ECC 2013 - Clinical Activity, Safety and Biomarkers of PD-L1 Blockade in Non-Small-Cell Lung Cancer (NSCLC)

Clinical Activity, Safety and Biomarkers of PD-L1 Blockade in Non-Small-Cell Lung Cancer (NSCLC): Additional Analysis From a Clinical Study of the Engineered Antibody MPDL3280A (anti PD-L1) J.C. Soria et al.

Background: Antitumor immune response may be inhibited by PD-L1 expression.  MPDL3280A is a human monoclonal antibody that contains an engineered Fc-domain whose aim is to restore tumor specific T cell immunity by blocking PD-L1 from binding with its receptors.

Methods: This is a phase 1 expansion study in patients with squamous or non-squamous non-small cell lung cancer receiving MPDL3280A IV q. three-weekly.  Patients were treated for up to one year.  Objective response rate was assessed by RECIST.  Cigarette smoking history was captured at baseline. IHC scores for PD-L1 expression were also assessed.

Results: There were 53 patients with NSCLC treated with this antibody.  76% had non-squamous cell carcinoma and 55% had multiple lines of previous treatment.  The agent was noted to be well tolerated with no episodes of pneumonitis and no grade 3 to 5 episodes of diarrhea.  The overall response rate was 23% with 21% in the non-squamous cell population and 27% in the squamous cell population.  In addition, IHC scores for PD-L1 expression demonstrated increasing response rates with increasing IHC scores.  The response rate for IHC 3 was 83% and 46% for IHC 2 and 3.  The median time to response was 12 weeks with a median duration of response of 48 weeks.  In addition, the response rates were noted to be increased in smokers although nonsmokers responded as well.

This study demonstrates a number of very interesting and provocative aspects of this novel agent including; the tolerability of this agent, the significant efficacy especially in heavily pretreated patients as well as patients with squamous cell carcinoma, it appears that there is a predictive biomarker for this agent with evidence that increasing PD-L1 expression correlates with a higher efficacy of the compound, finally, there appears to be differential activity of this agent in patients who are current or previous smokers.
This is the first time that evidence of smokers benefiting from a targeted agent has been documented. The theory behind the benefit in smokers relates to the mutational load in tumor cells which is significantly higher in smokers versus nonsmokers and the relationship between mutational load and immunogenicity. Thus, this agent is very promising from the early phase 1 data. There are rapid and durable responses observed and it is well tolerated. Results of further investigations are eagerly anticipated as we try to improve the outcome of patients with advanced NSCLC.
— CARE Lung Cancer Faculty