Nivolumab (Opdivo)

How Nivolumab Works

The PD-1/PD-L1 Checkpoint Pathway

Your immune system has built-in "checkpoints" that prevent it from attacking healthy tissue. Cancer cells exploit these checkpoints to hide from immune attack.

Normal Immune Function

• T cells patrol the body looking for abnormal cells (infected cells, cancer cells)
• PD-1 is a "checkpoint" protein on T cell surface
• PD-L1 and PD-L2 are ligands found on some normal cells
• When PD-L1 binds to PD-1, it sends "don't attack" signal to T cell
• Purpose: Prevents autoimmune disease, stops immune response once infection cleared

How Cancer Cells Evade Immunity

• Many cancer cells express high levels of PD-L1
• When cancer cell PD-L1 binds to T cell PD-1, it turns off the T cell
• T cell becomes "exhausted" and can't attack the cancer
• Cancer grows unchecked despite presence of immune cells

How Nivolumab Reverses This

1. Nivolumab antibody binds to PD-1 on T cells
2. Blocks PD-L1 from binding to PD-1
3. "Releases the brakes" on immune system
4. T cells reactivate and can attack cancer cells
5. Immune response amplifies - more T cells recruited, memory T cells formed

FDA-Approved Uses

Nivolumab has FDA approval for more cancer types than almost any other single drug:

Melanoma

• Unresectable or metastatic melanoma: First FDA approval (2014)
  • Can be used alone or with ipilimumab (another checkpoint inhibitor)
  • Response rate ~40% as monotherapy, ~60% with combination
  • 5-year survival ~40% (vs <10% before immunotherapy era)
• Adjuvant melanoma: After complete resection (stage IIB-IV)
  • Reduces recurrence risk ~40%
  • Given for 1 year

Lung Cancer

• Non-small cell lung cancer (NSCLC):
  • First-line: With chemotherapy (for any PD-L1 level) or with ipilimumab (if PD-L1 ≥1%)
  • Second-line: After platinum chemotherapy
  • Response rates: 15-45% depending on PD-L1 expression and line of therapy
  • Higher PD-L1 = better response
• Small cell lung cancer (SCLC):
  • After platinum chemotherapy and at least one other line
  • Limited-stage after chemoradiation (with ipilimumab)

Kidney Cancer (Renal Cell Carcinoma)

• Advanced renal cell carcinoma:
  • First-line: With ipilimumab (for intermediate/poor risk) or with cabozantinib (TKI)
  • After prior therapy: Monotherapy
  • Combination response rates: 40-50%
  • Some patients with complete responses lasting years
• Adjuvant RCC: After nephrectomy, high risk of recurrence

Head and Neck Cancer

• Recurrent or metastatic squamous cell carcinoma:
  • After platinum-based chemotherapy
  • Response rate ~15-20%
  • Improved survival vs standard chemotherapy

Hodgkin Lymphoma

• Classical Hodgkin lymphoma:
  • Relapsed or refractory after autologous stem cell transplant and brentuximab vedotin
  • Very high response rates (~65-70%)
  • Hodgkin lymphoma cells are PD-L1 positive due to genetic changes

Gastrointestinal Cancers

• Gastric, gastroesophageal junction, esophageal adenocarcinoma:
  • First-line with chemotherapy (CheckMate-649)
  • After two or more prior lines (monotherapy)
  • Improved outcomes with combination
• Esophageal squamous cell carcinoma:
  • First-line with chemotherapy or ipilimumab
  • After fluoropyrimidine/platinum
• Colorectal cancer:
  • MSI-high or dMMR ONLY (does NOT work in MSS colorectal cancer)
  • After fluoropyrimidine, oxaliplatin, irinotecan
  • Can use first-line with ipilimumab
  • Response rates 30-50% in MSI-high tumors
• Hepatocellular carcinoma: After sorafenib

Genitourinary Cancers

• Urothelial carcinoma (bladder/urinary tract):
  • Not eligible for cisplatin-based chemotherapy (first-line)
  • After platinum chemotherapy

Other Cancers

• Malignant pleural mesothelioma: First-line with ipilimumab
• MSI-high or dMMR tumors: Any solid tumor that has progressed after prior treatment (tissue-agnostic approval)
• TMB-high tumors: (≥10 mutations/megabase) after prior treatment

Dosing and Administration

Standard Dosing

• Monotherapy options:
  • 240 mg IV every 2 weeks, OR
  • 480 mg IV every 4 weeks
  • Both equally effective - choose based on convenience
• With ipilimumab (combination):
  • Nivolumab 1 mg/kg + ipilimumab 3 mg/kg every 3 weeks × 4 doses
  • Then nivolumab 240 mg every 2 weeks or 480 mg every 4 weeks
  • Higher toxicity but higher response rates
• With chemotherapy:
  • Nivolumab 360 mg every 3 weeks (with chemo)
  • Or 240 mg every 2 weeks

Infusion Process

• Infusion time: 30 minutes (can extend to 60 minutes if infusion reaction)
• Given through IV in arm or central line
• Outpatient procedure (go home same day)
• Monitored during and after for reactions

Duration of Treatment

• Metastatic disease: Continue until:
  • Disease progression
  • Unacceptable toxicity
  • Up to 2 years in some cases (melanoma, lung cancer)
  • Some oncologists continue beyond 2 years if ongoing benefit
• Adjuvant treatment: 1 year (melanoma, kidney cancer)

Premedications

• Generally not required (unlike chemotherapy)
• Some centers give acetaminophen and antihistamines for first few doses

Side Effects and Immune-Related Adverse Events

Common Side Effects (>20%)

• Fatigue (30-50%) - most common, can be significant
• Musculoskeletal pain (25-30%) - joints, muscles
• Rash (20-30%) - usually mild but can be severe
• Nausea (15-25%)
• Decreased appetite (15-25%)
• Diarrhea (15-20%) - may indicate colitis
• Cough (15-20%)
• Itching (pruritus) (15-20%)

Immune-Related Adverse Events (irAEs)

Can occur at any time during or after treatment, even months after stopping

1. Colitis (Inflammation of Colon)

• Incidence: 10-15% (higher with nivolumab + ipilimumab: 25-35%)
• Symptoms:
  • Diarrhea (≥4 loose stools/day above baseline)
  • Abdominal pain, cramping
  • Blood or mucus in stool
  • Urgency, tenesmus
• Timing: Usually 5-10 weeks but can occur anytime
• Management:
  • Grade 2+: Hold nivolumab, start prednisone 1 mg/kg
  • Grade 3-4: High-dose steroids, may need infliximab
  • Colonoscopy if severe or not improving

2. Pneumonitis (Lung Inflammation)

• Incidence: 3-6%
• Symptoms:
  • New or worsening shortness of breath
  • Cough
  • Chest pain
• Diagnosis: CT scan shows infiltrates
• Management:
  • Hold nivolumab
  • Steroids (prednisone 1-2 mg/kg)
  • May need hospitalization if severe
  • Permanently discontinue if grade 3-4

3. Hepatitis (Liver Inflammation)

• Incidence: 5-10%
• Symptoms: Often asymptomatic (detected on labs), jaundice if severe
• Monitoring: Liver function tests (AST, ALT, bilirubin) before each dose
• Management:
  • AST/ALT >3× ULN: Hold nivolumab
  • AST/ALT >5× ULN or bilirubin elevated: Steroids, permanently stop if grade 4

4. Endocrine Problems

Thyroid Disorders (Most Common Endocrine irAE):

• Hypothyroidism (underactive thyroid): 10-15%
  • Symptoms: Fatigue, weight gain, cold intolerance, constipation
  • Detected by TSH blood test
  • Treatment: Levothyroxine (thyroid hormone replacement) - usually lifelong
  • Can continue nivolumab with replacement
• Hyperthyroidism (overactive): 5-10%
  • Symptoms: Palpitations, weight loss, anxiety, tremor
  • Often transient, may progress to hypothyroidism
  • Sometimes requires beta-blockers, rarely anti-thyroid drugs

Other Endocrine Issues:

• Adrenal insufficiency (1-2%):
  • Symptoms: Severe fatigue, weakness, low blood pressure, nausea
  • Life-threatening if untreated
  • Requires immediate steroid replacement
• Hypophysitis (pituitary inflammation): 1%
  • Can affect multiple hormones
  • May require hormone replacement
• Type 1 diabetes: <1%
  • Sudden onset high blood sugar
  • Can present as DKA (diabetic ketoacidosis)
  • Requires insulin (permanent)

5. Kidney Problems (Nephritis)

• Incidence: 2-3%
• Usually detected by elevated creatinine on blood tests
• Often asymptomatic
• Treatment: Hold nivolumab, steroids if moderate-severe

6. Skin Reactions

• Rash and pruritus: Very common (20-30%)
  • Usually mild (grade 1-2)
  • Treated with topical steroids, antihistamines, moisturizers
• Vitiligo: Loss of skin pigmentation
  • More common in melanoma patients
  • Sign of immune response (associated with better outcomes)
• Severe reactions: Stevens-Johnson syndrome, toxic epidermal necrolysis (very rare but serious)

7. Rare But Serious irAEs

Myocarditis (Heart Inflammation):

• Incidence: <1% but potentially fatal (40% mortality if severe)
• Symptoms: Chest pain, shortness of breath, palpitations, severe fatigue, leg swelling
• Can be fulminant (rapid onset, life-threatening)
• Requires immediate discontinuation and high-dose steroids
• Higher risk with nivolumab + ipilimumab combination

Neurologic Toxicity:

• Myasthenia gravis, Guillain-Barré syndrome, encephalitis (all rare)
• Peripheral neuropathy (numbness, weakness)
• Aseptic meningitis

Other Rare irAEs:

• Pancreatitis, myositis (muscle inflammation)
• Uveitis, episcleritis (eye inflammation)
• Sarcoidosis-like reactions

Infusion Reactions

• Less common than with chemotherapy (<5%)
• Symptoms: Fever, chills, flushing, itching during or shortly after infusion
• Usually mild, managed by slowing infusion
• Severe reactions rare

Monitoring During Treatment

Before Each Infusion

• Clinical assessment:
  • Review all symptoms since last visit
  • Physical examination
  • Vital signs
• Blood tests:
  • Complete blood count (CBC)
  • Comprehensive metabolic panel (liver and kidney function)
  • Thyroid function (TSH) - baseline, then every 6-12 weeks

Periodic Testing

• Every 3-6 cycles:
  • Cortisol level (if symptoms of adrenal insufficiency)
  • Hemoglobin A1C (diabetes screening)
  • Free T4 if TSH abnormal
• As clinically indicated:
  • Chest imaging for pneumonitis
  • Colonoscopy for severe colitis
  • Cardiac workup (troponin, ECG, echo) if chest symptoms
  • Endocrine consultation for complex hormonal issues

Tumor Response Assessment

• CT or PET/CT scans every 6-12 weeks
• May show "pseudoprogression" - apparent growth before shrinkage
  • Immune infiltration into tumor can make it look larger
  • Usually evident on first scan, resolves by next scan
• Responses can continue after stopping treatment

How Well Does Nivolumab Work?

Response Patterns

• Not everyone responds: 15-45% depending on cancer type and biomarkers
• Delayed responses: Can take 2-6 months to see tumor shrinkage
• Durable responses: When it works, often works for years
  • Some patients remain in remission years after stopping
  • 5-year survival in melanoma/lung cancer transformed from <10% to 30-50%
• Complete responses possible: Some patients have complete disappearance of all tumors

Predictive Biomarkers

PD-L1 Expression

• Measured as TPS (tumor proportion score)
• General trend: Higher PD-L1 = Better response
  • PD-L1 ≥50%: ~45% response in NSCLC
  • PD-L1 1-49%: ~25% response
  • PD-L1 <1%: ~10-15% response
• Not perfect predictor - some PD-L1 negative patients respond, some positive don't

MSI-High / dMMR

• DNA mismatch repair deficiency
• Creates many mutations → many neoantigens → strong immune response
• Response rates 30-50% across tumor types
• Very durable responses

Tumor Mutational Burden (TMB)

• Number of mutations in tumor
• TMB-high (≥10 mut/Mb): Better response to immunotherapy
• Less well established than MSI/PD-L1

Cancer-Specific Response Rates

Combination Therapy

Nivolumab + Ipilimumab (Dual Checkpoint Blockade)

• Mechanism: Blocks two different checkpoints (PD-1 and CTLA-4)
• Higher efficacy: Response rates 50-60% vs 40% with nivo alone (melanoma)
• But higher toxicity: 55-60% severe irAEs vs 15-20% with monotherapy
• FDA-approved combinations:
  • Melanoma
  • Renal cell carcinoma
  • Colorectal cancer (MSI-high)
  • Hepatocellular carcinoma
  • Malignant pleural mesothelioma
  • Non-small cell lung cancer
  • Esophageal squamous cell carcinoma

Nivolumab + Chemotherapy

• Rationale: Chemotherapy releases tumor antigens, enhances immune response
• FDA-approved:
  • NSCLC: Nivo + platinum-doublet chemo
  • Gastric/GEJ/esophageal: Nivo + fluoropyrimidine + platinum
• Side effects: Combination of chemo toxicity + irAEs

Nivolumab + Targeted Therapy

• Renal cell carcinoma: Nivo + cabozantinib (TKI)
  • Response rate ~55%, median PFS ~17 months

Special Populations

Pregnancy and Breastfeeding

• Can cause fetal harm (PD-1 pathway important for maintaining pregnancy)
• Effective contraception required during and for 5 months after last dose
• Do not breastfeed during treatment and for 5 months after

Autoimmune Disease

• Patients with active autoimmune disease excluded from clinical trials
• Theoretical risk of worsening autoimmune condition
• Some patients with controlled/mild autoimmune disease can receive nivolumab with close monitoring
• Decision individualized based on cancer severity vs autoimmune risk

Organ Transplant Recipients

• High risk of transplant rejection (immune activation may attack transplanted organ)
• Generally avoided unless no other options
• Some case reports of successful use with intense monitoring

Elderly Patients

• No dose adjustment needed
• Efficacy similar to younger patients
• May have slightly higher risk of some irAEs

Kidney or Liver Impairment

• No dose adjustment needed for mild-moderate impairment
• Limited data in severe impairment

Cost and Access

Drug Cost

• Wholesale cost: ~$13,000-15,000 per 240 mg dose
• Annual cost: ~$170,000-195,000 (every 2 weeks dosing)
• One of the most expensive cancer drugs

Insurance Coverage

• Medicare Part B covers for FDA-approved indications
• Most private insurance covers for approved uses
• Prior authorization usually required
• Biomarker testing (PD-L1, MSI) may be required

Financial Assistance

• Bristol Myers Squibb Patient Assistance Foundation: For uninsured/underinsured
• Co-pay assistance: For commercially insured (not Medicare)
• Contact: 1-800-721-8909 or BMSAccessSupport.com
• Other foundations: PAN Foundation, The Assistance Fund, CancerCare

Frequently Asked Questions

How is nivolumab different from pembrolizumab (Keytruda)?

They are extremely similar - both are anti-PD-1 checkpoint inhibitors with the same mechanism of action. The main differences are: (1) dosing schedules - nivolumab every 2 or 4 weeks vs pembrolizumab every 3 or 6 weeks; (2) specific FDA approvals for different cancers; (3) manufacturer (BMS vs Merck). Head-to-head studies show no significant difference in effectiveness or side effects. Choice depends on what's approved for your cancer, physician preference, and convenience.

Will nivolumab work for my cancer?

It depends on your cancer type and biomarkers. Nivolumab works best in cancers with high PD-L1 expression, MSI-high/dMMR status, or high TMB. Even with favorable biomarkers, response rates typically range from 15-60% depending on the cancer. However, those who respond often have very durable benefit - some remaining in remission for years. Your oncologist will test your tumor to determine if nivolumab is appropriate.

How long does it take to work?

Unlike chemotherapy (which often works within weeks), immunotherapy responses can be delayed. Scans may show stable disease or even initial growth before shrinkage ("pseudoprogression"). Most responses become apparent by 2-6 months. If your cancer is clearly progressing rapidly by 2-3 months, nivolumab likely isn't working. Your oncologist uses special criteria (irRECIST) that account for this delayed response pattern.

How long will I need nivolumab?

For metastatic disease, treatment continues until cancer progresses, unacceptable side effects, or up to 2 years. Some oncologists stop at 2 years if excellent response, as many patients maintain remission after stopping. For adjuvant therapy (after surgery), standard duration is 1 year. Clinical trials are studying optimal duration - some data suggest stopping after 1 year may be adequate even for metastatic disease if in remission.

What if I have an autoimmune disease?

This is complicated and requires careful consideration. Active, severe autoimmune disease is generally a contraindication to nivolumab. However, patients with well-controlled or mild autoimmune conditions (stable hypothyroidism on replacement, rheumatoid arthritis in remission, etc.) have successfully received nivolumab with close monitoring. The decision weighs cancer treatment need vs risk of autoimmune flare. Discuss thoroughly with your oncologist and potentially your rheumatologist/autoimmune specialist.

Can I stop nivolumab if I have side effects?

It depends on severity. Mild irAEs (grade 1) can usually be managed while continuing treatment. Moderate irAEs (grade 2) typically require temporarily holding nivolumab and starting steroids - treatment can resume once resolved. Severe irAEs (grade 3-4) usually require permanent discontinuation of certain types (pneumonitis, myocarditis, colitis). However, endocrine irAEs (thyroid, adrenal) can often be managed with hormone replacement while continuing nivolumab.

Why do I need steroids for side effects if this boosts my immune system?

This seems counterintuitive but makes sense: nivolumab has already "released the brakes" on your immune system. Steroids are used to calm excessive immune responses (irAEs) attacking normal organs. Short-term steroids don't significantly impair the anti-cancer immune response already activated by nivolumab. The goal is to suppress harmful autoimmunity while preserving beneficial anti-tumor immunity. Studies show patients who need steroids for irAEs often have similar cancer outcomes as those without irAEs.

Will I lose my hair?

No, nivolumab does not cause hair loss (very different from chemotherapy). Some patients experience hair texture changes or, rarely, alopecia areata (patchy hair loss from autoimmune reaction), but complete hair loss like with chemotherapy doesn't occur. If you're receiving nivolumab with chemotherapy, hair loss may occur from the chemo component.

Can I drink alcohol while on nivolumab?

Moderate alcohol is generally okay, but discuss with your oncologist. Alcohol can worsen fatigue and may affect liver function. If you develop hepatitis (liver inflammation) from nivolumab, avoid alcohol completely. Never combine alcohol with steroids if you're being treated for irAEs. Moderation is key.

What's the difference between nivolumab alone and nivolumab + ipilimumab?

The combination blocks two different immune checkpoints (PD-1 and CTLA-4), leading to stronger immune activation. This increases response rates (60% vs 40% in melanoma) but also dramatically increases severe side effects (55-60% vs 15-20%). The combination is reserved for cancers where the benefit justifies the higher toxicity risk. Your oncologist will recommend based on your cancer type, extent of disease, and overall health.

Can nivolumab cure cancer?

For metastatic cancer, "cure" is rare but increasingly possible. Some patients (especially melanoma, renal cell carcinoma, Hodgkin lymphoma) have achieved complete responses lasting 5-10+ years off treatment - functionally cured. More commonly, nivolumab provides disease control for months to years. For adjuvant therapy (after surgery), the goal is cure by preventing recurrence, and nivolumab significantly improves cure rates in melanoma and kidney cancer.