KESTREL Study Misses Primary and Secondary End Points in Advanced HNSCC

Treatment with single-agent durvalumab did not improve overall survival when compared with the standard-of-care frontline combination of chemotherapy plus cetuximab as treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma whose tumors highly expressed PD-L1.

Treatment with single-agent durvalumab (Imfinzi) did not improve overall survival (OS) when compared with the standard-of-care frontline combination of chemotherapy plus cetuximab (Erbitux) as treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) whose tumors highly expressed PD-L1.1

Based on the lack of OS benefit, one of the primary end points of the phase 3 KESTREL clinical trial was missed, according to results announced in a press release issued by the drug developer, AstraZeneca. The results also showed no OS improvement with the addition of the investigational human monoclonal antibody tremelimumab to durvalumab in all-comers, which led the study to miss one of its secondary end points.

“Metastatic head and neck cancer is a complex and challenging disease with a poor prognosis. While we are disappointed by these results, insights from the KESTREL phase 3 trial will advance our understanding and application of immunotherapy across our clinical development program. We will continue to build on the established benefits of Imfinzi in early lung cancer and small cell lung cancer, to bring immunotherapy treatment options to all patients who may benefit,” said Dave Fredrickson, executive vice president, Oncology Business Unit, in a statement.

The protocol for KESTREL was first announced in 2016 during the American Society of Clinical Oncology (ASCO) Annual Meeting. At the time, Tanguy Y. Seiwert, MD, of the University of Chicago, explained during a presentation that the study aimed to establish a new treatment option that could improve on the poor survival and limited responses observed with existing therapies for patients with HNSCC. It was hypothesized that targeting the PD-L1 and CTLA-4 pathways would create synergy and promote antitumor activity.2

KESTREL was a global, open-label, randomized, multicenter trial. Patients enrolled were randomized 2:1:1 to receive either tremelimumab 75 mg (for a maximum of 4 doses) in combination with durvalumab 1500 mg every 4 weeks, durvalumab monotherapy at a dose level of 1500 mg every 4 weeks, or chemotherapy in combination with six 3-week cycles of cetuximab. Chemotherapy in the study consisted of the investigator's choice of either carboplatin AUC of 5 mg/mL/min on day 1 or cisplatin at a dose of 100 mg/m2 on day 1. Either carboplatin or cisplatin was given in combination with 5-fluorouracil 1000 mg/m2 on days 1 through 4, every 3 weeks, and cetuximab 400 mg/m2 on day 1 of cycle 1, followed by weekly doses at 250 mg/m2.

The study population was comprised of 628 patients with either cancer of the oral cavity, oropharynx, hypopharynx, or larynx. All patients enrolled had not received prior systemic therapy, and they had a WHO/ECOG performance status of 0 or 1 at screening, per the eligibility criteria.

KESTREL excluded patients who had HNSCC in an area not specified in the inclusion criteria, or who had tumor progression at screening, prior radiotherapy or hormonal therapy within 30 days of joining the study, major surgery within 28 days of joining the study, presence of an active or prior autoimmune disease or inflammatory disease within 3 years, history of another primary malignancy, brain metastasis, spinal cord compression or leptomeningeal carcinomatosis, current or prior use of an immunosuppressive agent with 14 days of enrolling, or an active infection.

Patients were stratified according to their PD-L1 expression level (tumor proportion score [TPS] ≥ 25% or TPS <25%), tumor location, smoking status, and human papillomavirus status.

No specific data points from the study have been reported, but AstraZeneca did announce that the safety and tolerability of the drugs used in the trial were consistent with previous reports. Results from the study will be announced at a later date.

References:

1. Update on KESTREL Phase III trial of Imfinzi with or without tremelimumab in the 1st-line treatment of recurrent or metastatic head and neck cancer. News release. AstraZeneca. February 5, 2021. Accessed February 5, 2021. https://bit.ly/3cMDp78

2. Seiwert TY, Weiss J, Baxi SS, et al. A phase 3, randomized, open-label study of first-line durvalumab (MEDI4736) ± tremelimumab versus standard of care (SoC; EXTREME regimen) in recurrent/metastatic (R/M) SCCHN: KESTREL. J Clin Oncol. 2016;34(suppl 15):TPS6101. doi:10.1200/JCO.2016.34.15_suppl.TPS6101