Here we present the data on efficacy and safety of setidegrasib in patients with advanced non-small cell lung cancer and KRAS G12D mutations. Setidegrasib is a broad track, so it is an agent that induces degradation of the KRAS G12D mutated protein and this is based on the data of a phase I trial where the 600mg dose of setidegrasib in monotherapy weekly has been chosen for further development.

Could you give us some more detail on the methodology?

In this trial where patients with non-small cell lung cancer with confirmed KRAS G12D mutations were actually included if they had a good PS and had progression prior to standard of care therapy. The patients were given in the phase I trial from 140mg to 800mg weekly. The recommended dose for further development is 600mg and here we have included some 45 patients in the expansion dose. This is the basis for this presentation.

Patients are typical patients having that mutation. I would say median age about 68 years, brain metastases in 13% of the cases. Some 64% of the cases were PD-L1 negative and about 60% of the patients had received two or more lines of prior therapy. Importantly, about one third of the patients were never smokers.

In terms of safety, I have to say that the drug was pretty well tolerated. I would say that grade 3 treatment-related adverse events were seen in all six patients, 13%. No patients required discontinuation, no patients had grade 5 events. The more frequent side effects were infusion reactions that were typically low-grade, 1 or 2, and other side effects that we have seen in about 20-30% of the cases included nausea, LAT or SAT increases, and peripheral oedema. So quite a well-tolerated drug.

What did you find?

In terms of activity the setidegrasib inhibitor has shown to be effective in this setting of pretreated patients with responses seen in about 37.5% of the patients included into this trial. Indeed, the overall response rate was 35.6%, being 37.5% in patients treated in the second- and third-line setting. Those patients that were never smokers or lighter smokers the response was higher, 47%.

In terms of the duration of the response, I have to say that at six months 76% of the patients, 3 out of 4 patients, were still responding. The median PFS was about 8.3 months, being a bit higher in patients treated in the second- or third-line setting or in patients that were light or never smokers, that was about 11 months.

Finally, I’d like to say here that when we were evaluating the evolution of the ctDNA levels, particularly the titres of KRAS G12D allelic fraction, we have seen overall a clear decrease in those patients that were responding. Of course those patients that had a molecular response did better in terms of PFS as compared to the other patients.

At the same time some patients actually had some biopsies at baseline and during the treatment, and we have seen in those patients a clear increase in T-cell infiltration, CD8 positive T-cells in most of the patients, somehow suggesting that the inhibition of the KRAS signal turned the microenvironment into a more immunogenic one.

What’s next?

There are a number of plans to evaluate this, this is not only in non-small cell lung cancer but further evaluation in pancreatic cancer. Importantly, there is a phase III trial planned as monotherapy in patients with pretreated advanced non-small cell lung cancer with G12D KRAS mutation.