivery of safe and effective cancer treatments to patients.

The full U.S. Prescribing Information for Rylaze is available at: View Source

Important Safety Information

RYLAZE should not be given to people who have had:

Serious allergic reactions to RYLAZE
Serious swelling of the pancreas (stomach pain), serious blood clots, or serious bleeding during previous asparaginase treatment
RYLAZE may cause serious side effects, including:

Allergic reactions (a feeling of tightness in your throat, unusual swelling/redness in your throat and/or tongue, or trouble breathing), some of which may be life-threatening
Swelling of the pancreas (stomach pain)
Blood clots (may have a headache or pain in leg, arm, or chest)
Bleeding
Liver problems
Contact your doctor immediately if any of these side effects occur.

Some of the most common side effects with RYLAZE include: liver problems, nausea, bone and muscle pain, tiredness, infection, headache, fever, allergic reactions, fever with low white blood cell count, decreased appetite, mouth swelling (sometimes with sores), bleeding, and too much sugar in the blood.

RYLAZE can harm your unborn baby. Inform your doctor if you are pregnant, planning to become pregnant, or nursing. Females of reproductive potential should use effective contraception (other than oral contraceptives) during treatment and for 3 months following the final dose. Do not breastfeed while receiving RYLAZE and for 1 week after the final dose.

Tell your healthcare provider if there are any side effects that are bothersome or that do not go away.

These are not all the possible side effects of RYLAZE. For more information, ask your healthcare provider.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch, or call 1-800-FDA-1088 (1-800-332-1088).

About Acute Lymphoblastic Leukemia (ALL)
ALL is a cancer of the blood and bone marrow that can progress quickly if not treated.1 Leukemia is the most common cancer in children, and about three out of four of these cases are ALL.2 Although it is one of the most common cancers in children, ALL is among the most curable of the pediatric malignancies due to recent advancements in treatment.3,4 Adults can also develop ALL, and about four of every 10 cases of ALL diagnosed are in adults.4 The American Cancer Society estimates that almost 6,000 new cases of ALL will be diagnosed in the United States in 2021.4 Asparaginase is a core component of multi-agent chemotherapeutic regimens in ALL.5 However, asparaginase treatments derived from E. coli are associated with the potential for development of hypersensitivity reactions.6

About Lymphoblastic Lymphoma (LBL)
LBL is a rare, fast-growing, aggressive subtype of Non-Hodgkin’s lymphoma, most often seen in teenagers and young adults.6 LBL is a very aggressive lymphoma – also called high-grade lymphoma – which means the lymphoma grows quickly with early spread to different parts of the body.[7],[8]

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.