Biomarkers Employed in CheckMate 739 for Patients With MPM

Solange Peters, MD, PhD, the president of the European Society of Medical Oncology (ESMO), discusses the biomarkers for immunotherapy used in the phase 3 CheckMate 743 trial (NCT02899299).

CheckMate 743 evaluated the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) in over 600 patients with untreated malignant pleural mesothelioma (MPM). Findings revealed that when used together, the combination significantly extended overall survival (OS) in patients with MPM and showed better results compared with patients who received platinum-based chemotherapy.

Peters explains the importance of the 3 biomarkers employed in the trial which included tumor mutational burden, lung immune prognostic index (LIPI), and an inflammatory signature. Each of these biomarkers showed promise in helping to predict which patients benefit from immunotherapy, if the combination was more effective than chemotherapy alone, if nivolumab and ipilimumab showed stronger benefits, and more.

Transcription:

0:08 | We tried to look at 3 important biomarkers for immunotherapy. The first one, which was not predictive, is TMB, or tumor mutational burden. We took the patients in this trial and evaluated the number of mutations, counting somatic missense mutations, and classified a patient into 3 subgroups: low, intermediate, or high [TMB]. Looking at TMB, what was interesting is to see that nivolumab/ipilimumab was better than chemotherapy across [both arms], and equivalently. TMB was not at all predictive of the added value of nivolumab/ipilimumab versus chemo in that trial. [TMB] is not a biomarker in mesothelioma. Let's keep in mind that in mesothelioma, the number of mutations in the disease is quite low, as compared, for example, to non–small cell lung cancer where it's up to 10 times higher.

1:06 | The second biomarker we looked at is the LIPI. This is an important index because it has been shown to be strongly prognostic in non–small cell lung cancer. The LIPI score assesses lactate dehydrogenase as well as the derived neutrophil-to-lymphocyte ratio from peripheral blood samples. In the trial, the LIPI was prognostic, but not at all predictive. Again, [it did not help] to predict who benefits from IO.

1:36 | The most promising is a third one. We look at what we call an inflammatory signature. Here we used a signature which was also shown to correlate with other larger inflammatory signatures. It's looking at the RNA level by RNA sequencing at 4 genes: CD8A, STAT-1, LAG-3, and PD-L1. You can create a Z-score and classify patients by a high or low relative to the median across the whole data set, so you're above or under the median. By doing that, we are able to show that when gene inflammatory signature score was high, it was predicting a way stronger benefit of nivolumab/ipilimumab as compared with the low inflammatory signature score subgroup at 2 years, with 35% of living patients in the high inflammatory score level versus 15% in the low inflammatory score level.