PD-L1 inhibitors approved for lung cancer

The FDA recently approved Roche’s Tecentriq for patients with metatastic non-small cell lung cancer (link is external) (NSCLC) in the United States. It received approval for the treatment of bladder cancer back in May, and is now the first and only cancer immunotherapy to target the PD-L1 check point ligand in NSCLC. It joins two PD-1 inhibitors that are licensed for cancer immunotherapy, but many predict that Tecentriq’s use of the PD-L1 target may be important for the way the medicine works.

Cancer immunotherapy has become one of the four accepted pillars of cancer treatment (link is external), along with surgery, radiotherapy and chemotherapy. Arming a patient’s own immune system against a cancer in this way is showing impressive results, with greater efficacy and improved patient quality of life than standard chemotherapy reagents.

Tecentriq is a monoclonal antibody therapy targeting the PD-L1 protein, that is expressed on tumour and tumour-infiltrating cells. Blocking its interaction with the PD-1 receptor on the surface of T cells with an immune checkpoint inhibitor, like Tecentriq, can awaken the T cells to the presence of the tumour and restore their ability to detect and attack the tumour cells. Once awakened the immune response to cancer generally persists in patients, offering durable responses.

Excitingly, the clinical activity of immune checkpoint inhibitors (link is external) doesn’t appear to be restricted to small subpopulations of patients or a particular histologic subtype, with very different and typically milder side effects than traditional chemotherapy treatments. Though immune checkpoint inhibitors clearly lack the decades of trials that support the efficacy of standard chemotherapy, studies being published increasingly show promising results for the use of checkpoint inhibitors and not just as second-line treatments. In particular, for hard-to-treat cancers such as NSCLC (link is external), melanoma (link is external) and bladder (link is external) cancer, checkpoint inhibitors targeting both PD-1 and PD-L1 are showing increased patient survival as first-line treatments.

We are currently developing Affimer® therapeutics to PD-L1, because we believe they will offer a range of benefits over conventional mAbs such as small size, stability and the possibility to build bi-specifics by combining two immune checkpoint therapies into one molecule to give superior efficacy and a better clinical outcome for the patient. Results from pre-clinical in vivo studies show clinically relevant doses of anti-PD-L1 Affimer proteins were very well tolerated with no adverse effects and good in-serum half-lives, reducing the need for repetitive injections to reach a therapeutically relevant concentration. The Affimer inhibitors were able to significantly reduce tumour growth in a syngeneic mouse model, demonstrating their bioavailability and functionality as therapeutic molecules.

Lung cancer

Despite the advancements in cancer treatment, lung cancer remains the leading cause of cancer death within the U.S., so new treatment options are needed. In the randomised Phase III OAK trial Tecentriq extended the life of patients with NSCLC by 27% from 9.6 months to 13.8 months compared to standard second-line docetaxel chemotherapy treatment alone. As a result of these and the Phase III POPLAR trial Tecentriq (link is external) is approved for NSCLC patients previously treated with platinum-containing chemotherapies, whose tumours carry mutations in either the epidermal growth factor receptor or anaplastic lymphoma kinase genes. As it is the only PD-L1 inhibitor currently licensed by FDA for NSCLC it could potentially offer a new strategy and hope in the treatment of this disease compared to the PD-1 inhibitors targeting this checkpoint.

There has been a lot of interest around these immune checkpoint targets, with different companies developing PD-1/ PD-L1 inhibitors for a diverse range of cancers and even interest in their use as a potential therapy for Alzheimer’s disease (link is external). With all these developments it may seem that we have adequately targeted this pathway, yet the results show that significantly more anti-tumour activity is possible with smaller therapeutic molecules (link is external) targeting PD-1/ PD-L1 compared with standard antibody molecules, with broader implications that the same advantages could be present for additional immunotherapeutic pathways outside of PD-1 and PD-L1.