Challenges with Head and Neck Cancer Drug Development
Head and neck cancer is not something we hear much about when it comes to new therapies, yet it is the sixth most common non-skin cancer in the world.
Head and neck squamous cell carcinoma (HNSCC) has an incidence of 600,000 cases a year, with 50,000 of those occurring in the United States.
Outcomes remain disappointing for patients, with disease free survival (DFS) rates of only 30-40% for patients with locally advanced HNSCC. Five-year survival rates of around 50% have improved little for many years.
Zalutumumab failed to show OS benefit
The challenge of drug development in this area was highlighted by the failure of the phase III trial for zalutumumab (Genmab). Zalutumumab was a monoclonal antibody against the epidermal growth factor receptor (EGFR).
Despite promising phase II data, the phase III trial did not show an improvement in overall survival against best supportive care (BSC) in patients with recurrent or metastatic squamous cell carcinoma of the head and neck who had failed standard platinum-based chemotherapy. Genmab subsequently dropped zalutumumab from its pipeline in June 2011.
These results are interesting because they raise the question of why this agent failed when Erbitux (cetuximab), an EGFR monoclonal from Lilly/BMS succeeded? Cetuximab is approved in the first-line setting in combination with radiation and in the relapsed setting with 5FU and as a single therapy in refractory patients. Clearly not all EGFR therapies are equal.
Oncolytics Biotech Phase III trial ongoing
Another company trying to crack head & neck cancer is Canadian based Oncolytics Biotech, who have started a phase III trial with REOLYSIN® in combination with paclitaxel and carboplatin for patients with platinum-failed head and neck cancers. A poster on their phase II data was presented at the AACR-EORTC molecular targets meeting in San Francisco last year (Abstract C22).
Reolysin is a proprietary formulation of the human reovirus (respiratory enteric orphan virus). According to the company website, “in tumour cells with an activated Ras pathway, reovirus is able to freely replicate and eventually kill the host tumour cells.” It’s beyond the scope of this post to go into the science of oncolytic viruses.
The company recently announced CDN $18.5M of additional financing. According to the clinicaltrials.gov site, the primary completion date for the 280 patient, 53 site trial (NCT01166542) is estimated to be June this year. The primary endpoint is again overall survival (OS) and it will be interesting to see whether they can succeed.
Which brings me to some interesting science in HNSCC that caught my attention earlier this week.
Low-level expression of miR-375 correlates with poor outcome & metastasis
Research published online first on January 9, 2012 in the American Journal of Pathology by the Albert Einstein College of Medicine and Montefiore Medical Center in New York showed that low-level expression of micro RNA-375 (miR-375) correlated with poor outcome in tumors of HNSCC patients.
Sally Church, Ph.D on Pharma Strategy Blog recently wrote about how microRNA (miRNA) can be used as a potential biomarker in breast cancer, allowing for earlier detection.
She noted, “miRNA looks to be a promising fledgling area for biomarker research in the early detection of cancer.”
Thomas Harris and colleagues showed that HNSCC patients with low miR-375 tumor-to-normal (T:N) expression ratio had a worse prognosis.
miRNA expression status was assessed as a ratio of miR-375 expression in the tumor relative to adjacent normal tissue collected from the same patient to provide a normalized ratio across the study population.
The Kaplan Meier curves in their paper show the significant correlation. The data showed that:
Patients with lower miR-375 T:N expression were more likely to die of disease (HR: 12.8, 95% CI: 3.4 to 48.6) than those with higher miR-375 T:N.
The authors suggest that the correlation between low miR-375 tumor versus normal tissue expression and outcome may be due to the effects of miR-375 on tumor cell invasion.
The identification of a potential biomarker associated with head and neck cancer prognosis is promising. The paper concluded that:
The identification of patients with a poor prognosis, especially in the case of early-stage disease, could lead to additional therapeutic interventions, such as suppressing tumor cell invasiveness, to achieve better outcomes.
Geoffrey Childs, Ph.D, the co-senior of the author of the paper noted in a news release:
we hope that miR-375 will become part of a laboratory test to determine which patients have potentially lethal tumors and therefore should be treated aggressively following initial diagnosis.
There is an unmet medical need for novel therapeutics in HSNCC. Hopefully, new drug development targets will follow from the identification of biomarkers and a greater understanding of the molecular biology.
Harris, T., Jimenez, L., Kawachi, N., Fan, J., Chen, J., Belbin, T., Ramnauth, A., Loudig, O., Keller, C., Smith, R., Prystowsky, M., Schlecht, N., Segall, J., & Childs, G. (2012). Low-Level Expression of miR-375 Correlates with Poor Outcome and Metastasis While Altering the Invasive Properties of Head and Neck Squamous Cell Carcinomas The American Journal of Pathology DOI: 10.1016/j.ajpath.2011.12.004
