Atezolizumab Combo Approved for PD-L1–positive TNBC

The first immune checkpoint inhibitor regimen for breast cancer earned FDA approval on March 8, when the FDA greenlighted atezolizumab (Tecentriq; Genentech), a PD-L1–targeted antibody, in combination with nab-paclitaxel (Abraxane; Celgene) for patients with locally advanced or metastatic triple-negative breast cancer (TNBC) expressing PD-L1.

“This is exciting because it's the first monoclonal antibody therapy approved for triple-negative breast cancer and the first immunotherapy for any type of breast cancer,” says Leisha Emens, MD, PhD, of the University of Pittsburgh's Hillman Cancer Center in Pennsylvania. “So, it really fulfills an unmet medical need.”

The agency made its decision based on data from the IMpassion130 study led by Emens and Peter Schmid, MD, PhD, of Barts Cancer Institute in London, UK. As reported last November, the 902-patient trial found that treatment with atezolizumab plus nab-paclitaxel had a modest benefit in the overall study population. However, participants with PD-L1–positive tumors reaped clinically meaningful survival benefits from the combination, with a median progression-free survival of 7.5 months, compared with 5 months for placebo plus nab-paclitaxel; median overall survival was 25 months and 15.5 months, respectively.

“That's the largest overall survival benefit ever seen for patients with triple-negative metastatic breast cancer,” says Shom Goel, MD, PhD, of Dana-Farber Cancer Institute in Boston, MA, who was not involved in the study. “However, there are caveats to the way we apply the results of this trial.”

For one thing, says Goel, care should be taken when employing the Ventana PD-L1 (SP142) Assay (Roche), a companion diagnostic approved to determine which patients are eligible for the regimen. Multiple studies comparing different commercially available PD-L1 assays have shown that the new test comes to different quantitative conclusions than other assays. Thus, “training pathologists to interpret this assay to ensure reproducibility will be critical,” he says.

Another issue is patient selection. IMpassion130 excluded patients who received prior treatment for metastatic disease. The FDA approval does place similar restrictions on the drug regimen, “but at the moment, we don't have strong evidence for using this approach outside of the first-line setting,” notes Goel.

The trial also left out anyone whose cancer progressed following adjuvant or neoadjuvant chemotherapy within a year of starting the trial. Ultimately, the study population skewed toward individuals who either had not received any previous treatment or had less aggressive tumors that responded favorably to initial curative-intent treatment.

It's thus unclear whether atezolizumab will benefit patients who relapse within 12 months of initial adjuvant or neoadjuvant therapy, says Sherene Loi, MD, PhD, a trial investigator from the Peter MacCallum Cancer Centre in Melbourne, Australia. “We still have much to learn in order to help the people with the most aggressive TNBC disease,” she says. The ongoing IMpassion132 study is testing the combination of atezolizumab plus investigator's choice of gemcitabine and carboplatin or capecitabine in this patient population.

Interest is also mounting in neoadjuvant use of atezolizumab and other immunotherapies, especially after Rita Nanda, MD, of the University of Chicago in Illinois, reported that participants in the I-SPY 2 trial who had TNBC and received the PD-1 inhibitor pembrolizumab (Keytruda; Merck) with preoperative chemotherapy had a threefold higher rate of pathologic complete response compared with standard therapy—60% versus 20%.

Both atezolizumab and pembrolizumab are being evaluated as neoadjuvant and adjuvant treatments for patients with operable TNBC. By administering checkpoint inhibitors earlier, Nanda says, “we're probably going to cure more people and prevent recurrences.” –Elie Dolgin