Preliminary results from the phase III NeoTRIPaPDL1 Michelangelo study showed that the addition of atezolizumab to combination carboplatin plus nab-paclitaxel did not result in a statistically significant increase in the pathologic complete response rate compared with the combination alone in patients with early high-risk and locally advanced triple-negative breast cancer.
Luca Gianni, MD
Preliminary results from the phase III NeoTRIPaPDL1 Michelangelo study (NCT002620280) showed that the addition of atezolizumab (Tecentriq) to combination carboplatin plus nab-paclitaxel (Abraxane) did not result in a statistically significant increase in the pathologic complete response (pCR) rate compared with the combination alone in patients with early high-risk and locally advanced triple-negative breast cancer (TNBC). These data were presented at the 2019 San Antonio Breast Cancer Symposium.1
Results showed that the pCR rate with atezolizumab was 43.5% (95% CI, 35.1%-52.2%) with the addition of atezolizumab compared with 40.8% (95% CI, 32.7%-49.4%) in the intent-to-treat population, which led to an odds ratio of 1.11 (95% CI, 0.69-1.79;P= .066).
“The addition of atezolizumab to nab-paclitaxel and carboplatin did not significantly increase the pCR rate in women with TNBC in the NeoTRIPaPDL1 trip study,” lead study author Luca Gianni, MD, president of the Fondazione Michelangelo in Milan, Italy, said in a press conference during the meeting. “In a multivariate analysis, the presence of PD-L1 expression was the most significant factor influencing the rate of pCR with and without atezolizumab.”
Patients with TNBC typically have a poor prognosis and rapidly progress to distant metastases and chemotherapy resistance; however, immune infiltration of TNBC is associated with prognosis and potential response to chemotherapy.
In March 2019, the FDA granted an accelerated approval to the frontline combination of the PD-L1 inhibitor atezolizumab and nab-paclitaxel for patients with unresectable locally advanced or metastatic PD-L1positive TNBC. The approval was based on findings from the phase III IMpassion130 trial, in which the addition of the PD-L1 inhibitor to nab-paclitaxel reduced the risk of progression or death by 40% compared with nab-paclitaxel alone in this patient population.2
In the open-label, multicenter, NeoTRIPaPDL1 Michelangelo study, investigators examined the combination of atezolizumab with chemotherapy in the neoadjuvant setting for 280 patients with early high-risk and locally advanced or inflammatory TNBC. Patients needed to be negative for HER2, estrogen receptor (ER), and progesterone receptor (PR), or have locally advanced unilateral breast cancer; ER, PR, and HER2, as well as PD-L1, via the Ventana SP142 immunohistochemistry assay, were centrally assessed before randomization. Tumor and plasma samples were also taken for correlative studies, Gianni added.
Patients were randomized to receive neoadjuvant carboplatin at area under the curve 2 and nab-paclitaxel at 125 mg/m2intravenously (IV) on days 1 and 8 with or without atezolizumab at 1200 mg intravenously on day 1. Both regimens were given every 3 weeks for 8 cycles and were followed by surgery and 4 cycles of an anthracycline regimen as per investigator’s choice.
Nearly half (49%) of patients had locally advanced disease, and 56% of patients were PD-L1 positive. The median age of the participants was 50 years (range, 24-79); 49% of patients had cT2 disease and 59% had cN1 nodal status.
The primary endpoint of the trial, which is ongoing, is to determine 5-year event-free survival (EFS) rates. The secondary aim is pCR, which can be a good predictor of long-term outcomes, explained Gianni.
In a multivariate analysis of pCR, results also showed that the presence of PD-L1 expression was the most significant factor that influenced pCR rate with atezolizumab over chemotherapy alone (overall response [OR], 2.08; 95% CI, 1.64-2.65;P<.0001).
Atezolizumab/chemotherapy versus chemotherapy alone showed little pCR benefit (OR, 1.11; 95% CI, 0.88-1.40;P= .39) in the multivariate analysis, nor was early-risk versus locally advanced disease a factor in benefit from the immunotherapy/chemotherapy regimen (HR, 0.84; 95% CI, 0.66-1.06;P= .15).
The clinical overall response was 76.1% with atezolizumab plus carboplatin/nab-paclitaxel and 68.3% with chemotherapy alone. The complete response (CR) and partial response (PR) rates were 29.0% and 47.1% with the atezolizumab regimen and were 26.1% and 42.3% in the control arm, respectively. The rates of stable disease and progressive disease were 3.6% and 5.8% with atezolizumab and 4.9% and 8.4% with chemotherapy alone, respectively. A total 14.5% and 18.3% of responses were not assessed, respectively.
Regarding safety, the treatment-related adverse events (TRAEs) were similar between arms, with most grade ≥3 TRAEs being neutropenia. However, grade ≥3 abnormal liver transaminases were significantly higher in the atezolizumab arm; serious adverse events (AEs) were also reported to be higher with atezolizumab, Gianni noted.
“[The abnormal liver transaminases] tended to be significantly more frequent with the atezolizumab administration, although the toxicity was very short lived and didn’t limit the possibility of administering the drug,” Gianni added.
Moreover, all-grade immune-mediated AEs were similar in both groups; however, hypothyroidism was in 5.8% of those on atezolizumab versus 1.4% of those receiving chemotherapy alone. All-grade infusion reactions were reported in 8.0% and 5.7% of patients, respectively, and were grade ≥3 in 1.4% and 0.7% of patients, respectively. Additionally, grade ≥3 immune-mediated AEs included colitis (0.7%), pancreatitis (1.5%), Coombs-positive hemolytic anemia (0.7%), and thrombotic thrombocytopenic purpura (0.7%).
Investigators will continue follow-up for the primary endpoint of EFS, and other efficacy end points are ongoing, concluded Gianni. Molecular studies are also underway.