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Atezolizumab in combination with paclitaxel did not demonstrate a statistically significant improvement in progression-free survival as a first-line treatment for patients with PD-L1–positive triple-negative breast cancer, failing to meet the primary end point of the IMpassion131 trial.
Atezolizumab (Tecentriq) in combination with paclitaxel did not demonstrate a statistically significant improvement in progression-free survival (PFS) as a first-line treatment for patients with PD-L1–positive triple-negative breast cancer (TNBC), failing to meet the primary end point of the IMpassion131 trial (NCT03125902).1
Although a negative trend was observed for overall survival (OS), the secondary end point of the trial, IMpassion131 was not powered for this end point and the data had been immature at the time of the analysis. OS follow-up will continue until the final analysis of the trial, according to Roche. The toxicity profile of the combination proved to be consistent with the known profiles of the agents alone; no new safety signals were reported.
“While we are disappointed by the results from the IMpassion131 study, we are grateful for all patients, families, and physicians who were involved in the study,” Levi Garraway, MD, PhD, chief medical officer and head of Global Product Development at Roche, stated in a press release. “Today’s results underscore the need to better understand the cancer and immune system interactions, including the chemotherapy backbone and associated regimens. We remain committed to finding optimal treatments for all people living with this aggressive disease.”
In the multicenter, randomized, double-blind phase 3 trial, investigators set out to examine the safety and efficacy of the PD-L1 inhibitor in combination with paclitaxel versus placebo plus paclitaxel in treatment-naïve patients with inoperable, locally advanced or metastatic TNBC.2
Patients were randomized 2:1 to receive intravenous (IV) atezolizumab at a dose of 840 mg on days 1 and 15 of every 28-day treatment cycle plus 90 mg/m2 of paclitaxel on days 1, 8, and 15 of every 28-day cycle, or placebo matching the schedule of atezolizumab plus paclitaxel given in the same schedule as the investigational arm. Patients were treated until either progressive disease, intolerable toxicity, or the end of the study period, whichever occurred first.
The primary end point of the trial is PFS in the PD-L1–positive patient population and in the intent-to-treat (ITT) population. Key secondary end points include OS in the PD-L1–positive population and in the ITT population, percentage of patients alive at 12 and 18 months, time to deterioration, percentage of patients alive without a progression event at month 12 assessed via RECIST v1.1 criteria, and percentage of patients with objective response per RECIST v1.1 in the PD-L1–positive and ITT populations, among others.
Full findings from the phase 3 trial are being discussed with global health authorities and are planned to be presented at a future medical conference. The insights gleaned from the trial will be utilized to inform ongoing and future trials with the atezolizumab combination in TNBC, according to Roche.
In March 2019, the FDA approved the frontline combination for use in patients with unresectable locally advanced or metastatic PD-L1–positive TNBC. The regulatory decision was based on data from the phase 3 IMpassion130 trial (NCT02425891), which showed that the addition of atezolizumab to nab-paclitaxel resulted in a 40% reduction in the risk of progression or death versus nab-paclitaxel alone in this patient population.3
In the double-blind trial, investigators evaluated the safety and efficacy of atezolizumab plus chemotherapy versus nab-paclitaxel alone in treatment-naïve patients with metastatic TNBC. Patients were randomized 1:1 to receive intravenous (IV) atezolizumab at 840 mg on days 1 and 15 of a 28-day treatment cycle and IV nab-paclitaxel at 100 mg/m2 on days 1, 8, and 15 of the 28-day cycle (n = 451) or nab-paclitaxel at the same schedule with placebo (n = 451). Patients received treatment until progressive disease or intolerable toxicity.
The co-primary end points of the trial were PFS and OS in the ITT and PD-L1–positive populations; key secondary end points included overall response rate, duration of response, and safety. Patients were stratified by previous taxane use, liver metastases, and PD-L1 expression.
Data from the primary PFS analysis in patients with PD-L1 positivity showed a clinically meaningful median PFS of 7.4 months with the atezolizumab combination versus 4.8 months with chemotherapy (HR, 0.60; 95% CI, 0.48-0.77; P <.0001). Additionally, the 1-year PFS rates with atezolizumab/nab-paclitaxel was 29% versus nab-paclitaxel at 16%.
In the ITT population, the median PFS was 7.2 months versus 5.5 months with atezolizumab/nab-paclitaxel and nab-paclitaxel, respectively (HR, 0.80; 95% CI, 0.69-0.92; P =.0025). The PFS rates at 1 year in investigational and control arms were 24% and 18%, respectively.
At a follow-up of 12.9 months, a clinically meaningful improvement was observed with the addition of atezolizumab in the PD-L1–positive patient population, at 25.0 months versus 15.5 months with nab-paclitaxel alone (HR, 0.62; 95% CI, 0.45-0.86). The 2-year OS rate was 54% with the combination versus 37% with chemotherapy alone. In the ITT population, the P value for OS was .0840 (95% CI, 0.69-1.02). Notably, OS was not formally tested in a statistical design in patients with PD-L1 positivity, although it was tested for in the overall study population.
At the second interim analysis, the median follow-up was 18.5 months in the atezolizumab arm versus 17.5 months in the placebo arm. Results showed a median OS in the ITT population was 21.0 months versus 18.7 months in the atezolizumab and placebo arms, respectively (stratified HR, 0.86; 95% CI, 0.72-1.02; P = .078). In patients with PD-L1–positive disease, the median OS was 25.0 months in the atezolizumab arm versus 18.0 months in the placebo arm (stratified HR, 0.71; 95% CI, 0.54-0.94).
With regard to safety, the most commonly reported grade 3/4 adverse effects in the investigational and control arms included neutropenia (8% vs 8%, respectively), peripheral neuropathy (6% vs 3%), decreased neutrophil count (5% vs 4%), and fatigue (4% vs 3%). Two treatment-related deaths were reported in the investigational arm versus 1 in the placebo arm. No new treatment-related deaths were reported since the primary data cutoff date of April 17, 2018.