On 5th February, AstraZeneca announced that its Phase III KESTREL clinical trial (NCT02551159) failed to achieve its primary endpoint for overall survival (OS) in patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC).

AstraZeneca/Medimmune Therapeutics’ Imfinzi (durvalumab), an immunotherapy targeting programmed death-ligand 1 (PD-L1) , is currently approved for use in several oncology indications, such as non-small cell lung cancer (NSCLC), smallcell lung cancer (SCLC), and bladder cancer, with international market access. The Phase III KESTREL clinical trial evaluated durvalumab monotherapy or durvalumab + tremelimumab versus the standard of care EXTREME regimen (cetuximab + fluorouracil), with cisplatin or carboplatin, in the first-line treatment of recurrent or metastatic HNSCC. The trial arm was unable to demonstrate improved OS in patients exhibiting PD-L1 expression and in all-comer patients treated with monotherapy or combination therapy. This is following Imfinzi’s previous failure to demonstrate improved OS in the Phase III EAGLE (NCT02369874) trial in second-line HNSCC in 2018. While these recent failures are a setback in AstraZeneca’s advancement of its clinical development program, the company plans to build on Imfinzi’s established benefits in NSCLC and SCLC, and remains committed to further exploring applications of this drug in several other oncology indications.

Over the last few years, there have been several such setbacks in late-stage HNSCC. The results of the Phase III JAVELIN study (NCT02952586), which were released in mid-2020, showed that EMD Serono/Pfizer’s Bavencio (avelumab) missed its primary endpoint for locally-advanced HNSCC population. This followed the failure of Merck & Co’s Keytruda’s (pembrolizumab) in earlier phase trials in the first-line recurrent/metastatic HNSCC setting in 2017. Additionally, despite achieving its primary endpoint of progression-free survival in a clinical study, Boehringer Ingelheim’s Gilotrif (afatinib),
which is indicated for use in NSCLC, did not receive marketing approvals in HNSCC, primarily due to a lack of clinically meaningful data in comparison to other established therapies and concerns over product safety.

Nearly 750,000 patients were diagnosed with head and neck cancer globally in 2020, according to the World Health Organization and the GLOBOCAN 2020 database. As such, the failure of late-stage drugs in clinical development for HNSCC poses further challenges to advances in treatment. HNSCC is largely a chemotherapy-dominated market, but the past few years have seen effective use of Keytruda and Bristol-Myers Squibb’s Opdivo (nivolumab) in the recurrent or metastatic settings. The current clinical development pipeline has around 20 late-stage agents in the immunomodulating therapy or cell inhibitor classes. Their clinical adoption depends on their ability to demonstrate an improved survival benefit. While the late-stage HNSCC pipeline holds promise, as evidenced in other solid tumors, it still remains to be seen whether or not this market will see further introductions of immunotherapies or other classes of targeted therapies.