October 02 ,2013 | By Márcio Barra
Roche has recently released data from an early-stage trial for its experimental drug MPDL3280A, that has been making waves in the scientific community in what the company as called a “potential game changer” in patients with non-small cell lung cancer (NSCLC), especially ones that are smokers.
The results, from a Phase 1a study of MPDL3280A in patients with metastatic NSCLC that had progressed on prior therapy, were presented at the European Cancer Congress (ECC) in Amsterdam. Of the 53 patients (the safety data comprised 85 patients, with clinical activity data available for 53), with NSCLC tumours treated with the drug, 23% saw their tumours shrink. Current and former smokers accounted for 80% of the study population. And it was in this population where the drug shined – the tumour shrinking rate was higher in smokers than in patients that never smoked, 26% to 10% respectively.
Research team suggested that smoking was associated with tumours that harbour more genetic mutations. So patients who smoke are more likely to have an immune system that targets more efficiently tumour cells (due to the increased number of mutations) once PD-L1 has been blocked.
Although the best results were seen in smokers or former smokers, Professor Jean-Charles Soria said, at the ECC, that the anti-PD-L1 antibody was also an important strategy for non-smokers. “Some of them benefited from this compound as well.”
MPDL3280A is an engineered antibody that targets the signalling protein PD-L1 –Programmed Death-Ligand 1 – a ligand that interacts with the PD-1 receptor and that is up regulated by tumours. PD-L1 inhibits the immune system’s CD8+ T cells, supressing them. By inhibiting PD-L1, the immune system returns to its normal functions and starts targeting the tumour cells. MPDL3280A does not disrupt the interaction between PD-1 and PD-L2, which mediates T-cell activation, thereby maintaining immunologic homeostasis and potentially preventing development of autoimmunity. This antibody has few serious adverse side effects (fatigue, nausea, dyspnoea and vomiting), and consists of one intravenous infusion every 3 week.
“This is the first study to suggest a potential relationship between smoking history and response to inhibiting the PD-L1/PD-1 pathway – a pathway that is instrumental in enabling cancer cells to escape detection by the immune system.” Said Professor Jean-Charles Soria. The lack of significant therapeutic options for patients with NSCLC could potentially make MPDL3280A an important piece in Roche’s portfolio.
Multiple studies of MPDL3280A in non-small cell lung cancer are ongoing and planned, and the research team is currently evaluating going directly from phase I to phase III clinical evaluation, due to the results attained.