Detailed instructions for Durvalumab: indications, usage and dosage, side effects and precautions

Durvalumab, developed by the British pharmaceutical company AstraZeneca, is a PD-L1 immune checkpoint inhibitor. It was approved for marketing by the U.S. Food and Drug Administration (FDA) in 2017.

Indications of durvalumab

1. Non-small cell lung cancer (NSCLC)

(1) Resectable NSCLC (tumor ≥4cm and/or positive lymph nodes) sex, no EGFR mutation or ALK rearrangement)

Adult preoperative neoadjuvant treatment: combination with platinum-containing chemotherapy (once every 3 weeks, up to 4 cycles);

Postoperative adjuvant treatment: monotherapy (up to 12 cycles).

(2) Unresectable stage III NSCLC

For adults who have not progressed after platinum-containing chemotherapy combined with concurrent radiotherapy, single-agent maintenance therapy (up to 12 months) is required.

(3) Metastatic NSCLC (without sensitive EGFR mutations or ALK genomic abnormalities)

Adults combined with temsitumumab and platinum-based chemotherapy.

2. Small cell lung cancer (SCLC)

(1) Limited-stage SCLC (FDA orphan drug designation)

For adults who have not progressed after concurrent platinum-containing chemotherapy combined with radiotherapy, single-agent consolidation therapy (up to 24 months).

(2) Extensive stage SCLC (FDA orphan drug designation)

First-line treatment for adults: combination of etoposide + carboplatin/cisplatin.

3. Biliary tract cancer (FDA orphan drug designation)

Local advanced or metastatic biliary tract cancer: adults combined with gemcitabine + cisplatin.

4. Hepatocellular carcinoma (FDA orphan drug designation)

Unresectable hepatocellular carcinoma: adults combined with temsitumumab.

5. Endometrial cancer

Advanced primary or recurrent endometrial cancer with mismatch repair deficiency (dMMR): Adults should be treated with carboplatin + paclitaxel (6 cycles), followed by single-agent maintenance therapy.

Administration method of durvalumab

1. Pre-administration screening

Endometrial cancer: detection of dMMR (FDA approved method)

NSCLC: detection of EGFR mutation/ALK rearrangement

Record baseline weight, creatinine, liver enzymes, thyroid function and pregnancy status.

2. Administration method

(1) Infusion requirements

Intravenous infusion, use sterile low protein binding 0.2-0.22μm filter;

(2) Dilution requirements

The original solution (50mg/mL) is diluted to 1-15mg/mL with 0.9% sodium chloride or 5% glucose; avoid shaking and mix gently by inverting.

(3) Infusion time

The infusion time exceeds 60 minutes.

3. Sequence of combination administration

(1) Combined with temsitumumab

Infuse temsitumumab first, then infuse durvalumab.

(2) When combined with temsitumumab and platinum-based chemotherapy

Infuse temsitumumab first, then infuse durvalumab, and then give platinum-based chemotherapy.

(3) When combined with temsitumumab and pemetrexed treatment

Infuse temsitumumab first, then infuse durvalumab, and then give pemetrexed.

(4) When combined with carboplatin and paclitaxel

Infuse durvalumab first, and then give carboplatin and paclitaxel.

Recommended dose of durvalumab for adults

1. Resectable non-small cell lung cancer (NSCLC)

(1) Body weight ≥30kg

Neoadjuvant treatment: 1500mg combined with chemotherapy every 3 weeks for up to 4 cycles. Treatment is continued postoperatively until disease progression that precludes curative surgery, recurrence, unacceptable toxicity, or up to 12 cycles postoperatively.

Adjuvant treatment: 1500mg as a single drug every 4 weeks after surgery, up to 12 cycles. Treatment was continued until disease progression that precluded curative surgery, recurrence, unacceptable toxicity, or up to 12 cycles postoperatively.

(2) Body weight <30kg

Neoadjuvant treatment: 20mg/kg combined with chemotherapy every 3 weeks for up to 4 cycles. Treatment is continued postoperatively until disease progression that precludes curative surgery, recurrence, unacceptable toxicity, or up to 12 cycles postoperatively.

Adjuvant treatment: 20 mg/kg as a single drug every 4 weeks after surgery, up to 12 cycles. Treatment was continued until disease progression that precluded curative surgery, recurrence, unacceptable toxicity, or up to 12 cycles postoperatively.

2. Unresectable stage III non-small cell lung cancer

(1) Body weight ≥30kg

Infuse 10mg/kg every 2 weeks or 1500mg every 4 weeks. Continue treatment until disease progression, unacceptable toxicity, or up to 12 months.

(2) Body weight <30kg

Infuse 10mg/kg every 2 weeks. Continue treatment until disease progression, unacceptable toxicity, or up to 12 months.

3. Metastatic non-small cell lung cancer

(1) Weight ≥30kg

Non-squamous: In cycles 1-5, infuse 1500mg every 3 weeks; in cycles 6-8, infuse 1500mg every 4 weeks; used in combination with appropriate doses of temsitumumab and platinum-based chemotherapy. Continue treatment until disease progression or unacceptable toxicity.

Squamous: 1500 mg infused every 3 weeks for cycles 1-5; 1500 mg infused every 4 weeks for cycles 6-8; used in combination with appropriate doses of temsitumumab and platinum-based chemotherapy. Continue treatment until disease progression or unacceptable toxicity.

(2) Body weight <30kg

Non-squamous: In cycles 1-5, infuse 20 mg/kg every 3 weeks; in cycles 6-8, infuse 20 mg/kg every 4 weeks; used in combination with appropriate doses of temsitumumab and platinum-based chemotherapy. Continue treatment until disease progression or unacceptable toxicity.

Squamous: 20 mg/kg every 3 weeks for cycles 1-5; 20 mg/kg every 4 weeks for cycles 6-8; used in combination with appropriate doses of temsitumumab and platinum-based chemotherapy. Continue treatment until disease progression or unacceptable toxicity.

4. Limited-stage small cell lung cancer (SCLC)

(1) Body weight ≥30kg

Infuse 1500mg every 4 weeks. Continue treatment until disease progression, unacceptable toxicity, or for up to 24 months.

(2) Body weight <30kg

Infuse 20mg/kg every 4 weeks. Continue treatment until disease progression, unacceptable toxicity, or for up to 24 months.

5. Extensive-stage small cell lung cancer

(1) Body weight ≥30kg

Use 1500mg in combination with chemotherapy every 3 weeks for a total of 4 cycles, and then use 1500mg as a single agent every 4 weeks. Continue treatment until disease progression or unacceptable toxicity.

(2) Body weight <30kg

Use 20mg/kg in combination with chemotherapy every 3 weeks for a total of 4 cycles, and then use 10mg/kg as a single agent every 2 weeks. Continue treatment until disease progression or unacceptable toxicity.

6. Biliary tract cancer

(1) Body weight ≥30kg

Use 1500mg in combination with chemotherapy every 3 weeks for up to 8 cycles, and then use 1500mg as a single agent every 4 weeks. Continue treatment until disease progression or unacceptable toxicity.

(2) Body weight <30kg

Use 20mg/kg in combination with chemotherapy every 3 weeks for up to 8 cycles, and then use 20mg/kg as a single agent every 4 weeks. Continue treatment until disease progression or unacceptable toxicity.

7. Unresectable hepatocellular carcinoma

(1) Weight ≥30kg

On day 1 of cycle 1, a single dose of temsilimumab 300 mg was given, followed by durvalumab 1500 mg, followed by a single dose of durvalumab 1500 mg every 4 weeks. Continue treatment until disease progression or unacceptable toxicity.

(2) Body weight <30kg

On day 1 of cycle 1, after a single dose of temsilimumab 4 mg/kg, durvalumab 20 mg/kg was given, and then every 4 weeks a single dose of durvalumab 20 mg/kg was given. Continue treatment until disease progression or unacceptable toxicity.

8. Endometrial cancer (mismatch repair deficient)

(1) Body weight ≥30kg

1120mg combined with carboplatin and paclitaxel every 3 weeks for a total of 6 cycles, followed by 1500mg of durvalumab as a single agent every 4 weeks. Continue treatment until disease progression or unacceptable toxicity.

(2) Body weight <30kg

15mg/kg combined with carboplatin and paclitaxel every 3 weeks for a total of 6 cycles, followed by durvalumab 20mg/kg as a single agent every 4 weeks. Continue treatment until disease progression or unacceptable toxicity.

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Dose adjustment of durvalumab

1. Pneumonia

Grade 2: Suspension of administration

Grade 3–4: Permanent discontinuation

2. Colitis

Grade 2: Suspension of administration

Grade 3 (containing tisemumab): Suspension or permanent Prolonged drug discontinuation

Grade 4: Permanent drug discontinuation

3. Hepatitis (no liver metastasis)

ALT/AST>3–8×ULN: Suspension of drug administration

ALT/AST>8×ULN: Permanent discontinuation

4. Infusion reaction

Grade 1-2: Slow down or suspend the infusion

Grade 3-4: Permanent discontinuation.

Common adverse reactions of durvalumab

1. Durvalumab combined with chemotherapy

In patients with resectable stage II/III non-small cell lung cancer (NSCLC) (neoadjuvant/adjuvant treatment), the most common adverse reactions (incidence ≥20%) are anemia, nausea, constipation, fatigue, musculoskeletal pain and rash.

2. Immobilumab monotherapy

In patients with unresectable stage III non-small cell lung cancer, the most common adverse reactions (incidence ≥20%) are cough, fatigue, pneumonia/radiation pneumonitis, upper respiratory tract infection, dyspnea and rash; in patients with limited-stage small cell lung cancer (LS-SCLC), the most common adverse reactions (incidence ≥20%) are pneumonia or radiation pneumonitis and fatigue.

3. Immobilumab combined with platinum-based chemotherapy

In patients with metastatic non-small cell lung cancer, the most common adverse reactions (incidence ≥20%) are nausea, fatigue, musculoskeletal pain, decreased appetite, rash and diarrhea.

4. Immobilumab combined with platinum-based chemotherapy

In patients with extensive-stage small cell lung cancer (ES-SCLC), the most common adverse reactions (incidence ≥20%) are nausea, fatigue/asthenia, and alopecia.

Durvalumab combined with gemcitabine and cisplatin: In patients with biliary tract cancer (BTC), the most common adverse reactions (incidence ≥20%) are fatigue, nausea, constipation, decreased appetite, abdominal pain, rash and fever.

5. Immobilumab combined with temsitumumab

In patients with unresectable hepatocellular carcinoma (uHCC), the most common adverse reactions (incidence ≥20%) are rash, diarrhea, fatigue, pruritus, musculoskeletal pain and abdominal pain.

6. Immobilumab combined with carboplatin and paclitaxel, followed by imrvalumab monotherapy

In patients with endometrial cancer, the most common adverse reactions (incidence ≥20%) were peripheral neuropathy, musculoskeletal pain, nausea, alopecia, fatigue, abdominal pain, constipation, rash, decreased magnesium, increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), diarrhea, vomiting, cough, decreased potassium, dyspnea, headache, and increased alkaline phosphatase.

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Precautions of durvalumab

1. Immune-mediated adverse reactions

Can involve any organ (pneumonia, hepatitis, colitis, endocrinopathy, etc.) and even lead to death; it may occur during treatment and after discontinuation of drug.

2. Infusion reaction

Grade 3-4 reactions require permanent discontinuation of the drug.

3. Complications of allogeneic hematopoietic stem cell transplantation (HSCT)

Including GVHD, hepatic veno-occlusive disease, etc.

4. Fetal toxicity

It is contraindicated during pregnancy. Effective contraception is required during treatment and 3 months after stopping the drug.

Special population use of durvalumab

1. Hepatic insufficiency

There are no dosage recommendations for patients with mild or moderate hepatic insufficiency. It has not been studied in patients with severe hepatic impairment.

2. Renal insufficiency

There are no dosage recommendations for patients with mild or moderate renal insufficiency. It has not been studied in patients with severe renal impairment.

3. Elderly patients

There are currently no specific dosage recommendations.

Pharmacokinetics of durvalumab

Absorption

Bioavailability reaches steady-state concentration in approximately 16 weeks.

At doses ≥3 mg/kg administered every 2 weeks, systemic exposure is dose-proportional.

Distribution

Extent

It is unknown whether durvalumab is distributed into human milk. Maternal IgG is secreted into human milk.

Elimination

The half-life is about 21 days.

Storage method of durvalumab

Durvalumab should be stored in the original packaging at 2-8°C and protected from light. Do not freeze. The diluted solution can be stored at room temperature (up to 25°C) for up to 8 hours, or at 2-8°C for up to 28 days (total storage time from first opening of the vial to initiation of intravenous infusion)