Utility of Clinical Next Generation Sequencing Tests in KIT/PDGFRA/SDH Wild-Type Gastrointestinal Stromal Tumors.

Objective: The vast majority of gastrointestinal stromal tumors (GISTs) are driven by activating mutations in KIT, PDGFRA, or components of the succinate dehydrogenase (SDH) complex (SDHA, SDHB, SDHC, and SDHD genes). A small fraction of GISTs lack alterations in KIT, PDGFRA, and SDH. We aimed to further characterize the clinical and genomic characteristics of these so-called "triple-negative" GISTs. Methods: We extracted clinical and genomic data from patients seen at MD Anderson Cancer Center with a diagnosis of GIST and available clinical next generation sequencing data to identify "triple-negative" patients. Results: Of the 20 patients identified, 11 (55.0%) had gastric, 8 (40.0%) had small intestinal, and 1 (5.0%) had rectal primary sites. In total, 18 patients (90.0%) eventually developed recurrent or metastatic disease, and 8 of these presented with de novo metastatic disease. For the 13 patients with evaluable response to imatinib (e.g., neoadjuvant treatment or for recurrent/metastatic disease), the median PFS with imatinib was 4.4 months (range 0.5-191.8 months). Outcomes varied widely, as some patients rapidly developed progressive disease while others had more indolent disease. Regarding potential genomic drivers, four patients were found to have alterations in the RAS/RAF/MAPK pathway: two with a BRAF V600E mutation and two with NF1 loss-of-function (LOF) mutations (one deletion and one splice site mutation). In addition, we identified two with TP53 LOF mutations, one with NTRK3 fusion (ETV6-NTRK3), one with PTEN deletion, one with FGFR1 gain-of-function (GOF) mutation (K654E), one with CHEK2 LOF mutation (T367fs*), one with Aurora kinase A fusion (AURKA-CSTF1), and one with FANCA deletion. Patients had better responses with molecularly targeted therapies than with imatinib. Conclusions: Triple-negative GISTs comprise a diverse cohort with different driver mutations. Compared to KIT/PDGFRA-mutant GIST, limited benefit was observed with imatinib in triple-negative GIST. In depth molecular profiling can be helpful in identifying driver mutations and guiding therapy.

Outcomes of Late-Line Systemic Treatment in GIST: Does Sequence Matter?

Ripretinib and avapritinib have demonstrated activity in the late-line treatment of gastrointestinal stomal tumors (GISTs). We investigated whether patients previously treated with ripretinib benefit from avapritinib, and vice versa. Patients diagnosed with metastatic/unresectable GIST and treated with both drugs at two institutions in 2000-2021 were included. Patients were grouped by drug sequence: ripretinib-avapritinib (RA) or avapritinib-ripretinib (AR). Radiographic response was evaluated using RECIST 1.1. Kaplan-Meier and log-rank tests were used to compare time-to-progression (TTP) and overall survival (OS). Thirty-four patients (17 per group) were identified, with a median age of 48 years. The most common primary site was the small bowel (17/34, 50%), followed by the stomach (10/34, 29.4%). Baseline characteristics and tumor mutations were not significantly different between groups. Response rates (RRs) for ripretinib were 18% for RA and 12% for AR; RRs for avapritinib were 12% for AR and 18% for RA. Median TTPs for ripretinib were 3.65 months (95%CI 2-5.95) for RA and 4.73 months (1.87-15.84) for AR. Median TTPs for avapritinib were 5.39 months (2.86-18.99) for AR and 4.11 months (1.91-11.4) for RA. Median OS rates following RA or AR initiation were 29.63 (95%CI 13.8-50.53) and 33.7 (20.03-50.57) months, respectively. Both ripretinib and avapritinib were efficacious in the late-line treatment of GIST, with no evidence that efficacy depended on sequencing.

Case report: Responses to the combination of gemcitabine with sirolimus in two patients with TSC-mutated sarcomas.

TSC-mutated sarcomas are rare molecular and histologic types of sarcoma. Due to the presence of their specific oncogenic driver mutation, these sarcomas are particularly sensitive to mTOR inhibitors. Recently, nab-sirolimus, an albumin-bound mTOR inhibitor, was approved by the Food and Drug Administration (FDA) for PEComas, which harbor a TSC mutation, and this drug remains the only FDA-approved systemic treatment for these tumors. We report on two cases of patients with TSC-mutated sarcomas who experienced significant responses to the combination of gemcitabine and sirolimus, after progression on prior gemcitabine-based chemotherapy and single agent mTOR inhibition with nab-sirolimus. Preclinical and clinical data support rationale for a synergistic effect of the combination. This combination may represent a valid therapeutic option after failure of nab-sirolimus in these patients, with no standard-of-care treatment options.

Optimal Avapritinib Treatment Strategies for Patients with Metastatic or Unresectable Gastrointestinal Stromal Tumors.

BACKGROUND: Avapritinib, a novel inhibitor of KIT/PDGFRA, is approved in the U.S. for the treatment of adults with PDGFRA exon 18-mutant unresectable or metastatic gastrointestinal stromal tumors (U/M GISTs). We assessed the safety of avapritinib and provide evidence-based guidance on management of avapritinib-associated adverse events (AEs), including cognitive effects and intracranial bleeding. MATERIALS AND METHODS: We performed a post hoc analysis of data from a two-part, single-arm dose escalation/expansion phase I study (NAVIGATOR; NCT02508532) in patients with U/M GISTs treated with oral avapritinib 30-600 mg once daily. The primary endpoints were safety and tolerability; the impact of dose modification (interruption and/or reduction) on progression-free survival (PFS) was a secondary endpoint. Efficacy analyses were limited to patients who started avapritinib at 300 mg (approved dose). RESULTS: Of 250 patients enrolled in the study, 74.0% presented with KIT mutation and 24.8% presented with PDGFRA exon 18-mutation; 66.8% started avapritinib at 300 mg. The most common treatment-related AEs (any grade) were nausea (59.2%), fatigue (50.0%), periorbital edema (42.0%), anemia (39.2%), diarrhea (36.0%), vomiting (36.0%), and increased lacrimation (30.8%). No treatment-related deaths occurred. Among 167 patients starting on 300 mg avapritinib, all-cause cognitive effects rate (grade 1-2) was 37.0% in all patients and 52.0% in patients ≥65 years. Cognitive effects improved to a lower grade more quickly with dose modification (1.3-3.1 weeks) than without (4.9-7.6 weeks). Median PFS was 11.4 months with dose modification and 7.2 months without. CONCLUSION: Tolerability-guided dose modification of avapritinib is an effective strategy for managing AEs in patients with GISTs. IMPLICATIONS FOR PRACTICE: Early recognition of adverse events and tailored dose modification appear to be effective approaches for managing treatment-related adverse events and maintaining patients on avapritinib. Dose reduction does not appear to result in reduced efficacy. Patients' cognitive function should be assessed at baseline and monitored carefully throughout treatment with avapritinib for the onset of cognitive adverse events. Dose interruption is recommended at the first sign of any cognitive effect, including grade 1 events.

Cell-surface vimentin-positive macrophage-like circulating tumor cells as a novel biomarker of metastatic gastrointestinal stromal tumors.

The clinical utility of circulating tumor cells (CTCs) has been investigated in numerous publications, but CTCs that express very typical immune cell markers have not been reported. Here we report a novel class of CTCs-CSV-positive macrophage-like CTCs (ML-CTCs). This nomenclature was based on the fact that this class of CTCs can be captured from blood samples of gastrointestinal stromal tumors (GISTs) patients using either the macrophage marker CD68 or our proprietary tumor-specific cell-surface vimentin (CSV) antibody 84-1; likewise, the captured ML-CTCs can be co-stained with both typical macrophage markers (CD14, CD68) and tumor cell markers (DOG-1, C-kit) but not CD45. Patients with metastatic GIST had significantly greater numbers of ML-CTCs than patients with localized GIST or cancer-free blood donors (P<0.0001). Unexpectedly, the classic CSV positive CTCs was abundant in metastatic disease but failed to predict GIST metastasis. Only CSV-positive ML-CTCs was able to serve as a solid and novel biomarker for prediction of metastatic risk in GIST patients.