Dr. Gordon was contracted with Bristol Myers Squibb for this article but did not receive any compensation for sharing his perspective for this story

Chimeric antigen receptor (CAR) T cell therapy is a personalized approach to treating certain blood cancers and is one of the most impactful advances in immunotherapy care seen in the last 20 years. CAR T cell therapy works by leveraging the immune system’s inherent ability to fight cancer, genetically engineering a patient’s own T cells to recognize and bind to proteins found on the surface of certain cancer cells. This interaction leads to the activation of the CAR T cells, which can then kill their target cells and continue to multiply within the body.

There are currently six U.S. Food and Drug Administration (FDA) approved CAR T cell therapies, each targeting B-cell markers CD19 or BCMA and indicated to treat select blood cancers. Investigational CAR Ts that recognize new targets and multiple antigens at once are also being developed to help expand cell therapy beyond blood cancers.

Leo Gordon, MD, is a professor of medicine in hematology and oncology at Northwestern University Feinberg School of Medicine and the Robert H. Lurie Comprehensive Cancer Center. He has seen the clinical development of CAR T treatments as a result of clinical research and is a passionate advocate for making cell therapies available for appropriate patients.

“Between my research and clinical activities, I have witnessed first-hand what CAR T cell therapies are capable of delivering, especially for patients that have run out of viable treatment options,” said Dr. Gordon. “Lymphoma, in particular, is an area where CAR T cell therapies have resulted in significant responses and long remissions, improving outcomes for patients who had limited options just five years ago.”

The promise and future of cell therapy in treating relapsed or refractory LBCL

Large B-cell lymphoma (LBCL) is a form of non-Hodgkin’s lymphoma that comprises about 30% of all non-Hodgkin’s lymphoma cases and is diagnosed in approximately 150,000 people worldwide annually.

 Roughly 60% of patients with LBCL achieve long-term remission with initial chemoimmunotherapy, leaving as many as 40% that do not respond or relapse after treatment.

Typical second-line treatments, including high-dose chemotherapy and stem-cell transplantation, can improve outcomes; however, patients who are resistant to initial treatment or relapse early often fail to achieve long-term benefits.

 Therefore, personalized therapy options have been approved for patients with relapsed or refractory (R/R) LBCL.

CD19 is a critical target as it is broadly expressed among many B-cell malignancies, including LBCL. With CD19-targeting CAR T cell therapies, T cells are genetically reprogrammed to help recognize and target CD19-expressing cells, which may include healthy and cancerous cells.

“The availability of a CAR T cell therapy as a second-line treatment is crucial, as some types of large B-cell lymphoma quickly worsen, and patients can’t afford to wait before finding a promising option,” said Dr. Gordon. “CAR T cell therapy is a personalized treatment for patients with certain relapsed or refractory blood cancers. Fortunately, CAR T cell therapies are available for relapsed or refractory large B-cell lymphoma patients earlier in the treatment journey, like 

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

adult patients with large B-cell lymphoma (LBCL), including diffuse large B-cell lymphoma (DLBCL) not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B, who have:

refractory disease to first-line chemoimmunotherapy or relapse within 12 months of first-line chemoimmunotherapy; or

refractory disease to first-line chemoimmunotherapy or relapse after first line chemoimmunotherapy and are not eligible for hematopoietic stem cell transplantation (HSCT) due to comorbidities or age; or

relapsed or refractory disease after two or more lines of systemic therapy.

Please see the Important Safety Information section below, on serious side effects including Boxed WARNINGS for 

regarding Cytokine Release Syndrome (CRS), Neurologic Toxicities (NT), and Secondary Hematologic Malignancies.

Serious side effects such as CRS, NT, hypersensitivity reactions, severe infections, including life-threatening or fatal infections, prolonged cytopenias, hypogammaglobulinemia, secondary hematological malignancies and effects on the ability to drive and use machines may occur with 

include fever, fatigue, musculoskeletal pain, and nausea.

was first approved for use later in a patient’s treatment journey, after two or more lines of systemic therapy. A few years later, the FDA approved it as a second-line treatment based on results from the TRANSFORM and PILOT clinical trials.

TRANSFORM is a pivotal, global, randomized, open-label multicenter Phase 3 trial evaluating 

compared to current standard therapy regimens (platinum-based salvage chemotherapy followed by high-dose chemotherapy and autologous HSCT in patients responding to salvage chemotherapy) in adult patients with LBCL that was primary refractory or relapsed within 12 months after first-line chemoimmunotherapy.

In the TRANSFORM study (n=184), at interim analysis after a median follow-up of 6.2 months, median event-free survival (mEFS) was 10.1 months for 

 vs 2.3 months for standard therapy, a 4x improvement.

 also demonstrated a 66% reduction in risk of EFS events.

 In the primary analysis with a median follow-up of 17.5 months, mEFS was not reached in patients who received 

vs 2.4 months for standard therapy. With 

, the majority (73.9%) of patients achieved a complete response (CR) compared to less than half (43.5%) of those who were treated with standard therapy.

PILOT is a multicenter Phase 2 single-arm, open-label trial evaluating 

as a second-line therapy in adults with R/R LBCL after first-line therapy who are ineligible for HSCT. In a median follow up at 11.2 months for the Phase 2 PILOT study (n=61), 80% (49/61) of patients achieved the primary endpoint of overall response rate (ORR) and over half (54%; 33/61) of the patients showed a CR to 

“By recognizing the advantages of using CAR T cell therapy treatments earlier, we can give patients an option to treat their large B-cell lymphoma,” said Dr. Gordon, a PILOT and TRANSCEND study investigator. “

offers significantly improved clinical outcomes and an established safety profile, demonstrating clinically meaningful complete responses, event-free survival, and progression-free survival compared to standard therapy (stem cell transplant) in patients with relapsed or refractory large B-cell lymphoma that are primary refractory or relapsed within 12 months after first-line therapy. These points are also evident for patients who have relapsed after primary treatment but who are not good candidates for stem cell transplant as demonstrated in the non-randomized PILOT study.”

Patients with R/R LBCL, which is typically diagnosed in elderly adults over 60 years of age, are more likely to have comorbidities that can limit their therapeutic options. So, while the recommended frontline therapies for LBCL can be effective for many patients, they often involve chemotherapeutic agents, which may not be appropriate for older patients or those who have undergone multiple treatment rounds.

Regarding this vulnerable LBCL patient population, Dr. Gordon adds, “If the first-line treatment fails, these patients may be unsure of their next steps, so it is important to address their concerns and provide them with the most appropriate options earlier in their treatment plan.”

“For physicians looking to guide their patients as they embark on their CAR T cell treatment journey, I would advise them to emphasize that CAR T cell therapy can be effective with a one-time infusion treatment which includes leukapheresis, manufacturing, administration, and adverse event monitoring,” said Dr. Gordon. “The possibility of serious side effects such as cytokine release syndrome or neurological toxicities is real and must be monitored.

 It is important to help patients weigh the potential risks against the potential benefits.”

All patients are monitored closely by their care team for four weeks for possible side effects, which may be severe, life-threatening or even fatal. These side effects can include but are not limited to CRS and NT, which can happen in the first few days to several weeks after a patient’s CAR T cells are infused into their body. Time at the treatment center and follow-up visits will vary based on the individual patient.

has a well-established safety profile based on results from the TRANSFORM and PILOT studies. Occurrences of CRS and neurologic events were generally low grade and mostly resolved quickly with standard protocols, and without the use of prophylactic steroids. Any-grade CRS was reported in less than half of patients (45%; 68/150), with Grade 3 CRS reported in 1.3% of patients. Any-grade neurologic events were reported in 27% (41/150) of patients treated with 

, with Grade 3 neurologic events reported in 7% of patients. Median time to onset of CRS was four days (range: 1 to 63 days) and median duration of CRS was four days (range: 1 to 16 days). The median time to onset of neurologic events was eight days (range: 1 to 63 days). The median duration of neurologic toxicities was six days (range: 1 to 119 days). 

Adding CAR T cell therapy to the list of approved and available second-line treatments for LBCL expands much-needed treatment options for high-risk patients earlier.

“Innovations in personalized cancer care, like CAR T therapies, are evolving rapidly, but these therapies can only be as transformative as their implementation allows, and physicians play an essential role in these efforts,” said Dr. Gordon. “Identifying the appropriate therapy and incorporating it into the patient’s treatment plan as early as they are eligible is a way to help realize the potential of these CAR T therapies.”

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

Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients receiving BREYANZI. Do not administer BREYANZI to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab with or without corticosteroids.

Neurologic toxicities, including fatal or life-threatening reactions, occurred in patients receiving BREYANZI, including concurrently with CRS, after CRS resolution, or in the absence of CRS. Monitor for neurologic events after treatment with BREYANZI. Provide supportive care and/or corticosteroids as needed.

T cell malignancies have occurred following treatment of hematologic malignancies with BCMA- and CD19-directed genetically modified autologous T cell immunotherapies, including BREYANZI.

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

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


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

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

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

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

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

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

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.

, or contact Bristol-Myers Squibb at 1-866-340-7332.

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

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

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

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

Viral reactivation: Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients treated with drugs directed against B cells. In patients who received BREYANZI for LBCL, 15 of 16 patients with a prior history of HBV were treated with concurrent antiviral suppressive therapy. Perform screening for HBV, HCV, and HIV in accordance with clinical guidelines before collection of cells for manufacturing. In patients with prior history of HBV, consider concurrent antiviral suppressive therapy to prevent HBV reactivation per standard guidelines.

Articles

CAR T cell therapies have shown remarkable clinical success in difficult-to-treat blood cancers. Read one oncologist’s perspective on what current CAR T therapies may offer patients with relapsed or refractory (R/R) large B-cell lymphoma (LBCL), including at earlier points in their disease journey.

The Impact of CAR T Cell Therapy on Managing R/R LBCL  

Certain metastatic gastroesophageal cancers, such as gastric cancer (GC), gastroesophageal junction cancer (GEJC) and esophageal adenocarcinoma (EAC), have been associated with challenging prognoses and poor survival rates.

 The five-year survival rates for people in the United States with metastatic gastric and esophageal cancers from 2012 to 2018 were approximately 5.9% and 5.7%, respectively. 

 Combined, gastric and esophageal cancers account for approximately 4.5% of all cancer deaths in the U.S.

 Therefore, there is a need for treatment advances and options that may offer hope and the chance for a longer life.

In recent years, one area of research in this setting has focused on immunotherapy-based treatment options. This led to the 2021 U.S. Food and Drug Administration (FDA) approval of 

® (nivolumab) (injection for intravenous use), in combination with fluoropyrimidine- and platinum-containing chemotherapy, for the treatment of adult patients with advanced or metastatic GC, GEJC, and EAC, regardless of PD-L1 expression status.

“This approval represented important progress in metastatic gastroesophageal cancer, providing an option to patients who have historically experienced high unmet need,” said Lee James, MD, PhD, vice president of U.S. Medical Oncology at Bristol Myers Squibb. “Ongoing research in this space continues to be critical, with the aim of expanding our understanding of the role of immunotherapy-based approaches in this treatment landscape.”

-based combination in this setting was supported by one-year results from CheckMate -649, a Phase 3 clinical trial. Follow-up three-year data were presented at the ASCO Gastrointestinal Cancers Symposium in January 2023, which analyzed long-term survival in patients regardless of PD-L1 expression status versus chemotherapy alone.

 is associated with the following Warnings and Precautions: severe and fatal immune-mediated adverse reactions including pneumonitis, colitis, hepatitis and hepatotoxicity, endocrinopathies, nephritis and renal dysfunction, dermatologic adverse reactions, other immune-mediated adverse reactions; infusion-related reactions; complications of allogeneic hematopoietic stem cell transplantation (HSCT); embryo-fetal toxicity; and increased mortality in patients with multiple myeloma when 

 is added to a thalidomide analogue and dexamethasone, which is not recommended outside of controlled clinical trials.

 Please see the Important Safety Information section below.

Data from CheckMate -649 Demonstrated Superior Overall Survival (OS) in Patients Regardless of PD-L1 Status at One Year

The CheckMate -649 clinical trial evaluated 

 in combination with mFOLFOX6 (fluorouracil, leucovorin, and oxaliplatin) or CapeOX (capecitabine and oxaliplatin), compared with chemotherapy (mFOLFOX6 or CapeOX) alone, in patients with previously untreated advanced or metastatic GC, GEJC, and EAC.

 The trial excluded patients who were known human epidermal growth factor receptor 2 (HER2) positive, or had untreated central nervous system (CNS) metastases.

The primary endpoints assessed in patients with PD-L1 combined positive score (CPS) ≥5 were overall survival (OS) and progression-free survival (PFS) assessed by Blinded Independent Central Review (BICR).

 At the primary analysis (minimum follow-up 12.1 months), median OS was 14.4 months (95% Confidence Interval [CI]: 13.1-16.2) with 

 plus chemotherapy versus 11.1 months (95% CI: 10.0-12.1) with chemotherapy alone (Hazard Ratio [HR] 0.71; 95% CI: 0.61-0.83; 

 Median PFS was 7.7 months (95% CI: 7.0-9.2) in the 

 plus chemotherapy arm versus 6.0 months (95% CI: 5.6-6.9) with chemotherapy alone (HR 0.68; 95% CI: 0.58-0.79; 

Secondary endpoints at the primary analysis included OS in patients with PD-L1 CPS ≥1 and in all randomized patients. 

 plus chemotherapy demonstrated superior OS compared with chemotherapy alone in both patient populations.

 Median OS was 14.0 months (95% CI: 12.6-15.0) with 

 plus chemotherapy versus 11.3 months (95% CI: 10.6-12.3) with chemotherapy alone (HR 0.77; 95% CI: 0.68-0.88; 

<0.0001) in patients with PD-L1 CPS ≥1.

 In all randomized patients, median OS was 13.8 months (95% CI: 12.6-14.6) with 

 plus chemotherapy versus 11.6 months (95% CI: 10.9-12.5) with chemotherapy alone (HR 0.80; 95% CI: 0.71-0.90; 

At the primary analysis in all randomized patients, 55% of patients on 

 in combination with chemotherapy were alive at one year versus 48% of patients on chemotherapy alone.

 The OS rates were not pre-specified within the study protocol and were not powered to detect differences between treatment arms.

 (nivolumab) and/or chemotherapy were discontinued in 44% of patients and at least one dose was withheld in 76% of patients due to an adverse reaction.

 Fatal adverse reactions occurred in 16 (2.0%) patients who were treated with 

 These included pneumonitis (4 patients), febrile neutropenia (2 patients), stroke (2 patients), gastrointestinal toxicity, intestinal mucositis, septic shock, pneumonia, infection, gastrointestinal bleeding, mesenteric vessel thrombosis, and disseminated intravascular coagulation.

 Serious adverse reactions occurred in 52% of patients treated with 

 The most frequent serious adverse reactions reported in ≥2% of patients treated with 

 in combination with chemotherapy were vomiting (3.7%), pneumonia (3.6%), anemia (3.6%), pyrexia (2.8%), diarrhea (2.7%), febrile neutropenia (2.6%), and pneumonitis (2.4%). The most common adverse reactions reported in ≥20% of patients treated with 

 in combination with chemotherapy were peripheral neuropathy (53%), nausea (48%), fatigue (44%), diarrhea (39%), vomiting (31%), decreased appetite (29%), abdominal pain (27%), constipation (25%), and musculoskeletal pain (20%).

Data from Extended Three-Year Follow-up of CheckMate -649 Analyzed Long-Term Survival Versus Chemotherapy Alone in Patients Regardless of PD-L1 Status

In the extended follow-up analysis (36.2 months minimum follow-up) in patients with PD-L1 CPS ≥5, median OS was 14.4 months (95% CI: 13.1-16.2) with 

 plus chemotherapy versus 11.1 months (95% CI: 10.0-12.1) with chemotherapy alone (HR 0.70; 95% CI: 0.61-0.81) (

Median PFS was 8.3 months (95% CI: 7.0-9.3) in the 

 plus chemotherapy arm versus 6.1 months (95% CI: 5.6-6.9) with chemotherapy alone (HR 0.70; 95% CI: 0.60-0.81).

The exploratory 36-month analysis was not statistically powered to detect differences between treatment arms.

In the extended follow-up analysis (36.2 months minimum follow-up) in patients with PD-L1 CPS ≥1, median OS was 13.8 months (95% CI: 12.4-14.8) with 

 plus chemotherapy versus 11.3 months (95% CI: 10.7-12.3) with chemotherapy alone (HR 0.76; 95% CI: 0.67-0.86) 

In all randomized patients, median OS was 13.7 months (95% CI: 12.4-14.5) with 

 plus chemotherapy versus 11.6 months (95% CI: 10.9-12.5) with chemotherapy alone (HR 0.79; 95% CI: 0.71-0.88) (

Please see additional Important Safety Information below.

 was FDA-approved in 2021 as the first and only approved immunotherapy combined with chemotherapy (please see below for full indication statement) to deliver superior OS compared with chemotherapy alone across first-line metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma based on the CheckMate -649 trial of these patients. It is currently the only first-line immunotherapy-based regimen approved in patients with gastric cancer regardless of PD-L1 expression, including patients with HER2- negative status.

“With these latest findings we see the potential for long term survival with 

 plus chemotherapy compared with chemotherapy alone over three years for certain patients, as we add to the available data for this treatment approach as an important option for certain metastatic gastroesophageal cancers,” said Dr. Lee James. “This is representative of our ongoing and deep commitment to patients facing these diagnoses and their loved ones, as well as the healthcare professionals caring for them – as we collectively hope for treatment options that may offer the chance at a longer life.”

OPDIVO® (nivolumab), in combination with fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the treatment of adult patients with advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma.

Severe and Fatal Immune-Mediated Adverse Reactions

Immune-mediated adverse reactions listed herein may not include all possible severe and fatal immune- mediated adverse reactions.

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. While immune-mediated adverse reactions usually manifest during treatment, they can also occur after discontinuation of OPDIVO. Early identification and management are essential to ensure safe use of OPDIVO. Monitor for signs and symptoms that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate clinical chemistries including liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment with OPDIVO. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue OPDIVO depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information). In general, if OPDIVO interruption or discontinuation is required, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy. Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (e.g., endocrinopathies and dermatologic reactions) are discussed below.

OPDIVO can cause immune-mediated pneumonitis. The incidence of pneumonitis is higher in patients who have received prior thoracic radiation. In patients receiving OPDIVO monotherapy, immune-mediated pneumonitis occurred in 3.1% (61/1994) of patients, including Grade 4 (<0.1%), Grade 3 (0.9%), and Grade 2 (2.1%).

OPDIVO can cause immune-mediated colitis. A common symptom included in the definition of colitis was diarrhea. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid- refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. In patients receiving OPDIVO monotherapy, immune-mediated colitis occurred in 2.9% (58/1994) of patients, including Grade 3 (1.7%) and Grade 2 (1%).

Immune-Mediated Hepatitis and Hepatotoxicity

OPDIVO can cause immune-mediated hepatitis. In patients receiving OPDIVO monotherapy, immune-mediated hepatitis occurred in 1.8% (35/1994) of patients, including Grade 4 (0.2%), Grade 3 (1.3%), and Grade 2 (0.4%).

OPDIVO can cause primary or secondary adrenal insufficiency, immune-mediated hypophysitis, immune- mediated thyroid disorders, and Type 1 diabetes mellitus, which can present with diabetic ketoacidosis. Withhold OPDIVO depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information). For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism; initiate hormone replacement as clinically indicated. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism; initiate hormone replacement or medical management as clinically indicated. Monitor patients for hyperglycemia or other signs and symptoms of diabetes; initiate treatment with insulin as clinically indicated.

In patients receiving OPDIVO monotherapy, adrenal insufficiency occurred in 1% (20/1994), including Grade 3 (0.4%) and Grade 2 (0.6%).

In patients receiving OPDIVO monotherapy, hypophysitis occurred in 0.6% (12/1994) of patients, including Grade 3 (0.2%) and Grade 2 (0.3%).

In patients receiving OPDIVO monotherapy, thyroiditis occurred in 0.6% (12/1994) of patients, including Grade 2 (0.2%).

In patients receiving OPDIVO monotherapy, hyperthyroidism occurred in 2.7% (54/1994) of patients, including Grade 3 (<0.1%) and Grade 2 (1.2%).

In patients receiving OPDIVO monotherapy, hypothyroidism occurred in 8% (163/1994) of patients, including Grade 3 (0.2%) and Grade 2 (4.8%).

In patients receiving OPDIVO monotherapy, diabetes occurred in 0.9% (17/1994) of patients, including Grade 3 (0.4%) and Grade 2 (0.3%), and 2 cases of diabetic ketoacidosis.

Immune-Mediated Nephritis with Renal Dysfunction

OPDIVO can cause immune-mediated nephritis. In patients receiving OPDIVO monotherapy, immune-mediated nephritis and renal dysfunction occurred in 1.2% (23/1994) of patients, including Grade 4 (<0.1%), Grade 3 (0.5%), and Grade 2 (0.6%).

Immune-Mediated Dermatologic Adverse Reactions

OPDIVO can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug rash with eosinophilia and systemic symptoms (DRESS) has occurred with PD-1/PD-L1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes.

Withhold or permanently discontinue OPDIVO depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information).

In patients receiving OPDIVO monotherapy, immune-mediated rash occurred in 9% (171/1994) of patients, including Grade 3 (1.1%) and Grade 2 (2.2%).

The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received OPDIVO monotherapy or were reported with the use of other PD- 1/PD-L1 blocking antibodies. Severe or fatal cases have been reported for some of these adverse reactions: 

meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy; 

uveitis, iritis, and other ocular inflammatory toxicities can occur; 

pancreatitis to include increases in serum amylase and lipase levels, gastritis, duodenitis; 

myositis/polymyositis, rhabdomyolysis, and associated sequelae including renal failure, arthritis, polymyalgia rheumatica; 

hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis (HLH), systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection.

Some ocular IMAR cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada–like syndrome, which has been observed in patients receiving OPDIVO, as this may require treatment with systemic corticosteroids to reduce the risk of permanent vision loss.

OPDIVO can cause severe infusion-related reactions. Discontinue OPDIVO in patients with severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions. Interrupt or slow the rate of infusion in patients with mild (Grade 1) or moderate (Grade 2) infusion-related reactions. In patients receiving OPDIVO monotherapy as a 60-minute infusion, infusion-related reactions occurred in 6.4% (127/1994) of patients. In a separate trial in which patients received OPDIVO monotherapy as a 60-minute infusion or a 30-minute infusion, infusion-related reactions occurred in 2.2% (8/368) and 2.7% (10/369) of patients, respectively. Additionally, 0.5% (2/368) and 1.4% (5/369) of patients, respectively, experienced adverse reactions within 48 hours of infusion that led to dose delay, permanent discontinuation or withholding of OPDIVO.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation

Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with OPDIVO. Transplant-related complications include hyperacute graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between OPDIVO and allogeneic HSCT.

Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with OPDIVO prior to or after an allogeneic HSCT.

Based on its mechanism of action and findings from animal studies, OPDIVO can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and for at least 5 months after the last dose.

Increased Mortality in Patients with Multiple Myeloma when OPDIVO is Added to a Thalidomide Analogue and Dexamethasone

In randomized clinical trials in patients with multiple myeloma, the addition of OPDIVO to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials.

There are no data on the presence of OPDIVO in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment and for 5 months after the last dose.

In Checkmate -649, serious adverse reactions occurred in 52% of patients treated with OPDIVO in combination with chemotherapy (n=782). The most frequent serious adverse reactions reported in ≥2% of patients treated with OPDIVO in combination with chemotherapy were vomiting (3.7%), pneumonia (3.6%), anemia (3.6%), pyrexia (2.8%), diarrhea (2.7%), febrile neutropenia (2.6%), and pneumonitis (2.4%). Fatal adverse reactions occurred in 16 (2.0%) patients who were treated with OPDIVO in combination with chemotherapy; these included pneumonitis (4 patients), febrile neutropenia (2 patients), stroke (2 patients), gastrointestinal toxicity, intestinal mucositis, septic shock, pneumonia, infection, gastrointestinal bleeding, mesenteric vessel thrombosis, and disseminated intravascular coagulation.

In Checkmate -649, the most common adverse reactions (≥20%) in patients treated with OPDIVO in combination with chemotherapy (n=782) were peripheral neuropathy (53%), nausea (48%), fatigue (44%), diarrhea (39%), vomiting (31%), decreased appetite (29%), abdominal pain (27%), constipation (25%), and musculoskeletal pain (20%).

Please see US Full Prescribing Information for 

Yang D, Hendifar A, Lenz C, et al. Survival of Metastatic Gastric Cancer: Significance of Age, Sex and Race/Ethnicity. J Gastrointest Oncol. 2011;2(2):77-84. doi:10.3978/j.issn.2078-6891.2010.025

Wang K, Johnson A, Ali SM, et al. Comprehensive Genomic Profiling of Advanced Esophageal Squamous Cell Carcinomas and Esophageal Adenocarcinomas Reveals Similarities and Differences. 

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Lin D, Khan U, Goetze TO, et al. Gastroesophageal Junction Adenocarcinoma: Is There an Optimal Management? 

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National Cancer Institute. Cancer Stat Facts: Stomach Cancer. Surveillance, Epidemiology, and End Results Program (SEER). Accessed February 2023. 

https://seer.cancer.gov/statfacts/html/stomach.html

National Cancer Institute. Cancer Stat Facts: Esophageal Cancer. Surveillance, Epidemiology, and End Results Program (SEER). Accessed January 2023. 

https://seer.cancer.gov/statfacts/html/esoph.html

US Product Information. Last Updated: May 2022. Princeton, NJ: Bristol Myers Squibb Company.

Moehler M, Shitara K, Garrido M, et al. Nivolumab Plus Chemotherapy versus Chemotherapy as First-line Treatment for Advanced Gastric Cancer/Gastroesophageal Junction Cancer/Esophageal Adenocarcinoma: Ffirst Rresults of the CheckMate 649 study. Late-breaker Presented at 2020 European Society for Medical Oncology (ESMO) Virtual Congress. September 19-21, 2020.

Janjigian Y, Shitara K, Moehler M, et al. Nivolumab (NIVO) Plus Chemotherapy (chemo) vs Chemo as First-line (1L) Treatment for Advanced Gastric Cancer/Gastroesophageal Junction Cancer/Esophageal Adenocarcinoma (GC/GEJC/EAC): 3-year Follow-up from CheckMate 649. Oral presentation at 2023 ASCO GI Cancers Symposium. January 19-21, 2023.

Data on File. Bristol Myers Squibb Company; 2022.

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