Everolimus in Advanced Neuroendocrine Tumors


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In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.

On February 26, 2016, everolimus (Afinitor) was approved for treatment of adult patients with progressive, well-differentiated, nonfunctional neuroendocrine tumors of gastrointestinal or lung origin that are unresectable, locally advanced, or metastatic.1,2

The drug was previously approved for treatment of neuroendocrine tumors of pancreatic origin, as well as to treat specific subsets of patients with breast cancer and renal cell carcinoma.

Supporting Efficacy Data

Approval was based on the finding of improved progression-free survival in a double-blind phase III trial where 302 patients were randomly assigned (2:1) to receive oral everolimus at 10 mg (n = 205) or placebo (n = 97) plus best supportive care.2,3 All patients were required to have disease progression within 6 months prior to randomization.

Overall, patients had a median age of 63 years (range = 22–86 years); 53% were female; 76% were white; 74% and 26% had World Health Organization performance status of 0 and 1; and the most common primary tumor sites were lung (30%), ileum (24%), and rectum (13%). Overall, 64% of everolimus patients were treated for at least 6 months and 39%, for at least 12 months.

Median progression-free survival on independent radiologic review was 11.0 months (95% confidence interval [CI] = 9.2–13.3 months) in the everolimus group vs 3.9 months (95% CI = 3.6–7.4 months) in the placebo group (hazard ratio [HR] = 0.48, P < .001). At interim analysis, no difference in overall survival was observed. Objective response rates were 2% vs 1%.

How It Works

Everolimus is an inhibitor of mTOR (mammalian target of rapamycin), a kinase downstream of the PI3K/AKT pathway. The mTOR pathway is dysregulated in several human cancers. Everolimus binds to the intracellular protein FKBP-12, resulting in an inhibitory complex formation with mTOR complex 1 (mTORC1) and inhibition of mTOR kinase activity.

Expanded Approval of Everolimus

  • Everolimus (Afinitor) has been approved to treat adult patients with progressive, well-differentiated, nonfunctional neuroendocrine tumors of gastrointestinal or lung origin that are unresectable, locally advanced, or metastatic.
  • The recommended dose of everolimus in advanced neuroendocrine tumors is 10 mg once daily, given until disease progression or unacceptable toxicity.

Everolimus reduces the activity of S6 ribosomal protein kinase (S6K1) and eukaryotic initiation factor 4E-binding protein, which are downstream effectors of mTOR involved in protein synthesis. S6K1 is a substrate of mTORC1 and acts to phosphorylate the activation domain 1 of the estrogen receptor, resulting in ligand-independent receptor activation. Everolimus also inhibits expression of hypoxia-inducible factor (eg, HIF-1) and vascular endothelial growth factor. Everolimus inhibition of mTOR in vitro and in vivo has been shown to reduce cell proliferation, angiogenesis, and glucose uptake.

How It Is Given

The recommended dose of everolimus in advanced neuroendocrine tumors is 10 mg once daily, given until disease progression or unacceptable toxicity. In dose reductions for toxicity, the dose should be reduced by approximately 50%. Recommended starting doses in hepatic impairment are 7.5 mg in mild, 5.0 mg in moderate, and 2.5 mg (if benefits outweigh risks) in severe impairment.

Treatment should be discontinued for grade 4 noninfectious pneumonitis, stomatitis, other nonhematologic toxicities, and metabolic events. For noninfectious pneumonitis of grade ≥ 2, infection should be ruled out and corticosteroid treatment considered. For grade 2 toxicity, interruption of treatment should be considered; treatment can be restarted at a lower dose with improvement to grade ≤ 1 and should be discontinued if symptoms do not improve within 4 weeks. For grade 3 toxicity, treatment should be interrupted until resolution to grade ≤ 1, with resumption at a lower dose and treatment discontinuation for recurrence.

For stomatitis of grade 2, treatment should be interrupted until recovery to grade ≤ 1 and then resumed at the same dose or at a reduced dose in case of recurrence. For grade 3 toxicity, treatment should be interrupted until recovery and resumed at a lower dose.

For other nonhematologic toxicities of grade 2, intolerable reactions should prompt interruption until recovery, with treatment resumed at the same dose or at a lower dose in case of recurrence. For grade 3 toxicity, treatment should be interrupted until recovery and can be resumed at a lower dose; treatment discontinuation should be considered for recurrence. For grade 3 metabolic events, treatment should be interrupted and can be resumed at a lower dose upon recovery.

Use of strong CYP3A4/PgP inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole), grapefruit, and grapefruit juice should be avoided with everolimus treatment. Caution is warranted in use of moderate CYP3A4/PgP inhibitors (eg, amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem); patients requiring coadministration of a moderate CYP3A4/PgP inhibitor should have the everolimus dose reduced to 2.5 mg.

Use of strong CYP3A4/PgP inducers (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) should be avoided. For patients requiring coadministration, doubling the everolimus dose using increments of ≤ 5 mg should be considered. St. John’s Wort, which also reduces everolimus exposure, should be avoided.

Safety Profile

In the phase III trial, the most common adverse events of any grade occurring in everolimus patients with an incidence at least 5% greater than in placebo patients were stomatitis (63% vs 22%), infections (58% vs 29%), diarrhea (41% vs 31%), peripheral edema (39% vs 6%), and rash (30% vs 9%). Grade 3 or 4 adverse events occurred in 69% vs 28%, with the most common including infections (11% vs 2%), stomatitis (9% vs 0%), and diarrhea (9% vs 2%).

The most common laboratory abnormalities of any grade were anemia (81% vs 41%), hypercholesterolemia (71% vs 37%), lymphopenia (66% vs 32%), elevated aspartate transaminase (57% vs 34%), and fasting hyperglycemia (55% vs 36%). The most common grade 3 or 4 abnormalities were lymphopenia (17% vs 2%), hyperglycemia (6% vs 1%), elevated alanine transaminase (6% vs 1%), and hypokalemia (6% vs 1%).

Serious adverse events occurred in 42% of the everolimus group and included three fatal events (cardiac failure, respiratory failure, and septic shock). Adverse events led to dose reduction or delay in 70% of patients receiving everolimus and to treatment discontinuation in 29%.

Everolimus carries warnings/precautions for noninfectious pneumonitis, infections, angioedema (with increased risk in patients taking angiotensin-converting enzyme inhibitors), oral ulceration, renal failure, impaired wound healing, laboratory test abnormalities (including elevations in serum creatinine, urinary protein, blood glucose, and lipids), use of live vaccine and contact with others who have received live vaccine, and embryofetal toxicity. Renal function, blood glucose, lipids, and hematologic parameters should be monitored prior to treatment and periodically thereafter. ■

References

1. U.S. Food and Drug Administration: Everolimus (Afinitor). Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm488028.htm. Accessed March 7, 2016.

2. Afinitor (everolimus) tablets prescribing information, Novartis Pharmaceuticals Corporation, February 2016. Available at ww.accessdata.fda.gov/drugsatfda_docs/label/2016/022334s036lbl.pdf. Accessed March 7, 2016.

3. Yao JC, Fazio N, Sing S, et al: Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): A randomised, placebo-controlled, phase 3 study. Lancet. December 15, 2015 (early release online).



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