Biomarkers of systemic inflammation linked to reduced clinical activity of atezolizumab monotherapy in metastatic TNBC

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Published: 18 Apr 2019
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Luciana Molinero - Genentech, San Francisco, USA

Luciana Molinero speaks to ecancer at the 2019 American Association for Cancer Research (AACR) meeting about a study looking at the biomarkers of systemic inflammation associated to reduced clinical activity of atezolizumab monotherapy in patients with metastatic triple negative breast cancer (TNBC).

She explains that it was found that patients that have activation of the IL-6 and CRP tend to have reduced clinical outcome.

This is in comparison to combination treatment where response rates increased dramatically, showing that the IL-6/CRP inflammatory axis is a factor leading to poorer outcomes.

 

Today’s presentation was related on the phase I study that we have on atezolizumab monotherapy in triple negative breast cancer patients. This study that was in metastatic breast cancer patients had evaluated previously which patients had the best outcome with our immune checkpoint inhibitor atezolizumab. We had seen that patients that had PD-L1 positive tumours were the only ones that responded to treatment and also displayed the longest overall survival.

But we did further work on the biology of this clinical study to try to understand what would be a possible mechanism of resistance that should be targeted to improve the outcome of this patient population. What we found is that patients that have activation of the IL-6 and CRP pathway tend to have a reduced clinical outcome. Very interestingly, when we performed a preclinical mouse model combining an anti-IL-6 receptor with anti-PD-L1 we found that the response rate to this combination increased dramatically compared to single agent activity in these mouse models. Interestingly, in our company we have not only the anti-PD-L1 that is atezolizumab but there is an anti-IL-6 receptor that has been widely used in inflammatory disease, that is tocilizumab. So the goal would be to move forward in a combination of an anti-PD-L1, atezolizumab, and an anti-IL-6 receptor, tocilizumab, to improve the clinical outcome of this patient population.

Also, importantly, is that we don’t think that this is a mechanism of resistance specific for the triple negative breast cancer patients treated with atezolizumab or not even for immune checkpoint inhibitors as a class action but rather a phenomenon that happens across tumour types and different types of therapies. So if we are able to combine anti-inflammatory drugs with immune checkpoint inhibitors or other types of therapies I feel that we are going to give this hard to treat patient population a new hope.

What do the toxicities look like in this case?

The toxicity for the single agent atezolizumab is quite manageable, it’s similar to what we have been describing before to other atezolizumab treated patients. This has been amply described in our publications led by Dr Yijin Li in The Journal of Oncology 2019.

How do you see this progressing over the next few years?

The activity of checkpoint inhibitors in metastatic triple negative breast cancer is not as high as one that we have observed with standard of care chemotherapy. So the idea is to improve the outcome by leading combinations with cancer immunotherapy. On that note, we as a company and Roche Genentech, we have read out a phase III clinical study where we combined nab-paclitaxel with atezolizumab. This is, in fact, the first cancer immunotherapy regimen that has improved the clinical outcome of triple negative breast cancer patients in the last thirty years. So we are very excited that we are moving forward.

Were the results positive across the board or was it more specific than that?

The next step for cancer immunotherapy in triple negative breast cancer is combination therapy. In that aspect we have combined immunotherapy with nab-paclitaxel, that is a chemotherapy, and we have found that the patients that are PD-L1 positive in their tumours have an enhanced clinical benefit, both in progression free survival and overall survival. This is something that had not been observed in the last thirty years of treating this patient population.