Durvalumab in novel combinations for head and neck cancer

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Published: 11 Sep 2017
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Dr Ezra Cohen - UC San Diego Health, San Diego, USA

Dr Cohen speaks with ecancer at the ESMO 2017 Congress in Madrid about the SCORES study assessing safety, tolerability, and preliminary anti-tumour activity of durvalumab plus AZD9150 or AZD5069 in patients with advanced solid malignancies and squamous cell carcinoma of the head and neck. 

He discusses how, of the two molecules targeting CXCR2 and STAT3 pathways, the influence of STAT3 on myeloid cells in the tumour microenvironment leads to significant response with a manageable toxicity profile.

Dr Cohen also spoke with ecancer about the KEYNOTE 40 trial of pembrolizumab in relapsed HNSCC, here.

The SCORES trial was a multi-arm study looking at durvalumab, an anti-PD-L1 antibody, in the context of two different agents that modulate the tumour microenvironment. What was really exciting and interesting to see is that one of those arms, the one with the STAT3 inhibitor, appeared to deliver a fairly significant response rate, and response rate was the primary endpoint, in a population of recurrent or metastatic squamous cell carcinoma of the head and neck patients.

Just to recap, the study involved a combination of durvalumab and either a STAT3 inhibitor or a CXCR2 inhibitor in patients who had either been pre-treated with an anti-PD1 or anti-PD-L1 or were naïve to those treatments. So a six arm study in those different patient populations. Fairly early on the arm that emerged was that one combining durvalumab with the STAT3 inhibitor showing truly an impressive response rate in those refractory patients.

Why do you think it might be that STAT3 and PD-1 are having this synergy?

When we think about STAT3, and the reason that we initially started the trial in the first place, was based and predicated on the science that STAT3 has a major influence on myeloid cells and especially myeloid cells in the tumour microenvironment. We now know that one of the major mechanisms of resistance, especially in head and neck cancer, to PD-1 or PD-L1 blockade is that tumour microenvironment that’s immunosuppressive. So that even as the T-cells are activated and they get there, if they encounter those myeloid cells they get shut off. So if we could reverse that, and we thought the STAT3 inhibitor could do that, we may be able to augment efficacy and that’s exactly what we saw.

That does bring me on to the next point of was there any toxicity associated with this combo?

There was some toxicity associated with it but exactly what we had expected. We saw a rate of immune-related adverse events that would be reminiscent of durvalumab alone, so nothing higher than what we expected, at least in the numbers so far. We saw toxicity related to the STAT3 oligonucleotide that would be exactly in keeping with what we expected. We know that oligonucleotides are metabolised in the liver so we saw in some patients a reversible rise in transaminases. We know that STAT3 can affect normal progenitor cells and so we did see reversible thrombocytopenia and some reversible anaemia in this study.

Then the big question is what comes next?

That’s, of course, the critical question in terms of where we go forward with this combination. I think that what we’re seeing is a real effect; there is merit to move forward. One can begin to think about, both in recurrent metastatic patients and going up against standards of care, chemotherapy and even other immunotherapy combinations. But more importantly, perhaps, for squamous cell carcinoma of the head and neck is in locally advanced disease. So we need to begin to think about how can we integrate this combination in patients who are being treated for cure but maybe we can improve those cure rates from currently about 50% to who knows, maybe 60%, 70% or even 80%. This type of combination has that kind of excitement and promise for squamous cell carcinoma of the head and neck.