Biotech Strategy Blog

Commentary on Science, Innovation & New Products with a focus on Oncology, Hematology & Cancer Immunotherapy

Posts tagged ‘Head and Neck Cancer’

Head and Neck cancer – or to be more precise – squamous cell carcinoma of the head and neck (SCCHN) has joined the checkpoint inhibitor club with two FDA approvals this year. National Harbor Maryland

Firstly, we saw the accelerated approval of pembrolizumab (Merck) based on objective response rate on August 5, 2016 for patients with recurrent or metastatic head and neck squamous cell carcinoma (SCCHN) that has continued to progress despite standard-of-care treatment with chemotherapy.

It’s a dismal disease with a generally poor prognosis in advanced patients once initial therapy fails.

While some patients do benefit with anti-PD–1 checkpoint therapy, the overall response rate in the KEYNOTE–012 trial of 174 patients was pretty low, i.e. 16%. In other words, the majority of patients do not respond or receive any clinical benefit.

Secondly, last week on November 10 nivolumab (BMS) was approved by the FDA based on the phase 3 CheckMate–141 data presented at ASCO earlier this year. The data was published in the New England Journal of Medicine to coincide with the FDA approval.

There were no statistically significant differences between the two arms for median PFS (2.0 months with nivolumab versus 2.3 months with standard therapy, HR for disease progression or death, 0.89; P=0.32) or ORR (13.3% vs. 5.8%) for nivolumab versus investigator’s choice, respectively. There was, however, a clear benefit in favour of nivolumab in median overall survival (7.5 months in the nivolumab group versus 5.1 months in the control group; HR 0.70; P=0.01).

This effect on patient outcome is a classic pattern for cancer immunotherapy with checkpoint blockade. Response rate and PFS are measurements that are very relevant to chemotherapy, but they are not as relevant to cancer immunotherapies where what is impacted more noticeably is overall survival and the long tail of the curve.

With two approved anti-PD–1 monotherapies in SCCHN, the next challenge has now become how can we improve on monotherapy by boosting the number of PRs to CRs potentially improving long term outcomes and/or turn non-responders into responders? This is the stage we are at in many tumour types now.

Combination approaches are believed to be the way forward, which is why we anticipated with great interest the lirilumab plus nivolumab head & neck combination data presented this past weekend at the 2016 Society for Immunotherapy of Cancer (SITC) meeting at National Harbor, MD. The presentation is available for download on the Innate Pharma website. The data raises numerous questions and scenarios that can be considered…

  • Are the data exciting, encouraging or disappointing?
  • Are the results enough to give confidence if a phase 3 trial with the combination were to follow?
To address these questions and other critical issues – including red and green flags – we took a deep dive into the data in the context of scientific facts and explored the landscape carefully.

To learn more insights, Subscribers can log in for more details…

With the sheer breadth and depth of immuno-oncology data being presented at even the American Association for Cancer Research (AACR), several readers were prompted to write in and ask:

“Is this the end of the road for TKI therapies? Should we even bother to continue working on these agents?”

Good question.

There was actually quite a bit of interesting data on regular novel targeted therapy to discuss, although I do concede that much of the mass media news focusing on the immuno-oncology tsunami in Philadelphia effectively drowned out targeted therapies and the results coming out in that space.

Reading Market Philly Chocolate TowerTo maintain the balance between novel targeted agents and immunotherapy, here’s a review of some of the interesting new developments that I came across at AACR, from both the poster halls, as well as some of the thought leaders in this space.

When you stack up the emerging evidence in several tumour subsets, there are quite a few tasty morsels that are worthy of further discussion!

I’d like to take this opportunity to extend a warm welcome to all the new subscribers who took advantage of the AACR Special Offer to continue their education and learning about the exciting new developments in cancer research.  Thank you for joining our conference coverage service, we really appreciate it.

To learn more about our latest insights, subscribers can log-in or you can purchase access to BSB Premium Content. 

2 Comments

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.DGeoffrey 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.

ResearchBlogging.orgHarris, 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

error: Content is protected !!