everolimus
Overview
Everolimus is an orally bioavailable mTOR (mechanistic target of rapamycin) inhibitor (rapalogue) with FDA approvals in advanced renal cell carcinoma, hormone receptor-positive HER2-negative breast cancer, pancreatic neuroendocrine tumors, and subependymal giant cell astrocytoma associated with tuberous sclerosis.
Evidence in the corpus
- In advanced hepatocellular carcinoma (HCC), 2 patients received everolimus based on mTOR-AKT pathway alterations (TSC1/TSC2) identified on tissue and confirmed by cfDNA; one patient with a TSC2 splice site mutation achieved stable disease for 5.4 months, while the other (TSC2 frameshift deletion) progressed after 2.5 months PMID:37769223.
- Clinically actionable mTOR pathway mutations (TSC1/TSC2: 18%, PIK3CA: 8%) were identified by cfDNA in 37% of advanced HCC patients, supporting cfDNA-guided enrollment in everolimus trials PMID:37769223.
- In a PDTO functional screen of 92 sarcoma specimens, osteosarcoma (OS) PDTOs were significantly more sensitive than the pan-sarcoma average to everolimus (p=0.012). Chordoma (CHDM) PDTOs were significantly less sensitive to everolimus (p=0.022). Tumors with prior systemic therapy were more sensitive to everolimus than treatment-naïve specimens (p=0.018). Everolimus is among the NCCN-listed top-five regimens for osteosarcoma observed in the screen PMID:39305899.
- In the AURORA US Metastasis Project, metastatic breast cancer treatment context included multiple therapy lines; everolimus-targeted mTOR/PI3K pathway was implicated through PIK3CA mutations (13%) detected across primary and metastatic paired specimens PMID:36585450
- mTOR pathway mutations (PTEN, TSC2, PIK3CA) in 14% of PanNETs provide a genetic rationale for stratifying patients for everolimus (RAD-001) therapy; RADIANT-3 trial showed increased progression-free survival in advanced PanNET PMID:21252315
- PI3K/AKT/mTOR pathway altered in ~28% of clear cell renal cell carcinoma (CCRCC) tumors in the TCGA cohort; the authors nominate this pathway as a therapeutic target citing prior trials of everolimus in advanced RCC PMID:23792563.
- MEN1 loss-of-function and/or high RICTOR expression guided everolimus selection in metastatic PanNEN/PulNEN patients (PN6, PN17, PN21, PN23, PN26) in the POG NEN WGTA cohort PMID:24326773
- Six of 10 ccRCC tumors in the TRACERx multi-region sequencing study received short-course preoperative everolimus (or sunitinib); authors argue these cytostatic exposures did not collapse subclonal diversity, though a treatment-naive baseline is absent PMID:24487277
- mTOR signaling is disrupted in 40–50% of HCCs; everolimus failed in unselected second-line HCC trials but the review proposes mTOR-pathway dysregulation as a biomarker to enrich future trials PMID:24735922
- Phase III second-line trial in HCC (post-sorafenib) failed to demonstrate OS benefit; cited as a negative result for mTOR inhibition in HCC PMID:24798001
- AR-amplified MSK-PCa2 CRPC organoid (PTEN loss + PIK3R1 mutation) was sensitive to everolimus in vitro and in CB17 SCID xenografts (tumor growth slowed without shrinkage); combination everolimus + enzalutamide significantly enhanced response over enzalutamide alone in MSK-PCa2 xenografts PMID:25201530
- TSC1/TSC2 mutations occur in 6.3% of HR+/HER2- metastatic breast cancer vs 0.7% of primary breast cancer (p=0.0004), enriched in endocrine-therapy-pre-treated patients; authors hypothesize TSC1/2-mutant tumors may be outlier responders to everolimus, which is approved for HR+/HER2- mBC PMID:28027327
- 1 MTOR-L2383F UMD patient received 1-month no-benefit course of everolimus in 860-patient MSK-IMPACT LUAD cohort; TSC1/TSC2 truncating mutations (level 2B) identified in 6 patients, none received matched mTOR-inhibitor therapy due to off-label barriers PMID:28336552.
- Proposed as potentially actionable agent for PTEN loss (10q deletion) identified in EWSR1::BEND2 bladder sarcoma via PI3K/AKT/mTOR pathway rationale; not administered to the patient PMID:28199314.
- Authors note prior efficacy of everolimus in leiomyosarcoma but flag the limitation of compensatory AKT activation; recommend evaluating dual PI3K/MTOR inhibitors given pervasive PTEN/AKT3/MTOR/IGF1R/RICTOR pathway alterations in 84% of ULMS+STLMS C1 PMID:29100075
- Cited as prior VEGF-targeted therapy in the ccRCC cohorts; PBRM1-LOF benefit from anti-PD-(L)1 was more pronounced in previously VEGF-inhibitor-treated patients, suggesting a treatment-sequencing interaction relevant to mTOR-pathway agents PMID:29301960
Resistance mechanisms
- TSC2 frameshift deletions may not confer the same clinical benefit from everolimus as TSC2 splice site mutations in HCC, based on differential outcomes in 2 patients PMID:37769223.
Cancer types (linked)
Sources
- PMID:37769223
- PMID:39305899
- PMID:36585450 — Fougner et al. 2023, AURORA US; PIK3CA mutations across primary/metastatic paired breast cancer specimens relevant to mTOR pathway targeting.
- PMID:21252315
- PMID:23792563 — TCGA CCRCC comprehensive molecular characterization; PI3K/AKT/mTOR pathway altered in ~28% of tumors, nominating everolimus as a therapeutic strategy in advanced RCC.
This page was processed by crosslinker on 2026-05-09. - PMID:24326773
This page was processed by crosslinker on 2026-05-09. - PMID:24487277
This page was processed by wiki-cli on 2026-05-11. - PMID:24735922
This page was processed by wiki-cli on 2026-05-11. - PMID:24798001
This page was processed by wiki-cli on 2026-05-11. - PMID:25201530
This page was processed by wiki-cli on 2026-05-11. - PMID:28027327 — Lefebvre et al. 2016, metastatic breast cancer WES; TSC1/2 mutations in 6.3% of HR+/HER2- mBC hypothesized as biomarker for everolimus outlier response.
*This page was processed by entity-page-writer on 2026-05-15. - PMID:28336552
This page was processed by wiki-cli on 2026-05-14. - PMID:28199314
This page was processed by wiki-cli on 2026-05-14. - PMID:29100075
This page was processed by wiki-cli on 2026-05-15. - PMID:29301960
This page was processed by entity-page-writer on 2026-05-15.