Metastatic NSCLC: Interpreting Data From NEPTUNE

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Suresh Ramalingam, MD: As interest in tumor mutation burden as a potential predictor biomarker grew, a number of studies have now been conducted to look at that in prospective clinical trials. Now, first let us take a step back and see why tumor mutation burden is relevant. The hypothesis is if a tumor has more mutations, it is likely that there will be more mutated neoantigens. And these neoantigens are now recognized by the immune system. So, if a tumor has high tumor mutation burden, the immune system has a better chance of seeing these new antigens and mounting an anti-tumor response.

We’ve seen studies that show a favorable trend toward outcomes with immunotherapy in patients with high tumor mutation burden. Tumor mutation burden can be measured in the tissue, and more recently it’s also been studied in the blood, which makes it easier to do it. Peripheral blood now is not only used for understanding resistance mechanisms to targeted therapy, but it can also be used to look at tumor mutation burden.

The NEPTUNE study was a prospective clinical trial to look at the combination of durvalumab and tremelimumab, basically PD-L1 [programmed death-ligand 1] inhibition in combination with CTLA-4 [cytotoxic T-lymphocyte—associated protein 4] inhibition, specifically in patients with high blood tumor mutation burden. The trial enrolled patients with blood tumor mutation greater than 20 mutations per mega base, and they were randomized to chemotherapy, standard platinum-based chemotherapy, or tremelimumab plus durvalumab combination.

There was a lot of anticipation that this could actually lead to a very simple way to test for mutations and then treat patients. The full results of NEPTUNE have not been reported, but what we heard from a press release was that the study did not meet the primary endpoint. This does raise the question of is it a function of the biomarker being not sufficiently good to predict which patients would benefit, or is it that the regimen of tremelimumab and durvalumab was not sufficiently efficacious to improve outcomes for patients? We’ll know more as the results of these studies report out.

There are other studies with durvalumab and tremelimumab that are being studied. There’s a study of chemotherapy plus durvalumab and tremelimumab compared to chemotherapy alone that’s ongoing and has not been reported. We will look forward to those results as well. There’s also another trial that compares durvalumab to chemotherapy in patients with advanced stage non—small cell lung cancer in the frontline setting. So the role of where durvalumab fits in in the frontline and what the role of durvalumab plus tremelimumab is are still open questions. What the NEPTUNE press release tells us is that the blood-based biomarker using 20 as a cutoff was not helpful in identifying which patients will benefit from the combination of durvalumab and tremelimumab.

Transcript Edited for Clarity