Abstract B23: Real-time dynamic assessment of RAF-signal transduction capacity as a predictive biomarker in patients with advanced neuroendocrine tumor (aNET) treated with sorafenib (S) and metronomic cyclophosphamide (mC): The SORNET study.
Bibliographic record
Abstract
Abstract Background: Preclinical rationale exists to combine VEGFR and PDGFR blockade with mC (J Clin Oncol 23:939–52), which led to this phase II trial of S and mC in patients (pts) with aNET. The dynamic evaluation of a signal transduction pathway in both its basal and stimulated states may more accurately reflect its functional status than the basal state alone. S enhances signal transduction through the RAF resulting in increased MEK phosphorylation (pMEK) in the presence of wild type RAS and RAF (Nature 464:427–30). Proof of putative pharmacodynamic effects early on during treatment may help select patients mostly likely to benefit. In this trial, a flow cytometry-based test was performed to measure pMEK dynamically in peripheral blood monocytes (PBMCs). Methods: Eligibility criteria: aNET; disease progression within 6 months prior to study entry; ECOG 0–2; concurrent octreotide and unlimited prior therapy were allowed. A phase II trial with intra-patient dose escalation of S and fixed dose mC of 50 mg daily was conducted. Patients started with a 7-day (d) run-in phase with S at 200 mg BID and fixed dose mC. Dose escalations of S from 200 to 400 to 600 to 800 mg BID occurred every 14 d until occurrence of either ≥ intolerable Gr 2 toxicity or a maximum S dose of 800 mg BID, with 28-d cycles then follow. PBMCs and plasma S trough levels were collected at baseline and at every S dose escalation. The MAPK pathway was stimulated in PBMCs by adding 20 ng/mL of IL3 to fresh blood aliquots. The difference between stimulated and basal pMEK (pShift) was quantified. The pShift value on d7 was compared to the pre-treatment value (d0), with pShift d7>d0=stimulation and pShift d0>d7=inhibition. Results: Demographics: 22 pts (18 carcinoid/4 islet cell cancers; 12 male) were enrolled; median age=58 (range 32–81); ECOG 0:1=7:15; prior treatment regimens 0:1:2:3+ = 8:10:2:2. Final S dose after the escalation process was 200, 400, 600 or 800 mg BID in 4:12:2:1 pts, 3 pts did not complete escalation due to toxicity. A total of 160 cycles of S and mC were administered (median=3; range=1–34). Toxicity: Gr 3 non-hematologic adverse events: diarrhea (3 pts), hand-foot reaction (3), hypophosphatemia (2), amylase/lipase (2/2), AST (1), hypertension, abdominal pain, ileal perforation, ALT, and vomiting (1 each). Efficacy: 1 pt had PR (5%), 13 SD (59%), 5 PD (23%) and 3 non-evaluable (14%). Median progression-free survival (PFS)=3 months (95% CI: 2–10.7); median overall survival (OS)=11.7 months (95% CI: 4.3-not reached (NR)). Biological Correlates: pShift change from d0 to d7 was predictive of clinical outcome, with 6 pts (27%) experiencing pShift stimulation and 16 pts (73%) inhibition. All 5 pts with PD had pShift inhibition. PFS in pts with pShift stimulation vs. inhibition: 14.9 (3-NR) vs. 2.8 months (1.8−6.7) (p=0.047); OS: 21.3 (7.9-NR) vs. 6.4 (2.8−6.4) (p=0.17). Neither S trough levels nor S dose were able to predict PFS, OS or pShift. pShift was not associated with toxicity (p=0.24). Conclusions: The combination of S and mC had modest antitumor activity in unselected pts with aNET. In this limited study, pShift from d0 to d7 seems to identify pts most likely to benefit, and thus may have predictive and/or prognostic significance warranting further validation Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B23.
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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) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
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".