Two trials suggest we must be somewhat concerned about the chemotherapy partner used with an immune checkpoint inhibitor in patients with advanced triple-negative breast cancer (TNBC) expressing programmed death–ligand 1 (PD-L1).
In the IMpassion131 trial, the combination of atezolizumab plus paclitaxel showed no improvement in progression-free survival (PFS) or overall survival (OS), compared with placebo plus paclitaxel.
However, results from the IMpassion130 trial showed improved PFS and OS in patients who received atezolizumab plus nab-paclitaxel versus placebo plus nab-paclitaxel.
Results from both trials were presented at the European Society for Medical Oncology Virtual Congress 2020. The divergent results from these trials were the topic of uncertainty and speculation at the congress.
IMpassion130IMpassion130 enrolled 902 patients with locally advanced or metastatic TNBC. They were randomized 1:1 to receive first-line nab-paclitaxel with either atezolizumab or an identical placebo, unselected for but stratified by PD-L1 tumor proportion status. Patients were treated until disease progression or unacceptable toxicity.
Previous results from this trial, published the New England Journal of Medicine, showed improved PFS with atezolizumab plus nab-paclitaxel. These results led to the U.S. approval of atezolizumab plus nab-paclitaxel for PD-L1-expressing, advanced TNBC.
|Leisha A. Emens, MD, PhD, of the University of Pittsburgh Medical Center, presented final OS results from the trial at ESMO 2020.
The median follow-up was 19.7 months in the atezolizumab arm and 18.0 months in the placebo arm.
In the overall population, the median OS with atezolizumab plus nab-paclitaxel was 21 months, which was not significantly different from the median OS of 18.7 months in the placebo arm (hazard ratio, 0.87; P = .077).
However, among the PD-L1-positive patients (about 41% of patients overall), the differences were more dramatic. The median OS was 25.4 months with atezolizumab and 17.9 months with placebo (HR, 0.67; 95% confidence interval, 0.53-0.86).
In the PD-L1-positive patients, this translated to a 3-year OS rate of 36% with atezolizumab and 22% with placebo.
No new safety signals were observed beyond those identified in the prior publication. The rate of adverse events leading to treatment discontinuation was 8% for atezolizumab and 1% for placebo.
Explaining the disparate resultsAfter ESMO 2020, we must be somewhat concerned about the chemotherapy partner used with an immune checkpoint inhibitor. Nab-paclitaxel was effective when combined with atezolizumab, but paclitaxel was not.
ESMO discussant Lisa A. Carey, MD, of the University of North Carolina at Chapel Hill, offered four possible explanations for the disparate results of IMpassion130 and IMpassion131:
• The chemotherapy partner matters. Results from KEYNOTE-355 run counter to this explanation. In patients with PD-L1-positive disease, pembrolizumab paired with a variety of chemotherapy partners produced significant improvements in PFS. In fact, in comparison with other regimens, taxanes (either paclitaxel or nab-paclitaxel) appeared somewhat superior to gemcitabine plus carboplatin.
• Steroid premedication played a role. Steroid premedication is required for paclitaxel but not for nab-paclitaxel. Dr. Carey said this might have impacted the effect of atezolizumab in IMpassion131. Again, KEYNOTE-355 results run counter to this explanation. Steroids were required as premedication for gemcitabine plus carboplatin as well, and this did not negate the benefit of that regimen in combination with pembrolizumab.
• The trial populations differed. Further analysis may prove this to be true, but it is not immediately apparent from the data presented and the analyses conducted thus far.
• The play of chance. Dr. Carey observed that the IMpassion131 hazard ratio of 0.82 for PFS had a 95% CI of 0.60-1.12 that overlapped with the IMpassion130 and KEYNOTE-355 estimates.
|The divergent results of IMpassion130 and IMpassion131 remain unexplained. However, nab-paclitaxel appears to be a completely safe choice to partner with an immune checkpoint inhibitor in PD-L1-positive, advanced TNBC.
For now, outside the context of a clinical trial, paclitaxel should not be used in this setting.
Both studies were funded by F. Hoffman–La Roche. Dr. Miles, Dr. Emens, and Dr. Carey disclosed financial relationships with Roche and other companies.
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.