Abstract PO4-10-12: Value of Molecular Targets and Genome-Targeted Therapies FDA-Approved for Metastatic Breast Cancer, 2006-2023
Bibliographic record
Abstract
Abstract Title: Value of Molecular Targets and Genome-Targeted Therapies FDA-Approved for Metastatic Breast Cancer, 2006-2023 Background: The number of FDA-approved genome-targeted cancer drugs for metastatic breast cancer has increased, providing the potential for personalized therapy. To help physicians, patients, and policymakers differentiate meaningful from trivial innovation in this field, we assessed the validity of the targets and value of the outcomes used in the pivotal trials supporting approval. Methods: We analyzed trials supporting genome-targeted breast cancer drugs FDA-approved between 2006-2023, defined as those using a genomic test in which the drug targeted a given genomic alteration. From FDA drug labels and trial reports, we extracted characteristics of pivotal trials. For Accelerated Approvals—a special FDA program allowing approval based on unvalidated surrogate measures—if the drug later received traditional approval based on a confirmatory trial, only the latter was analyzed. Strength of evidence supporting molecular targetability was evaluated using the European Society for Medical Oncology (ESMO) Scale for Clinical Actionability of molecular Targets (ESCAT). Clinical benefit for approved indications was assessed using the ESMO-Magnitude of Clinical Benefit Scale (ESMO-MCBS). Molecular targets qualifying for ESCAT category level I-A or I-B associated with ESMO-MCBS grade 4 or 5 were rated as high-benefit genomic-targeted breast cancer treatments. Results: Fifteen genome-targeted drugs covered 17 indications and targeted 8 driver alterations. Among the 17 pivotal trials supporting these indications, most were randomized (11, 65%), phase 3 (11, 65%) and open-label (14, 82%). The most common primary endpoint leading to approval (10, 59%) was progression-free survival. Eleven trials (65%) had a I-A ESCAT targetability, 5 (29%) had a I-C targetability score and 1 (6%) was categorized as II-A. ERBB2 amplification, germline BRCA1/2 mutations, PIK3CA mutations, and ESR1 mutation were classified as tier I-A due to randomized trials demonstrating the effectiveness of approved targeted therapies in patients with these alterations. RET fusions, NTRK fusions, and microsatellite instability were classified as tier I-C, while high-tumor mutational burden was categorized as tier II-A. Eighteen percent of trials (3/17) demonstrated ESMO-MCBS grades 4-5. Overall, 3 of 17 (18%) indications had high-benefit genomic-based cancer treatments. Conclusions: Among molecular-targeted cancer therapies approved for metastatic breast cancer, fewer than a fifth demonstrated substantial patient benefits at approval. Benefit frameworks like ESCAT and ESMO-MCBS can help stakeholders identify therapies with the greatest potential. Citation Format: Ariadna Tibau, Thomas J. Hwang, Consolacion Molto Valiente, Jerry Avorn, Aaron Kesselheim. Value of Molecular Targets and Genome-Targeted Therapies FDA-Approved for Metastatic Breast Cancer, 2006-2023 [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-10-12.
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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 | 0.011 | 0.063 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.003 | 0.005 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.007 | 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".