Historical controls for trials in pancreatic cancer

As of today, clinicaltrials.gov shows that there are 64 Phase II clinical trials for metastatic pancreatic adenocarcinoma that are actively recruiting. These studies aim to identify a signal of clinical efficacy. But what is the appropriate historical control to use for comparison? In 2011, a Phase II study (LINK) in the 1L metastatic setting reported that Gemcitabine (G) + Nab-paclitaxel (A) produced a response rate of 48% with a 1 year survival of 48%. Two years later in 2013, a Phase III study (LINK) was reported which showed that the same treatment regimen in the 1L metastatic setting produced a response rate of 23% and a 1-yr survival of 35%. These are remarkable differences in outcomes reported with the same regimen which likely reflects issues in patient selection bias that inevitably occur between Phase II and Phase III studies. As we here more results of ongoing Phase II studies using GA or FOLFIRINOX backbones in the 1L metastatic setting for pancreatic cancer, we need to mindful of whether the appropriate historical controls are being selected for comparison.

Biomarkers for CD40 immunotherapy

CD40 agonists have been under development for more than 20 years but have yet to become FDA approved. Pre-clinical models of cancer have shown the therapeutic potential for CD40 agonists in cancer. In addition, clear biomarkers of biological activity with CD40 activation have been defined, such as the release of cytokines (IFNg, CCL2) and the activation of monocytes, B cells and dendritic cells. However, these PD markers do not associate with outcomes. We recently found that the neutrophil to lymphocyte ratio (NLR) was a strong and simple prognostic marker of outcome in patients receiving CD40 agonist therapy with chemotherapy (1). Here, a high NLR associates with poor outcome whereas a low NLR associates with a more favorable outcome. Notably, this is a simple and translatable biomarker for selecting patients receiving CD40 immunotherapy. High NLR is an indicator of systemic inflammation and poor ‘immune health’. While many other downstream biomarkers determined by IHC, flow cytometry, or sequencing may also associate with outcomes, the NLR is perhaps the simplest and most straightforward approach to patient selection. It is suggest that trials incorporating immunotherapy should routinely report and discuss this biomarker (i.e. NLR) which may also help provide an assessment of the immunological status of the patients enrolled.

References:

1. Wattenberg et al. Systemic inflammation is a determinant of outcomes of CD40 agonist-based therapy in pancreatic cancer patients. JCI Insight. 2021 Mar 8;6(5):e145389

Welcome to the Beatty Lab Blog

Why a blog you might ask? Because the goal here is to inspire, educate, and guide not just comment and critique. Sure, perspective is commonly part of a writing piece but my hope is that blogging might be a way to disseminate our work with the hope of helping others in the field of cancer immunotherapy. We should all be in this for one goal - to cure cancer and help our patients. So, as I get started with this project, my hope is that my words and shared ideas will foster new paths that are productive, impactful, and rewarding.