Matching Adjusted Indirect Comparison to Assess the Relative Efficacy of Idelalisib in Double-Refractory Follicular Lymphoma
Authors: Rajakumaraswamy Nishanthan , Lovato Eleonora , Smith Harry , Bagguley Timothy , Smith Alexandra , Patmore Russell , Marcus Robert 
Published: October 2019

Abstract
Background
Idelalisib, an oral, first-in-class, selective phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor, is approved in the US and Europe as monotherapy for relapsed/refractory follicular lymphoma (FL). Its safety and efficacy were primarily established from a Phase 2 study in patients with double-refractory FL, which carries a poor prognosis and has no current standard of care. As this was a single-arm trial, data regarding the relative efficacy of idelalisib compared to other regimens used in this population are limited. Therefore, we conducted a Matching-Adjusted Indirect Comparison (MAIC) to derive measures of relative efficacy of idelalisib versus other therapies in double-refractory FL using a well-established registry.
Methods
Study 101-09 was a Phase 2, multi-centre, single-arm, open-label trial of 125 patients with relapsed or refractory indolent non-Hodgkin's lymphoma (iNHL) treated with idelalisib monotherapy which included 72 patients (58%) with FL. Summary data from this Phase 2 trial were compared with individual level patient data from the HMRN (Haematological Malignancy Research Network). HMRN is an ongoing population-based cohort registry in the Northern UK that includes a population of 3.8 million and collects information on all haematological malignancies in the region.
This analysis included all patients newly diagnosed with FL from 1st Sep 2004 to 31st Aug 2013. Outcomes in patients who had received ≥ 2 prior lines of chemo/immuno-chemotherapy and were refractory to both rituximab and an alkylating agent, or had a relapse within 6 months after receipt of those therapies and were subsequently treated, were examined. MAICs were conducted in order to match to the characteristics reported of the trial population using previously described methodology.
Results
In total, 1,007 patients were newly diagnosed with FL during the index period, of whom 675 received treatment either from time of diagnosis (n=556) or after a period of 'watch and wait' (n=119); the majority of patients were treated with chemotherapy (n=520), with 155 receiving radiotherapy. The most common regimen at first line was R-CVP (n=304) followed by R-CHOP (n=135). Number of patients receiving second line therapy was 185 either due to relapse (n=136) or being refractory to first line therapy (n=49), the most common regimens were R-CVP, R-CHOP and other agents such as DHAP or bendamustine. Overall, 68 patients received third line treatment, the most common being chlorambucil-based (19.1%), fludarabine-based (6.8%) and DHAP (20.6%); the overall response rate was 58.8%. In the 675 patients treated with therapy, survival diminished by treatment line with respective 5-year OS being 74.7% in first line, 50.6% in second line and 39.3% in third line.
Twenty-six patients had received two or more prior regimens, were refractory to both rituximab and an alkylating agent, or had a relapse within 6 months of those therapies and were subsequently treated with chemotherapy - this cohort was used for MAIC against the 101-09 study population. Demographically, both populations were relatively similar. Since HMRN included patients as soon as they reached the eligibility criteria, differences were seen in time since diagnosis and the median prior therapies, suggesting that patients with higher risk disease and a poorer prognosis may have been identified. Accordingly, HMRN patients had a poorer 2-year OS than trial patients (46.2% vs 69.8%). The variables included were: age (62 < or ≥62), sex, stage III/IV disease, bulky disease and time from diagnosis (< or ≥4.7y). The results of the MAIC analyses pre and post matching were as follows: 2 year OS decreased from 46.2% to 19.8% after matching and 1-year PFS decreased from 57.7% to 24.7%; the respective 2-year OS of the trial population was 69.8% and 1-year PFS of 43.0% demonstrating favourable efficacy of idelalisib in this population.
Conclusion
This MAIC analysis using real-world data suggests that idelalisib provides superior efficacy relative to the other therapies used for the treatment of patients with FL who are refractory to two prior lines. The small effective sample size is a potential limitation of this analysis, along with the possible converse effect on prognosis associated with time since diagnosis between the two studies. However, the favourable efficacy of idelalisib remained when the analysis was repeated excluding time from diagnosis (2-year OS 39.9%).

Disclosures
Rajakumaraswamy: Gilead Sciences: Employment. Lovato:Gilead Sciences: Employment. Smith:Gilead Sciences: Employment. Bagguley:Gilead Sciences: Consultancy. Smith:Jazz Pharmaceuticals: Research Funding; Johnson & Johnson: Research Funding; Novartis: Research Funding; Gilead Sciences: Consultancy. Patmore:Roche: Consultancy; Gilead Sciences: Consultancy. Marcus:Gilead Sciences: Consultancy; Roche/ Genentech: Consultancy, Honoraria.