Everolimus First Drug to Show Effect in Lung NETs

Zosia Chustecka

October 01, 2015

VIENNA — The latest clinical trial with everolimus (Afinitor, Novartis) in the treatment of neuroendocrine tumors (NETs) has shown that the drug is effective for NETs originating in the gastrointestinal tract and the lungs.

The effect on lung NETs is "remarkable," as no other drug has shown this before, said Christoph Zielinski, MD, director of the clinical division of oncology and coordinator of the Comprehensive Cancer Center at Medical University Vienna. He predicted that the new results would change clinical practice. Generally, NETs have a low mutational burden and are not responsive to targeted therapy, or to chemotherapy, he explained.

Dr Christoph Zielinski

Dr. Zielinski was commenting on the new results during a press briefing here at the European Cancer Congress 2015. He was not involved with the study.

Everolimus is already approved for use in the treatment of pancreatic NETs, on the basis of results from the RADIANT-3 trial, which showed that the drug significantly improved progression-free survival compared with placebo.

The latest study, known as RADIANT-4, was conducted in 302 patients with NETs of gastrointestinal or lung origin. About 30% of patients had lung NETs, and 24% had NETs in the ileum, commented lead investigator James Yao, MD, chair of gastrointestinal medical oncology at the University of Texas M.D. Anderson Cancer Center in Houston.

Dr James Yao

All patients received best supportive care, and were randomized 2:1 to receive either everolimus or placebo.

The results show a significant improvement in progression-free survival, with median progression-free survival (assessed by central review) of 11 months with everolimus vs 3.9 months with placebo (hazard ratio, 0.48; P < .00001). The overall survival data are not yet mature, but they show a positive trend suggesting that everolimus reduces the risk for death by 37%, Dr. Yao said.

Another secondary end point was overall response rate, which was 64% with everolimus vs 26% on placebo.

"Although we knew from previous studies that everolimus could delay the growth of pancreatic NETs, this is the first time that we have been able to conclusively show that it is effective in other NET sites," Dr. Yao said in a statement. These are "rare and aggressive cancers, with limited treatment options," he added.

The patients in this trial had previously been treated with somatostatin analogues such as octreotide (used in 53% of everolimus patients and 56% of placebo patients), chemotherapy (26% and 24%), and radiotherapy (22% and 20%).

Novartis, the manufacturer of everolimus, said that it will file these new data with regulatory authorities worldwide. The company also noted that the RADIANT series of trials is the largest ever clinical program in patients with advanced NET.

Adverse events reported in this trial were similar to what has been seen before, Dr. Yao noted. He said that 63% of patients on everolimus developed mouth ulcers, but he also commented that this adverse event appears to be associated with efficacy of the drug, as the patients who develop these mouth ulcers are also the ones who respond.

The most common treatment-related grade 3 or 4 adverse events were stomatitis (9% with everolimus vs 05 with placebo), diarrhea (7% vs 2%), and infections (7% vs 0%).

Effect Consistent, But New Player Is Coming

Discussing this presentation at the meeting, Enrique Grande, MD, from the Department of Medical Oncology at Ramón y Cajal University Hospital in Madrid, said that the RADIANT series of trials is "the most ambitious program in NET."

The results of all the RADIANT trials "are consistent and they support the use of everolimus for NET whatever the origin," he said.

However, he added, "despite the encouraging picture, we do not have the whole picture yet." The median progression-free survival of 11 months seen with everolimus in RADIANT-4 is not superior to what has been seen in other studies, he noted. For example, median progression-free survival of 14 months was achieved with octreotide LAR in the PROMID study (J Clin Oncol. 2009;27:4656-4663), while in the SWOG S0518 trial (J Clin Oncol 2015;33 Suppl;abstr 4004), a median progression-free survival of 16.6 months was achieved by a combination of octreotide LAR and bevacizumab (Avastin), and a median progression-free survival of 15.4 month by a combination of octreotide LAR plus interferon.

Also, there is a new player coming into this arena, Dr. Grande pointed out. The radiopharmaceutical 77Lu-DOTATATE (Lutathera, under development by Advanced Accelerator Applications) has achieved the "most impressive PFS that we have seen in NETs," Dr. Grande commented. The data on this product were presented at the same presidential session at the meeting, and while the median progression-free survival has not yet been reached, it is estimated at around 40 months, as reported by Medscape Medical News.

The RADIANT studies are funded by Novartis, the manufacturer of everolimus.

European Cancer Congress (ECC) 2015: Abstract LBA5. Presented September 27, 2015.

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