On September 8, 2020, the US Food and Drug Administration (FDA) issued an alert regarding the IMpassion131 trial (ClinicalTrials.gov Identifier: NCT03125902), citing efficacy and potential safety concerns.1 The trial which aimed to recruit 600 patients was testing the combination of atezolizumab and paclitaxel in patients with advanced or metastatic triple-negative metastatic breast cancer (mTNBC).

The trial was a phase 3, multicenter, double-blind, randomized trial of the 2 drugs compared with just paclitaxel and a placebo. The combination of atezolizumab and paclitaxel bound to protein (nab-paclitaxel) is currently approved for the treatment of patients with mTNBC who are programmed cell death ligand 1 (PD-L1)–positive, following significantly improved progression-free survival (PFS) and overall survival (OS) in the IMpassion 130 trial (ClinicalTrials.gov Identifier: NCT02425891).2

IMpassion131 aimed to test the combination of atezolizumab with paclitaxel, as a cheaper and more widely accessible drug than nab-paclitaxel.

“Around the world, nab-paclitaxel is a very expensive drug; it’s not widely available,” said Hal Burstein, MD, PhD, a breast cancer oncologist at Dana-Farber Cancer Institute and professor of medicine at Harvard Medical School in Boston, Massachusetts. “In early-stage studies — most backbone treatments are built around paclitaxel, not nab-paclitaxel, so the company likely wanted to get a parallel study with paclitaxel — to open up for the use of the drug in more parts of the world and enable more clearly the use of the drug in standard acumen programs,” added Dr Burstein.


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The alert expressed efficacy concerns after interim overall survival results showed no significant reduction in risk of cancer progression or death with the combination in patients positive for PD-L1.

“The first overall survival analysis of this study was triggered by the timing of the PFS (event-driven) analysis. At this point only about one-quarter of ‘events’ (deaths) had occurred. As a consequence, this analysis was immature, to say the least,” said David Miles, oncologist at Mount Vernon Cancer Centre in Northwood, UK, and one of the lead investigators of the trial.  “Analysis of overall survival at this time had a small number of events in it, meaning the hazard ratio was in favor of the placebo, but confidence intervals for the analysis were all over the place,” added Dr Miles.

However, the potential safety concerns were raised after the interim analysis showed a slight trend toward greater survival in the placebo and paclitaxel group in both the PD-L1–positive and total population.

“Perhaps people were a little anxious looking for a problem here. Is the atezolizumab compromising our ability to deliver the original chemotherapy; are patients being disadvantaged?” said Dr Miles.

In the work presented at the European Society of Medical Oncology (ESMO) Virtual Congress 2020 on September 19, 2020,3 4 patients (out of 218) had experienced an adverse event with fatal outcome on the paclitaxel and placebo combination, whereas at least 9 patients (out of 431) did on the atezolizumab and paclitaxel combination.

“It could be that the companies were anxious about it and didn’t want to be seen to be underplaying the importance of looking at it more closely. But I think this was a lesson to not analyze an endpoint until you are sure you know what the answer will be; there is all sorts of noise in the system,” said Dr Miles.