We all want immunotherapy to “work” for breast cancer patients. For the National Breast Cancer Coalition, that means therapy that will significantly prolong survival without adverse impact on quality of life. We expect that the evidence of that benefit will be shown by well-designed, well conducted prospective randomized clinical trials, sufficiently powered to support that result. The tale of atezolizumab shows us we are not there yet.
Not that long ago, many in the medical oncology community celebrated a “practice changing” result from Impassion130, a Phase III randomized clinical trial of atezolizumab (Tecentriq®), a PD-L1 immune checkpoint inhibitor, combined with nab-paclitaxel (Abraxane®) in patients with triple-negative breast cancer (TNBC).,, That excitement was a reaction to an analysis of a subgroup of patients with PD-L1+ tumors that suggested a benefit in overall survival, which the trial was not powered to test (meaning it didn’t include enough people to answer that question). But the drug was approved anyway under FDA accelerated approval and now costs around $13,450 per month, depending on the dosage schedule. There are now over 70 breast cancer clinical trials registered on clinicaltrials.gov that include this checkpoint inhibitor. One of them, the Phase III Impassion131 trial, recently has reported very different results from the previous trial.
On August 6, 2020, Genentech (a subsidiary of Roche) issued a press release reporting key preliminary results from its Impassion131 trial, which is testing atezolizumab or placebo combined with paclitaxel (chemotherapy) in first-line advanced or metastatic triple-negative breast cancer (TNBC). We expect that these results will be published in a peer reviewed journal. Atezolizumab plus paclitaxel failed to demonstrate improvement in its primary endpoint of progression-free survival (PFS) compared to paclitaxel alone. Moreover, the early results suggest that the treatment combination may have a negative or worsening impact on overall survival in TNBC patients, although the results are immature, and the investigators note that the study wasn’t powered to detect a change in overall survival. Also troubling is the fact that patients in this trial were randomized in a 2 to 1 fashion with twice as many patients in the atezolizumab arm. The results of Impassion131 present a complete reversal of findings reported in The Lancet in January 2020 from their Impassion130 trial.
Impassion130 served as the basis for atezolizumab’s accelerated approval by the U.S. Food and Drug Administration. That trial reported a statistically significant improvement in PFS of about 2.6 months in the intention-to-treat (ITT) population compared to the control group treated with nab-paclitaxel alone [7.4 months (6.6-9.2) versus 4.8 months (3.8-5.5). However, in the ITT population, median overall survival was not significantly improved, being 21·0 months (95% CI 19·0–22·6) with atezolizumab and 18·7 months (16·9–20·3) with placebo and nab-paclitaxel (stratified hazard ratio [HR] 0·86, 95% CI 0·72– 1·02, p=0·078).
While 2.6 months of improved PFS and no OS benefit doesn’t sound very impactful, a subgroup analysis in Impassion130 found that among those patients who showed ≥1% PD-L1 positive expression (N=369 of 902 total patients), for patients receiving atezolizumab plus nab-paclitaxel there was a 7-month increase in overall survival compared to those treated with nab-paclitaxel alone. Median overall survival in this smaller subgroup of patients was 25·0 months (95% CI 19·6–30·7) with atezolizumab versus 18·0 months (13·6–20·1) with placebo (stratified HR 0·71, 0·54–0·94]). Despite the fact that this was a subgroup analysis and not powered for the outcome reported, the researchers suggested that the difference represented a clinically meaningful overall survival benefit of atezolizumab in patients with PD-L1 immune cell-positive disease. But the fact remains that we have no idea if this finding is statistically significant because, again, this was a subgroup analysis, and the trial was not powered for this analysis. As such, under the rules of evidence, the finding should be considered hypothesis-generating and not evidence of anything, let alone clinical benefit.
So why the different results between Impassion130 and Impassion131, and what does it mean for the other four ongoing Impassion trials? You can find the description of the four Impassion trials and the over 60 additional trials of this drug, on clinicaltrials.gov.
Some have begun speculating that the different findings for Impassion130 and 131 have something to do with the choice of chemotherapy. In the earlier Impassion130 trial, the investigators employed Abraxane (nab-paclitaxel; an albumin-bound paclitaxel) instead of paclitaxel, arguing that it was a better choice because it doesn’t require upfront use of steroids which might have the effect of tempering the activity of the PD-LI inhibitor. However, that concern didn’t impact on the selection of paclitaxel in Impassion131, or two other ongoing Impassion trials (Impassion030 and 050) which both employ paclitaxel, along with another dozen or so trials listed in clinicaltrials.gov.
Or perhaps the positive results were the result of a type 1 error (false positive). We do not know. The FDA used to require evidence from at least two adequate and well-controlled studies, each convincing on its own, to establish effectiveness, largely for this reason. But those requirements have been relaxed in an effort to speed treatments to patients under accelerated approval on the proviso that should subsequent studies not demonstrate clinical benefit, their approval would be withdrawn.
What do these results mean for patients? We would argue that we really have no idea if atezolizumab is effective in breast cancer. The only results that we have in the setting of breast cancer from appropriately powered analyses show no overall survival benefit with atezolizumab, or a negative trend in OS, and either no or a 2.6-month benefit of PFS in patients with TNBC, regardless of their PD-L1 expression. That is what we “know” today.
We are all desperate to find interventions that will save lives or significantly prolong lives without reducing the quality of life. We shouldn’t accept less than real, high-level evidence that approved treatments actually do this. It is sobering to see that in a search of clinicaltrials.gov, there are currently 71 studies with planned accrual of over 26,000 patients examining the use of atezolizumab in breast cancer. All of this research, and yet we really don’t have a clear understanding of how these immune checkpoint inhibitors interact with other therapies and how these combination regimens will work in patients and what the right population should be.
Genentech’s press release, and we appreciate its transparency, is a key reminder that we need to be on guard and informed about the true value of a particular trial. An educated and informed advocacy community must understand these issues, continue to question researchers, industry, and clinicians, and be at the table when decisions are made. NBCC will continue to provide objective education and training opportunities to advocates everywhere.
Under the current rules of accelerated approval, we call on the FDA to withdraw of approval for Atezolizumab in this particular setting until clear evidence of clinical benefit can be demonstrated. We also hope that this will trigger an important discussion about accelerated approval in general, the cost of therapies, and the evaluation of trials ongoing or planned to ensure that they are not endangering patients’ lives.
 Schmid P, Rugo HS, Adams S, et al. Atezolizumab plus nab-paclitaxel as first-line treatment for unresectable, locally advanced or metastatic triple-negative breast cancer (IMpassion130): updated efficacy results from a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2020;21(1):44-59. doi:10.1016/S1470-
 Schmid P, Adams S, Rugo HS, et al. Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative Breast Cancer. N Engl J Med. 2018;379(22):2108-2121. doi:10.1056/NEJMoa1809615 https://www.nejm.org/doi/full/10.1056/nejmoa1809615
 Schmid P, Rugo HS, Adams S, et al. Atezolizumab plus nab-paclitaxel as first-line treatment for unresectable, locally advanced or metastatic triple-negative breast cancer (IMpassion130): updated efficacy results from a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2020;21(1):44-59.
 Schmid P, Adams S, Rugo HS, et al. Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative Breast Cancer. N Engl J Med. 2018;379(22):2108-2121. doi:10.1056/NEJMoa1809615
 Of the ongoing breast cancer trials listed on CT.gov, only four are listed as complete and three were terminated. A total of 47 are actively recruiting and 14 have completed recruitment. In addition, 13 are Phase III trials, 27 Phase II, and 9, Phase I/II. Many of these were first posted in 2019 and 2020, and are exploring the use of the checkpoint inhibitor in a variety of breast cancer subtypes and with varied combination regimens.