Genomic profiling of resistant tumor samples following progression on EGF816, a third generation, mutant-selective EGFR tyrosine kinase inhibitor (TKI), in advanced non-small cell lung cancer (NSCLC).
Bibliographic record
Abstract
11506 Background: Up to 60% of patients (pts) with NSCLC harboring an activating EGFR mutation (mut) and treated with a 1st generation EGFR TKI develop a secondary gatekeeper T790M mut. EGF816 is an irreversible EGFR TKI that is highly potent against activating mut (L858R, ex19del) and T790M mut, while sparing wild-type EGFR. As previously reported, in a Phase I dose escalation study, the overall response rate to EGF816 in pts with advanced EGFR T790M mut NSCLC was 47% and the disease control rate was 87%. However, pts ultimately develop disease progression. Tumor biopsies were obtained from pts who had progressed on EGF816 to identify mechanisms of resistance. Methods: Pts with NSCLC with locally or centrally confirmed T790M status were enrolled in this multicenter, dose escalation study to determine the safety, tolerability and antitumor activity of EGF816 (NCT02108964). EGF816 was administered at 7 dose levels ranging from of 75-350 mg QD. Following disease progression, a tumor sample was obtained and was analyzed by the Foundation Medicine next-generation sequencing (NGS) T7 panel, which interrogates 395 cancer-related genes for base substitutions, insertion-deletions, and copy number changes, as well as introns of 31 genes involved in rearrangements. Results: Tumor samples taken following disease progression on EGF816 were analyzed from 9 pts. Of the 8 pts whose tumors were T790M+ at baseline, this was detected in only 3 pts’ post-EGF816 progression samples. One patient developed an EGFR C797S mut and concurrent deletion in mTOR. Other identified alterations include BRAF fusions (n = 2) and c-MET amplification (n = 1). Only one patient was found to have concurrent TP53 mutation and RB1 truncating mutation. Individual patient response data, including duration of response, will be presented along with detailed genomic parameters. Conclusions: NGS analysis of tumors that developed resistance to EGF816 revealed multiple potential mechanisms of resistance. These data are hypothesis-generating and could lead to rational combination studies with EGF816 to improve the depth and/or duration of response to EGF816. Clinical trial information: NCT02108964.
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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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 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 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".