MUNICH – For the first time, a combination of an immune checkpoint inhibitor and a taxane has shown significant clinical benefit in patients with metastatic triple-negative breast cancer in a phase 3 trial, but the benefit was seen only in patients positive for programmed death-ligand 1 (PD-L1), investigators reported.

Among 902 patients with untreated metastatic triple-negative breast cancer (mTNBC) randomly assigned to receive the PD-L1 inhibitor atezolizumab (Tecentriq) plus nanoparticle albumin-bound (nab)-paclitaxel or placebo plus nab-paclitaxel, atezolizumab was associated with a 38% improvement in median overall survival among patients with PD-L1–positive disease in an interim analysis of the IMpassion 130 trial.

However, although there was a significant progression-free survival (PFS) benefit with atezolizumab in an intention-to-treat (ITT) analysis that included patients with PD-L1 negative tumors, there was no significant difference in median overall survival (OS) when all patients were considered together, said Peter Schmid, MD, PhD, Barts Cancer Institute, Queen Mary University of London.

“For patients with PD-L1–positive tumors, these data establish atezolizumab and nab-paclitaxel as a new standard of care,” he said at the European Society for Medical Oncology Congress.

The results were published online in the New England Journal of Medicine to coincide with the presentation of the data.

At a briefing prior to presentation of the data in a symposium, discussant Nadia Harbeck, MD, of the University of Munich Medical Center, a breast cancer specialist, confessed to being of envious of her colleagues in other oncology specialties in which immunotherapy has made great inroads.

“We have a lot of patients out there right now in clinical trials with immune therapy, but so far in breast cancer, we have not seen the tremendous effects we have seen in melanoma or lung cancer, so this is the first time we have a phase 3 trial proving that immune therapy in triple-negative breast cancer improves survival, and I think this is something that will change the way we practice in triple-negative breast cancer,” she said.

The rationale for using a PD-L1 inhibitor comes from the discovery that PD-L1 expression occurs primarily on tumor-infiltrating cells in TNBC rather than on tumor cells, which can inhibit immune responses directed against tumors.

The investigators enrolled 902 patients with previously untreated mTNBC and randomly assigned them to receive nab-paclitaxel 100 mg/m² intravenously on days 1, 8, and 15 of each 28-day cycle, plus either atezolizumab 804 mg intravenously or placebo on days 1 and 15 of each cycle.

Patients were stratified according to whether they received neoadjuvant or adjuvant taxane therapy, the presence of liver metastases at baseline, and PD-L1 expression at baseline.

Treatment was continued until disease progression or unacceptable toxicity.

The primary endpoints were PFS and OS in both the ITT and PD-L1–positive population.

In the ITT analysis, 1-year PFS rate was significantly improved in the atezolizumab arm, at 24% vs. 18% in the placebo arm. This translated into a stratified hazard ratio of 0.80 (P = .0025).

In the analysis restricted to the PD-L1-positive population (369 patients), the 1-year PFS rates were 29% for atezolizumab vs. 16% for placebo, translating into to an HR of 0.62 (P less than .0001).

As noted before, the interim OS analysis in the PD-L1 population showed a clinical benefit with atezolizumab, with a 2-year OS rate of 54% vs. 37%, respectively. The median OS in this analysis was 25 months with atezolizumab, vs. 15.5 months with placebo. The stratified HR favoring the PD-L1 inhibitor was 0.62, but because of the hierarchical statistical analysis design of the trial, formal testing of OS was not performed for the interim analysis.

Adverse events of any kind occurred in 99.3% of patients assigned to atezolizumab/nab-paclitaxel and 97.9% of those assigned to placebo/nab-paclitaxel.

Grade 1 or 2 immune-related hypothyroidism occurred more frequently with atezolizumab (17.3% vs. 4.3%), but none led to discontinuation of the drug regimen.

Six patients assigned to atezolizumab and three assigned to placebo died. Four of the deaths were deemed by investigators to be related to the trial regimen, include three deaths in the atezolizumab arm (from autoimmune hepatitis, mucosal inflammation, and septic shock), and one death in the placebo arm (from hepatic failure).

“A benefit with atezolizumab/nab-paclitaxel in patients with PD-L1–positive tumors that was shown in our trial provides evidence of the efficacy of immunotherapy in at least a subset of patients. It is important for patients’ PD-L1 expression status on tumor-infiltrating immune cells to be taken into consideration to inform treatment choices for patients with metastatic triple-negative breast cancer,” Dr. Schmid and his colleagues wrote in the study’s conclusion.

“I really do think that these results are going to make a very big difference,” said coinvestigator Hope S. Rugo, MD, a clinical professor of medicine and director of the Breast Oncology Clinical Trials Program at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center.

“We believed from the phase 1 data and the less-than-exciting phase 2 data that there was clearly some role for immunotherapy in breast cancer but were really struggling as to what that role was. We knew for example that if they had a response, patients lived longer and really dramatically longer,” she said in an interview.

But unlike the clinical revolution brought about by the introduction of trastuzumab, in which clinicians had a biomarker and a large number of patients benefited, “here we have no biomarker and a small number of patients benefited, but the benefit is huge,” she said.

Giuseppe Curigliano, MD, PhD, from the University of Milan and European Cancer Institute, Italy, the invited discussant at the symposium, agreed that the study “brings breast cancer into the immunotherapy era.”

Dr. Curigliano added, however, that the study was missing an arm – atezolizumab alone, which might be a good option for a subset of patients.

He also questioned whether nab-paclitaxel was the best partner for atezolizumab, vs. other drugs with known immunogenic effects, such as doxorubicin, cyclophosphamide, other taxanes, gemcitabine, or platinum salts.

The study was supported by F. Hoffmann–La Roche/Genentech. Dr. Schmid reported grant and nonfinancial support from Roche. Multiple coauthors reported financial relationships with Roche/Genentech and others. Dr. Harbeck has disclosed honoraria from and serving as a consultant for Roche and others. Dr. Rugo disclosed grants and nonfinancial support from F. Hoffmann–La Roche. Dr. Curigliano disclosed consulting/advising, speakers bureau participation, and travel/accommodations from Roche/Genentech.

SOURCE: Schmid P et al. N Engl J Med. 2018 Oct 20. doi: 10.1056/NEJMoa1809615.

Finally, immunotherapy shows benefit in TNBC