IMMUNOTHERAPY APPEARS to be the new upfront standard of care for patients with metastatic triple-negative breast cancer, based on a late-breaking presentation at the European Society for Medical Oncology (ESMO) 2018 Congress¹ and simultaneously published in The New England Journal of Medicine.²

In the phase III IMpassion130 trial, first-line treatment with atezolizumab (Tecentriq) plus nanoparticle albumin-bound (nab)-paclitaxel (Abraxane) significantly improved progression-free survival over chemotherapy alone and yielded a numerical benefit in overall survival. The results were most striking for the 41% of patients expressing the programmed cell death ligand 1 (PD-L1).

Peter Schmid, MD, PhD

In PD-L1–positive patients, the risk of disease progression was reduced by 38% and median overall survival was improved from 15.5 months in the control arm to 25.0 months with atezolizumab plus nab-paclitaxel, reported lead investigator Peter Schmid, MD, PhD, Clinical Director of St. Bartholomew’s Breast Cancer Centre and Lead of the Centre for Experimental Cancer Medicine, Barts Cancer Institute, London.

“Atezolizumab in combination with nab-paclitaxel is the first targeted treatment and the first immune therapy to improve survival in metastatic triple-negative breast cancer,” Dr. Schmid said. “For patients with PD-L1–positive tumors, these data establish atezolizumab plus nab-paclitaxel as a new standard of care.”

Other breast cancer experts agreed the regimen will greatly improve the prognosis of this challenging breast cancer subset. Nadia Harbeck, MD, PhD, Head of the Breast Center at the University of Munich, told journalists, “So far, we’ve not seen the tremendous impact of immunotherapy in breast cancer that we’ve seen in melanoma and lung cancer. Now, in a phase III trial, we see a survival benefit. This is something that will change the way we practice.”

Nadia Harbeck, MD, PhD

Marleen Kok, MD

Marleen Kok, MD, of the Netherlands Cancer Institute, Amsterdam, commented, “While the benefit in terms of progression-free survival was relatively small—around 3 months—the gain in overall survival in the PD-L1–positive subgroup was impressive, with a 10-month benefit. The IMpassion130 data will probably change the treatment landscape for our patients with metastatic triple-negative breast cancer.”

IMpassion 130 Details

The phase III IMpassion 130 trial enrolled 902 patients with metastatic triple-negative breast cancer who had received no prior treatment for metastatic disease. Patients were randomly allocated to receive standard chemotherapy (nab-paclitaxel) plus atezolizumab, an anti–PD-L1 antibody, or nab-paclitaxel plus placebo.

The investigators paired the checkpoint blocker with nab-paclitaxel to avoid the use of steroids, which are usually given with paclitaxel, Dr. Schmid said. “At the time the study was designed, there was a question of whether the use of steroids could interfere with the activity of immunotherapy. Nab-paclitaxel and paclitaxel have similar activity in metastatic breast cancer, but nab-paclitaxel does not require the use of steroids. We wanted to have the cleanest design and give the best possible chance to establish whether immune therapy adds to the benefit of chemotherapy.”

Patients were randomly assigned to receive nab-paclitaxel at 100 mg/m2 on days 1, 8, and 15 of a 28-day cycle plus placebo or atezolizumab at 840 mg intravenously (n = 451) on days 1 and 15.

The co-primary endpoints were progression-free survival and overall survival in both the intent-to-treat and PD-L1–positive populations. PD-L1 positivity was defined as ≥ 1% expression on tumor-infiltrating immune cells.

Impressive Hazard Ratios

THE COMBINATION therapy reduced the risk of disease progression or death by 20% in all patients and by 38% in the subgroup expressing PD-L1—which accounted for 41% of all patients. In the entire study population, by intent-to-treat analysis, the median progression-free survival was 7.2 months with the combination vs 5.5 months with chemotherapy alone (hazard ratio [HR] = 0.80, P = .0025). In the PD-L1–positive group, these numbers were 7.5 months vs 5.0 months (HR = 0.62, P < .0001).

With more than half the patients still alive, this was an interim analysis for overall survival, but the trend was clear, especially for the PD-L1–positive subgroup. Their median overall survival was 25.0 months with the combination compared to 15.5 months with nab-paclitaxel alone (HR = 0.62). Overall survival at 2 years was 54% and 37%, respectively. In all patients, survival was 21.3 months with the combination vs 17.6 months with chemotherapy alone (HR = 0.84; P = .0840), with 2-year survival rates of 42% and 40%, respectively, Dr. Schmid reported. He noted that a formal analysis of survival was not yet performed due to the study’s hierarchical design.

Responses were observed in 56% of all patients on the combination vs 46% of the control arm and in 59% and 43%, respectively, in the PD-L1–positive subgroup. Moreover, in the PD-L1– positive subset, 10% of patients achieved complete responses, and responses were more durable (median = 8.5 months). With the exception of PD-L1–negative tumors, a benefit of the combination was observed across all subgroups except for those with PD-L1–negative disease, Dr. Schmid reported.

Benefit in PD-L1–Positive Subset Alone

BASED ON preclinical studies and phase Ib research in triple-negative breast cancer and the activity of atezolizumab in non–small cell lung cancer, the researchers expected some degree of benefit in all comers, especially when given with chemotherapy, which enhances the immune microenvironment, he said. “We had a clear rationale why the biomarker (PD-L1) would not be as binary as it now appears. We had hoped we could widen the population of patients who could benefit.”

“But this is clearly a PD-L1–positive story,” he told journalists. “Although the intent-to-treat analysis is positive, if you look at the PD-L1–negative subgroup, you see no benefit justifying the use of atezolizumab in this group.”

Dr. Schmid added that the focus should be on the hazard ratios rather than the absolute differences. “If this were just a progression-free survival story, I would agree the findings are modest, but focusing on the medians can be misleading,” he said. “The important message is that we see the same hazard ratio in overall survival as for progression-free survival. Also, there is nearly a 10-month difference in overall survival, in a disease where we have not managed to improve survival at all.”

“Once [atezolizumab] is implemented [in this setting] in practice, it will generate more research, and we will amplify the findings we have observed.”

— Fabrice André, MD

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Fabrice André, MD, of the Institute Gustave Roussy in Villejuif, France, commented further on this point: “Once the drug is implemented in practice, it will generate more research, and we will amplify the findings we have observed. We will move the improvement from several months to several years.”

Combination Well Tolerated

ATEZOLIZUMAB PLUS nab-paclitaxel was well tolerated, with most adverse events related to the chemotherapy and similar between the arms. The most common grade 3/4 adverse events with atezolizumab/nab-paclitaxel and nab-paclitaxel alone, respectively, were neutropenia (8% vs 8%), decreased neutrophil count (5% vs 3%), peripheral neuropathy (6% vs 3%), fatigue (4% vs 3%), and anemia (3% vs 3%). Immune-related adverse events were rare, the most common being hypothyroidism in 17.3% of patients receiving the drug combination and 4.3% receiving chemotherapy alone.

Three deaths in the atezolizumab/nab-paclitaxel group (from autoimmune hepatitis, mucosal inflammation, and septic shock, in one patient each) and one death in the placebo/nab-paclitaxel group (from hepatic failure) were considered by the investigators to be related to the trial regimen. ■  

DISCLOSURE: Dr. Schmid has received grants and non-financial support from F. Hoffmann-LaRoche during the conduct of the study; grants and other support from AstraZeneca, Roche/Genentech, OncoGenex, Novartis, and Astellas; personal fees from Pfizer, AstraZeneca, Novartis, Roche, Merck, Boehringer Ingelheim, Bayer, Eisai, Celgene, and Puma; and is a uncompensated steering committee member for the IMpassion130 trial. Dr. Harbeck has received honoraria for lectures and consulting from Agendia, Amgen, AstraZeneca, Celgene, Daiichi-Sankyo, Genomic Health, Lilly, MSD, Nanostring, Novartis, Odonate, Pfizer, Roche, Sandoz/Hexal, and Seattle Genetics. Dr. Kok has received institutional funding from BMS and Roche. Dr. André reported no conflicts of interest.

REFERENCES

1. Schmid P, Adams S, Rugo HS, et al: IMpassion 130: Results from a global, randomized, double-blind, phase 3 study of atezolizumab + nab-paclitaxel vs placebo + nab-paclitaxel in treatment-naive, locally advanced or metastatic triple-negative breast cancer. ESMO 2018 Congress. Abstract LBA1_PR. Presented October 20, 2018.

2. Schmid P, Adams S, Rugo HS, et al: Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med. October 20, 2018 (early release online).