Durvalumab with or without tremelimumab in patients with recurrent or metastatic head and neck squamous cell carcinoma: EAGLE, a randomized, open-label phase III study

Abstract

Background: Targeting the programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) axis has demonstrated clinical benefit in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). Combining immunotherapies targeting PD-L1 and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) has shown evidence of additive activity in several tumor types. This phase III study evaluated the efficacy of durvalumab (an anti-PD-L1 monoclonal antibody) or durvalumab plus tremelimumab (an anti-CTLA-4 monoclonal antibody) versus standard of care (SoC) in R/M HNSCC patients. Patients and methods: Patients were randomly assigned to receive 1 : 1 : 1 durvalumab (10 mg/kg every 2 weeks [q2w]), durvalumab plus tremelimumab (durvalumab 20 mg/kg q4w plus tremelimumab 1 mg/kg q4w  4, then durvalumab 10 mg/kg q2w), or SoC (cetuximab, a taxane, methotrexate, or a fluoropyrimidine). The primary end points were overall survival (OS) for durvalumab versus SoC, and OS for durvalumab plus tremelimumab versus SoC. Secondary end points included progression-free survival (PFS), objective response rate, and duration of response. Results: Patients were randomly assigned to receive durvalumab (n ¼ 240), durvalumab plus tremelimumab (n ¼ 247), or SoC (n ¼ 249). No statistically significant improvements in OS were observed for durvalumab versus SoC [hazard ratio (HR): 0.88; 95% confidence interval (CI): 0.72e1.08; P ¼ 0.20] or durvalumab plus tremelimumab versus SoC (HR: 1.04; 95% CI: 0.85e1.26; P ¼ 0.76). The 12-month survival rates (95% CI) were 37.0% (30.9e43.1), 30.4% (24.7e36.3), and 30.5% (24.7 e36.4) for durvalumab, durvalumab plus tremelimumab, and SoC, respectively. Treatment-related adverse events (trAEs) were consistent with previous reports. The most common trAEs (any grade) were hypothyroidism for durvalumab and durvalumab plus tremelimumab (11.4% and 12.2%, respectively), and anemia (17.5%) for SoC. Grade !3 trAE rates were 10.1%, 16.3%, and 24.2% for durvalumab, durvalumab plus tremelimumab, and SoC, respectively. Conclusion: There were no statistically significant differences in OS for durvalumab or durvalumab plus tremelimumab versus SoC. However, higher survival rates at 12 to 24 months and response rates demonstrate clinical activity for durvalumab. Trial registration: ClinicalTrials.gov: NCT02369874.

Safety and efficacy of single cycle induction treatment with cisplatin/docetaxel/ durvalumab/tremelimumab in locally advanced HNSCC: first results of CheckRad-CD8

“…In the phase III EAGLE trial, both durvalumab alone and durvalumab with tremelimumab failed to prove a significant improvement of OS compared with second line chemotherapy in recurrent and/or metastatic HNSCC. 13 However, the 1-year survival rate of durvalumab with 37% was comparable to second line trials with nivolumab with 36% or pembrolizumab with 37%, whereas the 1-year survival rate of durvalumab with tremelimumab was only 30%. 2 13 28 The results of the phase III KESTREL trial with a durvalumab/tremelimumab combination in first-line treatment are still outstanding.…”

“…PD-L1 status was scored as percentage of total tumor cell area with the previously established cut-off value of 25% for durvalumab±tremelimumab in HNSCC. 13 PD-L1 was high (area ≥25%) on TCs in 10 patients (18%) and on ICls in 21 patients (38%). Six patients (11%) received carboplatin instead of cisplatin.…”

Immunotherapy Breakthroughs in the Treatment of Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma

“…Treatment related adverse events of any grade and grade 3-4 occurred in 64% and 13% of patients respectively. ORR is 18% (95% CI, [13][14][15][16][17][18][19][20][21][22][23][24] and does not depend much on prior treatment: 17% after platinum, 15% after cetuximab. Duration Of Response (DOR) is high with a not reached median (range, 2+ to 30+ months), 71% of responses lasted more than 12 months and five patients completed the study after 2 years of treatment with pembrolizumab.…”

“…Chronologically EAGLE [17] comes out after CHECKMATE-141 and KEYNOTE-040. Supported by solid phase Ib data [14], its purpose is not limited to measuring the efficacy of durvalumab (D) alone, in second line after progression after one, and only one, cisplatin based first line, but also in conjunction with an anti-CTL-4, tremelimumab (T) vs. standard of care (SoC: cetuximab, weekly paclitaxel or docetaxel, methotrexate or a fluoropyrimidine).…”

Adding Adjuvants to Fluoropyrimidine-based Neoadjuvant Chemoradiotherapy for Locally Advanced Rectal Cancer: An Option Worthy of Serious Consideration

“…Current research shows that immunotherapy targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death protein 1 (PD-1) and programmed death ligand-1 (PD-L1) can significantly improve patient survival of metastatic melanoma, urothelial carcinoma, prostate cancer, non-small cell lung cancer, and other malignant tumors [98][99][100][101]. So far, the drugs targeting CTLA-4 approved by FDA are ipilimumab, targeting PD-1 are nivolumab and pembrolizumab, and targeting PDL-1 include atezolizumab, durvalumab, avelumab, and cemiplimab-rwlc.…”