The evidence supporting this protocol comes from a phase III multicentre international randomised trial (INVICTUS) involving 129 patients comparing the "switch-control" kinase inhibitor ripretinib with placebo in patients with locally advanced or metastatic gastrointestinal stromal tumours (GIST).r Further evidence to be considered comes from a phase III randomised open label trial (INTRIGUE) which compared efficacy and safety of patients with advanced GIST who previously received imatinib.r
Between February 2018 and November 2018, 85 patients in the INVICTUS study were randomised to receive ripretinib 150 mg daily PO, continuous until progression or unacceptable toxicity, and 44 patients were randomised to receive placebo and best supportive care. The median age was 60 years and ECOG performance status was 0 (42%), 1 (50%) or 2 (8%). At the time of disease progression, patients assigned to placebo were permitted to cross over to ripretinib 150 mg daily, and patients assigned to ripretinib were permitted to dose escalate to ripretinib 150 mg twice a day. The primary end point was progression-free survival (PFS) (by blinded independent central review) and secondary end points included objective response rate (ORR), overall survival (OS), quality of life (QoL) and safety.r
In the INTRIGUE study 453 patients were randomly assigned to once daily ripretinib 150 mg (226 patients) or once daily sunitinib 50 mg (227 patients). The median age was 60 and most patients had a baseline ECOG performance status of ≤ 1 (99.1%). Primary end point was PFS, and was tested in two intention-to-treat (ITT) populations of KIT exon 11 participants, and all patients. Secondary endpoints were ORR, OS, QoL and safety.
While ripretinib was not superior to sunitinib in terms of PFS, there were fewer grade 3/4 treatment related adverse events (AE), and improved tolerability was observed with ripretinib.r
Efficacy
In the INVICTUS study, after a median follow-up of 6.3 months in the ripretinib group and 1.6 months in the placebo group, the median PFS by blinded independent central review (BICR) was 6.3 months (95% CI 4.6 to 6.9) with ripretinib compared with 1.0 months (95% CI 0.9–1.7) with placebo (HR=0.15, 95% CI 0.09 to 0.25, p=<0.0001). Median OS was 15.1 months (95% CI 12.3 to 15.1) in the ripretinib group and 6.6 months (95% CI 4.1 to 11.6) in the placebo group (HR=0.36, 95% CI 0.21 to 0.62), inclusive of the double-blind and open-label periods.r
In the INTRIGUE study, Median PFS for ripretinib and sunitinib was 8.3 and 7.0 months, respectively (hazard ratio, 0.88; 95% CI, 0.66 to 1.16; P = .36) neither was statistically significant. ORR was higher for ripretinib versus sunitinib in the KIT exon 11 ITT population (23.9% v 14.6%, nominal p=0.03).
Kaplan-Meier Survival Curve (A) PFS and (B) OS INVICTUSr
© Lancet Oncol 2020
Kaplan-Meier PFS (A) KIT Exon 11 ITT (B) ITT INTRIGUE r
© J Clin Oncol 2022
Toxicity
In the INVICTUS study the overall rate of grade 3 or 4 treatment-related adverse events was 24.7% in the ripretinib group and 16.3% in the placebo group. Common toxicities in the ripretinib group (>10%) and the modifications to study treatment are summarised below:
Treatment Related Adverse Eventsr
|
Ripretinib group (n=85) |
Placebo group (n=43) |
|
Grade 1–2 |
Grade 3 |
Grade 4 |
Grade 5 |
Grade 1–2 |
Grade 3 |
Grade 4 |
Grade 5 |
Alopecia |
42 (49%) |
- |
- |
- |
1 (2%) |
- |
- |
- |
Myalgia |
23 (27%) |
1 (1%) |
- |
- |
4 (9%) |
0 |
- |
- |
Nausea |
21 (25%) |
1 (1%) |
- |
- |
1 (2%) |
0 |
- |
- |
Fatigue |
20 (24%) |
2 (2%) |
- |
- |
6 (14%) |
1 (2%) |
- |
- |
Palmar–plantar erythrodysaesthesia syndrome |
18 (21%) |
0 |
- |
- |
0 |
0 |
- |
- |
Diarrhoea |
17 (20%) |
1 (1%) |
0 |
0 |
2 (5%) |
1 (2%) |
0 |
0 |
Constipation |
13 (15%) |
0 |
0 |
0 |
3 (7%) |
0 |
0 |
0 |
Decreased appetite |
12 (14%) |
1 (1%) |
0 |
0 |
2 (5%) |
1 (2%) |
0 |
0 |
Weight loss |
13 (15%) |
0 |
- |
- |
3 (7%) |
0 |
- |
- |
Blood bilirubin increased |
12 (14%) |
0 |
0 |
- |
0 |
0 |
0 |
- |
Arthralgia |
10 (12%) |
0 |
- |
- |
0 |
0 |
- |
- |
Muscle spasms |
10 (12%) |
0 |
- |
- |
2 (5%) |
0 |
- |
- |
Dose modifications, interruptions and discontinuationsr
Category |
Ripretinib group (n=85) |
Placebo group (n=43) |
Treatment-related AE leading to dose reduction |
5 (5.9%) |
1 (2.3%) |
Treatment-related AE leading to dose interruption |
12 (14.1%) |
3 (7.0%) |
Treatment-related AE leading to study treatment discontinuation |
4 (4.7%) |
1 (2.3%) |
In the INTRIGUE study fewer patients had grade 3/4 treatment-emergent TAEs with ripretinib (n = 92, 41.3%) compared with sunitinib (n = 145, 65.6%) nominal p < .0001. Similarly, there were fewer patients with grade 3/4 drug-related treatment-emergent AEs with ripretinib (n = 59, 26.5%) compared with sunitinib (n = 122, 55.2%).
Treatment Related Adverse Eventsr
© J Clin Oncol 2022