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).
- US Food and Drug Administration. FDA issues alert about efficacy and potential safety concerns with atezolizumab in combination with paclitaxel for treatment of breast cancer. Published September 8, 2020. Accessed October 30, 2020.
- US Food and Drug Administration. FDA approves atezolizumab for PD-L1 positive unresectable locally advanced or metastatic triple-negative breast cancer. Published March 18, 2019. Accessed October 30, 2020.
- Miles DW, Gligorov J, André F, et al. LBA15 Primary results from IMpassion131, a double-blind placebo-controlled randomised phase III trial of first-line paclitaxel (PAC) ± atezolizumab (atezo) for unresectable locally advanced/metastatic triple-negative breast cancer (mTNBC). Ann Oncol. 2020;31(suppl_4):S1142-S1215. doi:10.1016/annonc/annonc325