Encouraging Long-Term Survival Benefits with Atezolizumab Plus Nab-Paclitaxel in Metastatic Triple-Negative Breast Cancer

The approval of atezolizumab plus nab-paclitaxel has heralded a new era in the treatment of patients with triple-negative breast cancer (TNBC). Now, findings presented at ESMO Virtual Congress 2020 today show for the first time long-term benefits of the combination therapy in some patients but also highlight apparent efficacy differences when slightly different chemotherapy backbones are used.

In the phase III IMpassion 130 trial, final overall survival (OS) data of patients with previously untreated, locally advanced or metastatic TNBC showed a clinically meaningful extension of 7.5 months with atezolizumab–nab-paclitaxel versus placebo in PD-L1-positive patients (25.4 versus 17.9 months; hazard ratio [HR], 0.67; significance not formally tested per prespecified testing hierarchy) (LBA16). Conversely, in PD-L1-negative patients, no sign of efficacy was observed. However, differences in OS in the overall population remained not statistically significant (21.0 versus 18.7 months; HR 0.87; p=0.077). Significant improvements in progression-free survival (PFS) – a co-primary endpoint of the trial – had been reported previously.

Importantly, 3-year survival rates with atezolizumab–nab-paclitaxel versus placebo were 36% and 22% in the PD-L1 population, demonstrating for the first time the long-lasting benefit of atezolizumab in this group. In reviewing these data, Dr Giampaolo Bianchini from the IRCCS Ospedale San Raffaele, Milan, Italy, considers this the most important piece of information: “Although OS data in the overall population remained not statistically significant and precluded formal testing, the results are of clinical significance, and we cannot deny the OS advantage in the long term, reinforcing the role of this combination in the first-line setting.”

In this promising scenario, which has been reinforced earlier this year by the positive results reported for the KEYNOTE-355 trial, the data discussed today from the IMpassion 131 were disappointing and unexpected (LBA15). Investigator-assessed PFS – the primary endpoint – was not significantly different with atezolizumab plus paclitaxel versus placebo in either the PD-L1-positive (6.0 versus 5.7 months; HR 0.82; p=0.20) or the intent-to-treat population (5.7 versus 5.6 months; HR 0.86; significance not formally tested for hierarchy). In addition, atezolizumab plus paclitaxel did not improve OS versus placebo, which was a secondary endpoint, in either population (PD-L1-positive: 22.1 versus 28.3 months; HR 1.12; intent-to-treat: 19.2 versus 22.8 months; HR 1.11).

Bianchini notes that the negative trend in OS for the experimental arm reported in the first interim analysis was not confirmed with longer follow-up, and stresses the importance of waiting for full access to all data and trial results before drawing firm conclusions on the interpretation. In the meantime, based on the results available, Bianchini agrees with the recent FDA statement, that in clinical practice oncologists should be informed that it is more safe and reassuring to use only nab-paclitaxel in combination with atezolizumab in patients with inoperable, locally advanced or metastatic PD-L1-positive (SP142) TNBC. As Bianchini explains, clinical research in early and metastatic breast cancer has previously suggested, with some controversy, a different clinical activity between nab-paclitaxel and paclitaxel. Although the mechanism underlying this remains unclear, a different engagement and activation of macrophages, a possible association with levels of tumour-infiltrating lymphocytes at baseline, or requirement for steroids with the latter formulation might also result in immune engagement differences.

In reviewing these data together, Bianchini says, “Future research should assess how to improve the efficacy of immunotherapy in metastatic TNBC patients because, despite the impressive results of IMpassion130, many patients do not benefit from treatment, and there is a huge need to tailor treatment through predictive biomarkers and to improve available options. Also, we must challenge the assumption that because we see efficacy with backbone chemotherapy alone it will also work if we increase immunogenicity through combination with immune checkpoint inhibitors, such as atezolizumab. This is possibly not true, and we need to pinpoint the optimal chemotherapy partner to use and maybe revise the dose and schedule to optimise immune engagement.”

In both the IMpassion 130 and IMpassion 131 trials, Bianchini agrees that the safety profiles of the combinations were acceptable, but believes that engagement with multidisciplinary teams would be an advantage to enable prompt recognition and management of possible immune-related adverse events. He also believes that the aggressive nature of metastatic TNBC requires screening for biomarkers to be conducted at the earliest opportunity, using an optimal assay method to assess PD-L1 positivity, which currently is represented by SP142 for the combination of nab-paclitaxel and atezolizumab. “We still need answers to many clinically relevant questions, such as identifying the preferred site of metastatic disease to be assessed for predicting treatment response, and whether primary tumours and metastatic site are equally informative,” he concludes.

Several trials that will further inform the clinical use of atezolizumab plus chemotherapy in patients with TNBC are ongoing. 

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