Abstract 824: In vivo efficacy of VAL-083 in the treatment of non-small cell lung cancer
Bibliographic record
Abstract
Abstract The median overall survival time for patients with stage IV non-small cell lung cancer (NSCLC) is 4 months, and 1- and 5-year survival is less than 16% and 2%, respectively. NSCLC is usually treated with surgery followed by treatment with either Tyrosine Kinase Inhibitors (TKIs) (e.g. erlotonib, gefitinib) or platinum-based regimens (e.g. cisplatin). TKIs have resulted in vastly improved outcomes for patients with EGFR mutations; however, TKI resistance has emerged as a significant unmet medical need, and long-term prognosis with platinum-based therapies is poor. Additionally, the incidence of brain metastases is high in patients with NSCLC with a poor prognosis. VAL-083 is a structurally unique bi-functional alkylating agent mediating interstrand DNA crosslinks at targeting N7 of guanine, thus differing in mechanism of action from TKIs and cisplatin. VAL-083 further crosses the blood-brain barrier and accumulates in tumor tissue. VAL-083 has demonstrated activity against NSCLC in preclinical and clinical trials, both as a single agent and in combination with other treatment regimens, suggesting VAL-083 may be a therapeutic option for drug-resistant NSCLC and NSCLC patients with brain metastasis. VAL-083 is approved for treatment of lung cancer in China and has documented activity against NSCLC in historical NCI-sponsored clinical trials; however, specific questions regarding the efficacy of VAL-083 in comparison to cisplatin and in TKI-resistant NSCLC have to our knowledge not been addressed before. The purpose of this study is to evaluate the activity of VAL-083 in in vivo models of drug-resistant NSCLC in comparison to other drugs, including cisplatin. Rag2 mice bearing subcutaneous human lung adenocarcinoma xenograft tumors of either TKI-resistant (H1975) or TKI-sensitive (A549) origin were treated. The results will provide direction to clinical research aimed at influencing practice patterns under VAL-083's current label and support expanded global development. Two human NSCLC cell lines, A549 (TKI-sensitive) and H1975 (TKI-resistant), were used for xenograft tumor models in female Rag2 mice. VAL-083 was given i.p. 3 times/week for 3 weeks, and the in vivo efficacy of VAL-083 in controlling tumor growth compared to cisplatin. Saline was used as control treatment. Disease progression is evaluated by tumor volume, clinical observations and body weight measurements. Blood samples are analyzed for CBC/differential analyses to assess myelosuppression or other changes in blood chemistry. On study day 51, the mean tumor volume of the A549 tumor bearing control mice (saline solution) was 338 mm3, while the mean tumor volume of the cisplatin-treated (5 mg/kg) and the VAL-083-treated (6 mg/kg) mice was 260 mm3 and 156 mm3, respectively (study ongoing). Further results will be reported at AACR in April 2014. Citation Format: Anne Steino, Jeffrey Bacha, William J. Garner, Sarath Kanekal, Dawn Waterhouse, Nancy Dos Santos, Dennis M. Brown. In vivo efficacy of VAL-083 in the treatment of non-small cell lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 824. doi:10.1158/1538-7445.AM2014-824
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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 | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 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) | 0.004 | 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".