Anyone doubting the importance of Deciphera’s Invictus study of its lead project ripretinib would have been left rubbing their eyes this morning. A win in the trial, in fourth-line gastrointestinal stromal tumour (GIST) patients, sent the group’s stock up as much as 112% this morning, which looks like an overreaction for such a small niche.
However, Deciphera’s investors are clearly hoping that the Invictus result bodes well for an ongoing trial of ripretinib in second-line GIST. And the company did nothing to disabuse them of this notion, pointing to new phase I data across different lines of therapy, and refusing to rule out off-label use in earlier lines of therapy should ripretinib get the regulatory nod.
That second-line study, Intrigue, is testing ripretinib against Pfizer’s Sutent, the standard of care in second-line GIST, and is not set to complete until 2021. But Deciphera is already talking up ripretinib’s chances of transforming the GIST landscape, with its chief executive, Steve Hoerter, suggesting during a conference call today that the Kit-PDGFRα kinase inhibitor could be used straight after Novartis’s first-line drug Gleevec.
Indeed, in setting out progression-free survival and response rates with Sutent and Stivarga, the inference was clear that ripretinib could do better.
This appears to be supported by data from Invictus, caveats about cross-trial comparisons notwithstanding. The study met its primary endpoint, showing a median progression-free survival of 6.3 months with ripretinib versus 1 month with placebo, which was statistically significant at p<0.0001.
Overall survival also looked good, at 15.1 months with ripretinib compared with 6.6 months with placebo. However, this measure was not formally statistically analysed because ripretinib had already failed to show a statistically significant benefit on overall response rate.
The ORR with ripretinib was just 9.4%, and the miss raises a potentially worrying point: if patients were not responding, why did they apparently live longer without progressing?
When asked about this apparent disconnect, Mr Hoerter noted the heterogeneous nature of GIST and pointed out that a similar phenomenon had been seen with Sutent and Stivarga, but these drugs had still been approved.
He suggested that ripretinib’s mechanism – the project binds to the target kinase’s “switch pocket” and prevents the enzyme from being locked in its “on” state – might spur a prolonged survival benefit.
This is something Deciphera plans to explore further, but in the meantime it will file ripretinib for fourth-line GIST in the first quarter of 2020. Specifically, it will seek the go-ahead in patients who have already received Gleevec, Sutent and Stivarga, the population studied in Invictus.
Deciphera believes that it has done enough to get a label in all comers, not just Kit-mutation positive patients, who make up around 90% of GIST patients.
In this respect the company is taking a different approach to Blueprint Medicines, which is focusing on Kit-positive GIST patients with its Kit-PDGFRα inhibitor avapritinib. In fourth-line GIST, avapritinib’s ORR of 22% looks better than that seen with ripretinib, but the PFS appears worse. Blueprint’s stock was down 5% this morning.
|A cross-trial comparison of the Kit-PDGFRα inhibitors in ≥4L GIST|
|Ripretinib||Deciphera||Invictus, NCT03353753||6.3 months (centrally confirmed)||9.4%|
|Avapritinib||Blueprint||Navigator, NCT02508532||3.7 months (centrally confirmed);
5.5 months (investigator confirmed)
|Source: Company presentations.|