A phase II study of cabozantinib in metastatic or unresectable refractory gastrointestinal stromal tumour(GIST): a single-centre study from India

BACKGROUND: Beyond third-line therapy, options for metastatic/advanced GIST are limited, especially in low- and middle-income countries (LMICs) where access to fourth-line ripretinib is often restricted. Cabozantinib, a multi-kinase inhibitor targeting KIT and related resistance pathways, could serve as a pragmatic alternative. This Phase II study evaluated the efficacy and safety of cabozantinib in patients with metastatic/advanced GIST who had progressed after ≥ 3 prior Tyrosine Kinase Inhibitors (TKIs). METHODS: This is a single-arm phase II trial that enrolled patients with advanced GIST who had progressed on ≥ 3 TKIs with ECOG PS 0-2. Cabozantinib was given orally at 60 mg daily (40 mg if < 40 kg and/or ECOG PS 2). The primary endpoint was 3-month Progression Free Rate (PFR) by RECIST v1.1. Overall Response Rate (ORR) was assessed by RECIST v1.1 and Choi Criteria. Quality of Life (QoL) was done by EORTC-QLQ-C30. Using Ahern's single-stage phase II design, the trial tested whether cabozantinib could achieve a 3-month PFR of at least 25% in the fourth-line setting versus a null PFR of 5% or less. With a one-sided alpha of 0.05 and 90% power, the required sample size for this single-arm study was 25 patients. RESULTS: Sixteen patients were enrolled. The cohort had a median age of 54.3 years, and most patients were male (75%). Median prior lines were 3 (range 3-5), and 44% had ECOG PS 2. Primary sites were stomach (50%) and small intestine (25%). Liver was the predominant side of metastases (81.3%). Primary mutations included KIT exon 11 (56%), exon 9 (25%), and SDH-deficient GIST (12.5%); the most common secondary mutation pattern was exon 11 + 17 (43%). The 3-month PFR was 62.5% by RECIST v1.1, with median PFS of 4.0 months. ORR was 6.2% by RECIST and 18.8% by Choi criteria. Common grade 3 adverse events were hand-foot skin reaction (18.8%), hypertension (18.8%), and diarrhoea (12.5%). Treatment interruptions and dose reductions occurred in 80% and 73.3%, respectively. Overall, QoL and Global Health Status remained stable. CONCLUSION: Cabozantinib demonstrated clinically meaningful activity with manageable toxicity in refractory metastatic/advanced GIST after ≥ 3 TKIs, supporting its role as a potential option in LMIC contexts where ripretinib access is limited. Larger, comparative phase III trials are warranted to confirm efficacy and better define optimal patient selection and dosing strategies. TRIAL REGISTRATION: Trial Registration Number-CTRI/2024/06/068636. Our trial was registered with Clinical Trials Registry - India (CTRI) on 10/06/2024.