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Everolimus and Radiolabeled Somatostatin Analogs for Well-differentiated GI Tract Neuroendocrine Tumors

Reports from two trials, one published and the second presented at the 2015 meeting of the European Cancer Congress, address treatment options for advanced well-differentiated gastrointestinal tract neuroendocrine tumors (GINETs):

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* In the RADIANT-4 trial comparing everolimus or placebo in patients with advanced, nonfunctional NETs, everolimus was associated with a significant improvement in median progression-free survival (PFS, 11 versus 3.9 months). Adverse events were mainly grade 1 or 2 and included stomatitis, diarrhea, peripheral edema, fatigue, and rash.

* In a preliminary report of the NETTER-1 trial, comparing Lutetium-177 DOTA Tyr³-octreotate (¹⁷⁷Lu-Dotatate) every eight weeks plus 30 mg of octreotide LAR monthly with octreotide LAR 60 mg monthly in patients with inoperable, somatostatin receptor-positive GINETs experiencing progression on octreotide LAR, the projected PFS for the ¹⁷⁷Lu-Dotatate group octreotide was estimated at 40 months, compared with a PFS of 8.4 months for octreotide LAR alone. Limitations of ¹⁷⁷Lu-Dotatate include lack of information on long-term toxicity, limited access (available outside of a study setting in Europe and in Canada) and the lack of trials comparing this agent with other systemic therapies such as everolimus.

For patients with widespread well-differentiated GINETs who are not eligible for liver-directed therapy, authors suggest everolimus. For patients with a somatostatin receptor-positive GINET, treatment with ¹⁷⁷Lu-dotatate is a reasonable option, where available, either at the time of progression on a somatostatin analog or following progression on everolimus. There are no data specifically comparing ¹⁷⁷Lu-dotatate versus everolimus in patients progressing on long-acting somatostatin analog therapy, and the choice of therapy in this situation should be based upon availability of ¹⁷⁷Lu-dotatate and patient preference.

SEE RELATED ARTICLE ON PAGE 22.

Naloxone Intranasal Spray for Community-based Reversal of Opioid Overdose

Naloxone is an opioid antagonist that rapidly reverses the effects of opioid overdose. Take-home naloxone, along with education and training on its use for overdose, is increasingly provided to opioid-dependent patients and members of their households, making ease of administration a priority. The U.S. Food and Drug Administration recently approved an intranasal naloxone spray (Narcan nasal spray) in a dispenser that delivers a premeasured 4 mg dose. The nasal spray adds to treatment options, which include another easy-to-use device, a handheld naloxone auto-injector (Evzio) that was approved in 2014. Caregivers should contact emergency services as soon as the first dose is given; additional doses may be needed before first responders arrive.

Emergency Antidote Approved in the U.S. for Severe Fluoropyrimidine Toxicity

Uridine triacetate, an orally administered prodrug of uridine, is a safe and potentially life-saving treatment for overdoses of fluoropyrimidines including fluorouracil (FU) and capecitabine. Patients who develop severe fluoropyrimidine toxicity because of inherited deficiency in dihydropyrimidine dehydrogenase (DPD) should also benefit from uridine triacetate administration if the deficiency is identified soon enough after the fluoropyrimidine is administered, and uridine triacetate can be obtained within 96 hours of the last dose, although there are no published data for this use. Uridine triacetate was approved by the U.S Food and Drug Administration in December 2015 for emergency use following an FU or capecitabine overdose regardless of the presence of symptoms, and for patients who exhibit early-onset, life-threatening, or unusually severe adverse reactions after FU or capecitabine administration.

Combined BRAF Plus MEK Inhibition in BRAF V600 Mutated Advanced Melanoma

Inhibition of either BRAF or MEK in the MAPK pathway prolongs overall survival in patients with advanced cutaneous melanoma containing a V600 mutation in BRAF. In large stage III trials, the combinations of a BRAF inhibitor and a MEK inhibitor (dabrafenib plus trametinib or vemurafenib plus cobimetinib) significantly prolonged overall survival compared with a BRAF inhibitor alone. Combined inhibition of BRAF and MEK is the preferred treatment for patients with a V600 mutation who are candidates for targeted therapy. In November, cobimetinib was approved by the U.S. Food and Drug Administration for use in combination with vemurafenib for patients with metastatic melanoma and a V600 mutation in the BRAF.

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Febuxostat to Prevent Tumor Lysis Syndrome

Febuxostat, an oral selective inhibitor of xanthine oxidase, is approved for management of chronic hyperuricemia in gout. Compared with allopurinol, it has minimal effects on other enzymes involved in purine and pyrimidine metabolism, does not require renal dose adjustment, and has fewer drug-drug interactions. A randomized trial compared allopurinol and febuxostat in 346 patients receiving initial chemotherapy for a hematologic malignancy at intermediate to high risk of tumor lysis syndrome (TLS). Dosing for febuxostat was fixed (120 mg daily) but was variable (200, 300, or 600 mg daily) for allopurinol at the clinician's discretion. Mean serum uric acid levels up to day 8 were lower for febuxostat, but survival and rates of TLS following chemotherapy were not different from the allopurinol group.

Given the issue with disparate dosing in this trial, concerns about drug-induced liver dysfunction in patients receiving febuxostat for gout, and the possible interaction of febuxostat with potentially hepatotoxic chemotherapy, the authors suggest not using febuxostat to prevent TLS in most patients at intermediate to high risk for TLS. Febuxostat may be used judiciously in patients with hyperuricemia who cannot tolerate allopurinol in a setting in which rasburicase is not available or contraindicated.