In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms of action, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.
On May 15, 2020, the receptor tyrosine kinase inhibitor ripretinib was approved for the treatment of adult patients with advanced gastrointestinal stromal tumor (GIST) who have received prior treatment with three or more kinase inhibitors, including imatinib.1,2
Supporting Efficacy Data
Approval was based on findings in the international double-blind phase III INVICTUS study (ClinicalTrials.gov identifier NCT03353753).2,3 In the trial, 129 patients whose gastrointestinal stromal tumor (GIST) had previously been treated with imatinib, sunitinib, and regorafenib were randomly assigned 2:1 to receive oral ripretinib at 150 mg (n = 85) or placebo (n = 44) once daily until disease progression or unacceptable toxicity. Crossover from placebo to ripretinib was permitted at disease progression.
Ripretinib has warnings/precautions for palmar-plantar erythrodysesthesia syndrome, new primary cutaneous malignancies, hypertension, cardiac dysfunction, risk of impaired wound healing, and embryofetal toxicity.
Median patient age was 60 years (range = 29–83 years); 57% were male; 75% were white; 92% had ECOG performance status of 0 or 1; 63% had received three prior therapies, and 37% had received at least four prior therapies. A total of 66% of patients randomly assigned to placebo switched to ripretinib after disease progression.
The major efficacy outcome measure was progression-free survival, as assessed by blinded independent central review, using modified Response Evaluation Criteria in Solid Tumors, version 1.1, in which lymph nodes and bone lesions were not target lesions and a progressively growing new tumor nodule within a preexisting tumor mass had to meet specific criteria to be considered unequivocal evidence of disease progression.
Median progression-free survival was 6.3 months (95% confidence interval [CI] = 4.6–6.9 months) in the ripretinib group vs 1.0 month (95% CI = 0.9–1.7 months) in the placebo group (hazard ratio [HR] = 0.15, 95% CI = 0.09–0.25, P < .0001). Overall response rate on blinded independent central review was 9% vs 0% (P = .0504). Median overall survival was 15.1 months (95% CI = 12.3–15.1 months) vs 6.6 months (95% CI = 4.1–11.6 months), yielding a hazard ratio of 0.36 (95% CI = 0.21–0.62). Overall survival was not evaluated for formal statistical significance due to protocol-specified sequential testing for secondary endpoints and the lack of a significant difference in response rates.
How It Works
Ripretinib is a tyrosine kinase inhibitor that inhibits KIT proto-oncogene receptor tyrosine kinase and platelet-derived growth factor receptor A kinase, including wild-type, primary, and secondary mutations. Ripretinib inhibits other kinases in vitro, including PDGFRB, TIE2, VEGFR2, and BRAF.
How It Is Used
The recommended dosage of ripretinib is 150 mg once daily until disease progression or unacceptable toxicity. The recommended dose reduction for adverse reactions is to 100 mg once daily. Treatment should be permanently discontinued in patients who are unable to tolerate 100 mg once daily.
Prescribing information provides instructions on dosage medication, including withholding of treatment; dose reduction and re-escalation; and discontinuation for adverse reactions, including palmar-plantar erythrodysesthesia syndrome, hypertension, left-ventricular systolic dysfunction, arthralgia or myalgia, and other grade 3 or 4 adverse reactions. Treatment should be permanently discontinued for grade 4 hypertension, grade 3 or 4 left-ventricular systolic dysfunction, and recurrence of other grade 3 or 4 adverse reactions.
Concomitant use with strong CYP3A inducers should be avoided, and patients receiving such treatment should be monitored more frequently for adverse reactions.
Among the patients receiving ripretinib in the INVICTUS trial, 46% were exposed to treatment for at least 6 months and 3.5% for more than 1 year. The most common adverse events of any grade (≥ 20% of patients) were alopecia (52% vs 5% in the placebo group), fatigue (42% vs 23%), nausea (39% vs 12%), abdominal pain (36% vs 30%), constipation (34% vs 19%), myalgia (32% vs 12%), diarrhea (28% vs 14%), decreased appetite (27% vs 21%), palmar-plantar erythrodysesthesia syndrome (21% vs 0%), and vomiting (21% vs 7%). The most common grade 3 or 4 adverse events included hypertension (7% vs 0%), abdominal pain (7% vs 5%), fatigue (3.5% vs 2.3%), nausea (3.5% vs 0%), and vomiting (3.5% vs 0%). The most common grade 3 or 4 laboratory abnormalities were increased lipase (7%) and decreased phosphate (5%).
Serious adverse events occurred in 31% of patients in the ripretinib group, the most common being abdominal pain (4.7%), anemia (3.5%), nausea (2.4%), and vomiting (2.4%). Adverse events led to dosage interruption in 24% of patients (most commonly due to nausea [3.5%], increased bilirubin [2.4%], and palmar-plantar erythrodysesthesia syndrome [2.4%]) and to dose reduction in 7% (abdominal pain, agitation, alopecia, arthritis, dermatosis, gastrointestinal disorder, hyperesthesia, myalgia, palmar-plantar erythrodysesthesia syndrome, and decreased weight in ≥ 1.2% each). Adverse events led to permanent treatment discontinuation in 8% of patients. The most common causes were general physical health deterioration (2.4%), anemia (1.2%), cardiac failure (1.2%), palmar-plantar erythrodysesthesia syndrome (1.2%), and vomiting (1.2%).
Ripretinib has warnings/precautions for palmar-plantar erythrodysesthesia syndrome, new primary cutaneous malignancies, hypertension, cardiac dysfunction, risk of impaired wound healing, and embryofetal toxicity.Treatment should not be initiated in patients with uncontrolled hypertension, and blood pressure should be monitored during treatment. Ejection fraction should be assessed by ECG or multigated acquisition scan prior to initiating treatment and during treatment as clinically indicated.
Treatment should be withheld for at least 1 week prior to elective surgery and for at least 2 weeks after major surgery and until adequate wound healing. The safety of resuming treatment after resolution of wound-healing complications has not been established. Patients should be advised not to breastfeed while receiving ripretinib.
1. U.S. Food and Drug Administration: FDA approves ripretinib for advanced gastrointestinal stromal tumor. Available at https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-ripretinib-advanced-gastrointestinal-stromal-tumor. Accessed May 26, 2020.
2. U.S. Food and Drug Administration: Highlights of prescribing information for Quinlock (ripretinib) tablets. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/213973s000lbl.pdf. Accessed May 26, 2020.
3. 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 ≥ 4th-line therapy in patients with advanced gastrointestinal stromal tumors who have received treatment with prior anticancer therapies. 2019 ESMO Annual Meeting. Abstract LBA87. Presented September 30, 2019.