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PD-1 inhibitors – making immuno-oncology mainstream?

23 July 2014 Margaret Labban, Ph.D.

The world's first Programmed cell death 1 (PD-1) inhibitor was approved in Japan this month for the treatment of advanced melanoma. This novel class of investigational immuno-oncology drugs continues to receive considerable attention and interest globally - particularly at this year's annual American Society of Clinical Oncology (ASCO) meeting held last month in Chicago.

Preliminary survival results have started to shed light on the potential of these "breakthrough" therapies across a range of oncology indications. And while some uncertainties still lie ahead for these drug-candidates, everyone is definitely starting to take notice, because so far the outlook looks good... very good!

PD-1 inhibitors represent a promising new wave of immunotherapeutics that might alter the standard of care for cancer globally. Through a partially characterised mechanism involving T-cell activation, these antibodies re-awaken the body's own immune system to specifically target and attack cancer cells. Tumour cells are generally good at avoiding immune system detection; however, these immuno-oncology drugs reverse this inhibition. PD-1 receptor antibodies seem to have a localised cytotoxic effect on tumour cells in the majority of patients without the challenges faced by systemic chemotherapy treatment, or other personalised immuno-oncology medicines that entail re-engineering of the patient's own T-cells in a relatively costly preparation. Studies have initially focused on melanoma and non-small cell lung cancer, however development is also under way for the treatment of a wide range of cancers including renal cell carcinoma, metastatic castration-resistant prostate cancer, colorectal cancer, and glioblastoma, among many others.

Drug makers such as Merck & Co, Bristol-Myers Squibb, Roche, and AstraZeneca are among the pharmaceutical companies racing to develop these immuno-oncology treatments both as monotherapies and as combination regimens. In fact, some of the most popular combination agents being paired up with PD-1 or PD-1 Ligand (PD-L1) inhibitors are other immuno-oncology biologics, including BMS' Yervoy (ipilimumab) approved for the treatment of melanoma in 2011, or Incyte's investigational indoleamine 2, 3-dioxygenase (IDO) inhibitor, INCB24360, another immune system checkpoint target with the ability to enhance the anti-tumour activity of chemotherapeutic drugs.

Merck's anti-PD-1 pembrolizumab may become the first candidate to reach the market in the US and Europe after it was granted priority review by the US FDA with an anticipated action date set for October 2014 for advanced melanoma. BMS's nivolumab is not far behind with two anticipated regulatory submissions this year in both melanoma and NSCLC. Nivolumab, licensed to BMS from Ono Pharmaceutical, became the first PD-1 inhibitor to secure marketing authorisation in Japan this month, and will soon start demonstrating how well these candidates will perform in the market.

Future prospects PD-1 inhibitors have demonstrated robust efficacy and safety profiles through their targeted immunotherapeutic approach, but also hold considerable promise as "industrialised" or more widely-accessible treatments with broad applications across several cancer types. Development of combination regimens is likely to continue to be one the main themes surrounding immunotherapies as these partnerships are key to developing competitively strong and robust therapy regimens.

BMS's immuno-oncology drug Yervoy has performed particularly well in the market, and if its success provides a relevant example of the market potential for these game-changing drugs then the outlook certainly looks promising for PD-1/PD-L1 inhibitors. These immuno-oncology drugs may soon become a necessary part of any advanced cancer therapy and are likely to have a transformative impact on the standard of care across a wide range of malignancies.



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