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Adverse reaction profile from IMspire150

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Most common ARs
Laboratory abnormalities
Additional ARs
Most common ARs

Adverse reactions (ARs) were consistent with the known safety profiles of TECENTRIQ® (atezolizumab) and COTELLIC® (cobimetinib) + ZELBORAF® (vemurafenib)1,2

ARs occurring in ≥10% of patients with between-arm differences of ≥5% for all grades or ≥2% for grades 3 to 4

TECENTRIQ® (atezolizumab) adverse reactions
Laboratory abnormalities

Laboratory abnormalities worsening from baseline occurring in ≥20% of patients with between-arm differences of ≥5% for all grades or ≥2% for grades 3 to 41

TECENTRIQ® (atezolizumab) laboratory abnormalities

Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: TECENTRIQ + COTELLIC + ZELBORAF (28-277), placebo + COTELLIC + ZELBORAF (25-230).
ALT=alanine aminotransferase; AST=aspartate aminotransferase; CPK=creatine phosphokinase; NA=not applicable.
*Graded per National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (NCI CTCAE v4.0).
†Includes rash, rash maculopapular, dermatitis acneiform, rash macular, rash erythematous, eczema, skin exfoliation, rash papular, rash pustular, palmar-plantar erythrodysesthesia syndrome, dermatitis, dermatitis contact, erythema multiforme, rash pruritic, drug eruption, nodular rash, dermatitis allergic, exfoliative rash, dermatitis exfoliative generalized, and rash morbilliform.
‡Includes fatigue, asthenia, and malaise.
§Includes pyrexia and hyperpyrexia.
||Includes edema peripheral, lymphedema, edema, face edema, eyelid edema, periorbital edema, lip edema, and generalized edema.
Includes alanine aminotransferase increased, aspartate aminotransferase increased, blood bilirubin increased, transaminases increased, hepatitis, hepatic enzyme increased, hepatotoxicity, hypertransaminasemia, bilirubin conjugated increased, hepatocellular injury, hyperbilirubinemia, liver function test increased, hepatic failure, hepatitis fulminant, and liver function test abnormal.
#Includes stomatitis, mucosal inflammation, aphthous ulcer, mouth ulceration, cheilitis, and glossitis.
**Includes arthralgia, myalgia, pain in extremity, back pain, musculoskeletal pain, arthritis, neck pain, musculoskeletal chest pain, musculoskeletal stiffness, bone pain, spinal pain, immune-mediated arthritis, joint stiffness, and noncardiac chest pain.
††Includes hypothyroidism and blood thyroid-stimulating hormone increased.
‡‡Includes infusion-related reaction and hypersensitivity.
aIncludes pneumonitis and interstitial lung disease.
bIncludes hypertension, blood pressure increased, and hypertensive crisis.
cNCI CTCAE v4.0 does not include these laboratories.
dIncreased thyroid-stimulating hormone has a difference of <5% (all grades) between arms and is included for clinical completeness.

Additional ARs

Additional ARs in IMspire1501

  • Fatal ARs occurred in 3% of patients in the TECENTRIQ + COTELLIC + ZELBORAF arm
    • ARs leading to death were hepatic failure, fulminant hepatitis, sepsis, septic shock, pneumonia, and cardiac arrest
  • Serious ARs occurred in 45% of patients in the TECENTRIQ + COTELLIC + ZELBORAF arm
    • The most frequent (≥2%) serious ARs were hepatotoxicity (7%), pyrexia (6%), pneumonia (4.3%), malignant neoplasms (2.2%), and acute kidney injury (2.2%)
  • ARs leading to discontinuation of TECENTRIQ occurred in 21% of patients in the TECENTRIQ + COTELLIC + ZELBORAF arm
    • The most frequent (≥2%) ARs leading to discontinuation were increased ALT (2.2%) and pneumonitis (2.6%)
  • ARs leading to interruption of TECENTRIQ occurred in 68% of patients in the TECENTRIQ + COTELLIC + ZELBORAF arm
    • The most frequent (≥2%) ARs leading to TECENTRIQ interruption were pyrexia (14%), increased ALT (13%), hyperthyroidism (10%), increased AST (10%), increased lipase (9%), increased amylase (7%), pneumonitis (5%), increased CPK (4.3%), diarrhea (3.5%), pneumonia (3.5%), asthenia (3%), rash (3%), influenza (3%), arthralgia (2.6%), fatigue (2.2%), dyspnea (2.2%), cough (2.2%), peripheral edema (2.2%), uveitis (2.2%), bronchitis (2.2%), hypothyroidism (2.2%), and respiratory tract infection (2.2%)

Discontinuation of all treatment due to ARs was 13% vs 16% in patients treated with placebo + COTELLIC + ZELBORAF2

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Important Safety Information and Indication

Indication

TECENTRIQ, in combination with cobimetinib and vemurafenib, is indicated for the treatment of adult patients with BRAF V600 mutation-positive unresectable or metastatic melanoma.

Severe and Fatal Immune-Mediated Adverse Reactions
TECENTRIQ is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death-receptor 1 (PD-1) or the PD-ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. The following immune-mediated adverse reactions may not include all possible severe and fatal immune-mediated reactions.

Immune-mediated adverse reactions can occur in any organ system or tissue and at any time after starting TECENTRIQ. While immune-mediated adverse reactions usually manifest during treatment with TECENTRIQ, they can also manifest after discontinuation of treatment. Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of TECENTRIQ.

Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. 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 TECENTRIQ depending on severity. In general, if TECENTRIQ requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less, then 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.

Immune-Mediated Pneumonitis

  • TECENTRIQ can cause immune-mediated pneumonitis. The incidence of pneumonitis is higher in patients who have received prior thoracic radiation
  • Immune-mediated pneumonitis occurred in 3% (83/2616) of patients receiving TECENTRIQ alone, including fatal (<0.1%), Grade 4 (0.2%), Grade 3 (0.8%), and Grade 2 (1.1%) adverse reactions. Pneumonitis led to permanent discontinuation of TECENTRIQ in 0.5% and withholding of TECENTRIQ in 1.5% of patients
  • Systemic corticosteroids were required in 55% (46/83) of patients with pneumonitis. Pneumonitis resolved in 69% of the 83 patients. Of the 39 patients in whom TECENTRIQ was withheld for pneumonitis, 25 reinitiated TECENTRIQ after symptom improvement; of these, 4% had recurrence of pneumonitis
  • Immune-mediated pneumonitis occurred in 13% (29/230) of patients receiving TECENTRIQ in combination with cobimetinib and vemurafenib, including Grade 3 (1.3%) and Grade 2 (7%) adverse reactions. Pneumonitis led to permanent discontinuation of TECENTRIQ in 2.6% and withholding of TECENTRIQ in 7.4% of patients. Systemic corticosteroids were required in 55% (16/29) of patients with pneumonitis. Pneumonitis resolved in 97% of the 29 patients. Of the 17 patients in whom TECENTRIQ was withheld for pneumonitis, 10 reinitiated TECENTRIQ after symptom improvement; of these, 50% had recurrence of pneumonitis

Immune-Mediated Colitis

  • TECENTRIQ can cause immune-mediated colitis. Colitis can present with diarrhea, abdominal pain, and lower gastrointestinal (GI) bleeding. 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
  • Immune-mediated colitis occurred in 1% (26/2616) of patients receiving TECENTRIQ alone, including Grade 3 (0.5%) and Grade 2 (0.3%) adverse reactions. Colitis led to permanent discontinuation of TECENTRIQ in 0.2% and withholding of TECENTRIQ in 0.5% of patients. Systemic corticosteroids were required in 50% (13/26) of patients with colitis. Colitis resolved in 73% of the 26 patients. Of the 12 patients in whom TECENTRIQ was withheld for colitis, 8 reinitiated TECENTRIQ after symptom improvement; of these, 25% had recurrence of colitis

Immune-Mediated Hepatitis

  • TECENTRIQ can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 1.8% (48/2616) of patients receiving TECENTRIQ alone, including fatal (<0.1%), Grade 4 (0.2%), Grade 3 (0.5%), and Grade 2 (0.5%) adverse reactions. Hepatitis led to permanent discontinuation of TECENTRIQ in 0.2% and withholding of TECENTRIQ in 0.2% of patients. Systemic corticosteroids were required in 25% (12/48) of patients with hepatitis. Hepatitis resolved in 50% of the 48 patients. Of the 6 patients in whom TECENTRIQ was withheld for hepatitis, 4 reinitiated TECENTRIQ after symptom improvement; of these, none had recurrence of hepatitis
  • Immune-mediated hepatitis occurred in 6.1% (14/230) of patients receiving TECENTRIQ in combination with cobimetinib and vemurafenib, including Grade 4 (1.3%), Grade 3 (1.7%), and Grade 2 (1.3%) adverse reactions. Hepatitis led to permanent discontinuation of TECENTRIQ in 2.2% and withholding of TECENTRIQ in 1.7% of patients. Systemic corticosteroids were required in 50% (7/14) of patients with hepatitis. Hepatitis resolved in 93% of the 14 patients. Of the 4 patients in whom TECENTRIQ was withheld for hepatitis, 3 reinitiated TECENTRIQ after symptom improvement; of these, 33% had recurrence of hepatitis

Immune-Mediated Endocrinopathies
Adrenal Insufficiency

  • TECENTRIQ can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated
  • Adrenal insufficiency occurred in 0.4% (11/2616) of patients receiving TECENTRIQ alone, including Grade 3 (<0.1%) and Grade 2 (0.2%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of TECENTRIQ in 1 patient and withholding of TECENTRIQ in 1 patient. Systemic corticosteroids were required in 82% (9/11) of patients with adrenal insufficiency; of these, 3 patients remained on systemic corticosteroids. The single patient in whom TECENTRIQ was withheld for adrenal insufficiency did not reinitiate TECENTRIQ

Hypophysitis

  • TECENTRIQ can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field cuts. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as clinically indicated
  • Hypophysitis occurred in <0.1% (2/2616) of patients receiving TECENTRIQ alone, including Grade 2 (1 patient, <0.1%) adverse reactions. Hypophysitis led to permanent discontinuation of TECENTRIQ in 1 patient and no patients required withholding of TECENTRIQ. Systemic corticosteroids were required in 50% (1/2) of patients with hypophysitis. Hypophysitis did not resolve in these 2 patients

Thyroid Disorders

  • TECENTRIQ can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or medical management for hyperthyroidism as clinically indicated
  • Thyroiditis occurred in 0.2% (4/2616) of patients receiving TECENTRIQ alone, including Grade 2 (<0.1%) adverse reactions. Thyroiditis did not lead to permanent discontinuation of TECENTRIQ in any of these patients, but led to withholding of TECENTRIQ in 1 patient. Hormone replacement therapy was required in 75% (3/4) of patients with thyroiditis. Systemic corticosteroids were required in 25% (1/4) of patients with thyroiditis. Thyroiditis resolved in 50% of patients. The single patient in whom TECENTRIQ was withheld for thyroiditis reinitiated TECENTRIQ; this patient did not have recurrence of thyroiditis
  • Hyperthyroidism occurred in 0.8% (21/2616) of patients receiving TECENTRIQ alone, including Grade 2 (0.4%) adverse reactions. Hyperthyroidism did not lead to permanent discontinuation of TECENTRIQ in any of these patients, but led to withholding of TECENTRIQ in 0.1% of patients. Antithyroid therapy was required in 29% (6/21) of patients with hyperthyroidism. Of these 6 patients, the majority remained on antithyroid treatment. Of the 3 patients in whom TECENTRIQ was withheld for hyperthyroidism, 1 patient reinitiated TECENTRIQ; this patient did not have recurrence of hyperthyroidism
  • Hyperthyroidism occurred in 19% (43/230) of patients receiving TECENTRIQ in combination with cobimetinib and vemurafenib, including Grade 3 (0.9%) and Grade 2 (7.8%) adverse reactions. Hyperthyroidism led to permanent discontinuation of TECENTRIQ in 0.4% and withholding of TECENTRIQ in 10% of patients. Antithyroid therapy was required in 53% (23/43) of patients with hyperthyroidism. Of these 23 patients, the majority remained on antithyroid treatment. Of the 24 patients in whom TECENTRIQ was withheld for hyperthyroidism, 18 patients reinitiated TECENTRIQ; of these, 28% had recurrence of hyperthyroidism
  • Hypothyroidism occurred in 4.9% (128/2616) of patients receiving TECENTRIQ alone, including Grade 3 (0.2%) and Grade 2 (3.4%) adverse reactions. Hypothyroidism did not lead to permanent discontinuation of TECENTRIQ in any of these patients, but led to withholding of TECENTRIQ in 0.6% of patients. Hormone replacement therapy was required in 81% (104/128) of patients with hypothyroidism. The majority of patients with hypothyroidism remained on thyroid hormone replacement. Of the 17 patients in whom TECENTRIQ was withheld for hypothyroidism, 8 reinitiated TECENTRIQ after symptom improvement
  • Hypothyroidism occurred in 26% (60/230) of patients receiving TECENTRIQ in combination with cobimetinib and vemurafenib, including Grade 2 (9.1%) adverse reactions. Hypothyroidism did not lead to permanent discontinuation of TECENTRIQ in any of these patients, but led to withholding of TECENTRIQ in 2.6% of patients. Hormone replacement therapy was required in 52% (31/60) of patients with hypothyroidism. The majority of patients with hypothyroidism remained on thyroid hormone replacement. Of the 6 patients in whom TECENTRIQ was withheld for hypothyroidism, 4 reinitiated TECENTRIQ after symptom improvement. The majority of patients with hypothyroidism required long-term thyroid replacement

Type 1 Diabetes Mellitus, Which Can Present With Diabetic Ketoacidosis

  • Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated
  • Type 1 diabetes mellitus occurred in 0.3% (7/2616) of patients receiving TECENTRIQ alone, including Grade 3 (0.2%) and Grade 2 (<0.1%) adverse reactions. Type 1 diabetes mellitus led to permanent discontinuation of TECENTRIQ in 1 patient and withholding of TECENTRIQ in 2 patients. Treatment with insulin was required for all patients with confirmed Type 1 diabetes mellitus and insulin therapy was continued long-term. Of the 2 patients in whom TECENTRIQ was withheld for Type 1 diabetes mellitus, both reinitiated TECENTRIQ treatment

Immune-Mediated Nephritis With Renal Dysfunction

  • TECENTRIQ can cause immune-mediated nephritis
  • Immune-mediated nephritis with renal dysfunction occurred in <0.1% (1/2616) of patients receiving TECENTRIQ alone, and this adverse reaction was a Grade 3 (<0.1%) adverse reaction. Nephritis led to permanent discontinuation of TECENTRIQ in this patient. This patient required systemic corticosteroids. In this patient, nephritis did not resolve
  • Immune-mediated nephritis with renal dysfunction occurred in 1.3% (3/230) of patients receiving TECENTRIQ in combination with cobimetinib and vemurafenib, including Grade 2 (1.3%) adverse reactions. Nephritis led to permanent discontinuation of TECENTRIQ in 0.4% and withholding of TECENTRIQ in 0.9% of patients. Systemic corticosteroids were required in 67% (2/3) of patients with nephritis. Nephritis resolved in all 3 of these patients. Of the 2 patients in whom TECENTRIQ was withheld for nephritis, both reinitiated TECENTRIQ after symptom improvement and neither had recurrence of nephritis

Immune-Mediated Dermatologic Adverse Reactions

  • TECENTRIQ can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome (SJS), DRESS, and toxic epidermal necrolysis (TEN), has occurred with PD-1/PD-L1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes 
  • Immune-mediated dermatologic adverse reactions occurred in 0.6% (15/2616) of patients receiving TECENTRIQ alone, including Grade 3 (<0.1%) and Grade 2 (0.2%) adverse reactions. Dermatologic adverse reactions led to permanent discontinuation of TECENTRIQ in 0.1% and withholding of TECENTRIQ in 0.2% of patients. Systemic corticosteroids were required in 20% (3/15) of patients with dermatologic adverse reactions. Dermatologic adverse reactions resolved in 87% of the 15 patients. Of the 4 patients in whom TECENTRIQ was withheld for immune-mediated dermatologic adverse reactions, none reinitiated TECENTRIQ

Other Immune-Mediated Adverse Reactions

  • The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received TECENTRIQ or were reported with the use of other PD-1/PD-L1 blocking antibodies
    • Cardiac/Vascular: Myocarditis, pericarditis, vasculitis
    • Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy
    • Ocular: Uveitis, iritis, and other ocular inflammatory toxicities can occur. Some 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, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss
    • Gastrointestinal: Pancreatitis to include increases in serum amylase and lipase levels, gastritis, duodenitis
    • Musculoskeletal and Connective Tissue: Myositis/polymyositis, rhabdomyolysis and associated sequelae including renal failure, arthritis, polymyalgia rheumatic
    • Endocrine: Hypoparathyroidism
    • Other (Hematologic/Immune): Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection, other transplant (including corneal graft) rejection

Infusion-Related Reactions

  • TECENTRIQ can cause severe or life-threatening infusion-related reactions. Monitor for signs and symptoms of infusion-related reactions. Interrupt, slow the rate of, or permanently discontinue TECENTRIQ based on the severity. For Grade 1 or 2 infusion-related reactions, consider using pre-medications with subsequent doses
  • Infusion-related reactions occurred in 1.3% of patients receiving TECENTRIQ alone, including Grade 3 (0.2%) reactions
  • The frequency and severity of infusion-related reactions were similar across the recommended dose range

Complications of Allogeneic HSCT After PD-1/PD-L1 Inhibitors

  • Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1/PD-L1 blocking antibody
  • 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 PD-1/PD-L1 blockage and allogeneic HSCT
  • Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefits versus risks of treatment with a PD-1/PD-L1 blocking antibody prior to or after an allogeneic HSCT

Embryo-Fetal Toxicity

  • Based on its mechanism of action, TECENTRIQ can cause fetal harm when administered to a pregnant woman. There are no available data on the use of TECENTRIQ in pregnant women. Animal studies have demonstrated that inhibition of the PD-L1/PD-1 pathway can lead to increased risk of immune-related rejection of the developing fetus, resulting in fetal death
  • Verify pregnancy status of females of reproductive potential prior to initiating TECENTRIQ. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment with TECENTRIQ and for at least 5 months after the last dose

Use in Specific Populations
Nursing Mothers

  • There is no information regarding the presence of TECENTRIQ in human milk, the effects on the breastfed infant, or the effects on milk production. As human IgG is excreted in human milk, the potential for absorption and harm to the infant is unknown
  • Because of the potential for serious adverse reactions in breastfed infants from TECENTRIQ, advise female patients not to breastfeed while taking TECENTRIQ and for at least 5 months after the last dose

Fertility

  • Based on animal studies, TECENTRIQ may impair fertility in females of reproductive potential while receiving treatment

Most Common Adverse Reactions
The most common adverse reactions (rate ≥20%) in patients who received TECENTRIQ in combination with cobimetinib and vemurafenib for melanoma were rash (75%), musculoskeletal pain (62%), fatigue (51%), hepatotoxicity (50%), pyrexia (49%), nausea (30%), pruritus (26%), edema (26%), stomatitis (23%), hypothyroidism (22%), and photosensitivity reaction (21%).

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 full Prescribing Information for additional Important Safety Information.

Important Safety Information and Indication

Indication

TECENTRIQ, in combination with cobimetinib and vemurafenib, is indicated for the treatment of adult patients with BRAF V600 mutation-positive unresectable or metastatic melanoma.

Important Safety Information

Severe and Fatal Immune-Mediated Adverse Reactions
TECENTRIQ is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death-receptor 1 (PD-1) or the PD-ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. The following immune-mediated adverse reactions may not include all possible severe and fatal immune-mediated reactions.

Immune-mediated adverse reactions can occur in any organ system or tissue and at any time after starting TECENTRIQ. While immune-mediated adverse reactions usually manifest during treatment with TECENTRIQ, they can also manifest after discontinuation of treatment. Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of TECENTRIQ.

Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. 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 TECENTRIQ depending on severity. In general, if TECENTRIQ requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less, then 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.

Immune-Mediated Pneumonitis

  • TECENTRIQ can cause immune-mediated pneumonitis. The incidence of pneumonitis is higher in patients who have received prior thoracic radiation
  • Immune-mediated pneumonitis occurred in 3% (83/2616) of patients receiving TECENTRIQ alone, including fatal (<0.1%), Grade 4 (0.2%), Grade 3 (0.8%), and Grade 2 (1.1%) adverse reactions. Pneumonitis led to permanent discontinuation of TECENTRIQ in 0.5% and withholding of TECENTRIQ in 1.5% of patients
  • Systemic corticosteroids were required in 55% (46/83) of patients with pneumonitis. Pneumonitis resolved in 69% of the 83 patients. Of the 39 patients in whom TECENTRIQ was withheld for pneumonitis, 25 reinitiated TECENTRIQ after symptom improvement; of these, 4% had recurrence of pneumonitis
  • Immune-mediated pneumonitis occurred in 13% (29/230) of patients receiving TECENTRIQ in combination with cobimetinib and vemurafenib, including Grade 3 (1.3%) and Grade 2 (7%) adverse reactions. Pneumonitis led to permanent discontinuation of TECENTRIQ in 2.6% and withholding of TECENTRIQ in 7.4% of patients. Systemic corticosteroids were required in 55% (16/29) of patients with pneumonitis. Pneumonitis resolved in 97% of the 29 patients. Of the 17 patients in whom TECENTRIQ was withheld for pneumonitis, 10 reinitiated TECENTRIQ after symptom improvement; of these, 50% had recurrence of pneumonitis

Immune-Mediated Colitis

  • TECENTRIQ can cause immune-mediated colitis. Colitis can present with diarrhea, abdominal pain, and lower gastrointestinal (GI) bleeding. 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
  • Immune-mediated colitis occurred in 1% (26/2616) of patients receiving TECENTRIQ alone, including Grade 3 (0.5%) and Grade 2 (0.3%) adverse reactions. Colitis led to permanent discontinuation of TECENTRIQ in 0.2% and withholding of TECENTRIQ in 0.5% of patients. Systemic corticosteroids were required in 50% (13/26) of patients with colitis. Colitis resolved in 73% of the 26 patients. Of the 12 patients in whom TECENTRIQ was withheld for colitis, 8 reinitiated TECENTRIQ after symptom improvement; of these, 25% had recurrence of colitis

Immune-Mediated Hepatitis

  • TECENTRIQ can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 1.8% (48/2616) of patients receiving TECENTRIQ alone, including fatal (<0.1%), Grade 4 (0.2%), Grade 3 (0.5%), and Grade 2 (0.5%) adverse reactions. Hepatitis led to permanent discontinuation of TECENTRIQ in 0.2% and withholding of TECENTRIQ in 0.2% of patients. Systemic corticosteroids were required in 25% (12/48) of patients with hepatitis. Hepatitis resolved in 50% of the 48 patients. Of the 6 patients in whom TECENTRIQ was withheld for hepatitis, 4 reinitiated TECENTRIQ after symptom improvement; of these, none had recurrence of hepatitis
  • Immune-mediated hepatitis occurred in 6.1% (14/230) of patients receiving TECENTRIQ in combination with cobimetinib and vemurafenib, including Grade 4 (1.3%), Grade 3 (1.7%), and Grade 2 (1.3%) adverse reactions. Hepatitis led to permanent discontinuation of TECENTRIQ in 2.2% and withholding of TECENTRIQ in 1.7% of patients. Systemic corticosteroids were required in 50% (7/14) of patients with hepatitis. Hepatitis resolved in 93% of the 14 patients. Of the 4 patients in whom TECENTRIQ was withheld for hepatitis, 3 reinitiated TECENTRIQ after symptom improvement; of these, 33% had recurrence of hepatitis

Immune-Mediated Endocrinopathies
Adrenal Insufficiency

  • TECENTRIQ can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated
  • Adrenal insufficiency occurred in 0.4% (11/2616) of patients receiving TECENTRIQ alone, including Grade 3 (<0.1%) and Grade 2 (0.2%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of TECENTRIQ in 1 patient and withholding of TECENTRIQ in 1 patient. Systemic corticosteroids were required in 82% (9/11) of patients with adrenal insufficiency; of these, 3 patients remained on systemic corticosteroids. The single patient in whom TECENTRIQ was withheld for adrenal insufficiency did not reinitiate TECENTRIQ

Hypophysitis

  • TECENTRIQ can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field cuts. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as clinically indicated
  • Hypophysitis occurred in <0.1% (2/2616) of patients receiving TECENTRIQ alone, including Grade 2 (1 patient, <0.1%) adverse reactions. Hypophysitis led to permanent discontinuation of TECENTRIQ in 1 patient and no patients required withholding of TECENTRIQ. Systemic corticosteroids were required in 50% (1/2) of patients with hypophysitis. Hypophysitis did not resolve in these 2 patients

Thyroid Disorders

  • TECENTRIQ can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or medical management for hyperthyroidism as clinically indicated
  • Thyroiditis occurred in 0.2% (4/2616) of patients receiving TECENTRIQ alone, including Grade 2 (<0.1%) adverse reactions. Thyroiditis did not lead to permanent discontinuation of TECENTRIQ in any of these patients, but led to withholding of TECENTRIQ in 1 patient. Hormone replacement therapy was required in 75% (3/4) of patients with thyroiditis. Systemic corticosteroids were required in 25% (1/4) of patients with thyroiditis. Thyroiditis resolved in 50% of patients. The single patient in whom TECENTRIQ was withheld for thyroiditis reinitiated TECENTRIQ; this patient did not have recurrence of thyroiditis
  • Hyperthyroidism occurred in 0.8% (21/2616) of patients receiving TECENTRIQ alone, including Grade 2 (0.4%) adverse reactions. Hyperthyroidism did not lead to permanent discontinuation of TECENTRIQ in any of these patients, but led to withholding of TECENTRIQ in 0.1% of patients. Antithyroid therapy was required in 29% (6/21) of patients with hyperthyroidism. Of these 6 patients, the majority remained on antithyroid treatment. Of the 3 patients in whom TECENTRIQ was withheld for hyperthyroidism, 1 patient reinitiated TECENTRIQ; this patient did not have recurrence of hyperthyroidism
  • Hyperthyroidism occurred in 19% (43/230) of patients receiving TECENTRIQ in combination with cobimetinib and vemurafenib, including Grade 3 (0.9%) and Grade 2 (7.8%) adverse reactions. Hyperthyroidism led to permanent discontinuation of TECENTRIQ in 0.4% and withholding of TECENTRIQ in 10% of patients. Antithyroid therapy was required in 53% (23/43) of patients with hyperthyroidism. Of these 23 patients, the majority remained on antithyroid treatment. Of the 24 patients in whom TECENTRIQ was withheld for hyperthyroidism, 18 patients reinitiated TECENTRIQ; of these, 28% had recurrence of hyperthyroidism
  • Hypothyroidism occurred in 4.9% (128/2616) of patients receiving TECENTRIQ alone, including Grade 3 (0.2%) and Grade 2 (3.4%) adverse reactions. Hypothyroidism did not lead to permanent discontinuation of TECENTRIQ in any of these patients, but led to withholding of TECENTRIQ in 0.6% of patients. Hormone replacement therapy was required in 81% (104/128) of patients with hypothyroidism. The majority of patients with hypothyroidism remained on thyroid hormone replacement. Of the 17 patients in whom TECENTRIQ was withheld for hypothyroidism, 8 reinitiated TECENTRIQ after symptom improvement
  • Hypothyroidism occurred in 26% (60/230) of patients receiving TECENTRIQ in combination with cobimetinib and vemurafenib, including Grade 2 (9.1%) adverse reactions. Hypothyroidism did not lead to permanent discontinuation of TECENTRIQ in any of these patients, but led to withholding of TECENTRIQ in 2.6% of patients. Hormone replacement therapy was required in 52% (31/60) of patients with hypothyroidism. The majority of patients with hypothyroidism remained on thyroid hormone replacement. Of the 6 patients in whom TECENTRIQ was withheld for hypothyroidism, 4 reinitiated TECENTRIQ after symptom improvement. The majority of patients with hypothyroidism required long-term thyroid replacement

Type 1 Diabetes Mellitus, Which Can Present With Diabetic Ketoacidosis

  • Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated
  • Type 1 diabetes mellitus occurred in 0.3% (7/2616) of patients receiving TECENTRIQ alone, including Grade 3 (0.2%) and Grade 2 (<0.1%) adverse reactions. Type 1 diabetes mellitus led to permanent discontinuation of TECENTRIQ in 1 patient and withholding of TECENTRIQ in 2 patients. Treatment with insulin was required for all patients with confirmed Type 1 diabetes mellitus and insulin therapy was continued long-term. Of the 2 patients in whom TECENTRIQ was withheld for Type 1 diabetes mellitus, both reinitiated TECENTRIQ treatment

Immune-Mediated Nephritis With Renal Dysfunction

  • TECENTRIQ can cause immune-mediated nephritis
  • Immune-mediated nephritis with renal dysfunction occurred in <0.1% (1/2616) of patients receiving TECENTRIQ alone, and this adverse reaction was a Grade 3 (<0.1%) adverse reaction. Nephritis led to permanent discontinuation of TECENTRIQ in this patient. This patient required systemic corticosteroids. In this patient, nephritis did not resolve
  • Immune-mediated nephritis with renal dysfunction occurred in 1.3% (3/230) of patients receiving TECENTRIQ in combination with cobimetinib and vemurafenib, including Grade 2 (1.3%) adverse reactions. Nephritis led to permanent discontinuation of TECENTRIQ in 0.4% and withholding of TECENTRIQ in 0.9% of patients. Systemic corticosteroids were required in 67% (2/3) of patients with nephritis. Nephritis resolved in all 3 of these patients. Of the 2 patients in whom TECENTRIQ was withheld for nephritis, both reinitiated TECENTRIQ after symptom improvement and neither had recurrence of nephritis

Immune-Mediated Dermatologic Adverse Reactions

  • TECENTRIQ can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome (SJS), DRESS, and toxic epidermal necrolysis (TEN), has occurred with PD-1/PD-L1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes 
  • Immune-mediated dermatologic adverse reactions occurred in 0.6% (15/2616) of patients receiving TECENTRIQ alone, including Grade 3 (<0.1%) and Grade 2 (0.2%) adverse reactions. Dermatologic adverse reactions led to permanent discontinuation of TECENTRIQ in 0.1% and withholding of TECENTRIQ in 0.2% of patients. Systemic corticosteroids were required in 20% (3/15) of patients with dermatologic adverse reactions. Dermatologic adverse reactions resolved in 87% of the 15 patients. Of the 4 patients in whom TECENTRIQ was withheld for immune-mediated dermatologic adverse reactions, none reinitiated TECENTRIQ

Other Immune-Mediated Adverse Reactions

  • The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received TECENTRIQ or were reported with the use of other PD-1/PD-L1 blocking antibodies
    • Cardiac/Vascular: Myocarditis, pericarditis, vasculitis
    • Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy
    • Ocular: Uveitis, iritis, and other ocular inflammatory toxicities can occur. Some 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, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss
    • Gastrointestinal: Pancreatitis to include increases in serum amylase and lipase levels, gastritis, duodenitis
    • Musculoskeletal and Connective Tissue: Myositis/polymyositis, rhabdomyolysis and associated sequelae including renal failure, arthritis, polymyalgia rheumatic
    • Endocrine: Hypoparathyroidism
    • Other (Hematologic/Immune): Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection, other transplant (including corneal graft) rejection

Infusion-Related Reactions

  • TECENTRIQ can cause severe or life-threatening infusion-related reactions. Monitor for signs and symptoms of infusion-related reactions. Interrupt, slow the rate of, or permanently discontinue TECENTRIQ based on the severity. For Grade 1 or 2 infusion-related reactions, consider using pre-medications with subsequent doses
  • Infusion-related reactions occurred in 1.3% of patients receiving TECENTRIQ alone, including Grade 3 (0.2%) reactions
  • The frequency and severity of infusion-related reactions were similar across the recommended dose range

Complications of Allogeneic HSCT After PD-1/PD-L1 Inhibitors

  • Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1/PD-L1 blocking antibody
  • 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 PD-1/PD-L1 blockage and allogeneic HSCT
  • Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefits versus risks of treatment with a PD-1/PD-L1 blocking antibody prior to or after an allogeneic HSCT

Embryo-Fetal Toxicity

  • Based on its mechanism of action, TECENTRIQ can cause fetal harm when administered to a pregnant woman. There are no available data on the use of TECENTRIQ in pregnant women. Animal studies have demonstrated that inhibition of the PD-L1/PD-1 pathway can lead to increased risk of immune-related rejection of the developing fetus, resulting in fetal death
  • Verify pregnancy status of females of reproductive potential prior to initiating TECENTRIQ. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment with TECENTRIQ and for at least 5 months after the last dose

Use in Specific Populations
Nursing Mothers

  • There is no information regarding the presence of TECENTRIQ in human milk, the effects on the breastfed infant, or the effects on milk production. As human IgG is excreted in human milk, the potential for absorption and harm to the infant is unknown
  • Because of the potential for serious adverse reactions in breastfed infants from TECENTRIQ, advise female patients not to breastfeed while taking TECENTRIQ and for at least 5 months after the last dose

Fertility

  • Based on animal studies, TECENTRIQ may impair fertility in females of reproductive potential while receiving treatment

Most Common Adverse Reactions
The most common adverse reactions (rate ≥20%) in patients who received TECENTRIQ in combination with cobimetinib and vemurafenib for melanoma were rash (75%), musculoskeletal pain (62%), fatigue (51%), hepatotoxicity (50%), pyrexia (49%), nausea (30%), pruritus (26%), edema (26%), stomatitis (23%), hypothyroidism (22%), and photosensitivity reaction (21%).

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 full Prescribing Information for additional Important Safety Information.

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    • TECENTRIQ Prescribing Information. Genentech, Inc.

      TECENTRIQ Prescribing Information. Genentech, Inc.

    • Gutzmer R, Stroyakovskiy D, Gogas H, et al. Atezolizumab, vemurafenib, and cobimetinib as first-line treatment for unresectable advanced BRAFV600 mutation-positive melanoma (IMspire150): primary analysis of the randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2020;395:1835-1844.

      Gutzmer R, Stroyakovskiy D, Gogas H, et al. Atezolizumab, vemurafenib, and cobimetinib as first-line treatment for unresectable advanced BRAFV600 mutation-positive melanoma (IMspire150): primary analysis of the randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2020;395:1835-1844.

    • COTELLIC Prescribing Information. Genentech, Inc.

      COTELLIC Prescribing Information. Genentech, Inc.

    • ZELBORAF Prescribing Information. Genentech, Inc.

      ZELBORAF Prescribing Information. Genentech, Inc.

    • Data on file. Clinical Study Report CO39262. Genentech, Inc.

      Data on file. Clinical Study Report CO39262. Genentech, Inc.

    • Data on file. Roche.

      Data on file. Roche.