Savolitinib Plus Osimertinib in Epidermal Growth Factor Receptor-Mutated, MET-Amplified Advanced Non-Small Cell Lung Cancer: A Randomized Phase II trial
Bibliographic record
Abstract
Background MET amplification is the most common resistance mechanism to first-line osimertinib. We report safety and efficacy data from a phase 2 study assessing savolitinib plus osimertinib in epidermal growth factor receptor (EGFR)-mutated, MET-amplified, advanced non-small cell lung cancer (NSCLC). Patients and methods Patients with EGFR-mutated, MET-amplified (MET gene copy number ≥5 or MET:CEP7 ratio ≥2), advanced NSCLC post-osimertinib were enrolled. Patients received savolitinib 300 mg once daily (QD) plus osimertinib 80 mg QD or savolitinib plus placebo. The primary endpoint was investigator-assessed objective response rate (ORR). Secondary endpoints included progression-free survival (PFS) and safety. Exploratory analysis included retrospective efficacy assessment by higher MET cutoffs (immunohistochemistry 3+ staining ≥90% tumor cells and / or MET gene copy number ≥10). Results Thirty patients were randomized (14 savolitinib-osimertinib; 16 savolitinib-placebo). Among all patients, ORR (95% confidence interval [CI]) was 57% (29-82) vs. 13% (2-38); median PFS (95% CI) was 7.4 months (5.6-not calculable [NC]) vs. 1.6 months (1.3-4.1) for savolitinib-osimertinib and savolitinib-placebo, respectively. In patients with higher MET cutoffs, ORR was 63% (24-91) and 29% (4-71); median PFS was 8.2 months (4.1-NC) and 4.0 months (1.3-NC) for savolitinib-osimertinib (n = 8) and savolitinib-placebo (n = 7), respectively. There were no new safety signals. This study was terminated early and the contribution of osimertinib to savolitinib is being assessed further in SAVANNAH (NCT03778229) in patients with higher MET biomarker cutoffs. Conclusions Savolitinib plus osimertinib demonstrated numerically higher clinical activity vs. savolitinib plus placebo in all patients and patients with higher MET biomarker cutoffs. Micro abstract MET amplification is a genetic change associated with more aggressive cancers and specifically with osimertinib resistance. This randomized, phase 2, double-blind, multicenter trial demonstrated numerically higher clinical activity of savolitinib-osimertinib combination therapy vs. savolitinib-placebo in advanced NSCLC. This study was terminated early because savolitinib-osimertinib in this setting with higher MET cutoffs is being further assessed in SAVANNAH (NCT03778229).
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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 | 0.002 | 0.001 |
| Meta-epidemiology (narrow) | 0.003 | 0.001 |
| Meta-epidemiology (broad) | 0.003 | 0.002 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.002 | 0.002 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.002 | 0.004 |
| Insufficient payload (model declined to judge) | 0.006 | 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".