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Small molecule inhibitor appears effective, safe for advanced head and neck cancer
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An experimental therapy demonstrated promising efficacy when evaluated in a small cohort of patients with advanced head and neck squamous cell carcinoma, according to results of an open-label dose escalation study.
A majority of patients treated with AZD1775 (AstraZeneca) — a highly selective small molecule inhibitor of the WEE1 kinase — underwent successful surgery.
The agent also appeared safe.
“This trial is a great example of what can happen when basic science research leads to clinical research,” Cristina P. Rodriguez, MD, medical oncologist at Seattle Cancer Care Alliance and a HemOnc Today Editorial Board member, said in a press release. “[Although the study] was designed to assess the safety of AZD1775 and its most tolerable dose, the efficacy results were quite encouraging.”
The study included 10 patients with stage III and stage IVb HNSCC with borderline resectable or unresectable disease. All patients were candidates for definitive chemoradiation.
Researchers administered escalating doses of AZD1775 twice daily for 2.5 days during week 1, followed by AZD1775 plus fixed-dose cisplatin (25 mg/m2) and docetaxel (35 mg/m2) for an additional 3 weeks.
Adverse events to establish a maximum tolerated dose served as the primary outcome. Secondary outcomes included response rates, pharmacokinetics, pharmacodynamics and genomic data.
Researchers calculated a maximum tolerated dose for AZD1775 of 150 mg twice daily for 2.5 days.
Fifty percent of patients achieved response per RECIST v1.1, and three additional responders were identified after pathologic assessment. Grade 3 diarrhea was the only drug-limiting toxicity observed.
HemOnc Today spoke with Rodriguez about the need for more effective therapies for advanced HNSCC, the rationale for why AZD1775 plus chemotherapy may benefit these patients, the potential explanations for the greater-than-expected magnitude of benefit observed, and how it allows patients to undergo less invasive surgeries.
Question: Can you describe the need for more effective therapies for this patient population?
Answer: In head and neck oncology, we prioritize two things: optimizing oncologic outcomes, and ensuring the best functional outcome and patient quality of life. This novel treatment regimen offered to patients on a clinical trial was a direct result of the work done by the late Eduardo Mendez, MD, a physician-scientist at Fred Hutchinson Cancer Research Center, and his lab. One of the goals of the Mendez lab was to find an effective therapy for these patients with minimal impact on patients’ long-term functioning. From this standpoint, many patients who present with locally advanced cancer — especially in the oral cavity — require the surgery that could leave them with some disability in terms speech and swallowing. Using this experimental agent in combination with the two other chemotherapies was intended to further examine this approach in order to reduce the need for aggressive surgical resection in this patient population.
Q: Can you explain the rationale for why this regimen could be effective?
A: This paper exemplifies the success of bench-to-bedside research. Dr. Mendez and his lab were particularly interested in mechanisms of DNA repair among p53-deficient head and neck cancers. After exposure to DNA damaging agents, such as chemotherapy or radiation, these cancers rely on WEE1 to repair DNA damage and survive. Our thought was that if we inhibit WEE1 and expose cancers to chemotherapy, then we eliminate the cancer cells’ ability to repair DNA damage and push them toward cell death.
Q: Can you summarize the safety and efficacy observed in this early trial?
A: This is a small study, with the primary purpose to explore the safety and efficacy of administering these treatments together. By far, we found they were safe. The most common toxicity observed was gastrointestinal toxicity.
Q: You observed a greater-than-expected magnitude of benefit . Can you elaborate on the efficacy?
A: This question is controversial. These small phase 1 studies are not designed to examine how effective these treatments are compared with chemotherapy alone. The first step is to make sure they are safe. The next step is to increase the number of patients we treat with the regimen to see how effective the treatment truly is. This trial enrolled a small and heterogeneous patient population with varying prognoses. More clinical data will be needed to determine what AZD1775 truly adds to the efficacy of chemotherapy in this patient population.
Q: How did the combination regimen allow patients to undergo less invasive surgery, and why is this important?
A: Head and neck cancers occur in anatomic locations that are critical for day-to-day functioning. Oral cavity squamous cell carcinomas are primarily treated with upfront surgery, and less extensive surgery leads to less impact on the patient’s ability to eat, taste, speak and swallow. We want to maintain good function for these patients, even after they are cured of their cancer.
Q: What is the next step for research?
A: We are in the process of planning out the next steps. The applications of these inhibitors are also being extensively studied in malignancies other than head and neck cancers. Dr. Mendez’s life was dedicated to this, and we all want the success observed in this study to be further carried out and examined in larger studies. – by Jennifer Southall
Reference:
Mendez E, et al. Clin Cancer Res. 2018;doi:10.1158/1078-0432.CCR-17-3796.
For more information:
Cristina P. Rodriguez, MD, can be reached at Seattle Cancer Care Alliance, 825 Eastlake Ave. East, Seattle, WA 98109; email: rodrigcr@uw.edu.
Disclosures: The study was funded by NCI, American Cancer Society, NIH, University of Washington/Seattle Cancer Care Alliance and Fred Hutchinson Cancer Center. AstraZeneca provided AZD1775, as well as funding for pharmacokinetic data and genomic analysis. Rodriguez reports no relevant financial disclosures.