Role of CGP during relapse or disease progression in GIST

Dr. C N Patil,

Medical Oncologist, Apollo Hospitals, Bangalore

This is a case which demonstrates the benefits of Comprehensive Genome Profiling by NGS in identifying biomarkers for therapy resistance in GIST. Providing therapies to GIST patients with KIT mutations once they have progressed on first and second lines of treatment and understanding the underlying mechanisms of resistance.

APPROVED DRUGS FOR THE TREATMENTS OF PATIENTS WITH GIST

Gain of function mutations in the KIT and PDGFRA genes drive majority of the GIST cases present in 75%-80% and 5%-10% respectively. Imatinib, Sunitinib (First line) and Regorafenib and Ripretinib (during disease progression) have been approved by FDA in KIT mutant positive GIST. Recently, Avapritinib is approved in PDGFRA positive GIST.

CLINICAL PRESENTATION AND DIAGNOSIS

63-year-old male presented with weight loss and anemia was diagnosed with Gastrointestinal stromal tumor in 2014. The patient was on Imatinib as the tumor showed exon 11 activating mutation in KIT gene. The patient was on Imatinib (5 years) followed by Sunitinib (2019-2021). In July 2021, the patient developed clinical progression. Subsequently, the clinician recommended re-biopsy followed by CGP to understand the biological basis of mechanism of resistance to these drugs.

SUMMARY OF CGP OF PATIENT’S TUMOR SAMPLE

Exon 17 mutation (p.Tyr823Asp) which is known mechanism of resistance to exon 11 mutation (p.Trp557_Lys558del) in KIT gene was identified. Regorafenib, which is FDA-approved, is the next recommended course of treatment which has shown efficacy in patients who progressed on Imatinib and Sunitinib, with KIT exon 11 and cooccurring exon 17 mutations. The approval was based on the GRID trial, where 199 patients with GIST who had progressed on Imatinib and Sunitinib were randomised into two groups, to receive either Regorafenib or placebo. The patients receiving Regorafenib had a median PFS of 4.8 months, while the ones receiving placebo had the same of 0.9 months (p < 0·0001). This drug is a multi-targeted kinase inhibitor that acts on several pathways involved in tumor angiogenesis (VEGFR-1, -2, and -3, and TIE2), oncogenesis (KIT, RET and PI3K/ AKT/MTOR) and TME (PDGFR, FGFR).

The take home message here, is that Comprehensive Genomic Profiling will be able to identify the driver mutations and mechanisms of resistance in GIST, which is spread over an array of genes. Molecular subtypes of GIST are: GISTs with KIT mutation, PDGFRA mutation, KIT/PDGFR wild-type GISTs, SDH-deficient tumors, and other subtypes that may have a mutation in either the BRAF (p.Val600Glu) or NF1 gene and NTRK fusions.