Medicine Matters oncology

I've had the privilege of presenting the results of the ETOP 9-15 PROMISE-meso trial on behalf of my co-investigators. Now, this is a randomized phase III trial for patients with relapsed malignant pleural mesothelioma. All histologies were eligible, and patients had to have good performance status with PS-0 or 1 and adequate organ function.

Patients were randomized into one-by-one manner stratified by histology to either the investigational arm of pembrolizumab monotherapy and given a flat dose of 200 milligrams daily until progression or treatment beyond progression in case of ongoing clinical benefit, or for a maximum of two years, or to the standard arm of investigator choice chemotherapy, which was either gemcitabine chemotherapy or vinorelbine chemotherapy, both as monotherapies.

Importantly, patients that were randomized to chemotherapy could crossover to pembrolizumab monotherapy at the time of progression.

A total of 144 patients were randomized, results in about 70 patients per arm. The primary endpoint of the study was to evaluate to see whether pembrolizumab increased the progression-free survival compared to chemotherapy. Unfortunately, the primary endpoint was not met in this study. Pembrolizumab did not improve progression-free survival over standard chemotherapy. But the progression-free survival curves were very, very similar and overlapping.

When we look at secondary endpoints, we see that the response rate for pembrolizumab is nearly four times higher than what we see with chemotherapy, with a response rate of 22% compared to 6%, which is statistically significant. The duration of response, however, was similar between the two arms, without any significant differences.

When we look at the waterfall plots we can clearly see that the benefit of pembrolizumab is that there are a higher number of responses which are deeper than what we see with chemotherapy. When we look at the key secondary endpoint of overall survival, unfortunately there was no significant difference with overall survival with pembrolizumab compared to chemotherapy.

We tried to account for the significant crossover, because nearly 63% of patients crossed over from chemotherapy to pembrolizumab. And taking account of crossover, we still didn't statistically see a difference in overall survival. But that question is still ongoing, as to what the role of crossover is in this study.

We did perform some exploratory analyses by PD-L1 status using the E1L3N clone, but didn't see an obvious signal that PD-L1 positivity was associated with benefit with pembrolizumab.

So in summary, unfortunately pembrolizumab did not meet the primary endpoint of prolonging progression-free survival. However, this is a drug which still definitely shows activity in this disease.

Given the comparable survival, could pembrolizumab be an option for patients unable to tolerate chemotherapy?

So the study was statistically designed to test the hypothesis that pembrolizumab was superior in progression-free survival to chemotherapy. And the hypothesis was rejected. So we cannot say it's superior. It was not designed to test for non-inferiority. So all we can say from this trial is it's not superior.

However, when we look at the curves, they are overlapping. And we know that there's a higher response rate from pembrolizumab compared to chemotherapy. And we know that there was a big crossover to the pembrolizumab arm from the chemotherapy arm, which is likely making overall survival a very difficult endpoint to interpret. So therefore, in this setting, if individual clinicians wanted to use pembrolizumab in this scenario, of course they're at liberty to do so, but understanding the limitations of the trial data set that we have.

What is next for immunotherapy in this setting?

So the question is really how we take checkpoint inhibitors forward. And I think with the data that we have thus far in second line relapsed mesothelioma, if we draw the parallel of where we've been with lung cancer, particularly non-small cell lung cancer, we get better efficacy in the front line setting. So therefore, what we're doing now is combining immunotherapy with chemotherapy in the front line setting.

Indeed, the ETOP academic group is already running and leading a trial called BEAT-Meso, in which all patients receive combination chemotherapy plus bevacizumab, carboplatin, pemetrexed, bevacizumab, and randomized to receiving either atezolizumab or not on top of that.