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Immunotherapy Wins in Triple-Negative Breast Cancer

— Atezolizumab-chemo combo extends PFS, OS in metastatic disease

Last Updated July 8, 2019
MedpageToday

MUNICH -- An immunotherapy-chemotherapy combination improved both progression-free survival (PFS) and overall survival (OS) in patients with untreated metastatic triple-negative breast cancer (TNBC), according to a study reported here.

Overall, the combination of atezolizumab (Tecentriq) and nab-paclitaxel (Abraxane) led to a modest improvement in median PFS of 7.2 months versus 5.5 months with nab-paclitaxel and placebo. The advantage increased to 2.5 months in the subset of patients with PD-L1-positive tumors at 7.5 versus 5.0 months.

Median OS increased from 17.6 months in placebo group to 21.3 months with the addition of the PD-L1 inhibitor. Patients with PD-L1-positive tumors had a more robust improvement in OS with the addition of atezolizumab (25.0 months versus 15.5 months), reported Peter Schmid, MD, of St. Bartholomew's Breast Cancer Center in London, at the European Society for Medical Oncology congress.

The study was published simultaneously in the .

"These results will change the way triple-negative breast cancer is treated," Schmid said. "Atezolizumab in combination with nab-paclitaxel is the first targeted treatment to improve survival in metastatic triple-negative breast cancer. It is also the first immune therapy to improve outcome in this cancer."

Marlene Kok, MD, of The Netherlands Cancer Institute in Amsterdam, agreed with Schmid that results of the IMpassion30 trial "will probably change the treatment landscape for our metastatic triple-negative breast cancer patients."

"While the benefit, in terms of progression-free survival, was relatively small, the gain in overall survival in the PD-L1-positive subgroup was impressive," said Kok, who noted that about 40% of the patients in the trial had PD-L1-positive tumors.

Focusing on the median PFS in trials of cancer immunotherapy can be misleading, said Schmid. Anti-PD-1 therapy often produces long-lasting responses, which are not accurately reflected in median PFS values. The prolonged responses have the effect of "raising the tail" of survival curves. The reduction in the PFS hazard ratio with the addition of atezolizumab -- 20% in the overall population and almost 40% in the PD-L1-positive subgroup -- is a more useful statistic to gauge the impact of immunotherapy on PFS, he said.

The rationale for evaluating anti-PD-1/L1 therapy in TNBC included the recognition that PD-L1 expression occurs primarily on tumor-infiltrating immune cells rather than on tumor cells, which may inhibit innate anticancer immune responses. Inhibiting PD-1/L1 might be a useful strategy for treating TNBC.

Additionally, nab-paclitaxel may enhance atezolizumab's anticancer activity. Patients treated with conventional paclitaxel often receive steroid premedication, which has been hypothesized to interfere with immunotherapy activity. Selecting nab-paclitaxel to partner with atezolizumab made for a "cleaner" trial design, said Schmid.

The IMpassion130 trial involved patients who had previously untreated metastatic TNBC, as defined by American Society of Clinical Oncology/College of American Pathologists criteria. Patients had a representative tumor specimen adequate for central assessment of PD-L1 expression status (cutoff for a positive test: ≥1% expression in tumor infiltrating cells).

Investigators randomized patients to receive nab-paclitaxel in combination with placebo or atezolizumab. Treatment continued until disease progression or occurrence of unacceptable toxicity.

The trial had two primary efficacy endpoints: investigator-assessed PFS and OS, both evaluated in the intention-to-treat (ITT) population and in the subgroup of patients with PD-L1-positive tumors.

Data analysis included 902 patients enrolled at 246 sites in 41 countries. Schmid reported that 369 patients had PD-L1-positive tumors. Data cutoff occurred after a median follow-up of 12.9 months.

The ITT analysis of PFS yielded a hazard ratio of 0.80 in favor of the atezolizumab arm (95% CI 0.69-0.92, P=0.002). The PFS analysis of the PD-L1-positive subgroup produced an HR 0.62 in favor of the atezolizumab arm (95% CI 0.49-0.78, P<0.001). Schmid reported that 29% of patients in the atezolizumab group and 16.4% of patients in the placebo group were alive without disease progression at 1 year.

The difference in median OS in the ITT population translated into an HR 0.84, which did not achieve statistical significance (95% CI 0.69-1.02, P=0.08). The survival advantage with atezolizumab in the PD-L1-positive subgroup did achieve statistical significance (HR 0.62, 95% CI 0.45-0.86).

The atezolizumab/nab-paclitaxel regimen led to an overall response rate of 56.0% as compared with 45.9% for nab-paclitaxel and placebo. Response rates in the PD-L1-positive subgroup were 58.9% and 42.6% in the atezolizumab and placebo groups, respectively. Median duration of response in the ITT population was 7.4 months with atezolizumab and 5.6 months with placebo. Corresponding values in the PD-L1-positive group were 8.5 and 5.5 months.

A similar proportion of patients in each treatment group had adverse events. The type and severity of adverse events were similar in the groups. Immune-related side effects occurred infrequently, the most common being hypothyroidism (17.3% in the atezolizumab arm, 4.3% in the placebo group).

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    Charles Bankhead is senior editor for oncology and also covers urology, dermatology, and ophthalmology. He joined 鶹ý in 2007.

Disclosures

The trial was supported by F. Hoffmann-La Roche.

Schmid disclosed relevant relationships with F. Hoffman-La Roche, Genentech, AstraZeneca, Oncogenex, Novartis, Astellas, Pfizer, Merck, Boehringer Ingelheim, Bayer, Eisai, Celgene, and Puma.

Primary Source

European Society for Medical Oncology

Schmid P, et al "IMpassion130: Results from a global, randomized, double-blind, phase III study of atezolizumab + nab-paclitaxel vs placebo + nab-P in treatment-naive, locally advanced or metastatic triple-negative breast cancer" ESMO 2018; Abstract LBA1-PR.

Secondary Source

New England Journal of Medicine

Schmid P, et al. "Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer" N Engl J Med 2018; DOI: 10.1056/NEJMoa1809615.