The RADIANT-trials assess the efficacy and safety of mTOR-inhibitor everolimus for well differentiated neuroendocrine tumours (NET) based on the assumption that alterations of the mTOR-pathway play an important role in the development of NET. While results of the RADIANT-2 trial combining everolimus plus octreotide for functioning NET were less clear due to a possible influence of antiproliferative effects induced by somatostatin analogues (SSA) in the control arm, the RADIANT-3 trial published in 2011 was able to demonstrate a clear PFS benefit of 6.4 months versus placebo. Consequently, everolimus was approved by the EMA for the treatment of progressive pancreatic NET.
As of 2016, the therapeutic algorithm for advanced pancreatic NETs includes several approved options e.g. streptozotocin, sunitinib and everolimus. In contrast to this, the treatment options for (non-pancreatic) gastrointestinal (GI)-NET and typical/atypical carcinoids of the lung are limited. For decades the only approved drug was symptomatic application of SSA. However recently, the PROMID and the CLARINET trial have shown that SSA may have direct antiproliferative effects and these data resulted in the approval of SSA for this indication. Furthermore, first randomized data for radiopeptide therapy (PRRT) presented last year eventuated in a positive resonance also for this treatment approach.
Nevertheless, the median overall survival of midgut-NET patients is beyond 50 months in many cases, reflecting clearly the unmet need for further validated therapies.
The RADIANT-4 trial adds important new data to this problem. In this randomized, double-blind, phase III trial a total of 302 patients were enrolled in order to assess the efficacy and safety of everolimus versus placebo in patients with advanced, well-differentiated (G1/2), non-functional NETs of GI- or lung-origin. The primary endpoint was PFS. Patients were randomized in a 2:1 key for everolimus and stratified according to tumour origin, performance status and previous SSA. In terms of pretreatment patients were allowed to have not only prior therapy with SSA but either interferon, one line of chemotherapy or PRRT. All patients had to have a documented radiological progress upon or past the last treatment and at least one measurable target lesion. In line with prior data patients received everolimus 10 mg daily until progress or intolerable toxicity.
Median PFS assessed by central review was 11.0 months (95%CI 9.2-13.3) for the treatment group versus 3.9 months (95%CI 3.6-7.4) in the placebo group demonstrating a clear median PFS benefit of 7.1 months (HR 0.48, 95%CI 0.35-0.67; p=<0.00001) for everolimus. The first planned OS analysis was performed after a total of 70 deaths and favoured the treatment arm (HR 0.64, 95%CI 0.40-1.05; p=0.0379). However, statistical significance was missed and data are yet immature (median follow-up 21 months).
As expected, the most common site of tumour origin included in the RADIANT-4 trial was the GI-tract (n=175), followed by NET of the lung (n=90) and tumours of unknown origin (n=36). Importantly, the significant PFS benefit for everolimus was remained throughout all predefined subgroups; not only in terms of primary site but also absolute liver tumour burden, which constitutes an accepted prognostic factor in metastatic NET.
In terms of toxicity no new red flags were reported. 63% of patients treated with everolimus reported an episode of stomatitis, but this was low-grade in the majority of cases. Further common non-hematologic side effects of everolimus were diarrhea (31% all grades), infections (29%), and pneumonitis (16%). Treatment stop due to adverse events was documented in 12% of patients in the everolimus arm versus 3% for placebo.
Taken together, everolimus adds a new treatment approach to the anyhow small spectrum of treatment options for GI- and lung-NET. The RADIANT-4 trial was well designed and appears comparable to all major trials in the field in terms of study design and cohort. However, treatment with everolimus is toxic and should be reserved for patient with progressive disease as underlined by patient selection criteria (in contrast to the SSA trials PROMID and CLARINET were the majority of patients had stable disease at baseline). In total, only four patients treated with everolimus showed an objective response highlighting that the main effect of this treatment is disease stabilization but not decrease in tumour size. This should be communicated to the patient in order to prevent false expectations.
Finally, I have assessed the clinical benefit of everolimus in this setting with the ESMO-Magnitude of Clinical Benefit Scale (MCBS). This tool allows to quantify the potential clinical effect that may be expected of a novel treatment. With a median PFS gain of 7.1 months and a HR of 0.48 (95%CI 0.35-0.67) everolimus qualifies currently for a score of 3 implicating a moderate clinical benefit.
- What do you think about optimal sequencing of SSA, everolimus and PRRT?
- If you could design a trial involving everolimus for GI-NET which clinical setting and control arm would you use?
Barbara Kiesewetter declares no conflict of interests.
The content of this article reflects the personal opinions of the authors and is not necessarily the official position of the European Society for Medical Oncology.