Frontline Atezolizumab and Nab-Paclitaxel Demonstrate PFS Benefit in PD-L1+ mTNBC

Peter Schmid, FRCP, MD, PhD

The combination of atezolizumab (Tecentriq) and nab-paclitaxel (Abraxane) demonstrated a 2.5-month benefit in progression-free survival (PFS) over nab-paclitaxel alone in patients with PD-L1—positive metastatic triple-negative breast cancer (TNBC), according to findings of the phase III IMpassion130 trial presented at the 2018 ESMO Congress.

“IMpassion130 is the first phase III trial to demonstrate a benefit with first-line immunotherapy in triple-negative breast cancer,” said lead study author Peter Schmid, FRCP, MD, PhD, lead at the Centre for Experimental Cancer Medicine, Barts Cancer Institute in London, United Kingdom. “Atezolizumab with nab-paclitaxel resulted in a statistically significant benefit in progression-free survival, both in the intent-to-treat population and the PD-L1—positive population.”

The double-blind study evaluated the efficacy and safety of the PD-L1 inhibitor plus chemotherapy versus nab-paclitaxel alone in treatment-naïve patients with metastatic TNBC. Patients were randomized 1:1 to receive nab-paclitaxel at 100 mg/m²intravenously on days 1, 8, and 15 of the 28-day cycle with atezolizumab at 840 mg intravenously (n = 451) on days 1 and 15 of a 28-day cycle or with placebo (n = 451). Treatment was given until disease progression or unacceptable toxicity.

The co-primary endpoints were PFS and overall survival (OS) in both the intent-to-treat (ITT) and PD-L1—positive populations; secondary endpoints were overall response rate, duration of response, and safety. Patients were stratified by prior taxane use, liver metastases, and PD-L1 expression, which was defined as at least 1% on tumor-infiltrating immune cells to be positive.

Results of the primary PFS analysis in the PD-L1—positive population demonstrated a clinically meaningful median PFS of 7.5 months (95% CI, 6.7-9.2) with atezolizumab/nab-paclitaxel and 5.0 months (95% CI, 3.8-5.6) with chemotherapy (HR, 0.62; 95% CI, 0.49-0.78;P<.0001), demonstrating a 38% reduction in the risk of progression or death. Moreover, the 1-year PFS rates were 29% (95% CI, 22%-36%) and 16% (95% CI, 11%-22%) with atezolizumab/nab-paclitaxel and nab-paclitaxel, respectively.

In the ITT population, the median PFS with atezolizumab/nab-paclitaxel and nab-paclitaxel was 7.2 months (95% CI, 5.6-7.5) and 5.5 months (95% CI, 5.3-5.6), respectively (HR, 0.80; 95% CI, 0.69-0.92;P= .0025). Moreover, the 1-year PFS rates were 24% (95% CI, 20%-28%) in the combination arm and 18% (95% CI, 14%-21%) in the nab-paclitaxel arm.

At a 12.9-month follow-up, an interim OS analysis of the PD-L1—positive population showed a clinically meaningful improvement with added atezolizumab at 25.0 months versus nab-paclitaxel alone at 15.5 months (HR, 0.62; 95% CI, 0.45-0.86). Two-year OS rates were 54% and 37% in the immunotherapy/chemotherapy and chemotherapy arms, respectively. In the ITT population, thePvalue for OS was .0840 (HR, 0.84; 95% CI, 0.69-1.02). However, Schmid emphasized that OS was not formally tested in a statistical design.

&ldquo;For me, at the moment, this is clearly a PD-L1—positive story—all of the benefit was in the PD-L1&ndash;positive subgroup,&rdquo; Schmid explained. &ldquo;Although the ITT group is positive, if you look at the subgroups in the PD-L1&ndash;negative group, there is no benefit. There is no detriment, but there is no benefit that justifies the use [of the combination] in this [PD-L1&ndash;negative] group.&rdquo;

To be eligible for enrollment, patients must have had metastatic or inoperably locally advanced TNBC with no prior therapy for their advanced disease with an ECOG performance status of 0 or 1. Prior chemotherapy in the curative setting, including taxanes, were permitted if the treatment-free interval was longer than 12 months.

Regarding safety, most all-grade adverse events (AEs) were similar between arms. The most common grade 3/4 AEs with atezolizumab/nab-paclitaxel and nab-paclitaxel 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%), respectively.

TNBC accounts for 15% of breast cancers. Those with advanced or metastatic disease generally experience poor outcomes compared with other breast cancer subtypes, with a median OS of 18 months or less, Schmid explained. Standard frontline treatment includes taxane or anthracyclines, and no targeted therapies have improved OS to date, he said. The rationale to utilize checkpoint inhibition is due to how PD-L1 can inhibit anticancer immune responses and, in TNBC, PD-L1 is mainly expressed on tumor-infiltrating lymphocytes.

Nadia Harbeck, MD, PhD, head of the Breast Center and Oncology Day Clinic, Women's Hospital of the University of Munich, Germany, shared her perspective on the data in a press briefing at the meeting.

&ldquo;We have a lot of patients out there right now on clinical trials with immunotherapy, but so far in breast cancer we have not seen the tremendous effects that we&rsquo;ve seen in melanoma or lung cancer,&rdquo; Harbeck said. &ldquo;This is the first time we have a phase III trial proving that immunotherapy 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.&rdquo;

Reference:

Schmid P. IMpassion130: Results from a global, randomised, double-blind, phase 3 study of atezolizumab (atezo) + nab-paclitaxel (nab-P) vs placebo + nab-P in treatment-naive, locally advanced or metastatic triple-negative breast cancer (mTNBC). In: Proceedings from the 2018 ESMO Congress; October 19-23, 2018; Munich, Germany. Abstract LBA1_PR.