Deciphera CBO Morl talks lines of therapy for kinase inhibitor ripretinib

Deciphera
Deciphera's ripretinib is designed to inhibit every KIT mutation, but the company is not pursuing a first-line approval for multiple reasons. (Deciphera)

In 2019, Deciphera is teeing up for data from its phase 3 study testing ripretinib, its KIT/PDGFRα-targeted kinase inhibitor in resistant gastrointestinal stromal tumors (GIST). Deciphera aims to get it approved first as a fourth-line treatment for the cancer and then as a second-line treatment to rival Pfizer’s Sutent (sunitinib). It is not, however, looking to supplant Gleevec (imatinib), the first-line therapy for GIST.

Novartis’ KIT inhibitor, Gleevec works for the vast majority of patients—about 80% of them, said Deciphera Chief Business Officer Chris Morl at the J. P. Morgan Healthcare Conference. Problem is, the disease continues to mutate, even after effective treatment, which results in resistance to imatinib. As their cancer evolves, patients are then treated with second- and third-line treatments, which include Sutent and Bayer’s Stivarga (regorafenib). Beyond that, there is no approved treatment for patients who fail these late-line treatments.

 Ripretinib, also called DCC-2618, is designed to inhibit every known mutation in KIT, Morl said.

“Imatinib inhibits some. Sunitinib inhibits some as well. We believe we can treat all of them,” he said.

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RELATED: ESMO18: Deciphera's new data backs profile of DCC-2618 in GIST

At ESMO, Deciphera reported three-month data showing that ripretinib achieved disease control rates of 81% with DCC-2618 as second- and third-line GIST therapy, and 66% in fourth-line patients, with overall response rates of 21% and 9%, respectively. The same pattern was seen with median progression-free survival, which was 42 weeks for second-line patients, 40 weeks in third-line, and 24 for the fourth-line group.

Deciphera’s approach has obvious utility in fourth-line patients, whose cancer has become resistant to earlier treatments. The company chose to pursue this indication back in 2015 as a fast, capital-efficient way to prove that the drug worked. Now, Deciphera is pitting ripretinib against Sutent in a bid to unlock the larger commercial opportunity of treating second-line patients. 

 RELATED: Deciphera expands cancer trial after seeing early data

“With [ripretinib’s] phase 1 looking better than sunitinib, it has a good chance of replacing sunitinib as the standard of care,” Morl said.

But if ripretinib can inhibit all KIT mutations, why not go for approval as a frontline therapy? Why not replace a drug that might not work for all patients as a first treatment?

“Ripretinib inhibits all the same mutations as imatinib,” Morl said. “The issue in a frontline setting is that imatinib is a generic and the fact that some patients do quite well. It would require a powerful health economics argument and would be too challenging at this stage for a small biotech company to contemplate that.”

“Having said that, there are some patients on imatinib that don’t do well—the exon 9 mutation patients who make up only a small fraction. There may be opportunities for earlier use of ‘2618, but frontline use is going to require a health economics argument,” he said.

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