20

April

Durvalumab (Imfinzi®) Therapy Overview

Written by: Joshua Nubla, PharmD, NCODA
Download Here

The purpose of this PQI is to discuss the overall management of durvalumab and immune-mediated adverse events in the treatment of Stage III unresectable NSCLC and first-line extensive stage small cell lung cancer.

Background

Durvalumab is a PD-L1 blocking monoclonal antibody and immune checkpoint inhibitor indicated for: (1) the treatment of adult patients with unresectable Stage III non-small cell lung cancer (NSCLC) whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy and (2): in combination with etoposide and either carboplatin or cisplatin, as first-line treatment of adult patients with extensive-stage small cell lung cancer (ES-SCLC). In a clinical study known as the PACIFIC trial, patients with Stage III, unresectable NSCLC (who completed at least 2 cycles of concurrent platinum based chemotherapy and definitive radiation within 42 days prior to initiation of durvalumab) reported a 2-year OS rate was 66% for durvalumab vs 55% with placebo (HR=0.68) and an updated 4-year OS rate was 50% for durvalumab and 36% with placebo (HR=0.71).1,2,6 The median duration of PFS in the trial was 17.2 months for the durvalumab group versus 5.6 months in the placebo group (see Stage III NSCLC Disease Overview PQI).1,2 Within ES-SCLC, the CASPIAN study reported patients receiving durvalumab with chemotherapy (etoposide and either carboplatin or cisplatin) had a median OS of 13.0 months versus 10.3 with chemotherapy alone (HR=0.73). Durvalumab belongs to the class of drugs that bind 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 a T-cell-mediated immune response. Durvalumab also has the potential to break peripheral tolerance and induce immune-mediated adverse reactions (imARs). These reactions can occur during or after treatment with durvalumab has been completed or discontinued. In the PACIFIC study, imARs of any grade irrespective of cause were reported in 24% of patients receiving durvalumab vs 8 % of placebo. Similarly, in the CASPIAN study, 20% of patients in the durvalumab + chemotherapy arm experienced imARs versus 3% in the comparator arm. It is important to recognize key and potential imARs early when managing patients.2,3

PQI Process: Upon order of durvalumab:

  • Verify dosing of durvalumab as an intravenous infusion over 60 minutes
    • Stage III NSCLC
      • Weight 30 kg and more: 10 mg/kg every 2 weeks or 1500mg every 4 weeks
      • Weight less than 30 kg: 10 mg/kg every 2 weeks
    • Extensive-Stage small cell lung cancer (ES-SCLC)1
      • Weight >30 kg: With etoposide and either carboplatin or cisplatin, administer durvalumab 1500mg every 3 weeks in combination with chemotherapy, and then 1500 mg every 4 weeks as a single agent
      • Weight <30kg: With etoposide and either carboplatin or cisplatin, administer durvalumab 20 mg/kg every 3 weeks in combination with chemotherapy and then 10 mg/kg every 2 weeks as a single agent
  • Durvalumab comes in both 500 mg/10mL and 120 mg/2.4mL (both 50 mg/mL) single-dose vials
  • Withdraw durvalumab the required volume from the vial(s) and transfer into intravenous bag containing 0.9% Sodium Chloride or 5% Dextrose, mixing diluted solution by gentile inversion (do NOT shake). Final concentration should be between 1 mg/mL-15 mg/mL
  • Administer intravenously over 60 minutes through line containing a sterile, low-protein binding 0.2 or 0.22 micron in-line filter
  • Follow the table below for guidelines regarding immune mediated adverse reaction/events, dosage reduction is not recommended1
  • For more management details, consider utilizing the NCODA imAE Web Tool at NCODA.org
Immune Mediated Adverse ReactionWithhold DurvalumabPermanently Discontinue DurvalumabSteroids
PneumonitisGrade 2*

 

Grade 3 or 4Grade 2: Initial dose of 1–2 mg/kg/day prednisone or equivalent followed by a taper

Grade 3,4: Initial dose of 1–4 mg/kg/day prednisone or equivalent followed by a taper

ColitisGrade 2 or 3*

 

Grade 4Grade 2, 3, 4: Initial dose of 1-2mg/kg/day prednisone or equivalent followed by a taper
Hepatitis with no tumor involvement of the liverALT or AST > 3 and up to 8x ULN* Or

Total bilirubin 1.5 and up to 3x ULN*

ALT or AST >8x ULN

Or

Total Bilirubin >3x ULN

Grade 2, 3, 4: Initial dose of 1-2mg/kg/day prednisone or equivalent followed by a taper

 

 

Hepatitis with tumor involvement of the liverALT or AST at baseline>1 and up to 3x ULN and increase to >5 and up to 10x ULN* Or

ALT or AST at baseline>3 and up to 5x ULN and increase to >8 and up to 10x ULN*

ALT or AST >10x ULN

Or

Total Bilirubin >3x ULN

General GuidanceGrade 3 imARsGrade 4 imARs

Recurrent Grade 3 imARs

When withholding durvalumab, discontinue if no complete/partial resolution occurs or unable to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks of corticosteroid initiation

For other imARs:

Grade 4:

Initial dose of 1–4 mg/kg/day prednisone or

equivalent followed by a taper

 

Immune Mediated Adverse ReactionWithhold DurvalumabPermanently Discontinue DurvalumabSteroids
EndocrinopathiesGrade 3 or 4 withhold until stableGrade 3 or 4: permanently discontinue depending on severityFor Adrenal insufficiency

hypophysitis, and hypopituitarism Grades 2,3,4: Initiate 1–2 mg/kg/day prednisone or equivalent

followed by a taper and hormone replacement as clinically indicated

Nephritis with renal dysfunctionGrade 2 or 3 increased blood creatinine*Grade 4 increased blood creatinineGrade 2,3,4: Initial dose of 1–2 mg/kg/day prednisone or equivalent followed by a taper
SJS, TEN, or DRESSSuspectedConfirmedGrade 2,3,4: Initial dose of 1-2 mg/kg/day prednisone or equivalent followed by a taper
MyocarditisN/AGrade 2, 3, or 4
Neurological ToxicitiesGrade 2*Grade 3 or 4
Infusion Related

Reaction Management

Grade 1 or 2: Interrupt or slow the rate of infusion

Consider using pre-medications with subsequent doses

Grade 3 or 4

* Resume in patients with complete or partial resolution (Grade 0 or 1) after corticosteroid taper4,5

* For more information on additional imARs please refer to Prescribing Information

  • Additional Adverse Event Management
    • Reactions occurring for All Grades include cough (40%), pneumonitis (34%), dyspnea (25%), fatigue (34%), upper respiratory infections (26%), and rash (23%) with 15% discontinuation rate due to adverse reactions

 Patient Centered Activities:

  • Counsel patient on imAR symptoms and when to report symptoms to oncologist
  • Schedule regular visits for blood tests (CBC, renal, hepatic, pancreatic, thyroid) and monitoring
  • Consider early initiation of steroids as necessary

Supplemental Information:

  • Imfinzi Nurse Center available at https://www.imfinzihcp.com/nurse-center.html
  • Downloadable resources available
    • Nurse Symptom Tracker, imAR Handbook, Wallet Card, Patient Brochures, Dosing Guide, App

References:

  1. Imfinzi (durvalumab) [prescribing information]. Wilmington, DE. AstraZeneca Pharmaceuticals LP.; 2021.
  2. Antonia SJ, Villegas A, Daniel D, et al; for the PACIFIC Investigators. Overall Survival with Durvalumab after Chemoradiotherapy in Stage III NSCLC. N Engl J Med. 2018;379:2342-2350.
  3. Davies, M., Duffield E., Durvalumab Immunotherapy: Nursing Management of Immune-Related Adverse Events During the Journey of Patients With Stage III Non-Small Cell Lung Cancer. Clin J Oncol Nurs. 2020 Jun 1;24(3):277-283.
  4. Santini FC, Rizvi H, Plodkowski AJ, et al. Safety and efficacy of re-treating with immunotherapy after immune-related adverse events in patients with NSCLC.
  5. Sheth S, Gao C, Mueller N, et al. Durvalumab activity in previously treated patients who stopped durvalumab without disease progression. Journal for ImmunoTherapy of Cancer 2020;8:
  6. Faivre-Finn C, Vicente D, Kurata T, et al. Durvalumab after chemoradiotherapy in stage III NSCLC: 4-year survival update from the phase 3 PACIFIC trial. Presented at: 2020 ESMO Virtual Congress; September 19-21, 2020.
Important notice: National Community Oncology Dispensing Association, Inc. (NCODA), has developed this Positive Quality Intervention platform. This platform represents a brief summary of medication uses and therapy options derived from information provided by the drug manufacturer and other resources. This platform is intended as an educational aid and does not provide individual medical advice and does not substitute for the advice of a qualified healthcare professional. This platform does not cover all existing information related to the possible uses, directions, doses, precautions, warning, interactions, adverse effects, or risks associated with the medication discussed in the platform and is not intended as a substitute for the advice of a qualified healthcare professional. The materials contained in this platform are for informational purposes only and do not constitute or imply endorsement, recommendation, or favoring of this medication by NCODA, which assumes no liability for and does not ensure the accuracy of the information presented. NCODA does not make any representations with respect to the medications whatsoever, and any and all decisions, with respect to such medications, are at the sole risk of the individual consuming the medication. All decisions related to taking this medication should be made with the guidance and under the direction of a qualified healthcare professional.
Victoria

Victoria has blogged 1500 posts

View all PQI