CheckMate-057 Trial: The Future of PD-L1 as a Biomarker

H. Jack West MD


June 05, 2015

A groundbreaking presentation was delivered by Luis Paz-Ares, MD, in the Special Clinical Science Symposium on Saturday, May 30, on immunotherapy, which included presentations on colorectal cancer, hepatocellular carcinoma, and nonsquamous non-small cell lung cancer (NSCLC). I'll focus on the CheckMate-057 trial[1] of 582 patients with chemotherapy-pretreated advanced nonsquamous NSCLC, randomly assigned to receive second-line docetaxel (Taxotere®) or the PD-1 inhibitor nivolumab (Opdivo®) administered every 2 weeks. We had heard in April from a press release that the trial was stopped and was positive for a survival benefit for nivolumab, but here we saw the actual results of the trial.

It demonstrated a clinically very significant benefit, well beyond mere statistical significance. The response rate was 19 vs 12%, median overall survival (OS) was 9.4 vs 12.2 months, and 1-year OS was 51% vs 39%, all favoring nivolumab. Toxicity was also more favorable for nivolumab, with 5% stopping nivolumab for toxicity issues vs 15% stopping docetaxel.

This was gratifying but not surprising based on what we've seen trickle out in squamous NSCLC (for example, in the package insert[2] for approved nivolumab in this setting, preceding formal presentation of the data). What was most striking was seeing the differences in efficacy depending on whether patients had tumors with PD-L1 expression greater than 1% (so, any PD-L1 expression), which amounted to a little over half of the total patients who had tissue available. In the past few weeks, we've seen news of greater efficacy with the PD-1 inhibitor pembrolizumab (Keytruda®) in NSCLC, but not yet with nivolumab. We also haven't seen or heard of differences in the efficacy of nivolumab based on PD-L1 expression in squamous NSCLC. Here, however, Dr Paz-Ares noted that there was a striking survival and response benefit only in the PD-L1-positive patients, with no benefit vs docetaxel in the patients who were PD-L1 negative. There was also no benefit noted in the subsets of patients who were never-smokers or had an EGFR mutation or ALK rearrangement, so it seems that the patients with a driver mutation don’t have the plethora of immunotherapy-visible targets that those with smoking-induced cancers do.

As I noted, this is practice-changing, but we'll need to see whether the US Food and Drug Administration approves nivolumab for all previously treated nonsquamous NSCLC patients, based on the benefit in the entire population, or limits it to the large subset who are PD-L1 positive. And will oncologists want to do PD-L1 testing to determine an optimal therapy if it's approved in an unselected population? It's interesting to see now that there is converging evidence that PD-L1 is, in fact, a valuable biomarker in NSCLC, potentially for most or all immune checkpoint inhibitors.


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