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Safety, Efficacy, and Pharmacodynamics of Tremelimumab Plus Durvalumab for Patients With Unresectable Hepatocellular Carcinoma: Randomized Expansion of a Phase I/II Study
- Source :
- Journal of clinical oncology : official journal of the American Society of Clinical Oncology, vol 39, iss 27
- Publication Year :
- 2021
- Publisher :
- American Society of Clinical Oncology (ASCO), 2021.
-
Abstract
- PURPOSE This phase I/II study evaluated tremelimumab (anticytotoxic T-lymphocyte–associated antigen-4 monoclonal antibody) and durvalumab (antiprogrammed death ligand-1 monoclonal antibody) as monotherapies and in combination for patients with unresectable hepatocellular carcinoma (HCC), including a novel regimen featuring a single, priming dose of tremelimumab (ClinicalTrials.gov identifier: NCT02519348 ). PATIENTS AND METHODS Patients with HCC who had progressed on, were intolerant to, or refused sorafenib were randomly assigned to receive T300 + D (tremelimumab 300 mg plus durvalumab 1,500 mg [one dose each during the first cycle] followed by durvalumab 1,500 mg once every 4 weeks), durvalumab monotherapy (1,500 mg once every 4 weeks), tremelimumab monotherapy (750 mg once every 4 weeks [seven doses] and then once every 12 weeks), or T75 + D (tremelimumab 75 mg once every 4 weeks plus durvalumab 1,500 mg once every 4 weeks [four doses] followed by durvalumab 1,500 mg once every 4 weeks). Safety was the primary end point. Secondary end points included objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors v1.1 and overall survival; exploratory end points included circulating lymphocyte profiles. RESULTS A total of 332 patients were enrolled (T300 + D, n = 75; durvalumab, n = 104; tremelimumab, n = 69; and T75 + D, n = 84). Tolerability was acceptable across arms, with grade ≥ 3 treatment-related adverse events occurring in 37.8%, 20.8%, 43.5%, and 24.4%, respectively. Confirmed ORRs (95% CI) were 24.0% (14.9 to 35.3), 10.6% (5.4 to 18.1), 7.2% (2.4 to 16.1), and 9.5% (4.2 to 17.9), respectively. An early expansion of CD8+ lymphocytes was associated with response across arms, with highest proliferating CD8+ lymphocyte levels occurring in the T300 + D arm. The median (95% CI) overall survival was 18.7 (10.8 to 27.3), 13.6 (8.7 to 17.6), 15.1 (11.3 to 20.5), and 11.3 (8.4 to 15.0) months in the T300 + D, durvalumab, tremelimumab, and T75 + D arms, respectively. CONCLUSION All regimens were found to be tolerable and clinically active; however, the T300 + D regimen demonstrated the most encouraging benefit-risk profile. The unique pharmacodynamic activity and association with ORR of the T300 + D regimen further support its continued evaluation in HCC.
- Subjects :
- Male
0301 basic medicine
Oncology
Cancer Research
Durvalumab
0302 clinical medicine
Monoclonal
80 and over
Humanized
6.2 Cellular and gene therapies
Cancer
Aged, 80 and over
Liver Disease
Liver Neoplasms
Middle Aged
6.1 Pharmaceuticals
030220 oncology & carcinogenesis
Hepatocellular carcinoma
HIV/AIDS
Female
Patient Safety
Biotechnology
medicine.drug
Liver Cancer
Adult
medicine.medical_specialty
Carcinoma, Hepatocellular
medicine.drug_class
Clinical Trials and Supportive Activities
Clinical Sciences
Oncology and Carcinogenesis
Antibodies, Monoclonal, Humanized
Monoclonal antibody
Antibodies
03 medical and health sciences
Rare Diseases
Clinical Research
Internal medicine
medicine
Humans
Oncology & Carcinogenesis
Aged
business.industry
Carcinoma
Evaluation of treatments and therapeutic interventions
Hepatocellular
medicine.disease
Orphan Drug
030104 developmental biology
Phase i ii
Pharmacodynamics
Digestive Diseases
business
Tremelimumab
Subjects
Details
- ISSN :
- 15277755, 0732183X, and 02519348
- Volume :
- 39
- Database :
- OpenAIRE
- Journal :
- Journal of Clinical Oncology
- Accession number :
- edsair.doi.dedup.....140a2fcc92ec29522c1c3fd8efbcf87a