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Overman MJ et al. Lancet Oncol. 2017;18:1182–1191

Waterhouse D et al. Cancer Chemother Pharmacol. 2018;81:679–686

Zhao X et al. Annals Oncol. 2017;28:2002–2008

 

Nivolumab 3 mg/kg; administer intravenously over 30–60 minutes in a volume of 0.9% sodium chloride injection (0.9% NS) or 5% dextrose injection (D5W), not to exceed 160 mL and sufficient to produce a nivolumab concentration within the range 1–10 mg/mL, every 2 weeks (total dosage/2-week course = 3 mg/kg)

  • Administer nivolumab through an administration set that contains a sterile, nonpyrogenic, low protein-binding inline filter with a pore size within the range of 0.2–1.2 μm

Notes:

  • Nivolumab can cause severe infusion-related reactions

    • Interrupt or slow the administration rate in patients with mild or moderate infusion-related reactions

    • Discontinue nivolumab in patients who experience severe or life-threatening infusion-related reactions

  • Eligibility for treatment with nivolumab requires a patient’s colorectal cancer to be identified as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR).

  • The U.S. FDA-approved regimen for colorectal cancer includes a fixed dose of nivolumab and allows for a shortened infusion duration of 30 minutes, consistent with the regimen approved on March 5, 2018, thus:

 

Nivolumab 240 mg; administer intravenously over 30–60 minutes in a volume of 0.9% NS or D5W, not to exceed 160 mL and sufficient to produce a nivolumab concentration within the range 1–10 mg/mL, every 2 weeks (total dosage/2-week course = 240 mg)

  • Administer nivolumab through an administration set that contains a sterile, nonpyrogenic, low protein-binding inline filter with a pore size within the range of 0.2–1.2 μm.

 

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is MINIMAL

See Chapter 39 for antiemetic recommendations

 

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

 

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

  Antimicrobial primary prophylaxis to be considered:

  • Antibacterial—not indicated

  • Antifungal—not indicated

  • Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Patient Population Studied

A multicenter, open-label, phase 2 study involved 74 patients with histologically confirmed recurrent or metastatic dMMR or MSI-H colorectal cancer. Eligible patients were aged ≥18 years and had ECOG (Eastern Cooperative Oncology Group) performance status ≤1, measurable disease, and progression on or after, or intolerance of, at least 1 previous line of treatment, including a fluoropyrimidine and oxaliplatin or irinotecan. Patients who had refused chemotherapy were also eligible. Patients received intravenous nivolumab (3 mg/kg) every 2 weeks.

Efficacy (N = 74)

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Efficacy (N = 74)

Objective response

31.1%

Rate of complete response

0

Median progression-free survival

14.3 months

Overall survival at 12 months

73%

As assessed by the investigator according to RECIST criteria; the primary endpoint

Note: Median follow-up was 12.0 months

Therapy Monitoring

  1. CBC with differential at a minimum once per cycle, but initially also at day 10–14

  2. Every 2–3 months: CT scans to assess response

  3. Observe closely for hypersensitivity reactions, especially during the first and second infusions

  4. Draw AST, ALT, and bilirubin prior to each infusion and/or weekly if there are G1 LFT elevations. Note, no treatment is recommended for G1 LFT abnormalities. For ≥G2 toxicity implement workup for other causes of elevated LFTs, including viral hepatitis

  5. Measure glucose at baseline and with each treatment during the first 12 weeks and every 6 weeks thereafter

  6. Obtain a serum creatinine level prior to every dose. If creatinine is found to be newly elevated, consider holding therapy while other potential causes are evaluated. Note: Routine urinalysis is not necessary other than to rule out urinary tract infections

  7. Use basic metabolic panel (Na, K, CO2, glucose) and patient history as screening tools for hypophysitis including hypopituitarism and adrenal insufficiency. If in doubt, evaluate morning adrenocorticotropic hormone (ACTH) and cortisol levels. Consider ACTH stimulation test for indeterminate results

  8. Assess thyroid function at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation and for clinical signs and symptoms of thyroid disorders. Test for TSH and free thyroxine (FT4) every 4–6 weeks as part of routine clinical monitoring on therapy or for case detection in symptomatic patients

  9. Obtain CEA if being used to follow disease

  10. Initially at the time of each dose, and eventually every 6–12 weeks, perform a total body skin examination with attention to all mucous membranes as well as a complete review of systems

  11. Monitor patients for signs and symptoms of pneumonitis. Evaluate patients with suspected pneumonitis with chest x-ray, CT scan, and pulse oximetry. For ≥G2 toxicity may include nasal swab, sputum culture and sensitivity, blood culture and sensitivity, and urine culture and sensitivity

  12. Monitor patients for signs and symptoms of colitis. Encourage patients to report diarrhea immediately to any member of the health care team

  13. Obtain a complete rheumatologic history and perform an examination of all peripheral joints for tenderness, swelling, and range of motion. Examine the spine. Consider plain x-ray/imaging to exclude metastases and evaluate joint damage (erosions), if appropriate

  14. In patients at high risk for infections and in appropriately selected patients, based on an infectious disease evaluation, draw screening laboratories (HIV, hepatitis A and B, and blood quantiferon for TB) to prepare patients to start infliximab

Treatment Modifications

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RECOMMENDED DOSE MODIFICATIONS FOR NIVOLUMAB

Adverse Event

Grade / Severity

Treatment Modification

Colitis

G1

Loperamide 4 mg as starting dose then 2 mg before each meal and after each loose stool until without diarrhea for 12 hours, with maximum of 16 mg loperamide per day. If G1 diarrhea or colitis persists for >14 days, then add prednisolone 0.5–1 mg/kg (non-enteric coated) or consider oral budesonide 9 mg daily if no bloody diarrhea

G2/3 diarrhea or colitis

Withhold nivolumab. Loperamide 4 mg as starting dose then 2 mg before each meal and after each loose stool until without diarrhea for 12 hours, with maximum of 16 mg loperamide per day. Administer oral prednisone/prednisolone at a dose of 0.5–2 mg/kg/day or its equivalent. When symptoms improve to G1, begin a slow corticosteroid taper over at least 4 weeks. Resume nivolumab upon symptom control, or when prednisone/prednisolone daily dose <10 mg

G4 diarrhea or colitis

Permanently discontinue nivolumab. Loperamide 4 mg as starting dose then 2 mg before each meal and after each loose stool until without diarrhea for 12 hours, with maximum of 16 mg loperamide per day. Administer 1–2 mg/kg intravenous (methyl)prednisolone and convert to 0.5–2 mg/kg prednisone/prednisolone orally each day or its equivalent only after a response. Taper over at least 4 weeks when symptoms improve. If symptoms do not improve over 72 hours or worsen, perform flexible sigmoidoscopy/colonoscopy to document colitis then begin infliximab 5 mg/kg (if no perforation, sepsis, TB, hepatitis, NYHA III/IV CHF). If no response add MMF 500–1000 mg twice daily. If worse on MMF, consider addition of tacrolimus or ATG

Pneumonitis

G2

Withhold nivolumab. Consider pneumocystis prophylaxis depending on the clinical context and coverage with empiric antibiotics. Administer oral prednisone/prednisolone at a dose of 1–2 mg/kg/day or its equivalent. When symptoms improve to G1, begin a slow corticosteroid taper over at least 4 weeks. If response is not adequate after 48 hours, then administer 2–4 mg/kg intravenous (methyl)prednisolone and convert to 0.5–2 mg/kg prednisone/prednisolone orally each day or its equivalent only after a response, followed by a taper over at least 6 weeks when symptoms improve to G1, titrating to symptoms. Resume nivolumab upon symptom control, or when prednisone/prednisolone daily dose <10 mg

G3/4

Permanently discontinue nivolumab. Consider pneumocystis prophylaxis depending on the clinical context; cover with empiric antibiotics. Administer 2–4 mg/kg intravenous (methyl)prednisolone and convert to 1–2 mg/kg prednisone/prednisolone orally each day or its equivalent only after a response, followed by a taper over at least 8 weeks when symptoms improve to G1, titrating to symptoms. If, when initially treated, improvement does not occur within 48–72 hours begin infliximab 5 mg/kg (if no perforation, sepsis, TB, hepatitis, NYHA III/IV CHF). If no response to infliximab add MMF 500–1000 mg twice daily. Consider MMF especially if concurrent hepatic toxicity

Hepatitis

G2 (AST or ALT >3–5× ULN or total bilirubin >1.5–3× ULN)

Withhold nivolumab. Administer oral prednisone/prednisolone at a dose of 1–2 mg/kg/day or its equivalent. When symptoms improve to G1, begin a slow corticosteroid taper over at least 4 weeks. Resume nivolumab upon symptom control, or when prednisone/prednisolone daily dose <10 mg

G3/4 (AST or ALT >5× ULN or total bilirubin >3× ULN)

Permanently discontinue nivolumab. Administer 1–2 mg/kg intravenous (methyl)prednisolone and convert to 0.5–2 mg/kg prednisone/prednisolone orally each day or its equivalent only after a response. Taper over at least 6 weeks when symptoms improve. If no response add MMF 500–1000 mg twice daily. If worse on MMF, consider adding tacrolimus or ATG

Hypophysitis

G2/3 (moderate symptoms, ie, headache but no visual disturbance, or fatigue/mood alteration but hemodynamically stable, no electrolyte disturbance)

Administer analgesia as needed for headache. Withhold nivolumab. Administer oral prednisone/prednisolone at a dose of 0.5–2 mg/kg/day or its equivalent. When improves to G1, begin a slow corticosteroid taper over at least 4 weeks. If no improvement in 48 hours, administer 1–2 mg/kg intravenous (methyl)prednisolone and convert to 0.5–2 mg/kg prednisone/prednisolone orally each day or its equivalent only after a response. Taper over at least 4 weeks when symptoms improve to 5 mg prednisone/prednisolone or equivalent; do not stop steroids. Resume nivolumab upon symptom control, or when prednisone/prednisolone daily dose <10 mg

G4 (severe mass effect symptoms, ie, severe headache, any visual disturbance, or severe hypoadrenalism, ie, hypotension, severe electrolyte disturbance)

Permanently discontinue nivolumab. Administer analgesia as needed for headache. Administer 1–2 mg/kg intravenous (methyl)prednisolone and convert to 0.5–2 mg/kg prednisone/prednisolone orally each day or its equivalent only after a response. Taper over at least 4 weeks when symptoms improve to 5 mg prednisone/prednisolone or equivalent; do not stop steroids

Adrenal insufficiency

G2

Withhold nivolumab. Administer oral prednisone/prednisolone at a dose of 0.5–2 mg/kg/day or its equivalent. When symptoms improve to G1, begin a slow corticosteroid taper over at least 4 weeks. Serially assess adrenal function and continue steroids at replacement doses (20–40 mg hydrocortisone daily ~2/3 dose in morning upon awakening and ~1/3 at 4 pm) until recovery of adrenal function is documented. Resume nivolumab upon symptom control, or when prednisone/prednisolone daily dose <10 mg

G3/4

Permanently discontinue nivolumab. Administer oral prednisone/prednisolone at a dose of 0.5–2 mg/kg/day or its equivalent. When symptoms improve to G1, begin a slow corticosteroid taper over at least 4 weeks. Serially assess adrenal function and continue steroids at replacement doses (20–40 mg hydrocortisone daily ~2/3 dose in morning upon awakening and ~1/3 at 4 pm) until recovery of adrenal function is documented

Type 1 diabetes mellitus

G3 hyperglycemia

Withhold nivolumab. Admit to hospital to manage hyperglycemia. Role of corticosteroids in preventing complete loss of insulin-producing cells is unknown and not recommended. Resume nivolumab upon symptom control, or when prednisone/prednisolone daily dose <10 mg

G4 hyperglycemia

Permanently discontinue nivolumab. Admit to hospital to manage hyperglycemia. Role of corticosteroids in preventing complete loss of insulin-producing cells is unknown and not recommended

Nephritis and renal dysfunction

G2/3 (serum creatinine 1.5–6× ULN)

Withhold nivolumab. Administer oral prednisone/prednisolone at a dose of 0.5–2 mg/kg/day or its equivalent. When symptoms improve to G1, begin a slow corticosteroid taper over at least 4 weeks. If response is not adequate then administer 0.5–1 mg/kg intravenous (methyl)prednisolone and convert to 0.5–2 mg/kg prednisone/prednisolone orally each day or its equivalent only after a response, followed by a taper over at least 4 weeks when symptoms improve to G1. Resume nivolumab upon symptom control, or when prednisone/prednisolone daily dose <10 mg

G4 (serum creatinine >6× ULN)

Permanently discontinue nivolumab. Administer 0.5–1 mg/kg intravenous (methyl)prednisolone and convert to 0.5–2 mg/kg prednisone/prednisolone orally each day or its equivalent only after a response, followed by a taper over at least 4 weeks when symptoms improve to G1

Skin

G1/2

Continue nivolumab. Avoid skin irritants, avoid sun exposure; topical emollients recommended. Topical steroid (mild strength for G1, moderate/potent strength for G2) cream once or twice daily ± oral or topical antihistamines for itching

G3 rash or suspected SJS or TEN

Withhold nivolumab. Avoid skin irritants, avoid sun exposure, topical emollients recommended. Administer oral or topical antihistamines for itching. Administer oral prednisone/prednisolone at a dose of 0.5–2 mg/kg or its equivalent daily for 3 days followed by a slow corticosteroid taper over at least 4 weeks when the rash improves to G1. If response is not adequate then administer 0.5–1 mg/kg intravenous (methyl)prednisolone and convert to 0.5–2 mg/kg prednisone/prednisolone orally each day or its equivalent only after a response, followed by a taper over at least 4 weeks when the rash improves to G1. Resume nivolumab upon symptom control, or when prednisone/prednisolone daily dose <10 mg

G4 rash or confirmed SJS or TEN

Avoid skin irritants, avoid sun exposure; topical emollients recommended. Administer oral or topical antihistamines for itching. Administer 1–2 mg/kg intravenous (methyl)prednisolone and convert to oral steroids 0.5–2 mg/kg prednisone/prednisolone each day or its equivalent only after a response. Taper over at least 4 weeks when the rash improves to G1. Permanently discontinue nivolumab

Encephalitis

Confusion or altered behavior, headaches, alteration in Glasgow Coma Scale, motor or sensory deficits, speech abnormality, may or may not be febrile

Initially withhold nivolumab, but permanently discontinue nivolumab if there is no doubt as to diagnosis. Exclude bacterial and ideally viral infections prior to high-dose steroids. Administer oral prednisone/prednisolone at a dose of 0.5–2 mg/kg/day or its equivalent. When symptoms improve, begin a slow corticosteroid taper over at least 4–8 weeks. If symptoms are severe, administer 1–2 mg/kg intravenous (methyl)prednisolone and convert to 0.5–2 mg/kg prednisone/prednisolone orally each day or its equivalent only after a response. Consider concurrent empiric antiviral (intravenous acyclovir) and antibacterial therapy

Aseptic meningitis

Headache, photophobia, neck stiffness with fever, or may be afebrile, vomiting; normal cognition/cerebral function (distinguishes from encephalitis)

Other syndromes include neurosarcoidosis, posterior reversible leukoencephalopathy syndrome (PRES), Vogt-Harada-Koyanagi syndrome, demyelination, vasculitic encephalopathy, and generalized seizures

Transverse myelitis

Acute or subacute neurologic signs/symptoms of motor, sensory, or autonomic origin; most have sensory level; often bilateral symptoms

Initially withhold nivolumab, but permanently discontinue nivolumab if there is no doubt as to diagnosis. Administer 2 mg/kg intravenous (methyl)prednisolone or consider 1 g/day and convert to 0.5–2 mg/kg prednisone/prednisolone orally each day or its equivalent only after a response. When symptoms improve, begin a slow corticosteroid taper over at least 4–8 weeks. Plasmapheresis may be required if steroids do not bring about improvement

Myocarditis

G3

Permanently discontinue nivolumab. Administer 2 mg/kg intravenous (methyl)prednisolone or consider 1 g/day and convert to 0.5–2 mg/kg prednisone/prednisolone orally each day or its equivalent only after a response. When symptoms improve, begin a slow corticosteroid taper over at least 4–8 weeks. If no response, add MMF 500–1000 mg twice daily. If worse on MMF, consider adding tacrolimus

Peripheral neurologic toxicity

Moderate: some interference with ADLs, symptoms concerning to patient

Withhold nivolumab. Initial observation reasonable or initiate prednisone/prednisolone 0.5–1 mg/kg (if progressing, eg, from mild) and/or pregabalin or duloxetine for pain. When symptoms improve, begin a slow corticosteroid taper over at least 4 weeks. Resume nivolumab upon symptom control, or when prednisone/prednisolone daily dose <10 mg

Severe: limits self-care and aids warranted, life threatening, eg, respiratory problems

Permanently discontinue nivolumab. Administer 1–2 mg/kg intravenous (methyl)prednisolone and convert to 0.5–2 mg/kg prednisone/prednisolone orally each day or its equivalent only after a response. Taper over at least 4–8 weeks when symptoms improve to G1

Guillain-Barré syndrome

Progressive symmetrical muscle weakness with absent or reduced tendon reflexes—involves extremities, facial, respiratory, bulbar, and oculomotor muscles; dysregulation of autonomic nerves

Permanently discontinue nivolumab. Use of steroids not recommended in idiopathic Guillain-Barré syndrome; however, a trial of (methyl)prednisolone 1–2 mg/kg is reasonable, converting to 0.5–2 mg/kg prednisone/prednisolone orally each day or its equivalent only after a response. If no improvement or worsening, plasmapheresis or IVIG indicated

Myasthenia gravis

Fluctuating muscle weakness (proximal limb, trunk, ocular, eg, ptosis/diplopia or bulbar) with fatigability, respiratory muscles may also be involved

Permanently discontinue nivolumab. Administer pyridostigmine at an initial dose of 30 mg 3 times daily. Administer oral prednisone/prednisolone at a dose of 0.5–2 mg/kg/day or its equivalent or 1–2 mg/kg intravenous (methyl)prednisolone depending on the severity of symptoms. If treatment begins with intravenous drug convert to 0.5–2 mg/kg prednisone/prednisolone orally each day or its equivalent only after a response. If no improvement or worsening, plasmapheresis or IVIG may be considered. Additional immunosuppressants used in myasthenia gravis include azathioprine, cyclosporine, and mycophenolate. Avoid certain medications (eg, ciprofloxacin, beta-blockers) that may precipitate cholinergic crisis

Other syndromes, including motor and sensory peripheral neuropathy, multifocal radicular neuropathy/plexopathy, autonomic neuropathy, phrenic nerve palsy, cranial nerve palsies (eg, facial nerve, optic nerve, hypoglossal nerve)

Permanently discontinue nivolumab. Administer oral prednisone/prednisolone at a dose of 0.5–2 mg/kg/day or its equivalent or 1–2 mg/kg intravenous (methyl)prednisolone depending on the severity of symptoms. If treatment begins with intravenous drug convert to 0.5–2 mg/kg prednisone/prednisolone orally each day or its equivalent only after a response

Arthralgia

G1 (mild pain with inflammation, erythema or joint swelling)

Continue nivolumab. Administer acetaminophen (paracetamol) and ibuprofen

G2 (moderate pain with inflammation, erythema or joint swelling that limits ADLs)

Withhold nivolumab. Administer higher doses of acetaminophen (paracetamol) and ibuprofen and use diclofenac or naproxen or etoricoxib. If inadequately controlled, consider intra-articular steroid injections for large joints or administer oral prednisone/prednisolone at a dose of 0.5–2 mg/kg/day or its equivalent. When symptoms improve to G1, begin a slow corticosteroid taper over at least 4 weeks. If response is not adequate then administer 0.5–1 mg/kg intravenous (methyl)prednisolone and convert to 0.5–2 mg/kg prednisone/prednisolone orally each day or its equivalent only after a response, followed by a taper over at least 4 weeks when symptoms improve to G1. Resume nivolumab upon symptom control, or when prednisone/prednisolone daily dose <10 mg

G3 (severe pain; irreversible joint damage; disabling; limits self-care ADLs)

Withhold nivolumab. Administer 0.5–1 mg/kg intravenous (methyl)prednisolone and convert to 0.5–2 mg/kg prednisone/prednisolone orally each day or its equivalent only after a response, followed by a taper over at least 4 weeks when symptoms improve to G1. In severe cases, infliximab or another anti–TNF-alpha drug may be required for improvement of arthritis. Resume nivolumab upon symptom control, or when prednisone/prednisolone daily dose <10 mg

Other

First occurrence of other G3

Withhold nivolumab. Administer oral prednisone/prednisolone at a dose of 0.5–2 mg/kg/day or its equivalent. When symptoms improve to G1, begin a slow corticosteroid taper over at least 4 weeks. Resume nivolumab upon symptom control, or when prednisone/prednisolone daily dose <10 mg

Recurrence of same G3

Permanently discontinue nivolumab. Administer 1–2 mg/kg intravenous (methyl)prednisolone and convert to 0.5–2 mg/kg prednisone/prednisolone orally each day or its equivalent only after a response. Taper over at least 4–8 weeks when symptoms improve to G1

Life-threatening or G4

Requirement for ≥10 mg/day prednisone or equivalent for >12 weeks

Permanently discontinue nivolumab

Persistent G2/3 adverse reactions lasting ≥12 weeks

Abbreviations: ADL, activities of daily living; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ATG, anti-thymocyte globulin; CHF, congestive heart failure; IVIG, intravenous immunoglobulin; MMF, mycophenolate mofetil; NYHA, New York Heart Association; SJS, Stevens-Johnson syndrome; TB, tuberculosis; TEN, toxic epidermal necrolysis; TNF, tumor necrosis factor; ULN, upper limit of normal

Notes on general supportive care:

  • Steroid taper in most cases will proceed over a minimum of 1 month but if symptoms improve rapidly a 2-week taper can be considered. If steroids are administered for more than 4 weeks, consider PCP prophylaxis (cotrimoxazole 480 mg twice daily M/W/F or inhaled pentamidine if cotrimoxazole allergy), regular random blood glucose, vitamin D level, and starting calcium/vitamin D supplementation as per guidelines

Notes on pregnancy and breast feeding:

  • Nivolumab can cause fetal harm. If used during pregnancy, or if the patient becomes pregnant during treatment, apprise the patient of the potential hazard to a fetus. Females of reproductive potential should use highly effective contraception during treatment and for 5 months after the last dose of nivolumab

It is not known whether nivolumab is excreted in human milk. Therefore, it is recommended that women discontinue nursing during treatment with nivolumab

Adverse Events (N = 74)

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Adverse Events (N = 74)

Grade (%)

Grade 1/2

Grade 3/4

Any event

49

20

Fatigue

22

1

Diarrhea

20

1

Pruritus

14

0

Increased lipase

4

8

Rash

11

0

Hypothyroidism

10

0

Nausea

10

0

Asthenia

7

0

Increased AST

7

0

Increased amylase

3

3

Maculopapular rash

5

1

Increased ALT

4

1

Arthralgia

5

0

Dry skin

5

0

Pyrexia

5

0

Stomatitis

3

1

Abdominal pain

1

1

Decreased lymphocyte count

1

1

Increased creatinine

1

1

Acute kidney injury

0

1

Adrenal insufficiency

0

1

Colitis

0

1

Esophagitis

0

1

Gastritis

0

1

Increased GGT

0

1

Pain

0

1

According to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03

Note: Treatment-related toxicities are included in the table if grade 1/2 events occurred in ≥10% of patients or if any grade 3/4 events occurred. No treatment-related deaths were recorded. In total, 70% of patients experienced a treatment-related adverse event. Six patients discontinued treatment because of treatment-related adverse effects

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