(P 097) COMBINATION THERAPY OF TYROSINE KINASE INHIBITORS WITH RIPRETINIB AS THERAPEUTIC EXPLORATION FOR REFRACTORY GASTROINTESTINAL STROMAL TUMORS AFTER PROGRESSION FROM STANDARD THERAPY: A CASE REPORT

Objective: Gastrointestinal stromal tumors (GIST) are known to harbor oncogenic mutations more frequently either in the KIT (CD117) or platelet derived growth factor receptor alpha (PDGFRA) tyrosine kinase receptor (1). Standard treatment for metastatic or unresectable GISTs includes tyrosine-kinase inhibitors (TKIs) such as imatinib as first-line therapy followed by sunitinib, regorafenib and ripretinib as second-, third- and fourth-line therapies, respectively (2). Although remarkably effective during earlier phase of treatment, over time many patients develop resistance to TKIs due to heterogenous secondary resistance mutations which further complicates optimal choice of treatment for GISTs (3). Therefore, there is an urgent unmet need for innovative strategies such as TKI combination therapies that can effectively inhibit tyrosine kinase receptors after disease progression on standard therapies. Currently, TKI combination therapies are under clinical exploration due to their differential mechanism of action and different sensitivity towards heterogenous secondary mutations in advanced GISTs. However, appropriate drug selection and dosage in combination therapy remains a challenge, while tolerability, safety and efficacy of TKIs in combination still remain unexplored.

Methods: In this case report we present two clinical cases of metastatic GIST that have progressed on multiple lines of therapies, with treatment history ranging from 6-14 years. After continuous disease progression, patients were exposed to imatinib, sunitinib, regorafenib and ripretinib as first-, second-, third- and fourth-line targeted therapies respectively. Thereafter, based on genetic testing results, ripretinib IPDE and ripretinib in combination with other TKIs (Imatinib or sunitinib) were administered to patients with metastatic GISTs.

Results: Case 1: In September 2008, a 57-year-old woman underwent surgical resection for retroperitoneal GIST harboring KIT exon 11 mutation. In October 2009, CT showed recurrence, liver and spleen metastasis, lymphadenopathy, for which R2 surgery was performed, followed by imatinib treatment with complete response for more than 8 yrs. Imatinib was followed by sunitinib and regorafenib treatment. In March 2021, due to disease progression, patient started ripretinib (150 mg QD) and achieved partial response. On follow-up, in September 2021, CT showed slightly enlarged lesions (Fig1D), while genetic testing showed KIT exon 11, 13, and 17 mutations. Subsequently, 150 mg twice-daily ripretinib IPDE was administered with noted acceptable safety profile. In December 2021, CT showed slightly enlarged lesions resulting in co-administration of ripretinib 100 mg with imatinib 200 mg QD based on genetic tests, clinical efficacy and tolerability profile of prior drug treatments along with multidisciplinary team (MDT) discussion. CT performed in February 2022 revealed stable lesions with internal visible necrosis (Fig 1E) which are now under continuous follow-up.
Case 2: In 2016, a 73-year-old female was diagnosed with unresectable duodenal GIST with liver, lung and lymph node metastasis. After the patient was treated with imatinib, followed by sunitinib, regorafenib, and by imatinib, 150 mg QD ripretinib was administered in May 2021 (Fig 2B) and had achieved stable disease.Due to disease progression in December 2021 (Fig 2D), ripretinib 200 mg QD was administered considering patient's advanced age. The tumor showed heterogeneous manifestations, with overall size increase and regression in right posterior lobe. In February 2022 (Fig 2E), the treatment was expanded to ripretinib 150 mg plus sunitinib 25 mg QD due to spotting of KIT exon 11, 13 mutations and MDT discussion. The follow-up CT conducted in April 2022 (Fig 2F), showed slightly improved symptoms with stable blood parameters.

Conclusion: Conclusion: This case report is a microcosm of the latest GIST treatments. It provides the evidence that combination therapy of ripretinib with sunitinib or imatinib can be an efficacious therapeutic option for arresting GIST progression in selective patients, who are refractory to current standard therapies.