A single-arm biomarker-based phase II trial of savolitinib in patients with advanced papillary renal cell cancer (PRCC).
Bibliographic record
Abstract
436 Background: Savolitinib (HMPL504/Volitinib, AZD6094) is a potent, selective MET inhibitor (IC50 of 4nM). MET and its ligand, HGF, are known to play an important role in the molecular events underlying oncogenesis in PRCC, a disease without a clear standard of care and marked by alterations of chromosome 7 (containing both MET and HGF genes) in a majority of patients as well as gene amplification or MET kinase domain mutations (Albiges et al. 2014, Linehan et al., 2015). Methods: This study evaluates savolitinib in PRCC patients dosed at 600mg daily until disease progression. ORR is the primary endpoint. PFS & DoR are secondary endpoints. PRO & HRQoL questionnaires are exploratory endpoints. Eligibility includes naive and previously treated metastatic PRCC, ECOG PS 0 or 1. Archival tumor was used to centrally confirm PRCC pathology post hoc and to determine MET status using Next Generation Sequencing (Foundation Medicine Inc, USA). Results: As of 27 June 2016, 109 pts were dosed. Best response was PR n=8, SD n=43, PD n=48 and 10 patients were not evaluable for response. 44 pts are MET-driven (MET/HGF gene copy number gain or kinase domain mutations), 46 pts were MET-negative, 19 pts are status unknown. MET-driven pts included Papillary Type I & II histologies. All 8 responders were in the MET-driven group, 18% RR in this subset. Median PFS in the MET-driven group was 6.2 months (95% CI: 4.1–7.0) vs. 1.4 months (95% CI: 1.4–2.7) in the MET-negative group (p = 0.002). Overall 10/109 pts had AEs leading to discontinuation. 23/109 pts had ≥ Grade 3 toxicity related to savolitinib. The most common AEs (all grades) includes: nausea (39%), fatigue (27%), edema (18%), and abnormal LFTs (17%). One death from hepatic encephalopathy was considered related to savolitinib. PRO & HRQoL data was not statistically analysed, descriptive data support main efficacy findings. Conclusions: In the largest biomarker-profiled trial dedicated to PRCC, savolitinib was generally well tolerated with anti-tumor activity in MET-driven patients. These findings warrant further clinical investigation of savolitinib in MET-driven PRCC. Clinical trial information: NCT02127710.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.007 | 0.002 |
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 source (direct Gemma or distilled Codex), 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".