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The combination of durvalumab and tremelimumab demonstrated a significant improvement in overall survival vs sorafenib as frontline therapy in patients with unresectable hepatocellular carcinoma, according to findings from the phase 3 HIMALAYA trial.
The combination of durvalumab (Imfinzi) and tremelimumab demonstrated a significant improvement in overall survival (OS) vs sorafenib (Nexavar) as frontline therapy in patients with unresectable hepatocellular carcinoma (HCC), according to findings from the phase 3 HIMALAYA trial (NCT03298451) that will be presented at the 2022 Gastrointestinal Cancers Symposium.1
At data cutoff, the results showed 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). Additionally, durvalumab demonstrated noninferior OS vs sorafenib (HR, 0.86; 96% CI, 0.73-1.03). The median OS was 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.
“Pending FDA approval, this novel dual immunotherapy regimen could be readily available to all patients and would not require additional safety assessments prior to treatment,” said lead study author Ghassan K. Abou-Alfa, MD, a medical oncologist at Memorial Sloan Kettering Comprehensive Cancer Center, in a news release.2
In the phase 2 Study 22 trial (NCT02519348), the STRIDE (Single T Regular Interval D) regimen, consisting of 1 dose of 300 mg of tremelimumab plus 1500 mg of durvalumab plus 1500 mg of durvalumab every 4 weeks, led to promising antitumor activity and minimal toxicity.
In January 2020, the FDA granted an orphan drug designation to durvalumab plus tremelimumab for the treatment of patients with HCC.3
In the randomized, open-label, multicenter HIMALAYA study, investigators evaluated the efficacy and safety of the STRIDE regimen and durvalumab alone vs sorafenib in patients with unresectable HCC who had not received prior systemic therapy.
When the study was started, sorafenib was the only approved frontline standard of care for patients with advanced HCC. Now, lenvatinib (Lenvima) and atezolizumab (Tecentriq) plus bevacizumab (Avastin) are also approved for use as frontline therapy.
According to the planned protocol, 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.
Enrollment to the lower-dose tremelimumab-containing arm was stopped after a planned analysis of Study 22 failed to show a meaningful efficacy difference between that arm and durvalumab alone.
The primary end point of HIMALAYA was OS for durvalumab/tremelimumab vs sorafenib. The secondary end point was OS noninferiority between durvalumab and sorafenib, with a noninferiority margin of 1.08. Secondary end points included progression-free survival (PFS), objective response rate (ORR) per RECIST v.1.1 criteria, duration of response (DOR), and safety.
Overall, 1171 patients were randomized to durvalumab/tremelimumab (n = 393), durvalumab alone (n = 389), and sorafenib alone (n = 389).
Patients with known risk factors for the disease were included in the trial, including those with viral hepatitis B, hepatitis C, and other non-viral origins.
The 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 data cutoff, 66.7%, 72%, and 75.3% of patients had died, respectively.
Additional results showed that the 24-month OS rate was 40.5% with durvalumab/tremelimumab, 39.6% with durvalumab, and 32.6% with sorafenib. The 36-month OS rates were 30.7%, 24.7%, and 20.2%, respectively.
The median PFS was 3.8 months (95% CI, 3.7-5.3) with durvalumab/tremelimumab, 3.7 months (95% CI, 3.2-3.8) with durvalumab, and 4.1 months (95% CI, 3.8-5.5) with sorafenib.
Furthermore, the ORR was higher with durvalumab/tremelimumab (20.1%) and durvalumab (17.0%) vs sorafenib (5.1%).
The median DOR was 22.3 months, 16.8 months, and 18.4 months, respectively.
In terms of safety, no new signals were identified. Grade 3/4 treatment-related adverse effects (TRAEs) occurred in 25.8% of patients on durvalumab/tremelimumab, 12.9% of patients on durvalumab, and 36.9% of patients on sorafenib. Grade 3/4 hepatic TRAEs occurred in 5.9%, 5.2%, and 4.5% of patients, respectively.
Serious TRAEs occurred in 17.5% of patients on durvalumab/tremelimumab, 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, respectively.
No TRAE of esophageal varices hemorrhage occurred.
TRAEs leading to discontinuation occurred in 8.2% of patients on durvalumab/tremelimumab, 4.1% of patients on durvalumab, and 11.0% of patients on sorafenib.
“To date, the HIMALAYA study is one of the largest phase 3 studies conducted with long-term follow-up demonstrating the role of immunotherapy in surgically unresectable HCC. HIMALAYA chose a novel approach of priming with a single dose of combination immunotherapy followed by the single agent durvalumab. While the primary end point was met, based on the current data, the secondary end point of PFS was not superior in either investigational arm relative to the control arm, requiring further discussion,” Cathy Eng, MD, FACP, FASCO, the David H. Johnson Chair in Surgical and Medical Oncology at Vanderbilt-Ingram Cancer Center, concluded.2