Patient Selection

The inclusion criteria differed from study to study.

The RADIANT-2 enrolled only NETs associated with a carcinoid syndrome, from any primary site. The Ki-67 was not required as an inclusion criterion. Prior therapies were allowed. Neither stratification nor pre-planned analysis for lung NETs were included in the design of the trial. Radiologic baseline progressive disease within the last 12 months, not necessarily RECIST-based, was required. With regards to the carcinoid syndrome inclusion criteria reported “history of symptoms attributed to carcinoid syndrome (flushing, diarrhea, or both)”.


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The RADIANT-4 included only non-functioning NETs, from GI or lung, with up to 20% Ki-67 (grade 1 or grade 2 in accordance with the WHO 2010 classification). Previous treatments were allowed. Radiologic baseline progressive disease within the last 6 months, not necessarily RECIST-based, was required.

While in the RADIANT-2 no stratification was planned for lung NETs, a prognostic stratification into two subgroups was decided in the RADIANT-4, by including lung NETs into the poor prognosis category, together with stomach, colon and rectum.

The ITMO study included just therapy-naïve (a true first-line) mixed population well differentiated, G1-2, NETs. No specific analysis for lung NETs was pre-planned.

While in the aforementioned trials lung NETs could be included regardless of their definition of TC or AC, in the LUNA trial all included lung NETs had to be defined as TC or AC. The LUNA required a radiologic baseline progressive disease within the last 12 months, not necessarily RECIST-based. Patients with severe functioning disease requiring symptomatic treatment with SSA were ineligible and stratification was performed according to histology (TC versus AC) and to line of study treatment (first line of systemic medical treatment versus other).

No specific inclusion criteria regarded tumor burden in any trials.

Efficacy Data

Primary endpoints were progression-free survival (PFS) by central radiology review for the RADIANT-2 trial, PFS by real-time central radiology review for the RADIANT-4, 9-month PFS rate for the LUNA trial and overall response rate (ORR) for the ITMO study.

While RADIANT-4 and LUNA were positive studies according to their met statistical goal, RADIANT-2 was a negative study due to the unmet pre-specified threshold of p=0.024.

No statistical significant improvement of OS was reported so far in favor of EVE from the two phase III RCTs.

Table 4 comprises all the efficacy data of the selected studies.

Publishers Alliance 081420 Table 4

Special Consideration: Which Tumor Population

Median age (58–67 years), males (51–68%), Caucasians (84–100%) and WHO PS score of 0 (45.5–75%) were similar from all the studies, except for ITMO study that enrolled only patients with PS of 0.

Among the patients in whom tumor morphology was reported, the majority were TC, except for LUNA trial that selected a more aggressive tumor population.

The EVE-arm included lung NETs who had mainly been previously treated with other therapies whereas the rate of first-line treatment was 14–36%.

Prior SSA therapy was administered in 43–46% of EVE treated population (except for RADIANT-2 trial that enrolled a higher percentage (67%) of patients previously treated with SSA).

Radiotherapy, including PRRT, had been received before EVE in 19.5–40% of patients.

The tumor burden of lung NET treated with EVE was described as presence of metastatic hepatic lesions (ranging from 68% to 81%) and elevated level of CgA (76% of cases in ITMO trial and 1278.8 ng/mL as median value in RADIANT-2).

Apart from RADIANT-2 and −4, the others studies included patients with syndrome ranging from 17% to 29%.

Table 5 comprises all the toxicities reported in the selected studies.

Publishers Alliance 081420 Table 5

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