M7824, or bintrafusp alfa, is a novel agent that not only targets PD-L1 as an antibody but on the FC portion of the antibody it has two TGF-β receptor 2 molecules that can sequester or trap TGF-β, thus targeting both PD-L1 as well as TGF-β, removing that from the biology implications in the tumour microenvironment.
We did the first in human study of M7824 at the National Cancer Institute. We did the dose escalation starting with 0.3mg/kg and going up all the way to 30mg/kg with bintrafusp alfa. What we saw was that, a) it was safe, we got similar types of side effects as one would expect to get with anti-PD-1 or anti-PD-L1 agents with the addition of [?? 0:55] xanthomas which is often seen with the inhibition of TGF-β. We also noted more recently that there has been some low grade bleeding events like gingival bleeding that has been seen with this. This has also been associated in previous studies with TGF-β inhibition.
What we found in that phase I study was that at doses of 3mg/kg and above you could get complete saturation of PD-L1 throughout the entire dosing period every two weeks and you could also sequester all the activated TGF-β in the serum so that the levels of TGF-β were below the lower limit of quantitation of the assay. We also noted in that very first study that there was some evidence of clinical activity. We had two partial responses and a complete response in those patients. Actually, interestingly, several of those responders were patients that had HPV associated malignancies.
We went on to do multiple dose expansion cohorts and in those dose expansion cohorts we enrolled patients with head and neck cancer, with cervical cancer and so we were able to get more data from HPV associated malignancies.
Here at the American Association of Cancer Research meeting we showed the responses in those patients with HPV associated malignancies. These included patients with anal cancer, patients with cervical cancer and patients with head and neck squamous cell carcinoma. What we found was that again we saw pretty good response rates in these patients. What we saw was about a 35-40% response rate, depending on whether these were patients with HPV associated malignancies only or HPV confirmed malignancies. The majority of them were confirmed and the response rates approached 40% in those patients.
What we also looked at was the depth and duration of the responses. What was pretty interesting to see is that you got really deep responses with these patients getting this bintrafusp alfa and these responses were very prolonged. So you looked at the overall survival of these patients and you’re looking at the twelve month overall survival above 50% which was quite good for this patient population. The duration of the responses were maintained in 11 out of the 15 patients at the time of data cut off with a median follow-up of over 16 months. So this is, again, suggestive that we’re getting really good activity in these patients.
To put this a little bit into context, what we have seen with PD-1 inhibition in patients with HPV associated malignancies are response rates between 15% and 24%. So it’s difficult to compare across different studies but this suggests that we’re getting good activity, at least as good as we’ve seen with the PD-L1 and PD-1 inhibition in this disease category.
It’s interesting to note the discussant today noted that E6 and E7 HPV proteins can actually cause an increase in TGF-β production, so it combined to the transcription, driving the transcription of TGF-β. So perhaps this is why targeting not only PD-L1 but also TGF-β is important in the HPV associated malignancy setting.
What are the clinical implications of this?
The clinical implications for this type of therapy is we need to do additional studies; there’s an ongoing phase II study at the National Cancer Institute that is taking all HPV associated malignancies. But if these results are confirmed this will lead to a registration pathway for this agent in HPV associated malignancies.