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Dosage modifications for adverse reactions1

No dosage reduction for COLUMVI™ is recommended

Recommendations for Management of Cytokine Release Syndrome

Identify CRS based on clinical presentation. Evaluate for and treat other causes of fever, hypoxia, and hypotension. If CRS is suspected, withhold COLUMVI and manage according to the recommendations in the table below and current practice guidelines. Administer supportive care for CRS, which may include intensive care for severe or life-threatening cases.

Grade* Presenting Symptoms Actions

Grade 1

Temperature ≥100.4 °F (38 °C)†
  • Withhold COLUMVI and manage per current practice guidelines
    • If symptoms resolve, restart infusion at a slower rate‡
  • Ensure CRS symptoms are resolved for at least 72 hours before next dose§
  • Consider slower infusion rate for next dose

Grade 2

Temperature ≥100.4 °F (38 °C)† with:

Hypotension not requiring vasopressors

and/or

Hypoxia requiring low-flow oxygen|| by nasal cannula or blow-by
  • Withhold COLUMVI and manage per current practice guidelines
    • If symptoms resolve, restart infusion at a slower rate‡
  • Ensure CRS symptoms are resolved for at least 72 hours before next dose§
  • For the next dose, consider a slower infusion rate, monitor more frequently, and consider hospitalization
  • For recurrent Grade 2 CRS, manage per Grade 3 CRS

Grade 3

Temperature ≥100.4 °F (38 °C)† with:

Hypotension requiring vasopressor (with or without vasopressin)

and/or

Hypoxia requiring high-flow oxygen|| by nasal cannula, face mask, non-rebreather mask, or Venturi mask
  • Withhold COLUMVI and manage per current practice guidelines, which may include intensive care
  • Ensure CRS symptoms are resolved for at least 72 hours before next dose§
  • Hospitalize for the next dose, monitor more frequently, and consider a slower infusion rate‡
  • For recurrent Grade 3 CRS, permanently discontinue COLUMVI

Grade 4

Temperature ≥100.4 °F (38 °C)† with:

Hypotension requiring multiple vasopressors (excluding vasopressin)

and/or

Hypoxia requiring oxygen by positive pressure (eg, CPAP, BiPAP, intubation, and mechanical ventilation)
  • Permanently discontinue COLUMVI and manage per current practice guidelines, which may include intensive care

*American Society for Transplantation and Cellular Therapy (ASTCT) 2019 consensus grading criteria.
†Premedication may mask fever. Therefore, if clinical presentation is consistent with CRS, follow these management guidelines.
‡Duration of infusion may be extended up to 8 hours, as appropriate for that cycle (see Dosing and Administration for more information).
§Refer to Recommendations for restarting therapy after a dose delay for information on restarting COLUMVI after dose delays.
‖Low-flow oxygen defined as oxygen delivered at <6 L/minute; high-flow oxygen defined as oxygen delivered at ≥6 L/minute.

Recommendations for management of neurologic toxicity (including ICANS)

At the first sign of neurologic toxicity, including ICANS, consider neurology evaluation and withholding COLUMVI based on the type and severity of neurotoxicity. Rule out other causes of neurologic symptoms. Provide supportive therapy, which may include intensive care.

Adverse Reaction Severity*† Actions

Neurologic Toxicity* (including ICANS†)

Grade 1
  • Continue COLUMVI and monitor neurologic toxicity symptoms
  • If ICANS, manage per current practice guidelines

Grade 2
  • Withhold COLUMVI until neurologic toxicity symptoms improve to Grade 1 or baseline‡
  • Provide supportive therapy, and consider neurologic evaluation
  • If ICANS, manage per current practice guidelines

Grade 3
  • Withhold COLUMVI until neurologic toxicity symptoms improve to Grade 1 or baseline for at least 7 days§‖
  • For Grade 3 neurologic events lasting more than 7 days, consider permanently discontinuing COLUMVI
  • Provide supportive therapy, and consider neurology evaluation
  • If ICANS, manage per current practice guidelines

Grade 4
  • Permanently discontinue COLUMVI
  • Provide supportive therapy, which may include intensive care, and consider neurology evaluation
  • If ICANS, manage per current practice guidelines

*Based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.03.
†Based on American Society for Transplantation and Cellular Therapy (ASTCT) 2019 grading for ICANS.
‡Consider the type of neurologic toxicity before deciding to withhold COLUMVI.
§See Dosage and Administration on restarting COLUMVI after dose delays.
‖Evaluate benefit-risk before restarting COLUMVI.

Adverse Reactions* Severity* Actions
Infections Grades 1 – 4
  • Withhold COLUMVI in patients with active infection until the infection resolves†
  • For Grade 4, consider permanent discontinuation of COLUMVI
Tumor flare Grade 1
  • Monitor for signs and symptoms of compression or obstruction due to mass effect secondary to tumor flare
Grades 2 – 4
  • Monitor for signs and symptoms of compression or obstruction due to mass effect secondary to tumor flare, and institute appropriate treatment including antihistamine and corticosteroids
  • Withhold COLUMVI until tumor flare resolves†
Neutropenia Absolute neutrophil count less than 0.5 × 109/L
  • Withhold COLUMVI until absolute neutrophil count is 0.5 × 102/L or higher†
Thrombocytopenia Platelet count less than 50 x 109/L
  • Withhold COLUMVI until platelet count is 50 x 109/L or higher†
Other Adverse Reactions Grade 3 or higher
  • Withhold COLUMVI until the toxicity resolves to Grade 1 or baseline†

*Based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.03.
†See Dosage and Administration on restarting COLUMVI after dose delays.

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BiPAP=bilevel positive airway pressure; CPAP=continuous positive airway pressure; CRS=cytokine release syndrome; ICANS=immune effector cell-associated neurotoxicity syndrome.

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Important Safety Information & Indication

Indication

COLUMVI (glofitamab-gxbm) is indicated for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma not otherwise specified (DLBCL), or large B-cell lymphoma (LBCL) arising from follicular lymphoma, after two or more lines of systemic therapy.

This indication is approved under accelerated approval based on response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

BOXED WARNING

Cytokine Release Syndrome (CRS), including serious or fatal reactions, can occur in patients receiving COLUMVI. Premedicate before each dose, and initiate treatment with the COLUMVI step-up dosing schedule to reduce the risk of CRS. Withhold COLUMVI until CRS resolves or permanently discontinue based on severity.

Warnings and Precautions

Cytokine Release Syndrome (CRS)

COLUMVI can cause serious and fatal CRS.

Among the 145 patients who received COLUMVI, CRS occurred in 70%, with Grade 1 CRS developing in 52% of patients, Grade 2 in 14%, Grade 3 in 2.8% of patients, and Grade 4 in 1.4%. The most common manifestations of CRS included fever, tachycardia, hypotension, chills, and hypoxia.

CRS occurred in 56% of patients after the 2.5 mg dose of COLUMVI, 35% after the 10 mg dose, 29% after the initial 30 mg target dose, and 2.8% after subsequent doses. With the first step-up dose of COLUMVI, the median time to onset of CRS (from the start of infusion) was 14 hours (range: 5 to 74 hours). CRS after any dose resolved in 98% of cases, with a median duration of CRS of 2 days (range: 1 to 14 days). Recurrent CRS occurred in 34% of all patients. CRS can first occur with the 10 mg dose; of 135 patients treated with the 10 mg dose of COLUMVI, 15 patients (11%) experienced their first CRS event with the 10 mg dose, of which 13 events were Grade 1, 1 event was Grade 2, and 1 event was Grade 3.

Administer COLUMVI in a facility equipped to monitor and manage CRS. Initiate therapy according to the COLUMVI step-up dosing schedule to reduce the risk of CRS, administer pretreatment medications, and ensure adequate hydration. Patients should be hospitalized during and for 24 hours after completing infusion of the 2.5 mg step-up dose. Patients who experienced any grade CRS during the 2.5 mg step-up dose should be hospitalized during and for 24 hours after completion of the 10 mg step-up dose. For subsequent doses, patients who experienced Grade ≥2 CRS with their previous infusion should be hospitalized during and for 24 hours after the next COLUMVI infusion.

At the first sign of CRS, immediately evaluate patients for hospitalization, manage per current practice guidelines, and administer supportive care; withhold or permanently discontinue COLUMVI based on severity.

Neurologic Toxicity

COLUMVI can cause serious neurologic toxicity, including Immune Effector Cell-Associated Neurotoxicity (ICANS).

Among 145 patients who received COLUMVI, the most frequent neurologic toxicities of any grade were headache (10%), peripheral neuropathy (8%), dizziness or vertigo (7%), and mental status changes (4.8%, including confusional state, cognitive disorder, disorientation, somnolence, and delirium). Grade 3 or higher neurologic adverse reactions occurred in 2.1% of patients and included somnolence, delirium, and myelitis. Cases of ICANS of any grade occurred in 4.8% of patients.

Coadministration of COLUMVI with other products that cause dizziness or mental status changes may increase the risk of neurologic toxicity. Optimize concomitant medications and hydration to avoid dizziness or mental status changes. Institute fall precautions as appropriate.

Monitor patients for signs and symptoms of neurologic toxicity, evaluate, and provide supportive therapy; withhold or permanently discontinue COLUMVI based on severity.

Evaluate patients who experience neurologic toxicity such as tremors, dizziness, or adverse reactions that may impair cognition or consciousness promptly, including potential neurology evaluation. Advise affected patients to refrain from driving and/or engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, until the neurologic toxicity fully resolves.

Serious Infections

COLUMVI can cause serious or fatal infections.

Serious infections were reported in 16% of patients, including Grade 3 or 4 infections in 10%, and fatal infections in 4.8% of patients. Grade 3 or higher infections reported in ≥ 2% patients were COVID-19 infection (6%), including COVID-19 pneumonia, and sepsis (4.1%). Febrile neutropenia occurred in 3.4% of patients.

COLUMVI should not be administered to patients with an active infection. Administer antimicrobial prophylaxis according to guidelines. Monitor patients before and during COLUMVI treatment for infection and treat appropriately. Withhold or consider permanent discontinuation of COLUMVI based on severity.

Tumor Flare

COLUMVI can cause serious tumor flare. Manifestations included localized pain and swelling at the sites of the lymphoma lesions and/or dyspnea from new pleural effusions.

Tumor flare was reported in 12% of patients who received COLUMVI, including Grade 2 tumor flare in 4.8% of patients and Grade 3 tumor flare in 2.8%. Recurrent tumor flare occurred in two (12%) of the affected patients. Most tumor flare events occurred during Cycle 1, with a median time to first onset of 2 days (range: 1 to 16 days) after the first dose of COLUMVI. The median duration was 3.5 days (range: 1 to 35 days).

Patients with bulky tumors or disease located in close proximity to airways or a vital organ should be monitored closely during initial therapy. Monitor for signs and symptoms of compression or obstruction due to mass effect secondary to tumor flare, and institute appropriate treatment. Withhold COLUMVI until tumor flare resolves.

Embryo-Fetal Toxicity

Based on its mechanism of action, COLUMVI may cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with COLUMVI and for 1 month after the last dose.

Most Common Adverse Reactions

The most common (≥ 20%) adverse reactions, excluding laboratory abnormalities, are CRS (70%), musculoskeletal pain (21%), rash (20%), and fatigue (20%). The most common Grade 3 to 4 laboratory abnormalities (≥ 20%) are lymphocyte count decreased (83%), phosphate decreased (28%), neutrophil count decreased (26%), uric acid increased (23%), and fibrinogen decreased (21%).

Drug Interactions

For certain CYP substrates where minimal concentration changes may lead to serious adverse reactions, monitor for toxicities or drug concentrations of such CYP substrates when coadministered with COLUMVI.

Glofitamab-gxbm causes the release of cytokines that may suppress the activity of CYP enzymes, resulting in increased exposure of CYP substrates. Increased exposure of CYP substrates is more likely to occur after the first dose of COLUMVI on Cycle 1 Day 8 and up to 14 days after the first 30 mg dose on Cycle 2 Day 1 and during and after CRS.

Use in Specific Populations

Lactation
There are no data on the presence of glofitamab-gxbm in human milk or the effects on the breastfed child or milk production. Because human IgG is present in human milk, and there is potential for glofitamab-gxbm absorption leading to B-cell depletion, advise women not to breastfeed during treatment with COLUMVI and for 1 month after the last dose of COLUMVI.

Geriatric Use
Of the 145 patients with relapsed or refractory LBCL who received COLUMVI in study NP30179, 55% were 65 years of age or older, and 23% were 75 years of age or older. There was a higher rate of fatal adverse reactions, primarily from COVID-19, in patients 65 years of age or older compared to younger patients. No overall differences in efficacy were observed between patients 65 years of age or older and younger patients.

You may report side effects to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Genentech at 1-888-835-2555.

Please see the COLUMVI full Prescribing Information for additional Important Safety Information, including BOXED WARNING.

    • COLUMVI. Prescribing Information. Genentech, Inc.

      COLUMVI. Prescribing Information. Genentech, Inc.

    • Dickinson MJ, Carlo-Stella C, Morschhauser F, et al. Glofitamab for relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2022;387(24):2220-2231. doi:10.1056/NEJMoa2206913.

      Dickinson MJ, Carlo-Stella C, Morschhauser F, et al. Glofitamab for relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2022;387(24):2220-2231. doi:10.1056/NEJMoa2206913.

    • Bacac M, Colombetti S, Herter S, et al. CD20-TCB with obinutuzumab pretreatment as next-generation treatment of hematologic malignancies. Clin Cancer Res. 2018;24(19):4785-4797. doi: 10.1158/1078-0432.CCR-18-0455.

      Bacac M, Colombetti S, Herter S, et al. CD20-TCB with obinutuzumab pretreatment as next-generation treatment of hematologic malignancies. Clin Cancer Res. 2018;24(19):4785-4797. doi: 10.1158/1078-0432.CCR-18-0455.

    • Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for B-Cell Lymphomas V.5.2023. © National Comprehensive Cancer Network, Inc. 2023. All rights reserved. Accessed July 7, 2023. To view the most recent and complete version of the guideline, go online to NCCN.org.

      Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for B-Cell Lymphomas V.5.2023. © National Comprehensive Cancer Network, Inc. 2023. All rights reserved. Accessed July 7, 2023. To view the most recent and complete version of the guideline, go online to NCCN.org.

    • Data on file. Genentech, Inc.

      Data on file. Genentech, Inc.