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Durvalumab Plus Chemotherapy for Extensive-Stage Small Cell Lung Cancer


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On March 27, 2020, durvalumab (Imfinzi) was approved for use in combination with etoposide and either carboplatin or cisplatin as first-line treatment of patients with extensive-stage small cell lung cancer.1,2

OF NOTE

Durvalumab carries warnings/precautions for immune-mediated adverse reactions (eg, pneumonitis, hepatitis, colitis, endocrinopathies, nephritis, and dermatologic reactions), infection, infusion-related reactions, and embryofetal toxicity.

Supporting Efficacy Data

Approval was based on the findings of the open-label phase III CASPIAN trial (ClinicalTrials.gov identifier NCT03043872).2,3 In the trial, patients were randomly assigned to receive durvalumab at 1,500 mg every 3 weeks plus investigator choice of carboplatin (AUC = 5 or 6) or cisplatin (75–80 mg/m2) on day 1 and etoposide (80–100 mg/m2) on days 1, 2, and 3 of each 21-day cycle for 4 cycles, followed by durvalumab every 4 weeks (n = 268) or chemotherapy alone at the same dosage (n = 269). Patients in the chemotherapy group could receive prophylactic cranial irradiation after chemotherapy at the investigator’s discretion.

The median age of patients was 63 years (range = 28–82 years, 40% ≥ 65 years); 70% were male; 84% were white and 15% were Asian; 65% had an Eastern Cooperative Oncology Group performance status of 1; 93% were former or current smokers; 90% had stage IV disease; and 10% had brain metastasis. A total of 25% of patients received cisplatin, and 74% received carboplatin. In the chemotherapy-alone group, 8% of patients received prophylactic cranial irradiation.

The median overall survival was 13.0 months (95% confidence interval [CI] = 11.5–14.8 months) with durvalumab plus chemotherapy vs 10.3 months (95% CI = 9.3–11.2 months) with chemotherapy alone (hazard ratio [HR] = 0.73, P = .0047). The median progression-free survival on investigator assessment was 5.1 vs 5.4 months (HR = 0.78, 95% CI = 0.65–0.94). The investigator-assessed confirmed objective response rate was 68% vs 58%.

How It Works

Durvalumab is a human immunoglobulin G1 kappa monoclonal antibody that binds to programmed cell death ligand 1 (PD-L1) and blocks the interaction of PD-L1 with programmed cell death protein 1 (PD-1) and CD80 (B7.1). Expression of PD-L1 can be induced by inflammatory signals (eg, interferon-gamma), and the ligand can be expressed on both tumor cells and tumor-associated immune cells in the tumor microenvironment. PD-L1 blocks T-cell function and activation through interaction with PD-1 and CD80 (B7.1). Through binding to its receptors, PD-L1 reduces cytotoxic T-cell activity and proliferation and cytokine production. Blockade of PD-L1/PD-1 and PD-L1/CD80 interactions releases inhibition of immune responses, without inducing antibody-dependent cell-mediated cytotoxicity. PD-L1 blockade with durvalumab increased T-cell activation in vitro and decreased tumor size in co-engrafted human tumor and immune cell xenograft mouse models.

How It Is Used

The recommended dose of durvalumab in the current indication is 1,500 mg via 60-minute intravenous infusion every 3 weeks in combination with chemotherapy for four cycles, followed by 1,500 mg every 4 weeks as a single agent. It is given prior to chemotherapy when given on the same day. Treatment is continued until disease progression or unacceptable toxicity.

KEY POINTS

  • Durvalumab (Imfinzi) was approved for use in combination with etoposide and either carboplatin or cisplatin as first-line treatment of patients with extensive-stage small cell lung cancer.
  • The recommended dose of durvalumab in the current indication is 1,500 mg via 60-minute intravenous infusion every 3 weeks in combination with chemotherapy for four cycles, followed by 1,500 mg every 4 weeks as a single agent.

No dose reductions of durvalumab are recommended. Prescribing information provides instructions on withholding or discontinuing durvalumab for the following adverse reactions: pneumonitis; hepatitis; colitis or diarrhea; hyperthyroidism or thyroiditis; adrenal insufficiency or hypophysitis/hypopituitarism; type 1 diabetes; nephritis; rash or dermatitis; infection; infusion-related reactions; other immune-mediated adverse reactions; persistent grade 2 or 3 adverse reactions (excluding endocrinopathies); inability to taper corticosteroid treatment; and recurrent grade 3 or 4 adverse reactions. Treatment should be permanently discontinued for grade 3 or 4 infusion-related reactions.

Safety Profile

In the CASPIAN trial, the most common adverse events of any grade (≥ 20%) in patients in the durvalumab-plus-chemotherapy group were nausea (34% vs 34% in the chemotherapy-alone group), fatigue/asthenia (32% vs 32%), and alopecia (31% vs 34%). The most common grade 3 or 4 adverse events included fatigue/asthenia, diarrhea, and alopecia. The most common grade 3 or 4 laboratory abnormalities were neutropenia, lymphopenia, and anemia.

Serious adverse events occurred in 31% of patients receiving durvalumab plus chemotherapy, with the most common being febrile neutropenia, pneumonia, anemia, pancytopenia, pneumonitis, and chronic obstructive pulmonary disease. Adverse events led to discontinuation of durvalumab in 7% of patients, with causes including pneumonitis, hepatotoxicity, neurotoxicity, sepsis, diabetic ketoacidosis, and pancytopenia in one patient each. Adverse events led to death in 4.9% of patients receiving durvalumab plus chemotherapy, with causes including pancytopenia, sepsis, septic shock, pulmonary artery thrombosis, pulmonary embolism, and hepatitis in one patient each and sudden death in two patients.

Durvalumab carries warnings/precautions for immune-mediated adverse reactions (eg, pneumonitis, hepatitis, colitis, endocrinopathies, nephritis, and dermatologic reactions), infection, infusion-related reactions, and embryofetal toxicity. Patients should be monitored for changes in liver function and renal function. Treatment should be permanently discontinued for severe or life-threatening pneumonitis, transaminase or total bilirubin elevation, colitis, nephritis, rash, or infusion-related reactions. Patients should be advised not to breastfeed while receiving durvalumab. 

REFERENCES

1. U.S. Food and Drug Administration: FDA approves durvalumab for extensive-stage small cell lung cancer. Available at https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-durvalumab-extensive-stage-small-cell-lung-cancer. Accessed April 16, 2020.

2. Imfinzi (durvalumab) injection for intravenous use, AstraZeneca, March 2020. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/761069s018lbl.pdf. Accessed April 16, 2020.

3. Paz-Ares L, Dvorkin M, Chen Y, et al: Durvalumab plus platinum-etoposide vs platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): A randomised, controlled, open-label, phase III trial. Lancet 394:1929-1939, 2019.

 


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