Priority review for a biologics license application has been granted by the FDA for tremelimumab as treatment of patients with unresectable hepatocellular carcinoma.
The FDA has granted priority review to a biologics license application (BLA) for tremelimumab for the treatment of patients with unresectable hepatocellular carcinoma (HCC), supporting the indication of a single priming dose of the anti-CTLA4 antibody added to Imfinzi (durvalumab), according to an announcement by AstraZeneca.
Additionally, a supplemental BLA has also been submitted for durvalumab in this indication with the novel dose and schedule of the combination called the STRIDE regimen (Single T Regular Interval D).
The basis of the application is the final results from the HIMALAYA Phase III trial (NCT03298451) which showed treatment with durvalumab plus tremelimumab to demonstrate a significant improvement in overall survival(OS) compared with sorafenib (Nexavar) as frontline therapy. These findings were presented at the 2022 American Society of Clinical Oncology Gastrointestinal Cancers Symposium
“The HIMALAYA phase 3 trial showed an unprecedented 3-year overall survival in this setting with a single priming dose of tremelimumab added to Imfinzi, highlighting the potential for this regimen to improve longer-term survival outcomes. Patients with advanced liver cancer are in great need of new treatment options, and we are working closely with the FDA to bring this novel approach to patients in the US as soon as possible,” stated Susan Galbraith, executive vice president, Oncology R&D of AstraZeneca, in the press release.
The randomized, open-label, multicenter, global study aims to assess the efficacy and safety of the combination of durvalumab plus tremelimumab and durvalumab monotherapy versus sorafenib (Nexavar) in the treatment of patients with no prior systemic therapy for unresectable HCC.
Enrollment was open to those with HCC based on histopathological confirmation. To be eligible in the trial, one must have no prior systemic therapy for HCC, a Barcelona Clinic Liver Cancer stage B that is not eligible for locoregional therapy or stage C, a Child-Pugh Score of class A, and an ECOG performance status of 0 or 1 at the time of enrollment.
Overall, 1171 patients were randomized to durvalumab/tremelimumab (n = 393), durvalumab alone (n = 389), and sorafenib alone (n = 389). Patients were randomized to the STRIDE regimen, 1500 mg of durvalumab every 4 weeks, 400 mg of sorafenib twice daily, or 75 mg of tremelimumab plus 1500 mg of durvalumab every 4 weeks.
The primary end point of the HIMALAYA study was OS for durvalumab/tremelimumab vs sorafenib with secondary end points including progression-free survival (PFS), objective response rate (ORR) per RECIST v.1.1 criteria, disease control rate, duration of response (DOR), and safety.
Patients in all arms with confirmed progressive disease (PD) who benefit from their assigned treatment and meet the criteria for treatment in the setting of PD could continue to receive their assigned treatment based on the investigator's opinion.
If a patient discontinued due to disease progression, they would enter survival follow-up. Those who have discontinued treatment due to toxicity or symptomatic deterioration or who have commenced subsequent anticancer therapy, will have tumor assessments until confirmed PD and will be followed for survival.
At the time of the data cutoff, findings revealed that the combination of durvalumab and tremelimumab led to a significant improvement in OS vs sorafenib, meeting the primary end point of the study (HR, 0.78; 96% CI, 0.65-0.92; P =.0035). Durvalumab also demonstrated noninferior OS vs sorafenib (HR, 0.86; 96% CI, 0.73-1.03). The median OS was reported as being 16.4 months (95% CI, 14.2-19.6) with durvalumab/tremelimumab, 16.6 months (95% CI, 14.1-19.1) with durvalumab, and 13.8 months (95% CI, 12.3-16.1) with sorafenib.
Median follow-up was 16.1 months in the durvalumab/tremelimumab arm, 16.5 months in the durvalumab arm, and 13.3 months in the sorafenib arm. At the time of the data cutoff, 66.7%, 72%, and 75.3% of patients had died, respectively.
Findings also showed the 24-month OS rate to be 40.5% with durvalumab/tremelimumab, 39.6% with durvalumab, and 32.6% with sorafenib, with 36-month OS rates being 30.7%, 24.7%, and 20.2%, respectively.
The median PFS was 3.8 months (95% CI, 3.7-5.3) in the durvalumab/tremelimumab arm, 3.7 months (95% CI, 3.2-3.8) in durvalumab alone, and 4.1 months (95% CI, 3.8-5.5) in sorafenib alone. The ORR reported with the combination of durvalumab and tremelimumab was higher (20.1%) than with durvalumab (17.0%) or sorafenib (5.1%). The median DOR was 22.3 months, 16.8 months, and 18.4 months, respectively.
Overall, patients treated with the STRIDE regimen experienced a 22% reduction in the risk of death versus sorafenib (HR 0.78, 96.02% CI, 0.65 - 0.93; P =0.0035). About 31% of these patients were still alive at 3 years vs 20% of those treated with sorafenib.
In regard to safety, no new signals were identified. Grade 3 or 4 treatment-related adverse effects (TRAEs) occurred in a total of 25.8% of patients on durvalumab/tremelimumab, 12.9% of patients on durvalumab, and 36.9% of patients on sorafenib. Further, grade 3 or 4 hepatic TRAEs occurred in 5.9%, 5.2%, and 4.5% of patients, respectively.
A total of 17.5% of patients on durvalumab/tremelimumab reported serious TRAEs compared with 8.2% of patients on durvalumab, and 9.4% of patients on sorafenib. Grade 5 TRAEs occurred in 2.3%, 0%, and 0.8% of patients. No TRAE of esophageal varices hemorrhage occurred, but TRAEs did lead to discontinuation of the trial in 8.2% of patients on durvalumab/tremelimumab, 4.1% of patients on durvalumab, and 11.0% of patients on sorafenib.