Personalized N-of-1 Combination Therapies for Advanced Gastrointestinal Stromal Tumors.
Gastrointestinal stromal tumor (GIST) resistance to imatinib and other tyrosine kinase inhibitors poses an ongoing clinical challenge. We investigated molecularly matched combination therapies for treatment-refractory GIST, including drugs not previously combined in human studies.
Patients of all ages with unresectable and/or metastatic GIST treated with combination therapies were included (February 13, 2015-December 31, 2022). These patients were discussed at molecular tumor board and enrolled in the prospective Investigation of Profile-Related Evidence Determining Individualized Cancer Therapy (I-PREDICT) study (ClinicalTrials.gov identifier: NCT02534675). Patient demographics, tumor next-generation sequencing (NGS), treatment responses, and survival outcomes were retrospectively analyzed.
Six (1.6%) patients met the inclusion criteria. The median age at diagnosis was 59.5 years with the majority (4/6) of patients being male. NGS revealed median of six deleterious genomic alterations per patient excluding variants of unknown significance. Five (5/6) patients had KIT-mutant GIST, and one patient had BRAFV600E-mutant GIST. Two thirds of tumors had CDKN2A/B loss. Patients received median of 1 (range, 1-3) customized combination therapy consisting of median of 2 (range, 2-3) drugs targeting median of 2 (range, 2-4) genomic alterations. One patient experienced a treatment-related grade ≥3 adverse event (hypertension). For all patients, the best response by RECIST v1.1 was stable disease (SD). Combination therapies led to SD ≥6 months (range, 6.2-11.3 months) in four (4/6) patients compared with none in the immediate previous single-agent targeted therapies (SD range, 1.5-5.4 months). Most (5/6) patients had at least 60% prolongation of their progression-free survival compared with their immediate previous single-agent targeted therapy.
Our results demonstrate that a multitargeted, biomarker-matched combination approach can be safely administered to obtain disease control. Tailored combination therapies for advanced GIST with multiple genomic alterations warrant further investigation.
Patients of all ages with unresectable and/or metastatic GIST treated with combination therapies were included (February 13, 2015-December 31, 2022). These patients were discussed at molecular tumor board and enrolled in the prospective Investigation of Profile-Related Evidence Determining Individualized Cancer Therapy (I-PREDICT) study (ClinicalTrials.gov identifier: NCT02534675). Patient demographics, tumor next-generation sequencing (NGS), treatment responses, and survival outcomes were retrospectively analyzed.
Six (1.6%) patients met the inclusion criteria. The median age at diagnosis was 59.5 years with the majority (4/6) of patients being male. NGS revealed median of six deleterious genomic alterations per patient excluding variants of unknown significance. Five (5/6) patients had KIT-mutant GIST, and one patient had BRAFV600E-mutant GIST. Two thirds of tumors had CDKN2A/B loss. Patients received median of 1 (range, 1-3) customized combination therapy consisting of median of 2 (range, 2-3) drugs targeting median of 2 (range, 2-4) genomic alterations. One patient experienced a treatment-related grade ≥3 adverse event (hypertension). For all patients, the best response by RECIST v1.1 was stable disease (SD). Combination therapies led to SD ≥6 months (range, 6.2-11.3 months) in four (4/6) patients compared with none in the immediate previous single-agent targeted therapies (SD range, 1.5-5.4 months). Most (5/6) patients had at least 60% prolongation of their progression-free survival compared with their immediate previous single-agent targeted therapy.
Our results demonstrate that a multitargeted, biomarker-matched combination approach can be safely administered to obtain disease control. Tailored combination therapies for advanced GIST with multiple genomic alterations warrant further investigation.
Authors
Noh Noh, Sharma Sharma, Fanta Fanta, Kato Kato, Kurzrock Kurzrock, Sicklick Sicklick
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