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Durvalumab

Durvalumab,[8] sold under the brand name Imfinzi, is an anti-cancer medication used for treatment of various types of cancer.[6] It was developed by Medimmune/AstraZeneca.[9] It is a human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody that blocks the interaction of programmed cell death ligand 1 (PD-L1).[6]

Durvalumab
Antigen-binding fragment of durvalumab (pale green) in complex with PD-L1 (pink). PDB: 5X8M​.
Monoclonal antibody
TypeWhole antibody
SourceHuman
TargetCD274
Clinical data
Trade namesImfinzi
Other namesMEDI4736, MEDI-4736
AHFS/Drugs.comMonograph
MedlinePlusa617030
License data
Pregnancy
category
Routes of
administration		Intravenous
ATC code
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
  • none
UNII
KEGG
Chemical and physical data
FormulaC6502H10018N1742O2024S42
Molar mass146322.36 g·mol−1

Durvalumab is an immune checkpoint inhibitor drug.[10] It was approved in for medical use in the United States in May 2017,[6][9][11][12] and in the European Union in September 2018.[7]

Medical uses

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The US Food and Drug Administration (FDA) approved durvalumab for certain types of bladder, lung, and biliary tract cancer:[6][13][14]

  • Adults with locally advanced or metastatic urothelial carcinoma who either have disease progression during or following platinum-containing chemotherapy or have disease progression within twelve months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
  • Adults with unresectable, Stage III non-small cell lung cancer whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy.
  • In combination with etoposide and either carboplatin or cisplatin, as first-line treatment for adults with extensive-stage small cell lung cancer.
  • In combination with gemcitabine and cisplatin for adults with locally advanced or metastatic biliary tract cancer (BTC).[13]

In June 2024, the US FDA approved durvalumab with carboplatin plus paclitaxel, followed by single-agent durvalumab, for adults with primary advanced or recurrent endometrial cancer that is mismatch repair deficient.[15][16]

In August 2024, the FDA approved durvalumab with platinum-containing chemotherapy as neoadjuvant treatment, followed by single-agent durvalumab as adjuvant treatment after surgery for adults with resectable (tumors ≥ 4 cm and/or node positive) non-small cell lung cancer (NSCLC) and no known epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) rearrangements.[17] Efficacy was evaluated in AEGEAN (NCT03800134), a randomized, double-blind, placebo-controlled multicenter trial in 802 participants with previously untreated and resectable squamous or non-squamous NSCLC (stage IIA to select stage IIIB [AJCC, 8th edition]).[17][18] Participants were randomized (1:1) to either durvalumab or placebo, with platinum-based chemotherapy, every 3 weeks for up to 4 cycles (neoadjuvant treatment) followed by either continued single-agent durvalumab or placebo, every 4 weeks for up to 12 cycles (adjuvant treatment).[17]

In December 2024, the FDA expanded the indication of durvalumab to include adults with limited-stage small cell lung cancer whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy.[19]

History

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Clinical trials

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Immunotherapy: mechanism of action for Durvalumab, Pembrolizumab, Ipilimumab, Atezolizumab.[20]

A phase Ib clinical trial of durvalumab and tremelimumab showed some activity in non-small cell lung cancer (NSCLC)[21] Phase I data in advanced metastatic urothelial bladder (Study 1108) has led to FDA breakthrough therapy designation.[10][22] Early results of a phase I trial combining durvalumab and gefitinib in participants with lung cancer "showed promise".[23] A phase I clinical trial is currently underway using durvalumab with a TLR 7/8 agonist (MEDI 9197) for solid tumors.[24] A phase 1b/2a trial is underway combining durvalumab with an HPV DNA vaccine (MEDI 0457) in participants with HPV-associated recurrent/metastatic head and neck cancer.[25]

MYSTIC

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In July 2017, AstraZeneca announced that a phase III trial of durvalumab with tremelimumab as a first-line treatment of non-small cell lung cancer failed to meet its primary endpoint of progression-free survival.[26]

PACIFIC

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In November 2017, the double-blinded phase III AstraZeneca PACIFIC clinical trial demonstrated the efficacy of durvalumab in the treatment of stage III non-small cell lung cancer.[27] 709 participants with stage III NSCLC who did not have disease progression after two or more cycles of a platinum-based chemotherapy were randomly assigned to receive durvalumab or a placebo as consolidation therapy for their lung cancer. Durvalumab increased the median progression-free survival from 5.6 months (placebo) to 16.8 months (durvalumab); the 12 month progression-free survival rate was increased from 35.3% (placebo) to 55.9% (durvalumab), and the 18 month progression-free survival rate was increased from 27.0% (placebo) to 44.2% (durvalumab).[10] The median time to death or distant metastases was also increased from 14.6 months (placebo) to 23.2 months (durvalumab). Extreme side effects were also increased from 26.1% of participants (placebo) to 29.9% of participants (durvalumab).[28]

CASPIAN

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In March 2021, the open-label, sponsor-blind (AstraZeneca), randomised, controlled phase III trial at 209 cancer treatment centres in 23 countries worldwide (CASPIAN) demonstrated the efficacy of durvalumab in combination with platinum-based chemotherapy in the treatment of small cell lung cancer.[29]

Between March 2017, and May 2018, 972 participants were screened and 805 were randomly assigned (268 to durvalumab plus tremelimumab plus platinum–etoposide, 268 to durvalumab plus platinum–etoposide, and 269 to platinum–etoposide). As of 27 January 2020, the median follow-up was 25·1 months (IQR 22·3–27·9). Durvalumab plus tremelimumab plus platinum–etoposide was not associated with a significant improvement in overall survival versus platinum–etoposide (hazard ratio [HR] 0·82 [95% CI 0·68–1·00]; p=0·045); median overall survival was 10·4 months (95% CI 9·6–12·0) versus 10·5 months (9·3–11·2). Durvalumab plus platinum–etoposide showed sustained improvement in overall survival versus platinum–etoposide (HR 0·75 [95% CI 0·62–0·91]; nominal p=0·0032); median overall survival was 12·9 months (95% CI 11·3–14·7) versus 10·5 months (9·3–11·2). The most common any-cause grade 3 or worse adverse events were neutropenia (85 [32%] of 266 participants in the durvalumab plus tremelimumab plus platinum–etoposide group, 64 [24%] of 265 participants in the durvalumab plus platinum–etoposide group, and 88 [33%] of 266 participants in the platinum–etoposide group) and anaemia (34 [13%], 24 [9%], and 48 [18%]). Any-cause serious adverse events were reported in 121 (45%) participants in the durvalumab plus tremelimumab plus platinum–etoposide group, 85 (32%) in the durvalumab plus platinum–etoposide group, and 97 (36%) in the platinum–etoposide group. Treatment-related deaths occurred in 12 (5%) participants in the durvalumab plus tremelimumab plus platinum–etoposide group (death, febrile neutropenia, and pulmonary embolism [n=2 each]; enterocolitis, general physical health deterioration and multiple organ dysfunction syndrome, pneumonia, pneumonitis and hepatitis, respiratory failure, and sudden death [n=1 each]), six (2%) participants in the durvalumab plus platinum–etoposide group (cardiac arrest, dehydration, hepatotoxicity, interstitial lung disease, pancytopenia, and sepsis [n=1 each]), and two (1%) in the platinum–etoposide group (pancytopenia and thrombocytopenia [n=1 each]).[30]

TOPAZ-1

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Efficacy was evaluated in TOPAZ-1 (NCT03875235), a randomized, double-blind, placebo-controlled, multiregional trial that enrolled 685 participants with histologically confirmed locally advanced unresectable or metastatic BTC who had not previously received systemic therapy for advanced disease.[13]

Trial demographics were as follows: 56% Asian, 37% White, 2% Black, and 4% other race; 7% Hispanic or Latino; 50% male and 50% female; median age was 64 years (range 20-85) and 47% were 65 years or older.[13] Fifty-six percent had intrahepatic cholangiocarcinoma, 25% had gallbladder cancer, and 19% had extrahepatic cholangiocarcinoma.[13]

The major efficacy outcome measure was overall survival (OS).[13] Tumor assessments were conducted every 6 weeks for the first 24 weeks, then every 8 weeks until confirmed objective disease progression.[13] A statistically significant improvement in OS was demonstrated in participants randomized to receive durvalumab with gemcitabine and cisplatin compared to those randomized to receive placebo with gemcitabine and cisplatin.[13] Median OS was 12.8 months (95% CI: 11.1, 14) and 11.5 months (95% CI: 10.1, 12.5) in the durvalumab and placebo arms, respectively (hazard ratio 0.80; 95% CI: 0.66, 0.97, p=0.021).[13] The median progression-free survival was 7.2 months (95% CI: 6.7, 7.4) and 5.7 months (95% CI: 5.6, 6.7) in the durvalumab and placebo arms, respectively. Investigator-assessed overall response rate was 27% (95% CI: 22% - 32%) and 19% (95% CI: 15%-23%) in the durvalumab and placebo arms, respectively.[13]

DUO-E

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Efficacy was evaluated in DUO-E (NCT04269200), a randomized, multicenter, double-blind, placebo-controlled trial in participants with primary advanced or recurrent endometrial cancer.[15] Participants were randomized (1:1:1) to one of the following treatment arms: durvalumab 1,120 mg with carboplatin plus paclitaxel every three weeks for a maximum of six cycles.[15] Following completion of chemotherapy, participants received durvalumab 1,500 mg every four weeks as maintenance until disease progression;[15] placebo with carboplatin and paclitaxel every three weeks for a maximum of six cycles[15] Following completion of chemotherapy, participants received placebo every four weeks until disease progression;[15] an additional investigational combination regimen.[15][31][32]

The most common adverse reactions (>25%) with durvalumab, in combination with carboplatin and paclitaxel, were peripheral neuropathy, musculoskeletal pain, nausea, alopecia, fatigue, abdominal pain, constipation, rash, diarrhea, vomiting, and cough.[15]

AEGEAN

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Efficacy was evaluated in AEGEAN (NCT03800134), a randomized, double-blind, placebo-controlled multicenter trial in 802 patients with previously untreated and resectable squamous or non-squamous NSCLC (Stage IIA to select Stage IIIB [AJCC, 8th edition]). Patients were randomized (1:1) to either durvalumab or placebo, with platinum-based chemotherapy, every 3 weeks for up to 4 cycles (neoadjuvant treatment) followed by either continued single-agent durvalumab or placebo, every 4 weeks for up to 12 cycles (adjuvant treatment).[17][18]

The major efficacy outcome measures were event-free survival (EFS) by blinded independent central review assessment and pathological complete response (pCR) by blinded central pathology review. Median EFS was not reached (95% CI: 31.9, not estimable [NE]) in the durvalumab arm and 25.9 months (95% CI: 18.9, NE) in the placebo arm (hazard ratio 0.68 [95% CI: 0.53, 0.88]; p-value=0.0039). The pCR rate was 17% (95% CI: 13, 21) and 4.3% (95% CI: 2.5, 7) in the durvalumab and placebo arms, respectively. At the time of the prespecified interim analyses, overall survival (OS) was not formally tested for statistical significance; however, a descriptive analysis revealed no clear detriment.[17]

The most common adverse reactions (≥20%) were anemia, nausea, constipation, fatigue, musculoskeletal pain, and rash. Of the patients who received neoadjuvant durvalumab, 1.7% were unable to receive surgery due to adverse reactions compared with 1% in the placebo arm. [17]

References

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  1. ^ "Durvalumab (Imfinzi) Use During Pregnancy". Drugs.com. 30 August 2019. Archived from the original on 29 August 2021. Retrieved 7 February 2020.
  2. ^ "Imfinzi (AstraZeneca Pty Ltd)". Therapeutic Goods Administration (TGA). 5 December 2022. Archived from the original on 18 March 2023. Retrieved 9 April 2023.
  3. ^ "Auspar: Imfinzi". 8 December 2023. Retrieved 18 June 2024.
  4. ^ "Regulatory Decision Summary - Imfinzi". Health Canada. 23 October 2014. Archived from the original on 7 June 2022. Retrieved 6 September 2022.
  5. ^ "Cancer therapies". Health Canada. 8 May 2018. Retrieved 13 April 2024.
  6. ^ a b c d e "Imfinzi- durvalumab injection, solution". DailyMed. 5 June 2020. Archived from the original on 28 August 2021. Retrieved 30 September 2020.
  7. ^ a b "Imfinzi EPAR". European Medicines Agency (EMA). 30 October 2018. Archived from the original on 28 August 2021. Retrieved 30 September 2020.
  8. ^ World Health Organization (2015). "International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 74". WHO Drug Information. 29 (3). hdl:10665/331070.
  9. ^ a b "Durvalumab (Imfinzi)". U.S. Food and Drug Administration (FDA). Archived from the original on 8 May 2017. Retrieved 6 May 2017.
  10. ^ a b c Syn NL, Teng MW, Mok TS, Soo RA (December 2017). "De-novo and acquired resistance to immune checkpoint targeting". The Lancet. Oncology. 18 (12): e731–e741. doi:10.1016/s1470-2045(17)30607-1. PMID 29208439.
  11. ^ "FDA approves durvalumab for extensive-stage small cell lung cancer". U.S. Food and Drug Administration (FDA). 27 March 2020. Retrieved 19 July 2024.
  12. ^ Mathieu L, Shah S, Pai-Scherf L, Larkins E, Vallejo J, Li X, et al. (May 2021). "FDA Approval Summary: Atezolizumab and Durvalumab in Combination with Platinum-Based Chemotherapy in Extensive Stage Small Cell Lung Cancer". The Oncologist. 26 (5): 433–438. doi:10.1002/onco.13752. PMC 8100557. PMID 33687763.
  13. ^ a b c d e f g h i j "FDA approves durvalumab". U.S. Food and Drug Administration. 2 September 2022. Archived from the original on 6 September 2022. Retrieved 5 September 2022. Public Domain  This article incorporates text from this source, which is in the public domain.
  14. ^ "Imfinzi (durvalumab) plus chemotherapy approved in the US as the first immunotherapy regimen for patients with advanced biliary tract cancer". AstraZeneca (Press release). 5 September 2022. Retrieved 19 July 2024.
  15. ^ a b c d e f g h "FDA approves durvalumab with chemotherapy for mismatch repair deficient primary advanced or recurrent endometrial cancer". U.S. Food and Drug Administration (FDA). 14 June 2024. Retrieved 18 June 2024. Public Domain  This article incorporates text from this source, which is in the public domain.
  16. ^ "Imfinzi (durvalumab) plus chemotherapy approved in the US for mismatch repair deficient advanced or recurrent endometrial cancer". AstraZeneca (Press release). 17 June 2024.
  17. ^ a b c d e f "FDA approves neoadjuvant/adjuvant durvalumab for resectable non-small cell lung cancer". U.S. Food and Drug Administration. 15 August 2024. Retrieved 16 August 2024. Public Domain  This article incorporates text from this source, which is in the public domain.
  18. ^ a b "A Study of Neoadjuvant/adjuvant Durvalumab for the Treatment of Patients with Resectable Non-small Cell Lung Cancer - AEGEAN". clinicaltrials.gov. Retrieved 20 August 2024.
  19. ^ "FDA approves durvalumab for limited-stage small cell lung cancer". U.S. Food and Drug Administration (FDA). 4 December 2024. Retrieved 5 December 2024. Public Domain  This article incorporates text from this source, which is in the public domain.
  20. ^ Nasser NJ, Gorenberg M, Agbarya A (November 2020). "First line Immunotherapy for Non-Small Cell Lung Cancer". Pharmaceuticals. 13 (11). Basel, Switzerland: 373. doi:10.3390/ph13110373. PMC 7695295. PMID 33171686.
  21. ^ Ribrag V, Lee ST, Rizzieri D, Dyer MJ, Fayad L, Kurzrock R, et al. (May 2021). "A Phase 1b Study to Evaluate the Safety and Efficacy of Durvalumab in Combination With Tremelimumab or Danvatirsen in Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma". Clinical Lymphoma, Myeloma & Leukemia. 21 (5): 309–317.e3. doi:10.1016/j.clml.2020.12.012. PMID 33632668.
  22. ^ "AstraZeneca's (AZN) Durvalumab Granted FDA Breakthrough Therapy Designation". StreeInsider.com. 17 February 2016. Archived from the original on 28 August 2021.
  23. ^ "Promising Drug for Lung Cancer and Mesothelioma Patients". 19 May 2016. Archived from the original on 28 August 2021. Retrieved 27 May 2016.
  24. ^ Clinical trial number NCT02556463 for "A Study of MEDI9197 in Subjects With Solid Tumors or CTCL and in Combination With Durvalumab and/or Palliative Radiation in Subjects With Solid Tumors" at ClinicalTrials.gov
  25. ^ Clinical trial number NCT03162224? for "Safety and Efficacy of MEDI0457 and Durvalumab in Patients With HPV Associated Recurrent/Metastatic Head and Neck Cancer" at ClinicalTrials.gov
  26. ^ "AstraZeneca reports initial results from the ongoing MYSTIC trial in Stage IV lung cancer". www.astrazeneca.com. 27 July 2017. Archived from the original on 28 August 2021. Retrieved 23 August 2017.
  27. ^ "AstraZeneca presents superior progression-free survival for Imfinzi in the PACIFIC trial of patients with locally-advanced unresectable lung cancer at ESMO 2017 Congress". www.astrazeneca.com. September 2017. Archived from the original on 28 August 2021. Retrieved 9 December 2017.
  28. ^ Fitzpatrick O, Naidoo J (2 November 2021). "Immunotherapy for Stage III NSCLC: Durvalumab and Beyond". Lung Cancer: Targets and Therapy. 12: 123–131. doi:10.2147/LCTT.S305466. PMC 8572112. PMID 34754256.
  29. ^ "A Phase III, Randomized, Multicenter, Open-Label, Comparative Study to Determine the Efficacy of Durvalumab or Durvalumab and Tremelimumab in Combination with Platinum-Based Chemotherapy for the First-Line Treatment in Patients with Extensive Disease Small-Cell Lung Cancer (SCLC) (CASPIAN)". 30 September 2021. Archived from the original on 3 June 2021. Retrieved 6 September 2022.
  30. ^ Goldman JW, Dvorkin M, Chen Y, Reinmuth N, Hotta K, Trukhin D, et al. (January 2021). "Durvalumab, with or without tremelimumab, plus platinum-etoposide versus platinum-etoposide alone in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): updated results from a randomised, controlled, open-label, phase 3 trial". The Lancet. Oncology. 22 (1): 51–65. doi:10.1016/S1470-2045(20)30539-8. PMID 33285097. S2CID 227948919.
  31. ^ Westin SN, Moore K, Chon HS, Lee JY, Thomes Pepin J, Sundborg M, et al. (January 2024). "Durvalumab Plus Carboplatin/Paclitaxel Followed by Maintenance Durvalumab With or Without Olaparib as First-Line Treatment for Advanced Endometrial Cancer: The Phase III DUO-E Trial". Journal of Clinical Oncology. 42 (3): 283–299. doi:10.1200/JCO.23.02132. PMC 10824389. PMID 37864337.
  32. ^ AstraZeneca (4 March 2024). A Randomised, Multicentre, Double-blind, Placebo-controlled, Phase III Study of First-line Carboplatin and Paclitaxel in Combination With Durvalumab, Followed by Maintenance Durvalumab With or Without Olaparib in Patients With Newly Diagnosed Advanced or Recurrent Endometrial Cancer (DUO-E) (Report). clinicaltrials.gov.
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