In a late-breaking, oral presentation at the ESMO Congress 2019, Margaret von Mehren, MD, presented results from ­INVICTUS, a pivotal phase III clinical trial of ripretinib in patients with advanced gastrointestinal stromal tumor (GIST).¹ Ripretinib is an investigational tyrosine kinase inhibitor that was engineered to broadly inhibit KIT- and PDGFRα-mutated kinases. Study findings revealed a statistically significant improvement in progression-free survival with ripretinib vs placebo in patients previously treated with imatinib, sunitinib, and regorafenib for advanced GIST.

Margaret von Mehren, MD

“For patients with GIST [in whom currently approved agents have failed], there exists an urgent need for effective and well-tolerated treatment options,” Dr. von Mehren, lead author of the study, said in a statement issued by Deciphera Pharmaceuticals, which owns the commercial rights for the drug product. Dr. von Mehren is with the Department of Medical Oncology, Fox Chase Cancer Center, in Philadelphia.

Pivotal Phase III Study

In the phase III clinical study, 129 patients with advanced GIST were randomly assigned in a 2:1 fashion to receive ripretinib or placebo following previous treatment with at least imatinib, sunitinib, and regorafenib.  The study achieved the primary endpoint of improved progression-free survival compared with placebo in the fourth-line or later setting, as determined by blinded independent central radiologic review using modified Response Evaluation Criteria in Solid Tumors version 1.1.

Investigators reported that ripretinib significantly reduced the risk of disease progression or death by 85% compared with placebo and demonstrated a median progression-free survival of 6.3 months compared with 1.0 month in the placebo arm (hazard ratio = 0.15, 95% confidence interval = 0.09–0.25, P < .0001). This benefit in progression-free survival was consistent across all assessed patient subgroups.

Eight patients (9.4%) had a confirmed objective response with ripretinib (P = .05) compared with no confirmed responses in the placebo arm, as measured by blinded independent central review, but this was not statistically significant. Treatment-emergent adverse events occurred in 99% of patients on the ripretinib arm compared with 98% on the placebo arm. Grade 3 or 4 adverse events related to treatment occurred in 49% of patients on the ripretinib arm compared with 44% on the placebo arm.

The investigators concluded that the experimental agent improved progression-free survival vs placebo in patients with advanced GIST who experienced disease progression following treatment with imatinib, sunitinib, and regorafenib. Further ripretinib was associated with a favorable tolerability profile. The investigators noted that for patients with advanced GIST that has progressed following treatment with standard therapy, ripretinib could represent a new standard of care.

A new drug application is expected to be submitted to the U.S. Food and Drug Administration in 2020 for ripretinib for the treatment of patients with advanced GIST who have had disease progression after prior treatment with imatinib, sunitinib and regorafenib.

Further Clinical Perspective

Javier Martin Broto, MD, of University Hospital Virgen del Rocio in Sevilla, Spain, included the INVICTUS trial in his discussion of the “Best of ESMO” abstracts. According to Dr. Broto, the results achieved with ripretinib as fourth-line therapy in advanced GIST render it a new standard of care and herald its use in earlier lines of treatment.

Javier Martin Broto, MD

“INVICTUS is a very important study of a new compound that acts in a new way, as a KIT switch control inhibitor. The primary endpoint was successfully met, with median progression-free survival (by blinded central review) of 6.3 months with ripretinib vs 1.0 month with placebo. The hazard ratio of 0.15 is impressive,” he commented.

The fact that the placebo arm had a median progression-free survival of only 1 month points to a study population with aggressive disease, he added. The progression-free survival rate at 6 months of 51% vs 3% is also a “huge difference, and the overall survival rate of 65% at 1 year is very impressive in the fourth line, as well.”

Dr. Broto further noted that while the toxicity profile was acceptable, alopecia was seen in about half the patients and hand-foot syndrome in about one-fifth. These adverse events are not usually seen with tyrosine kinase inhibitors, he pointed out, however, he added that “ripretinib favorably compared, in terms of tolerability, with sunitinib and regorafenib.”

“Ripretinib represents a new standard of care and a new and relevant milestone,” Dr. Broto concluded. “We are changing clinical practice, because as fourth-line therapy we’ve only been able to rechallenge patients with imatinib. The results also open new opportunities for this compound perhaps in earlier phases of disease.” 

Disclosure: Deciphera has an exclusive license agreement with Zai Lab in Shanghai, China, for the development and commercialization of ripretinib in Greater China. The company retains development and commercial rights for ripretinib in the rest of the world. Dr. von Mehren reported advisory, consultancy, research grant, funding (institution), travel/accommodation expenses from Deciphera Pharmacetucials. Dr. Broto has received honoraria or travel funds from Pharma Mar, Lilly, Bayer, and Eisai. For further disclosure information and disclosure information from all of the study authors, visit oncologypro.esmo.org. 

Reference

1. von Mehren M, Serrano C, Bauer S, et al: INVICTUS: A phase III, interventional, double-blind, placebo-controlled study to assess the safety and efficacy of ripretinib as fourth-line therapy in advanced GIST. 2019 ESMO Congress. Abstract LBA87. Presented September 30, 2019.