Ripretinib has become the first therapy specifically approved for the fourth-line treatment of gastrointestinal stromal tumors, a clinical setting with an unmet medical need because of the poor prognosis of patients with progressive disease.
Suzanne George, MD
Ripretinib (Qinlock) has become the first therapy specifically approved for the fourth-line treatment of gastrointestinal stromal tumors, a clinical setting with an unmet medical need because of the poor prognosis of patients with progressive disease.1
On May 15, 2020, the FDA approved ripretinib for adults with advanced GIST who have received prior treatment with 3 or more kinase inhibitors, including imatinib (Gleevec). The drug, which inhibits KIT and PDGFRA tyrosine kinases, was approved based on efficacy data from the phase 3 INVICTUS study (NCT03353753). Findings demonstrated a statistically significant 5.3-month improvement in progression-free survival (PFS) compared with placebo (6.3 months vs 1.0 months; HR, 0.15; 95% CI, 0.090.25; 2-sided P < .001).2,3
“This was a very marked difference,” Suzanne George, MD, an author on the INVICTUS study and director of clinical research at the Sarcoma Center at Dana-Farber Cancer Institute in Boston, Massachusetts, said in an interview with OncologyLive®. “The improvement in PFS between the patients who were randomized to ripretinib versus those randomized to placebo was really impressive.”
The benefit seen with single-agent ripretinib extended to the overall survival (OS) analysis, where investigators observed a median OS of 15.1 months (95% CI, 12.3-15.1) and 6.6 months (95% CI, 4.1-11.6) in the ripretinib and placebo arms, respectively (HR, 0.36; 95% CI, 0.21-0.62).2 OS was not evaluated for statistical significance due to the sequential testing procedure for INVICTUS’ secondary end points. Additionally, the overall response rate was 9% in the ripretinib cohort and 0% in the placebo group, with a P value of .0504 that was not statistically significant.2,3
INVICTUS enrolled 129 patients with unresectable, locally advanced, or metastatic GIST who received prior treatment with imatinib, sunitinib (Sutent), and regorafenib (Stivarga) and were randomized 2:1 to 150 mg of ripretinib (n = 85) or placebo (n = 44), each administered once daily. Patients assigned to the placebo arm were eligible to receive ripretinib at the time of disease progression, and 66% were subsequently treated with the broad-spectrum kinase inhibitor.3
Ripretinib has a manageable safety profile, according to George. The most common adverse events (AEs; ≥ 20%) with ripretinib were alopecia, fatigue, nausea, abdominal pain, constipation, myalgia, diarrhea, decreased appetite, palmar-plantar erythrodysesthesia syndrome (PPES), and vomiting. “Overall, ripretinib is very well tolerated by the vast majority of patients. It does lead to some alopecia, which is unique in this space, but most patients just have some hair thinning if they even experience this adverse effect at all,” George said.
George added that some patients who receive ripretinib will develop PPES, but this AE “typically [presents] at a much lower severity than [with] other approved kinase inhibitors in this space, specifically sunitinib or regorafenib.”
Alopecia was not a reason for drug discontinuation; however, it did drive some patients to have ripretinib dose reductions. AE-related dose reductions occurred in 7% of patients. The AEs that prompted permanent discontinuation in 1% or more of patients included general health deterioration (2.4%) and anemia, cardiac failure, PPES, and vomiting, each of which affected 1.2% of patients.3
Patient-reported outcome data (PRO) from the INVICTUS study, detailed in a poster presentation at the 2020 American Society of Clinical Oncology Virtual Scientific Program, demonstrated a clinically significant difference between ripretinib and placebo regarding quality of life (QOL). Five key QOL measures were evaluated: physical functioning, role functioning, visual analog scale, overall health, and overall QOL. PROs were collected using EuroQol-5D and European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire.4
Whereas patients randomized to the ripretinib arm had consistently stable PROs, PROs “declined sharply” in the placebo arm, according to investigators, suggesting that individuals receiving ripretinib were better able to maintain QOL than placebo- treated patients. Results showed that the average physical functioning score improved 1.6 points with ripretinib and decreased 8.9 with placebo (P = .004; improvement or no change, 68% vs 44%).4
Role functioning was also better with ripretinib, increasing an average of 3.5 points versus a decrease of 17.1 with placebo (P = .001; improvement or no change, 77% vs 50%). Visual analog scale scores improved an average 3.7 points from baseline to cycle 2, day 1, with ripretinib compared with an average decline of 8.9 with placebo (P = .004; improvement or no change, 67% vs 41%). The overall health and QOL scores rose an average 0.20 and 0.28 points, respectively, with ripretinib, and decreased 0.78 and 0.76 with placebo (both P = .001; improvement or no change, 74% vs 47% and 79% vs 59%, respectively).4
George noted that the vast majority of GISTs are driven by gain-of-function mutations. “Patients who develop resistance to the current approved therapies have secondary KIT mutations that function as the primary resistance mechanism. Ripretinib is unique in how it interacts with KIT slightly differently than other approved agents in this space. It is a switch control inhibitor that binds in both the activation loop and the switch pocket to stabilize KIT in the inactive confirmation.”
The next steps for optimizing ripretinib therapy in GIST include determining whether the drug can find utility in earlier lines of therapy. Data from the phase 3 Intrigue study (NCT03673501) will help answer this question, George said. Intrigue is comparing ripretinib monotherapy with single-agent sunitinib in approximately 426 patients with advanced GIST who either progressed on or were intolerant to frontline imatinib. The primary end point is PFS. Secondary end points include objective response rate and OS.
“[Intrigue] is a very large international effort that is actively accruing patients, and it is going to be very interesting to see if this drug has a role in earlier lines of therapy. It will be a really important question for us to answer,” George said, noting that combinations with ripretinib are also under investigation for GIST. “It is really exciting for the sarcoma community to have another tool to help treat our patients with advanced GIST,” she concluded.