Mutation profile of drug resistant gastrointestinal stromal tumor (GIST) patients (pts) enrolled in the phase 1 study of DCC-2618.
Bibliographic record
Abstract
11511 Background: GIST is driven by primary and secondary driver mutations in KIT/PDGFRα and cell-free tumor (ct) DNA may provide the opportunity to assess disease status and response to therapy. The pan-KIT/PDGFRα switch control inhibitor DCC-2618 has demonstrated durable disease control in heavily pre-treated GIST pts in the ongoing Phase 1 study (NCT02571036). Methods: Pts with advanced GIST were treated in either the escalation stage or in expansion cohorts of the Phase 1 study with oral DCC-2618. Tissue and liquid biopsies were performed and tested via next generation sequencing (NGS) of tumor tissue and/or plasma ctDNA. Results: A total of 136 2nd to 7th line (median of 3 prior therapies) GIST pts (KIT or PDGFRα mutations by local testing) were enrolled as of January 18, 2018 and treated with doses of ≥100 mg per day. 132 patients had a ctDNA sample available for baseline assessment by NGS. To date, activating mutations in KIT or PDGFRα were identified in 71% of baseline ctDNA analyzed from 77 pts. In the 53 confirmed KIT mutant GIST pts, exon 13/14 mutations were detected in 16 patients (30%); while exon 17/18 mutations were detected in 33 patients (62%). Notably, multiple patients had mutations in both exons 13/14 and 17/18. 92 GIST patients had at least one additional ctDNA sample available at first restaging. The correlation between tumor tissue and ctDNA, and the change in KIT/PDGFRA mutant allele frequency for GIST pts following the first 2 cycles of treatment with DCC-2618 will be presented. 76% of 136 pts are still on treatment. In 99 GIST pts with ≥1 on-study tumor assessment, the overall response rate (ORR) was 16%. Conclusions: Identification of ctDNA by NGS in the majority of patients in this cohort was feasible. The mutation profile of GIST in both tumor and plasma suggests the need for a pan-KIT inhibitor across various lines of therapy. DCC-2618 is being tested in a pivotal, randomized phase 3 study, INVICTUS, (NCT03353753) in the 4th+ line population with plans to be tested in a second Phase 3 study in 2nd line GIST. ctDNA in this patient population deserves further study as a non-invasive marker of disease heterogeneity and response assessment. Clinical trial information: NCT02571036.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.004 | 0.008 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".