At AACR I presented the phase I study of DYK709. It’s an IKZF2 degrader alone and in combination with a PD-1 inhibitor.

What was the study design?

This was a phase I study of an IKZF2 degrader. So, just as an explanation, IKZF2, Helios, is really a transcription factor that is expressed in regulatory T-cells. DYK709 mediates the degradation of IKZF2 by binding to the cereblon complex and recruiting IKZF2 for ubiquitination and proteasome-mediated degradation. So it’s a molecular glue degrader and it has been shown that DKY709 can lead to reducing Treg suppressing function and to enhance effector T-cell cytokine production.

So the study design that I presented was the phase I study with a dose escalation part. We had two different escalation parts – patients included in monotherapy and patients included in the combination of DKY709 plus PDR 001, a PD-1 inhibitor. We included patients with melanoma and non-small cell lung cancer that had progressed to immune checkpoint inhibitors and also patients with nasopharyngeal carcinoma that had progressed on standard treatment.

We presented mainly patients included in both parts of the dose escalation and then the initial part of the dose expansion of DKY709 in monotherapy.

What were the results of this study?

At the time of the data cutoff we had included 58 patients in monotherapy and 40 patients in the combination. In general it was a heavily pretreated population, median prior lines was in general around 2-3, both for the melanoma, the non-small cell and the nasopharyngeal carcinoma.

We had different results in the study, so PK-wise we observed that the drug was well behaved. We had a bit of accumulation with an effective half-life of around 26 hours but the PK profile was good. We also had a PD effect. So we observed that there was robust peripheral IKZF2 degradation in CD4-positive, FOXP3-positive T-cells. We also observed that this degradation happened in the tumour infiltrating lymphocytes. So we did see that there was a reduction in these IKZF2-positive TILs across all dose levels although we didn’t see any clear dependency.

As a phase I study, of course, we were very focussed on the safety signals. For monotherapy in general it was well tolerated. We did have some myalgias and fatigue. I believe what is more relevant is that we did observe a composite peripheral neuropathy signal in around 28% of patients in the monotherapy and 30 patients in the combination. The most relevant, probably, adverse event was this peripheral neuropathy that happened mainly in doses above 10mg but it was in general reversible and manageable with neuropathic medications and dose reductions. There was also some QTc prolongation that was also dose dependent.

Activity-wise we did see activity, both in monotherapy and combination. In monotherapy there was really single-agent activity with three partial responses, two in melanoma and one in non-small cell, and one complete response in melanoma, and a disease control rate of around 41%. In combination we also see responses in patients that had progressed to previous checkpoint inhibitors. We had three partial responses, two in melanoma and one in non-small cell, and two partial responses of immunotherapy-naïve nasopharyngeal carcinoma.

Importantly, these responses were pretty durable with 18 patients remaining on treatment for more than six months with a stable disease partial response or a complete response. So in general a favourable PK/PD profile, manageable safety and I would say a meaningful anti-tumour activity, both in monotherapy and in combination.

What do you think is the importance of these results and what is next for this study?

What is particularly relevant of this study is it validates the degradation of IKZF2 as a relevant target and as a way of being able to modulate T-regulators in the tumour microenvironment. So it opens transcription factors that are very difficult to target because they don’t have binding space. So the molecular glues are a good platform to target this and this is a good example of this and also the validation of IKZF2 as a target for T-effectors and the possibility of obtaining response in patients in monotherapy that had progressed to immune checkpoint inhibitors.

So this study has been discontinued, however, there are other IKZF2s in the clinic that are being tested. So it will be important to gain further evidence to understand what is the value of this degradation of IKZF2-positive T-cells for immune therapy and hopefully also find biomarkers to be able to learn which are the patients that benefit from this type of strategy.