AstraZeneca's Imfinzi Fails to Meet Primary Endpoint in Phase 3 KESTREL Trial for First-Line Head and Neck Cancer

Compiled by Keke

In late 2018, AstraZeneca’s Imfinzi failed in clinical trials for head and neck cancer, after which the company pinned its hopes on the Phase 3 KESTREL study, believing that the drug might demonstrate benefit in patients with high levels of the PD-L1 biomarker. However, this study also failed to meet its endpoints.

On February 5, AstraZeneca announced the results of the Phase 3 KESTREL trial evaluating first-line treatment for patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) whose tumors express high levels of PD-L1. Compared with the standard EXTREME regimen (chemotherapy combined with cetuximab), the checkpoint inhibitor Imfinzi (durvalumab) failed to meet the primary endpoint of improving overall survival (OS). Meanwhile, Imfinzi in combination with tremelimumab also showed no OS benefit in the overall patient population, failing to meet the secondary endpoint. However, the safety and tolerability profiles of Imfinzi monotherapy and its combination with tremelimumab were consistent with those observed in previous trials.

AstraZeneca introduced KESTREL, a randomized, open-label, multicenter, global Phase 3 clinical trial for the first-line treatment of recurrent or metastatic HNSCC. The trial evaluated the efficacy of Imfinzi alone or Imfinzi in combination with the second immunotherapy tremelimumab versus the EXTREME regimen (cetuximab combined with cisplatin or carboplatin plus 5-fluorouracil). High PD-L1 expression was defined as PD-L1 expression in ≥50% of tumor cells or ≥25% of tumor-infiltrating immune cells.

This trial was conducted at more than 200 centers across 23 countries, including sites in the United States, Europe, South America, and Asia. The primary endpoint was overall survival (OS) in patients with high PD-L1 expression treated with Imfinzi monotherapy. OS in all enrolled patients receiving Imfinzi in combination with tremelimumab was included as a key secondary endpoint.

Imfinzi (durvalumab) is a human monoclonal antibody that has been approved in the European Union, the United States, Japan, China, and multiple other countries for the treatment of patients with unresectable stage III non-small cell lung cancer (NSCLC) following chemoradiotherapy, based on the results of the phase 3 PACIFIC trial. Based on the results of the phase 3 CASPIAN trial, the drug has been approved in the European Union, the United States, Japan, and multiple other countries for the treatment of extensive-stage small cell lung cancer (SCLC). Additionally, in the United States and several other countries, Imfinzi is also approved for the treatment of patients with advanced bladder cancer.

Tremelimumab is a human monoclonal antibody targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and a potential novel drug. This agent is being evaluated in clinical trials in combination with Imfinzi for the treatment of non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), bladder cancer, and hepatocellular carcinoma (HCC).

“Although this failure does not represent a significant financial setback for AstraZeneca, with the peak potential revenue for the head and neck squamous cell carcinoma indication in the U.S. and EU projected to be less than $150 million, it still poses certain disadvantages for the company,” wrote Geoffrey Porges, an analyst at healthcare investment bank SVB Leerink, in a report to clients. “It may limit Imfinzi’s expansion opportunities beyond its ‘safe’ Phase 3 non-small cell lung cancer (NSCLC) indication, which currently serves as Imfinzi’s largest revenue source and remains unchallenged by other PD-1/PD-L1 inhibitors.”

In the first nine months of 2020, Imfinzi’s sales reached $1.48 billion, representing a 42% increase and making it AstraZeneca’s fastest-growing product.

“Speaking of other players, the failure of this trial has further weakened perceptions of Imfinzi and Merck’s Keytruda,” Boggs pointed out. Keytruda, the market leader in checkpoint inhibitors, gained U.S. FDA approval for patients with head and neck cancer after demonstrating a 23% improvement in survival rates compared to standard therapy.

Is the significance of the research failure ultimately negative for AstraZeneca? Perhaps so, as the study also points to the “limited incremental value” of tremelimumab. The drug has yet to find a suitable market niche, despite its inclusion in numerous clinical trials. However, AstraZeneca may not have to wait long for an opportunity to recoup its losses, as the Phase III Himalaya trial is evaluating the combination of Imfinzi and tremelimumab in patients with previously untreated liver cancer, while the Phase III Poseidon trial is investigating the impact of tremelimumab on survival rates in lung cancer. Results from both studies are expected to be released later this year.

Reference Sources:

1.AstraZeneca's PD-L1 med Imfinzi strikes out again in head and neck cancer

2.AstraZeneca's Checkpoint Inhibitor Misses Mark in Head & Neck Cancer