Atezolizumab/Nab-Paclitaxel the First Immunotherapy Combo to Demonstrate Positive Phase III Results in TNBC

Sandra Horning, MD

Sandra Horning, MD

In patients with metastatic or unresectable locally advanced triple-negative breast cancer (TNBC), frontline treatment with atezolizumab (Tecentriq) plus nab-paclitaxel (Abraxane) significantly reduced the risk of disease progression or death compared with nab-paclitaxel, according to topline results from the phase III IMpassion130 study. 

“Overall survival (OS) is encouraging in the PD-L1—positive population at this interim analysis, and follow-up will continue until the next planned analysis,” Genentech (Roche), the manufacturer of the PD-L1 inhibitor, noted in a press release. The company also reported that no new safety signals emerged with the combination and adverse events (AEs) were consistent with previous single-agent use of the drugs.

“IMpassion130 is the first positive phase III immunotherapy study in triple-negative breast cancer, an aggressive disease with limited treatment options,” Sandra Horning, MD, chief medical officer and head of Global Product Development, Genentech, said in a statement.

“Highly encouraged by these results, we plan to submit to authorities globally with the aim of bringing this combination to people with triple-negative breast cancer as soon as possible,” added Horning.

The phase III IMpassion130 study enrolled 902 patients with locally advanced or metastatic TNBC who had not receiving systemic treatment in the metastatic breast cancer setting. Patients were evenly randomized between the 2 treatment arms.

All patients received 100 mg/m²of IV nab-paclitaxel on days 1, 8, and 15 of each 28-day cycle, for a target of 6 cycles, with no maximum. Depending on their randomization, patients also received either a fixed dose of 840 mg of IV atezolizumab on days 1 and 15 of each cycle, or placebo. Treatment on both arms was administered until disease progression or unacceptable toxicity.

Progression-free survival and OS were the coprimary endpoints. These endpoints were evaluated in both the intention-to-treat population and in patients with PD-L1—positive tumors. Secondary outcome measures included objective response rate (ORR) and duration of response.

The phase III IMpassion130 study followed a phase Ib study of atezolizumab plus nab-paclitaxel presented at the 2015 San Antonio Breast Cancer Symposium. In the early-stage trial, the combination had a confirmed ORR of 66.7% as a frontline treatment for patients with metastatic TNBC.

The study explored atezolizumab plus nab-paclitaxel across several lines of treatment regardless of PD-L1 status for patients with metastatic TNBC. In the second-line setting, the confirmed ORR was 25% and in the third-line and beyond the ORR was 28.6%. Across the full trial, the ORR was 41.7%.

In the serial biopsy arm, a pretreatment biopsy was taken ≥7 days before the first cycle. Additional biopsies were obtained between days 10 and 15 during the first cycle then again 4 weeks after the first dose of atezolizumab. Responses were confirmed if seen on two or more sequential scans. The primary endpoint of the study was safety, with key secondary endpoints focused on ORR, duration of response, progression-free survival, and biomarker analyses.

The median age of patients in the study was 55.5 years, and most had an ECOG PS of 0 (19%) or 1 (81%). The number of prior systemic therapies received was 5, although a group of patients were enrolled in the frontline setting (n = 9). Prior to entering the study, 87% of patients had received a taxane.

At the time of the data cutoff, 24 patients with a minimum follow-up of ≥3 months were evaluable for efficacy. Across all groups, when considering unconfirmed responses, the ORR was 70.8%, which included a complete response rate of 4.2%. Additionally, the stable disease rate was 20.8%, for an overall disease control rate of 91.6%. At the time of the analysis, 11 of 17 responses (65%) remained ongoing.

In the frontline setting, the confirmed/unconfirmed ORR was 88.9% for nab-paclitaxel and atezolizumab. The complete response in the frontline setting was 11.1%. In the second-line setting, the ORR was 75% and in the third-line setting or beyond the ORR was 42.9%, which consisted of all partial responses.

For the biomarker analysis, PD-L1 expression in archival and fresh tumor specimens were centrally evaluated by immunohistochemistry using the Ventana PD-L1 assay. Levels were examined on both tumor cells and immune cells. Additionally, blood was analyzed for changes in proliferating CD8+ T cells.

In this analysis, activated CD8+ T cells transiently peaked at the end of the first cycle of atezolizumab. Moreover, PD-L1 expression appeared to be primarily restricted to immune cells. Out of those evaluable for efficacy (n = 24), 9 had PD-L1 expression on immunes cells, 7 were negative for PD-L1, and 8 had unknown biomarker status.

In patients with PD-L1—positive TNBC, the ORR was 77.8% and the stable disease rate was 22.2%. In the unknown biomarker arm, the ORR was 75%, which included 1 complete response and 2 patients with progressive disease. In the PD-L1–negative group, the ORR was 57.1% and the stable disease rate was 42.9%.

After a median follow-up of 5.2 months for all 32 patients, grade 3/4 AEs had occurred in 56% of patients, including neutropenia (41%), thrombocytopenia (9%), and anemia (6%). At least one AE of any grade occurred in all patients in the trial.

Overall, there were no treatment-related deaths observed in the study. Five patients discontinued nab-paclitaxel as a result of an AE. Per the protocol, these patients continued single-agent atezolizumab. Treatment discontinuations were related to fatigue (n = 1; grade 2), asthenia (n = 1; grade 2), and peripheral neuropathy (n = 3; grade 1, 2, and 3).

Reference:

Adams S, Diamond J, Hamilton E, et al. Safety and clinical activity of atezolizumab (anti-PDL1) in combination with nab-paclitaxel in patients with metastatic triple-negative breast cancer. Presented at: San Antonio Breast Cancer Symposium; December 8-12, 2015; San Antonio, TX. Abstract P2-11-06.

In the trial, 32 patients received concurrent treatment with nab-paclitaxel at 125 mg/m²and atezolizumab at 800 mg. In the initial safety cohort of the study (n = 8), atezolizumab was administered on days 1 and 15 along with nab-paclitaxel on days 1, 8, and 15 in a 28-day cycle. In a serial biopsy cohort, 24 patients received nab-paclitaxel on days 1 and 8 for the first cycle followed by concurrent treatment with both agents using the safety cohort schedule.