Both indications for the CTLA-4 inhibitor were approved by the FDA in 2022.
Approved by the FDA for 2 indications in 2022, tremelimumabactl (Imjudo; AstraZeneca) is a CTLA-4 inhibitor and the second agent in its class. The first approval was granted on October 21, 2022, for unresectable hepatocellular carcinoma (uHCC), followed by the approval on November 10, 2022, for metastatic non–small cell lung cancer (mNSCLC) with no sensitizing EGFR mutation or ALK genomic tumor aberrations.
Mechanism of Action
Tremelimumab-actl is a human IgG2 monoclonal antibody that targets CTLA-4, a negative regulator of T-cell activity. Thevdrug works by binding to CTLA-4 and blocking the interaction with its ligands CD80 and CD86, releasing CTLA-4–mediated inhibition of T-cell activation.1
Dosage and Administration
Tremelimumab-actl should be administered prior to durvalumab (Imfinzi; AstraZeneca) on the same day. It is infused over a period of 1 hour, and patients should be observed for an additional hour following completion of tremelimumab-actl infusion before durvalumab is administered (TABLE 1 and TABLE 2).1
On October 21, 2022, the FDA approved tremelimumab-actl in combination with durvalumab for adult patients with uHCC. The FDA approval was based on results from the HIMALAYA trial (NCT03298451), a phase 3, open-label, randomized, and multicenter trial that included 1171 patients with uHCC.2
HCC is the most common type of liver cancer, accounting for approximately 90% of cases. Infections by hepatitis B virus (HBV) and hepatitis C virus (HCV) are the main risk factors for HCC development, although nonalcoholic steatohepatitis associated with metabolic syndrome or diabetes is becoming a more frequent risk factor in the Western World.3
The current National Comprehensive Cancer Network–preferred category 1 first-line therapy for uHCC consists of atezolizumab (Tecentriq; Genentech) plus bevacizumab (Avastin; Genentech) and the recently approved tremelimumab-actl plus durvalumab combination. Other recommended first-line agents include sorafenib (Nexavar; Bayer) (category 1), lenvatinib (Lenvima; Eisai) (category 1), durvalumab (category 2A, monotherapy not FDA approved), pembrolizumab (Keytruda; Merck) (category 2B), and nivolumab (Opdivo; Bristol Myers Squibb) (category 2B).
In the HIMALAYA trial, patients were randomly assigned 1:1:1 to the combination arm of tremelimumabactl and durvalumab, the single-agent durvalumab arm, or the sorafenib arm. Adult patients with previously unmanaged uHCC, an ECOG performance status score of 0 or 1, Child-Pugh score in class A, and Barcelona Clinic Liver Cancer stage B or C were included. Exclusion criteria included HBV and HCV coinfection, active or prior documented gastrointestinal bleeding within 12 months, clinically meaningful ascites, hepatic encephalopathy, and active or prior documented autoimmune or inflammatory disorders.4
The primary end point was overall survival (OS) in the tremelimumab-actl and durvalumab arm vs the sorafenib arm, whereas noninferiority for OS for durvalumab vs sorafenib was a secondary objective. The results of the trial showed that the tremelimumabactl and durvalumab arm had a statistically significant OS benefit compared with the sorafenib arm (16.4 months vs 13.8 months; HR, 0.78; P = .0035). Median progression-free survival (PFS) was 3.8 months vs 4.1 months (HR, 0.9; 95% CI, 0.77-1.05) and overall response rate was 20.1% vs 5.1% for the tremelimumab and durvalumab arm vs sorafenib arm, respectively.4 OS with durvalumab monotherapy was noninferior to sorafenib (HR, 0.86; 95.67% CI, 0.73-1.03; noninferiority margin, 1.08).
On November 10, 2022, the FDA approved tremelimumab-actl in combination with durvalumab and platinum-based chemotherapy for adult patients with mNSCLC with no sensitizing EGFR mutation or ALK genomic tumor aberrations. The FDA approval was based on results from the POSEIDON trial (NCT03164616), an open-label, phase 3 study that evaluated 1014 patients with mNSCLC in the first-line setting.5
Lung cancer is the leading cause of cancer death in the United States. Much progress has been made recently for lung cancer, including new targeted therapies and immunotherapies associated with improved survival rates for patients with NSCLC. Furthermore, the addition of tremelimumab-actl to a durvalumabbased regimen is expected to broaden clinical activity, potentially overcoming primary resistance to PD-L1 blockade by enabling novel T-cell responses.6,7
In the POSEIDON trial, patients were randomly assigned 1:1:1 to durvalumab 1500 mg plus chemotherapy (D + CT) for up to 4 cycles of 21 days each followed by durvalumab 1500 mg once every 4 weeks until disease progression vs tremelimumab-actl 75 mg plus durvalumab 1500 mg and chemotherapy (T + D + CT) for up to 4 cycles of 21 days each followed by durvalumab 1500 mg once every 4 weeks until disease progression, with 1 additional tremelimumab-actl dose after chemotherapy at week 16 vs chemotherapy alone (CT) for up to 6 cycles of 21 days each. Chemotherapy options comprised carboplatin (Paraplatin; Bristol Myers Squibb) plus nab-paclitaxel for patients with either squamous or nonsquamous histology, cisplatin or carboplatin plus gemcitabine for patients with squamous histology, and cisplatin or carboplatin plus pemetrexed (Alimta; Eli Lilly) for patients with nonsquamous histology.7
Patients in the study included those who had no previous systemic therapy for mNSCLC, an ECOG performance status 0 or 1, measurable disease according to RECIST v1.1.22 criteria, and tumors that had no sensitizing EGFR mutations or ALK rearrangements (by local assessment).8 The primary end point was PFS and OS in D + CT vs CT, and the secondary end points were PFS and OS in T + D + CT vs CT. PFS was significantly improved with D + CT vs CT, with a median PFS of 5.5 months vs 4.8 months (HR, 0.74; 95% CI, 0.62-0.89; P = .0009). Median OS was 13.3 vs 11.7 months, and 24-month OS was 29.6% vs 22.1%, trending in favor of D + CT vs CT, but did not reach statistical significance (HR, 0.86; 95% CI, 0.72-1.02; P = .0758).7
For the secondary end points, median PFS was 6.2 months vs 4.8 months with T + D + CT vs CT (HR, 0.72; 95% CI, 0.60-0.86; P = .0003). Median OS was 14 months vs 11.7 months (HR, 0.77; 95% CI, 0.65-0.92; P = .0030), and 24-month OS was 32.9% vs 22.1% for T + D + CT vs CT, respectively.7
For patients with uHCC, the most common adverse events (AEs) in the HIMALAYA trial were rash, diarrhea, fatigue, pruritus, musculoskeletal pain, and abdominal pain. During the trial, the rate of AEs leading to discontinuation was 8.2% in the combination arm.4,6
For patients with mNSCLC, the most common AEs seen in the POSEIDON trial (occurring in ≥ 20% of patients receiving T + D + CT) were nausea, fatigue, musculoskeletal pain, decreased appetite, rash, and diarrhea.7 These AEs, even with the addition of cytotoxic chemotherapy, are similar to the adverse reaction profile seen in patients who received tremelimumabactl with durvalumab in the HIMALAYA trial.
Warnings and Precautions
Tremelimumab-actl has labeled warnings and precautions for immune-mediated adverse reactions, infusion-related reactions, and embryo-fetal toxicity. Immune-mediated adverse reactions, which may be severe or fatal and can occur in any organ system or tissue, include: immunemediated pneumonitis, colitis, hepatitis, endocrinopathies, dermatologic AEs, nephritis with renal dysfunction, and pancreatitis. Infusion-related reactions occurred in 2.6% of patients treated with tremelimumab and durvalumab.5
Pregnancy and Lactation
There are no available data on the use of tremelimumabactl in women who are pregnant. CTLA-4 plays a role in maintaining maternal immune tolerance to the fetus to preserve pregnancy and regulates immunity in the newborn. Based on this mechanism of action, tremelimumab-actl may increase the risk of developing immune-mediated disorders or altering the normal immune response. Animal studies have demonstrated an association between CTLA-4 blockade and an increased risk of immune-mediated rejection of the developing fetus and fetal death.
Female patients with reproductive potential should be advised to use effective contraception during treatment with tremelimumab-actl and for 3 months after the last dose of tremelimumab-actl. In addition, because of the potential for serious adverse reactions in the breastfed child, female patients should be advised not to breastfeed during treatment with tremelimumabactl and for 3 months after the last dose.5
1. Imjudo. Package insert. AstraZeneca Pharmaceuticals; 2022.
2. FDA approves tremelimumab in combination with durvalumab for unresectable hepatocellular carcinoma. FDA. October 21, 2022. Accessed November 11, 2022. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-tremelimumabcombination-durvalumab-unresectable-hepatocellular-carcinoma
3. Llovet JM, Kelley RK, Villanueva A, et al. Hepatocellular carcinoma. Nat Rev Dis Primers. 2021;7(1):6. doi:10.1038/s41572-020-00240-3
4. Abou-Alfa GK, Lau G, Kudo M, et al. Tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. NEJM Evid. 2022;1(8). doi:10.1056/EVIDoa2100070
5. NCCN. Clinical Practice Guidelines in Oncology. Non–small cell lung cancer, version 5.2022. Accessed December 14, 2022. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf
6. FDA approves tremelimumab in combination with durvalumab and platinum-based chemotherapy for metastatic non-small cell lung cancer. FDA. November 10, 2022. Accessed December 14, 2022. http://www.fda.gov/drugs/resources-information-approveddrugs/fda-approves-tremelimumab-combination-durvalumab-and-platinum-basedchemotherapy-metastatic-non
7. Johnson ML, Cho BC, Luft A, 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. Published online November 3, 2022. doi:10.1200/JCO.22.00975
About the Authors
Jane Lee, PharmD, BCPS, BCOP, is a clinical oncology pharmacist at Yale New Haven Hospital in Connecticut.
Samantha Brongiel, PharmD, BCOP, is a clinical oncology pharmacist at Smilow Cancer Hospital in New Haven and Yale New Haven Health, both in Connecticut.