Adding atezolizumab to paclitaxel did not delay disease progression in PD-L1 positive patients with triple negative metastatic breast cancer
The positive results of the phase III IMpassion130 trial established the combination of atezolizumab and nab-paclitaxel as a new standard of care for patients with PD-L1 expressing triple negative breast cancer (TNBC). In the subsequent IMpassion131 trial, researchers investigated the potential benefit of adding atezolizumab to paclitaxel in this setting. Surprisingly, the primary results of this trial, presented at ESMO 2020, failed to show a benefit in progression-free survival (PFS) with the atezolizumab-paclitaxel combination over paclitaxel alone in PD-L1 positive patients with metastatic TNBC. The potential reasons for the conflicting results of IMpassion130 and IMpassion131 requires further exploration.
TNBC is a heterogeneous disease is characterised by hormone targeted therapy resistance. However, some TNBC do exhibit immune infiltrate and high PD-L1 expression, providing a rationale for immunotherapy in TNBC. Previously, the IMpassion130 trial established the use of the anti-PD-L1 monoclonal antibody atezolizumab in combination with nab-paclitaxel as a new standard of care for PD-L1 positive metastatic TNBC patients. The IMpassion131 trial attempts to evaluate the use of paclitaxel with atezolizumab. This double-blind, placebo-controlled randomised phase III trial recruited 943 patients into two arms, to receive atezolizumab 840 mg every 2 weeks plus paclitaxel 90 mg/m2 every week, or a placebo every 2 weeks plus paclitaxel 90 mg/m2 every week, until disease progression or unacceptable toxicity. Patients were eligible provided they had metastatic or locally advanced TNBC and did not receive prior chemotherapy or targeted therapy for advanced TNBC. Pretreatment for early breast cancer was allowed if the treatment free interval between that treatment line and the study drug was at least 12 months. Finally, patients had to be taxane eligible, have measurable disease and have an ECOG performance status of 0/1. Patients were stratified using the following criteria: prior taxane (yes/no), tumour PD-L1 status (IC <1%, IC >1%), liver metastasis (yes/no) and geographical region. Using a hierarchical design, the primary endpoint was investigator assessed progression-free survival (PFS), testing the PD-L1 positive population first. Provided a statistical difference was observed, analysis of the ITT population would be initiated. Secondary objectives of the study included overall survival (OS), overall response rate (ORR), patient reported outcomes (PROs) and safety
In total, 622 patients were randomised in a 2:1 ratio to receive either atezolizumab plus paclitaxel (N=431) or placebo-paclitaxel (N= 220). Baseline characteristics were well balanced across the two arms. In the primary analysis, zooming in on the PD-L1 positive population (N-292), no PFS difference was observed between the two arms. The PFS of PD-L1 positive patients treated with paclitaxel and placebo was 5.7 months, which was fairly similar to the 6.0 months median PFS seen with atezolizumab-paclitaxel in PD-L1 positive patients (HR[95%CI]: 0.82[0.60-1.12]), p=0.20). Not subject to formal statistical testing, the PFS in the ITT population was 5.6 vs 5.7 months, in the placebo and atezolizumab arms, respectively (HR[95%CI]: 0.86[0.7-1.05], p= not tested). A subsequent subgroup analysis failed to identify a subgroup in which paclitaxel-atezolizumab induced a significant PFS benefit.
Investigator assessed unconfirmed ORR in the PD-L1 positive population was found to be 55.4% (95%CI: 45.2-65.3) in the placebo-paclitaxel arm and 63.4% (95%CI: 56.1-70.2) in the atezolizumab-paclitaxel arm. In the ITT population, unconfirmed ORR was found to be 47.5% (95%CI: 40.7-54.3) in the control arm as compared to 53.6% (95%CI: 48.8-58.4) with the atezolizumab-containing treatment regimen. In an updated interim OS analysis (data cut-off: 19 Aug 2020), the hazard ratios did not favour atezolizumab-paclitaxel in PD-L1 positive patients (HR[95CI%]: 1.12[0.76-1.65]) nor in the ITT populations (HR[95CI%]: 1.11[0.87-1.42]).
Grade 3/4 treatment-related adverse events (AEs) occurred in 34% and 38% of the control and atezolizumab arms, respectively. AEs resulting in treatment cessation occurred in 15% of placebo arm patients and 20% of patients in the atezolizumab arm. Fatal AEs occurred at a rate of 2% in both study arms.
The primary objective of the IMpassion131 trial was not met as the addition of atezolizumab to paclitaxel did not significantly improve the PFS in PD-L1 positive metastatic TNBC patients. Despite the unconfirmed ORR data, overlapping hazard ratios imply no statistical significance. This is further supported by the unfavourable hazard ratios at the updated interim OS analysis. The safety profile of the combination was consistent with the known effects of the individual study drugs. The potential reason for the contrast in the benefit seen in the IMpassion130 trial, in which nab-paclitaxel was used, requires further exploration.
Miles DW, Gligorov J, André F, et al. Primary results from IMpassion131, a double-blind placebo-controlled randomised phase 3 trial of first-line paclitaxel (PAC) +/- atezolizumab (atezo) for unresectable locally advanced/metastatic triple-negative breast cancer (mTNBC). Presented at ESMO 2020; Abstract LBA15.