FDA Issues Efficacy and Safety Warning Based on Results From IMpassion131

By: Victoria Forster, PhD

From: cancertherapyadvisor.com

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.

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.

The updated data presented at ESMO 2020 confirm that there is no statistically significant survival benefit to the paclitaxel and atezolizumab combination, but questions still remain as to why concerns about safety of the combination were raised.

“If there truly is an adverse effect on OS, which there isn’t, is this due to high-grade adverse effects due to treatment? There was no evidence of this. No excess mortality because of the treatment and no survival difference between these 2 groups,” said Dr Miles.

Other adverse events reportedly occurred at a frequency and severity that would be expected with the combination.

“Ordinarily, a safety alert would go out when new or unrecognized side effects were occurring. But the safety profile was exactly as predicted from the drugs used and their known side effects. So, I think the safety alert was about a perceived potential adverse effect in patient outcome,” Dr Miles said.

“I think at some level, the FDA concern was that clinicians would substitute old-fashioned paclitaxel for nab-paclitaxel — they wanted to alert people that this isn’t the right thing to do and perhaps there were negative consequences beyond it being just ineffective,” said Dr Burstein.

As opposed to the use of nab-paclitaxel in IMpassion130, steroid pretreatment is required with conventional paclitaxel. Could this additional drug be why IMpassion131 did not show the same survival benefit as seen in IMpassion130?

Answered Dr Burstein: “The steroid pretreatment is not likely to be responsible. There are many situations where we use steroids and immune checkpoint inhibition together and there haven’t been these concerns.”

On this question, Dr Miles said: “This is possible, however, when you look at other studies of PD-1 inhibition, people do use steroids and this generally does not seem to impact response.”

So if not the steroids, why was the study with nab-paclitaxel positive and the study with paclitaxel, negative?

“Nobody has a good answer for this, except perhaps regression to the mean. One should not underestimate the play of chance here, if you do the same experiment 10 times, there will always be regression to the mean,” said Dr Burstein.

Both the IMpassion130 and IMpassion131 trials had similar numbers of patients who were considered to be PD-L1–positive, as well as other similar demographics. So what is next for trying to figure out why IMpassion131 did not replicate the positive results of IMpassion130?

“There are lots of biomarkers that will be looked at from bloods taken on these patients. But our understanding of these agents and how they are best used and who benefits most is currently pretty limited. We are a long way from understanding how we best target those people likely to benefit from it, and looking at a single biomarker like PD-L1 is only one small piece towards understanding,” said Dr Miles.

Disclosures: Dr Miles has received honoraria for consultancy/advisory boards from Roche/Genentech, Eisai, and Genomic Health (as listed on title slide of his ESMO presentation).

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