In patients with advanced lung or thymus carcinoid receiving everolimus, pasireotide LAR or the combination of the two drugs, statistically significant positive impact was seen on proportion of patients’ progression free at 9 months (primary endpoint) in all three arms, more relevant in the combination arm, according to phase II study findings presented at the ESMO 2016 Congress in Copenhagen, Denmark on 10 October, 2016.
Everolimus has shown clinical benefit in a variety of cancer types, including neuroendocrine tumours (NETs) by blocking mTOR pathway while pasireotide LAR is a somatostatin analogue.
Piero Ferolla, from the Multidisciplinary NET Group and the Department of Medical Oncology, Umbria Regional Cancer Network and University of Perugia in Perugia, Italy and the co-investigators pointed out that on the basis of the current ESMO and ENETS guidelines, of which he is a co-author, advanced carcinoid of the lung or thymus remains an area of high unmet medical need with few treatment options and no previous study was entirely focused on these tumours. He underlines that everolimus showed improved progression-free survival (PFS) in the phase III RADIANT-4 study in patients with gastrointestinal or lung NETs and that pasireotide LAR has demonstrated potential antitumour activity in patients with NETs. These observations prompted Dr. Ferolla and colleagues to assess the efficacy and safety of pasireotide LAR and everolimus alone and in combination in patients with progressive carcinoids of lung and thymus.
The LUNA phase II trial randomised 41 patients to pasireotide LAR at 60 mg/month intramuscular, 42 patients to oral everolimus at 10 mg/day orally, and 41 patients to pasireotide LAR plus everolimus at the same single-agent doses.
The primary endpoint of the trial was the progression-free rate at 9 months (PFR-9), defined as the proportion of patients with documented complete response (CR), partial response (PR), or stable disease (SD) by RECIST v.1.1 criteria at 9 months. Secondary end points included PFS, disease control rate (DCR), and safety.
Patients had a median age of 64 years. Atypical carcinoid was present in 68.5% of patients while 31.5% of the patients had typical carcinoid. Primary tumour site was the lung in 93.5% of patients and thymus in 6.5%. WHO performance status was 0, 1, or 2 in 64%, 34%, and 2% of patients, respectively. Prior drug treatment had been administered to 44% of patients, radiotherapy to 27%, surgery/locoregional therapy to 97%, and 48% of patients had received prior somatostatin analogues.
The study met primary end-point in all the 3 arms
The trial’s primary endpoint, PFR-9, was achieved by 39.0% of patients on single agent pasireotide LAR (95% confidence interval [CI] 24.2, 55.5), 33.3% of patients on sole everolimus (95% CI 19.6, 49.5), and by 58.5% of patients on combined everolimus and pasireotide LAR (95% CI 42.1, 73.7).
Complete response was not observed in any of the 3 treatment groups. The best overall response at 9 months was PR, which was achieved by 2% of patients in each treatment arm. Stable disease was attained by 34% of pasireotide LAR patients, 31% of everolimus patients and by 49% of patients receiving the combination. Progressive disease (PD) occurred in 17% receiving pasireotide LAR versus 2% of patients receiving everolimus. None of the patients receiving the combined treatment reported PD.
Study treatment was discontinued by 65% of patients during the 12 month core phase of treatment. Discontinuation due to PD or adverse events (AEs) was each reported in 27% of patients. AEs were mostly grades 1/2 across treatment groups. The most common AEs (any grade) with combined pasireotide LAR and everolimus were hyperglycaemia, which was reported by 88% of patients, diarrhoea in 78%, weight decrease in 56%, asthenia in 37%, and stomatitis was reported in 34% of patients.
James Yao who discussed the study findings said that single arm and “pick the winner” randomised phase II studies reply on indirect comparison with historical control. Reliability is compromised when quality of historical data is low, confidence interval is wide or where outcome are heterogeneous. Outcome of each arm is compatible with clinical activity but do not demonstrate superior efficacy with confidence. The results from the LUNA study are compatible with improvement but comparitive randomised phase II study is needed, according to Dr. Yao.
According to Dr. Ferolla and co-authors, the LUNA study was the first randomised trial specifically designed for patients with lung and thymic carcinoids. He emphasised that LUNA met the primary endpoint and noted that promising PFR-9 was seen, primarily with combined everolimus and pasireotide LAR, but also with the single agent treatments.
No new safety signals were seen with the combination of pasireotide LAR and everolimus in these patients with advanced disease.
Efficacy and safety of pasireotide LAR or everolimus alone, or in combination in patients with advanced carcinoids (NET) of the lung/thymus: Results from the randomized, phase 2 LUNA study
P. Ferolla, M.P. Brizzi, T. Meyer, W. Mansoor, J. Mazieres, C.D. Cao, H. Lena, A. Berruti, W. Buikhuisen, M. Stankovic, N. Singh, E. Chiodini, G. Gislimberti, K. Oberg, E. Baudin
This trial was sponsored by Novartis.