Everolimus
Rapamycin analog (RAD001); used in oncology and tested for immune function in older adults.
A rapamycin derivative used in clinic. A modified version of rapamycin. Used in cancer treatment and also studied for boosting immune responses in older adults.
RAD001. Same FKBP12-dependent allosteric mechanism as rapamycin, better oral pharmacokinetics; the clinical evidence base here is trial evidence, not mechanism.
TL;DR. Everolimus appears in 23 curated studies in Oliver's mTOR Atlas: 17 in people (2 syntheses of human data, 15 human studies); 4 in animal models; 1 at the molecular level (cells, biochemistry, structure); 1 registered trial without results yet. It has 7 interactions in the curated pathway model.
In the pathway model
| Interaction | Mechanism | Evidence | Studies |
|---|---|---|---|
| Everolimus inhibits Breast cancer mechanism: clinical-outcome · this link in full · on the map table | Adding everolimus to hormone therapy roughly doubled the time before certain advanced breast cancers got worse. Holds under: Progression-free survival, in combination with exemestane - overall survival was not significantly improved. shown in people · settled in the literature | H | BAS2012, PIC2014 |
| Everolimus context-dependent Immune function mechanism: clinical-outcome · this link in full · on the map table | At a low, occasional dose, an mTOR-blocking drug helped older people respond better to a flu vaccine. At the high continuous dose used after transplants, mTOR inhibitors damp the immune system down. A larger phase 3 trial of a DIFFERENT mTOR inhibitor (RTB101, which blocks the kinase itself rather than working like rapamycin) found no reduction in respiratory illness – so what this arrow means depends on the dose, the schedule and the drug. Holds under: Dose-dependent and duration-dependent: this is not the immunosuppressive regimen. The corpus supports an improved vaccine response under one regimen, not improved immune function in general. MAN2021 is recorded as conflicting for two reasons, and the earlier wording here got the first one wrong. Its phase 3 arm tested RTB101 monotherapy - a different drug, ATP-competitive rather than rapamycin-like - and found no reduction in clinically symptomatic respiratory illness. But the same paper's phase 2b part 2 DID include everolimus: 115 participants were randomised to RTB101 10 mg plus everolimus 0.1 mg daily, and that arm did not reach significance in the first prespecified analysis of the primary endpoint. So the randomised everolimus-containing evidence in MAN2021 points away from benefit as well, at a different dose and in a different population from MAN2014, rather than being irrelevant to this edge. Note also that the positive RTB101 10 mg result in that paper comes from a second prespecified analysis pooling parts 1 and 2, not from the first. Direction depends on dose and schedule. Transplant-level dosing is immunosuppressive; intermittent low dosing improved vaccine responses in older adults. Treating this as one effect with one sign is the error. shown in people · disputed: at least one study points the other way | H | MAN2014 conflicting: MAN2021 |
| Everolimus inhibits Renal angiomyolipoma mechanism: clinical-outcome · this link in full · on the map table | In another trial, everolimus shrank kidney growths in patients with tuberous sclerosis or a related lung disease, working in 42% of patients versus 0% on placebo. Holds under: Scope: the endpoint was the kidney lesion, not LAM lung disease, which is why this arrow lands on the angiomyolipoma and not on LAM. The evidence that mTOR inhibition treats the lung disease itself is the MILES trial with sirolimus - see the RAPA-LAM edge. shown in people · settled in the literature | H | BIS2013, GAO2026B |
| Everolimus inhibits mTORC1 mechanism: allosteric-inhibition · this link in full · on the map table | Everolimus is rapamycin with a small chemical tweak that makes it easier to take as a pill – same mechanism, better drug. Holds under: Clinical evidence from phase 3 trials of everolimus in specific diseases (kidney cancer, breast cancer, pancreatic neuroendocrine tumours, TSC and LAM) at the doses used for those diseases. It does not speak to low-dose use in healthy ageing. shown in people · settled in the literature | H | MOT2008, YAO2011, BAS2012, KRU2010, BIS2013, IYE2012, MEI2008 |
| Everolimus inhibits Pancreatic neuroendocrine tumor mechanism: clinical-outcome · this link in full · on the map table | In a trial, everolimus more than doubled the time before advanced pancreatic neuroendocrine tumours got worse. Holds under: One phase 3 trial (RADIANT-3, n=410) in advanced pancreatic neuroendocrine tumours. The result applies to that disease, stage and dose, and it is a progression-free survival result. shown in people · settled in the literature | H | YAO2011 |
| Everolimus inhibits Renal cell carcinoma (RCC) mechanism: clinical-outcome · this link in full · on the map table | In a clinical trial, everolimus roughly doubled the time before advanced kidney cancer got worse, after other treatments had stopped working. Holds under: Second-line setting, after VEGF-targeted therapy - not first-line. shown in people · settled in the literature | H | MOT2008 |
| Everolimus inhibits Tuberous sclerosis complex mechanism: clinical-outcome · this link in full · on the map table | In patients with the genetic disease tuberous sclerosis, everolimus shrank both brain and kidney tumours. It works one step downstream of the mutation: it replaces the brake the mutation removed, so the tumours shrink while the drug is given and regrow when it stops. The mutation itself is untouched. Holds under: Lesions regrow when the drug is stopped - this is suppression, not cure. shown in people · settled in the literature | H | KRU2010, BIS2013, GAO2026B |
Evidence at a glance
| Evidence | What it means | Studies |
|---|---|---|
| S | Synthesis of human data | 2 |
| H | Human study | 15 |
| A | Animal model | 4 |
| M | Molecular — cells, biochemistry, structure | 1 |
| RT | Registered trial, no results yet | 1 |
Human studies in the Atlas
Studies
| Year | Evidence | Study |
|---|---|---|
| 2026 | S | Efficacy and safety of everolimus in heart transplant recipients: A meta-analysis VITTE2026 Meta-analysis of 60 studies (1786 heart transplant recipients): everolimus-based immunosuppression reduced cardiac allograft vasculopathy progression on IVUS (RR ~0.57) and preserved renal function (eGFR +10-15 mL/min) when combined with calcineurin-inhibitor minimisation, with neutral all-cause mortality (RR ~0.98) but more adverse events and treatment discontinuation. |
| 2024 | S | Targeting ageing with rapamycin and its derivatives in humans: a systematic review LEE2024 Described by its authors as the first systematic review of rapamycin/rapalogs in humans for aging. Screened 18,400 articles, included 19 studies. Found improvements in immune, cardiovascular, and skin (integumentary) parameters; NO significant effect on endocrine, muscular, or neurological systems. No serious adverse events in healthy people, but more infections and raised cholesterol/triglycerides in people with age-related disease. This is the highest-tier human-evidence summary in the whole Atlas - it aggregates many individual human studies rather than reporting one. |
| 2026 | H | EVERolimus effectiveness after proGREssion on ENdocrine therapy plus CDK4/6 inhibitor for ER-positive/HER2-negative advanced breast cancer: EVERGREEN study MAR2026 Everolimus added to endocrine therapy provided modest but statistically significant PFS benefit (5.0 vs 4.3 months; HR 0.68) in ER+/HER2- advanced breast cancer post-CDK4/6 inhibitor progression, without demonstrable OS benefit, supporting selective use. Retrospective and non-randomised, so treatment-selection bias cannot be excluded. |
| 2026 | H | Everolimus for the treatment of neuropsychological deficits in tuberous sclerosis complex: findings from the TRON multicentre randomised controlled trial SAX2026 In a multicentre RCT of TSC patients (n=38 randomised, 2:1 everolimus:placebo), 24 weeks of everolimus produced similarly large 'responder' rates for neuropsychological improvement as placebo (87% vs 75%), suggesting large practice/placebo effects rather than a clear drug benefit on cognition -- despite everolimus's established efficacy for TSC tumours and epilepsy. Adverse events were more frequent with everolimus (88% vs 61.5%). |
| 2026 | H | Tumor fat composition predicts response to everolimus and supports low-dose therapy in TSC-associated renal angiomyolipomas: a multicenter prospective study GAO2026B In a multicenter prospective cohort of 183 TSC-associated renal angiomyolipoma patients, everolimus reduced tumor volume by >=50% in 44% of patients at 3 months and 83% at 6 months; fat-poor lesions responded significantly better than fat-rich ones. No significant difference in response was detected between the low-dose and standard-dose groups in an exploratory, non-randomised subset, and oral mucositis was less frequent on the low dose; tumor regrowth occurred after treatment discontinuation. |
| 2026 | H | [177Lu]Lu-edotreotide versus everolimus for gastroenteropancreatic neuroendocrine tumours (COMPETE): a phase 3, multicentre, randomised, open-label, superiority trial. WALTER2026 Phase 3 open-label RCT (n=309, 2:1): 177Lu-edotreotide gave longer PFS than everolimus (23.9 vs 14.1 months; HR 0.67) with fewer grade 3-4 treatment-related adverse events (18% vs 40%), supporting PRRT in early lines for progressive SSTR-positive GEP-NETs. |
| 2026 | H | Does the duration of exposure to everolimus influence the occurrence of chronic lung allograft dysfunction? LANDOAS2026 In lung transplant recipients, later introduction of everolimus and a greater number of treatment interruptions were both risk factors for chronic lung allograft dysfunction; earlier, uninterrupted treatment was associated with lower CLAD risk (retrospective, single-centre; causality not established). |
| 2018 | H | TORC1 inhibition enhances immune function and reduces infections in the elderly MAN2018 A phase 2a RCT in 264 older adults: 6 weeks of a low-dose combination of BEZ235 (a catalytic PI3K/mTOR inhibitor) and everolimus (RAD001) was associated with fewer reported infections over the following year, plus higher antiviral gene expression and a better flu-vaccine response. The later phase 3 trial of RTB101 (BEZ235) alone (MAN2021) did not confirm a clinical benefit. |
| 2016 | H | Adjunctive everolimus therapy for treatment-resistant focal-onset seizures associated with tuberous sclerosis (EXIST-3): a phase 3, randomised, double-blind, placebo-controlled study FRE2016 EXIST-3 was a phase 3, double-blind trial in 366 patients aged 2 to 65 with tuberous sclerosis complex and focal seizures that had not responded to standard drugs. They were randomised 1:1:1 to placebo (n=119), everolimus dosed to a low blood trough of 3-7 ng/mL (n=117) or a high trough of 9-15 ng/mL (n=130), added to their existing antiepileptic drugs. For the primary endpoint, at least a 50% fall in seizure frequency during the 12-week maintenance period, the response rate was 15.1% with placebo, 28.2% with low exposure (p=0.0077) and 40.0% with high exposure (p<0.0001); median seizure reduction was 14.9%, 29.3% and 39.6%. Grade 3-4 adverse events occurred in 11%, 18% and 24%, and serious adverse events in 3%, 14% and 14% of patients, respectively. The result showed a dose-dependent effect of mTOR inhibition on seizures in TSC, beyond its known effect on TSC tumours. Boundary: patients with TSC and treatment-resistant focal-onset seizures already on 1-3 antiepileptic drugs; comparator was placebo add-on; 18-week core phase (6-week titration, 12-week maintenance), so long-term durability is not addressed here. |
| 2014 | H | mTOR inhibition improves immune function in the elderly MAN2014 Older volunteers took the rapalog everolimus (RAD001) before a flu shot, and their antibody response to the vaccine rose by about 20% at doses that were fairly well tolerated. The share of T cells carrying the exhaustion marker PD-1 also fell. The PEARL authors summarise the doses as 0.5 mg daily or 5 mg weekly for 6 weeks. This is the human result behind the weekly low-dose idea. Boundary: a stronger vaccine response is a lab marker, not fewer infections, and the later RTB101 trial (MAN2021) shows how that gap can matter. |
| 2014 | H | Everolimus plus exemestane for hormone-receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: overall survival results from BOLERO-2† PIC2014 This is the final overall-survival report of BOLERO-2, the phase III double-blind trial (published primary analysis: BAS2012) in which postmenopausal women with hormone-receptor-positive, HER2-negative advanced breast cancer that had progressed on a nonsteroidal aromatase inhibitor received exemestane 25 mg/day plus either everolimus 10 mg/day or placebo. The primary endpoint, progression-free survival by local investigator, remained improved: median 7.8 vs 3.2 months (P < 0.0001), a 4.6-month gain. Overall survival, a key secondary endpoint, was not significantly improved: median 31.0 vs 26.6 months, hazard ratio 0.89 (95% CI 0.73-1.10), P = 0.14, at 410 deaths. Most patients went on to further treatment after the trial (84% vs 90%), with less chemotherapy in the everolimus arm (53% vs 63%), which may have diluted any survival difference. No new safety concerns were identified. Boundary: postmenopausal women with HR+/HER2- advanced breast cancer previously treated with a nonsteroidal aromatase inhibitor; comparator was exemestane plus placebo; the survival benefit of adding mTOR inhibition was not shown. |
| 2013 | H | Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre, randomised, placebo-controlled phase 3 trial FRA2013 Phase 3 RCT (n=117) in tuberous sclerosis, the disease where mTOR is stuck ON by a genetic fault. Everolimus shrank brain tumors (SEGA) by >=50% in 35% of patients versus 0% on placebo. Because the underlying cause here is direct mTOR overactivation, this is arguably the cleanest randomised human evidence that blocking mTOR works in a genetically defined mTORopathy -- which does not extend to mTOR inhibition in people without such a mutation. |
| 2013 | H | Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multicentre, randomised, double-blind, placebo-controlled trial BIS2013 The companion phase 3 RCT (n=118) to EXIST-1, targeting kidney tumors (angiomyolipomas) in tuberous sclerosis and LAM. Everolimus shrank them by >=50% in 42% of patients versus 0% on placebo. Together EXIST-1 and -2 sealed everolimus as a disease-modifying therapy across multiple TSC tumor types. |
| 2012 | H | Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer (BOLERO-2) BAS2012 A phase 3 RCT (n=724) proving mTOR matters in a common cancer. Resistance to hormone therapy in breast cancer is associated with mTOR activation. Adding everolimus more than doubled progression-free survival (10.6 vs 4.1 months by central review) - leading to FDA approval. Main toxicity was stomatitis. |
| 2011 | H | Everolimus for advanced pancreatic neuroendocrine tumors (RADIANT-3) YAO2011 A phase 3 RCT (n=410) that made everolimus a standard treatment for pancreatic neuroendocrine tumors. It more than doubled progression-free survival (11.0 vs 4.6 months, a 65% reduction in risk of progression/death) with mostly mild side effects. Another FDA-approved indication built on blocking mTOR. |
| 2010 | H | Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis KRU2010 In patients whose TSC1/TSC2 mutations cause brain tumors, everolimus shrank tumor volume by 30%+ in three-quarters of patients. Open-label and uncontrolled (n=28); randomised confirmation came later (FRA2013). |
| 2008 | H | Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial MOT2008 Everolimus extended median progression-free survival from 1.9 to 4.0 months versus placebo in metastatic renal cell carcinoma. |
| 2026 | A | mTOR inhibition augments antitumor immune effector response by reprogramming the TP53-mutant, immune-cold HNSCC tumor microenvironment NAT2026 In syngeneic TP53-mutant HNSCC mouse models, the mTOR inhibitor everolimus reprogrammed the immune-cold tumor microenvironment: it increased CD8+ T cell and dendritic cell infiltration, reduced Tregs and HIF-1α/VEGFA-driven MDSC recruitment, boosted TNF-α/CXCL10 chemokine signaling, and reduced PD-1/PD-L1 expression — restoring T-cell cytotoxic competence and suppressing tumor growth. |
| 2026 | A | SPOP-mediated ZMYND8 ubiquitination and phase separation exclusion drives mTOR inhibitor resistance in kidney cancer TAN2026 Identifies a mechanism of mTOR-inhibitor (everolimus/temsirolimus) resistance in clear cell renal cell carcinoma: SPOP-driven K63-linked ubiquitination of ZMYND8 excludes it from phase-separation compartments, enabling a ZMYND8-ZHX2 complex that drives NEK7 transcription and alternative p70S6K activation independent of mTOR inhibition. A NEK7-targeting PROTAC restored everolimus sensitivity in ccRCC cells and mouse tumors, nominating NEK7 as a target to overcome mTOR-inhibitor resistance. |
| 2013 | A | Circadian regulation of mTOR by the ubiquitin pathway in renal cell carcinoma OKA2013 In mouse kidney tumours, active phosphorylated mTOR and total mTOR protein followed a 24-hour rhythm, set by the clock through the ubiquitin ligase Fbxw7. Giving everolimus when mTOR was high improved survival compared with other dosing times. Same drug, same dose - the clock time of dosing changed the outcome. |
| 2008 | A | Response of a neuronal model of tuberous sclerosis to mammalian target of rapamycin (mTOR) inhibitors: effects on mTORC1 and Akt signaling lead to improved survival and function MEI2008 mTOR inhibition rescues a neuronal tuberous-sclerosis model, supporting rapamycin for TSC neurology. |
| 2006 | M | mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt ORE2006 mTORC1 inhibition relieves feedback and activates upstream RTK-PI3K-Akt signalling. The Akt activation was demonstrated both in cancer cell lines and in patient tumours treated with RAD001 (everolimus), so this record carries a human pharmacodynamic component, not only in-vitro data. |
| RT | Everolimus Aging Study (EVERLAST): Clinical Evaluation of mTORC1 Inhibition for Geroprotection NCT05835999 Phase 2 trial (NCT05835999, EVERLAST) testing this Atlas's open dosing hypothesis directly: whether daily low-dose (0.5 mg/day) or weekly (5 mg/week) everolimus for 24 weeks can improve physiological and molecular hallmarks of aging in insulin-resistant or prediabetic adults aged 55-80, without the metabolic penalty seen with continuous higher-dose rapalog use. Double-blind and placebo-controlled with four arms (everolimus daily, everolimus weekly, and a matching placebo for each), n=106, plus a separate untreated 18-35 cohort for comparison. Primary endpoint is peripheral insulin sensitivity by dual-tracer OGTT; mTORC1 and mTORC2 signalling are secondary endpoints in muscle and blood cells. STATUS: the registry records the trial as COMPLETED, with primary completion 2026-06-30 and completion 2026-07-22. No results are posted yet, so there is nothing to read into the outcome either way. |
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