FDA approves tremelimumab in combination with durvalumab for unresectable hepatocellular carcinoma
What is the potential role for tremelimumab in the treatment of unresectable hepatocellular carcinoma (uHCC)?
HIMALAYA is a phase III study that included 1,171 patients randomized 1:1:1 to treatment with tremelimumab in combination with durvalumab (STRIDE regimen or Single Tremelimumab Regular Interval Durvalumab), durvalumab alone, or sorafenib in treatment naive uHCC.1
- STRIDE showed a median overall survival (OS) of 16.43 months (95% confidence interval [CI], 14.16 to 19.58) compared to 16.56 months (95% CI, 14.06 to 19.12) with durvalumab monotherapy and 13.77 months (95% CI, 12.25 to 16.13) with sorafenib.1 OS at 36 months was 30.7%, 24.7%, and 20.2%.1
- Improved OS for STRIDE compared to sorafenib was statistically significant (HR 0.78, 96.02% CI, 0.65 to 0.93;P=0.0035).1 OS for durvalumab monotherapy was noninferior to sorafenib (hazard ratio, 0.86; 95.67% CI, 0.73 to 1.03; non-inferiority margin, 1.08).1
- Median progression-free survival (PFS) was not significantly different among the three groups.1
The FDA approved tremelimumab in combination with durvalumab for first-line treatment of uHCC in October 2022 based on HIMALAYA.
The regimen is a category 1 recommendation for first-line treatment of uHCC per the National Comprehensive Cancer Network (NCCN), regardless of Child-Pugh classification.2
At the start of HIMALAYA, the vascular endothelial growth factor (VEGF) inhibitor sorafenib was standard of care systemic therapy in uHCC.
In May 2020, the United States Food and Drug Administration (FDA) approved atezolizumab for use in combination with bevacizumab for first line therapy in uHCC based on the IMbrave150 trial.3 The NCCN guidelines include this as a category 1 recommendation for patients with Child-Pugh Class A hepatic function only.2
- There are no head-to-head studies comparing tremelimumab to bevacizumab in combination with immune checkpoint inhibitor therapy in uHCC.
- STRIDE may be a preferred regimen for patients with bleeding risks where bevacizumab may not be appropriate due to anti-angiogenesis activity.
What is the potential role for tremelimumab in the treatment of metastatic non-small cell lung cancer (mNSCLC)?
POSEIDON is a phase III trial of 1,013 mNSCLC patients randomized 1:1:1 to tremelimumab plus durvalumab and chemotherapy (T + D + CT), durvalumab plus chemotherapy (D + CT) or chemotherapy alone (CT) in the first line treatment setting.4
- T + D + CT had improved OS compared to CT (hazard ratio [HR] of 0.77 [95% CI: 0.65, 0.92], P=0.00304); median OS was 14 months (95% CI: 11.7, 16.1) versus 11.7 months (95% CI: 10.5, 13.1) respectively.4 Median PFS was 6.2 months (95% CI: 5.0, 6.5) and 4.8 months (95% CI 4.6, 5.8) in the treatment arms, respectively (HR 0.72 [95% CI: 0.60, 0.86], P=0.00031).4
In November 2022, the FDA approved tremelimumab in combination with durvalumab and platinum-based chemotherapy for first-line treatment of mNSCLC with no EGFR or ALK mutations based on POSEIDON.
NCCN recommendations for tremelimumab with durvalumab and platinum-based chemotherapy in mNSCLC depend on mutational status.
- Category 1 for first-line treatment of adenocarcinoma, large cell, and squamous cell mNSCLC with PD-L1 >1%-49%.5
- Category 2B for first-line treatment of adenocarcinoma, large cell, and squamous cell mNSCLC with PD-L1 >50%.5
- The regimen is not a preferred option for patients with actionable driver mutations.5 The NCCN panel has stratified other regimens above tremelimumab-based therapies in all mNSCLC settings.5
What role can the pharmacist play in the management of patients on tremelimumab?
Dosing for tremelimumab differs between indications and patient body weight
Dosing for uHCC:
- For patients weighing 30 kg or more, tremelimumab is given as a single dose of 300 mg IV over 60 minutes in combination with durvalumab 1500 mg IV over 60 minutes every 4 weeks until disease progression or unacceptable toxicity.6
- For patients weighing less than 30 kg, tremelimumab should be given as a single dose of 4 mg/kg IV over 60 minutes in combination with durvalumab 20 mg/kg IV over 60 minutes every 4 weeks until disease progression or unacceptable toxicity.6
Dosing for mNSCLC:
- For patients weighing 30 kg or more, tremelimumab is given as 75 mg IV over 60 minutes every 3 weeks in combination with durvalumab 1,500 mg IV over 60 minutes and platinum-based chemotherapy for 4 cycles. After 4 cycles, durvalumab 1,500 mg every 4 weeks as a single agent with histology-based pemetrexed therapy every 4 weeks is administered, and a fifth dose of tremelimumab 75 mg in combination with durvalumab dose 6 is administered at week 16.6
- For patients weighing less than 30 kg, tremelimumab is given as 1 mg/kg IV over 60 minutes every 3 weeks in combination with durvalumab 20 mg/kg IV over 60 minutes and platinum-based chemotherapy for 4 cycles. After 4 cycles, durvalumab 20 mg/kg every 4 weeks as a single agent with histology-based pemetrexed therapy every 4 weeks is administered, and a fifth dose of tremelimumab 1 mg/kg in combination with durvalumab dose 6 is administered at week 16.6
Immune-mediated adverse events requiring high-dose steroids occurred in 78% of uHCC patients receiving STRIDE.1 A grade 3/4 immune-mediated event was experienced by 33.6% of mNSCLC patients receiving T + D + CT.4
- Most common adverse reactions (≥ 20%) in patients with uHCC were rash, diarrhea, fatigue, pruritus, musculoskeletal pain, and abdominal pain. Most common laboratory abnormalities (≥ 40%) in patients with uHCC were AST increased, ALT increased, hemoglobin decreased, sodium decreased, bilirubin increased, alkaline phosphatase increased, and lymphocytes decreased.6
- Most common adverse reactions (≥ 20%) in patients with mNSCLC were nausea, fatigue, musculoskeletal pain, decreased appetite, rash, and diarrhea.6
- Monitor for immune-mediated adverse reactions. Evaluate liver enzymes, creatinine, adrenocorticotropic hormone level, and thyroid function at baseline and before each dose.6
There are no dosing adjustments for severe hepatic or renal dysfunction; effects of pharmacokinetics of tremelimumab are unknown in these settings.6
Infusion-related reactions occurred in 2.6% of patients receiving STRIDE and 2.9% of patients receiving T + D + CT.7 Interrupt, slow the rate of infusion, or permanently discontinue treatment based on severity of reaction.6 For grade 1 or 2 infusion-related reactions, consider pre-medications with subsequent doses.6
Clinical Pearls
Tremelimumab is a cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) blocking monoclonal antibody that results in decreased tumor growth and increased proliferation of T-cells in tumors.7 Tremelimumab is an IgG2 monoclonal antibody and differs slightly from ipilimumab which is an IgG1 monoclonal antibody with anti-CTLA-4 activity.
Exclusion criteria for HIMALAYA included ascites requiring intervention, main portal vein thrombosis, or coinfection with hepatitis B and C viruses.1
POSEIDON excluded patients with epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) mutations.4
There is some evidence to suggest that acetaminophen, some systemic antibiotics, corticosteroids and ketoconazole, as well as proton pump inhibitors may diminish therapeutic effects of immune checkpoint inhibitors.7
Tremelimumab is available in 25 mg/1.25 mL and 300 mg/15 mL single dose vials.
To prepare tremelimumab, dilute the required volume in NS or D5W to a final concentration not to exceed 10 mg/mL.6 Total time from preparation to the start of administration should not exceed 24 hours. Store at room temperature up to 30oC or refrigerated at 2oC to 8oC.6 Infuse over 60 minutes through an IV line containing a sterile, low-protein binding 0.2- or 0.22-micron filter.6
Administer tremelimumab prior to durvalumab. Observe patient for 60 minutes following completion of tremelimumab infusion prior to administering durvalumab.6
Patient assistance programs are offered through AztraZeneca Access 360 (1-844-ASK-A360) and AZ&Me Prescription Savings Program (1-800-AZandMe).
References
1.Abou-Alfa GK, Lau G, Kudo M, et al. Tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. NEJM Evid. 2022;1(8):8.
2.National Comprehensive Cancer Network. Hepatocellular Carcinoma (Version 1.2023). https://www.nccn.org/professionals/physician_gls/pdf/hcc.pdf. Accessed June 20, 2023.
3.Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020;382:1894-1905.
4.Johnson ML, et al. Durvalumab with or without tremelimumab in combination with chemotherapy as first-line therapy for metastatic non-small-cell lung cancer: the Phase III POSEIDON study. J Clin Oncol 2023;41:1213-1227.
5.National Comprehensive Cancer Network. Non-Small Cell Lung Cancer (Version 3.2023). https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Accessed June 20, 2023.
6.Imjudo (tremelimumab-actl) [package insert]. Wilmington, DE: AstraZeneca; 2022.
7.Lexicomp Online, Waltham, MA:UpToDate, Inc; May 9, 2023. https://online.lexi.com. Accessed June 20, 2023.
