Lessons From the Withdrawal of Atezolizumab in Metastatic TNBC

The landscape of immunotherapy in triple-negative breast cancer (TNBC) has been marked by both rapid breakthroughs and sobering setbacks. One of the most significant shifts occurred following the differing results of the phase 3 IMpassion130 (NCT02425891) and the phase 3 IMpassion131 (NCT03125902) trials, which eventually led to the voluntary withdrawal of the FDA indication for atezolizumab (Tecentriq) in metastatic TNBC.^1-3

While IMpassion130 initially paved the way for an accelerated approval—showing a clear benefit when atezolizumab was paired with nab-paclitaxel—the subsequent IMpassion131 trial failed to replicate these results using a paclitaxel backbone. This discrepancy left the oncology community questioning whether the choice of chemotherapy, the use of concomitant steroids, or trial design nuances were the primary drivers of these conflicting outcomes.

In a recent interview, Sarah Poland, MD, a fellow from the University of Chicago Medicine, explored these take-home lessons for clinicians, emphasizing the vital importance of confirmatory trials and the need to scrutinize the biological interactions between cytotoxic agents and immune checkpoint inhibitors. She delved deeper into this research in her recently published review in ONCOLOGY titled, Advances in Immunotherapy for Breast Cancer.⁴

Transcript:

These are some interesting trials to think about, particularly because their outcomes were so different. There was excitement around atezolizumab initially being FDA approved. The IMpassion trials investigated a PD-L1–blocking agent called atezolizumab, and IMpassion-130 showed that increase in overall survival, and that led to the accelerated FDA approval for atezolizumab. However, the follow-up trial, IMpassion-131, was negative. It didn’t show a significant improvement in progression-free survival in the intention-to-treat population, and atezolizumab didn’t improve overall survival, which was also an important secondary end point. That was in the intention-to-treat population or overall [population], and they even looked specifically in the PD-L1–positive patient population. They again did not see an improvement. That leads us, as a breast cancer and oncology community, to try to figure out why they seemed so different.

You want to look at the baseline patient populations between the 2 trials. Looking at the demographics, those were very similar. [You also want to] look at the control arms to see if they maybe performed differently or even better than expected, particularly in the IMpassion-131 trial, [which] was negative. Looking at the median progression-free survival in the control arms, it was similar between the two: 5.6 months and 5.5 months between the 2 [arms]. However, the median overall survival was quite different, especially in the [PD-L1–positive] patient population in IMpassion-131, which was our negative trial. The median overall survival was 28.3 months with the paclitaxel group vs 17.9 months with the nab-paclitaxel group in the positive trial, IMpassion-130. That does lend itself to thinking, “Could there maybe have been a longer overall survival in a control group than we expected?” As I just mentioned, there were different chemotherapy backbones—paclitaxel as compared with nab-paclitaxel—and paclitaxel does require a steroid pre-medication.

There were some conversations around [whether] giving steroids prior to giving the immunotherapy could potentially blunt an immune response. That’s still debatable. KEYNOTE-355 [NCT02819518] was a positive trial, and it did investigate pembrolizumab [Keytruda] with nab-paclitaxel, paclitaxel, and gemcitabine and carboplatin.⁵ There was no evidence, at least from that trial, that paclitaxel performed worse than nab-paclitaxel. Overall, this is just an important lesson that these trials show how important it is to do confirmatory trials, especially when you get that accelerated FDA approval, just to make sure that we’re giving the most appropriate and the best options for our patients.

References

1. Emens LA, Adams S, Barrios CH, et al. First-line atezolizumab plus nab-paclitaxel for unresectable, locally advanced, or metastatic triple-negative breast cancer: IMpassion130 final overall survival analysis. Ann Oncol. 2021;32(8):983-993. doi:10.1016/j.annonc.2021.05.355
2. Miles D, Gligorov J, André F, et al. Primary results from IMpassion131, a double-blind, placebo-controlled, randomised phase III trial of first-line paclitaxel with or without atezolizumab for unresectable locally advanced/metastatic triple-negative breast cancer. Ann Oncol. 2021;32(8):994-1004. doi:10.1016/j.annonc.2021.05.801
3. Roche provides update on Tecentriq US indication for PD-L1-positive, metastatic triple-negative breast cancer. News release. Roche. August 26, 2021. Accessed February 26, 2026. https://tinyurl.com/36z7fhuf
4. Poland S, de Oliveira Andrade M, Nanda R. Advances in immunotherapy for breast cancer. Oncology (Williston Park). 2026;40(1):8-15. doi: 10.46883/2026.25921061