Idelalisib Monotherapy and Durable Responses in Patients with Relapsed or Refractory Marginal Zone Lymphoma (MZL)
Authors: Martin Peter , Armas Armando , Gopal Ajay K , Gyan Emmanuel , Wagner-Johnston Nina D. , Walewski Jan , Abella Steve , Ye Wei , Philip Betsy , Sorenson Bess , de Vos Sven 
Published: October 2019

Abstract
Background: MZL, a group of indolent B-cell lymphomas, arises from marginal zone B cells present in lymph nodes and/or extranodal tissues. MZL comprises 5-17% of all non-Hodgkin lymphomas in adults (Cervetti et al. Ann Oncol. 2010; 21:851-854). World Health Organization (WHO) classification of MZL consists of the following subtypes: splenic marginal zone lymphoma (SMZL) with or without villous lymphocytes, nodal marginal zone lymphoma (NMZL) and extranodal marginal zone B-cell lymphoma, also called mucosa-associated lymphoid tissue (MALT; Harris et al. Blood. 1994; 84:1361-1392; Chan et al. Am J Clin Pathol. 1995;103:543-560). Subgroups of MZL share some common features but are different in their biology and behavior. Owing to the rarity of MZL, few randomized trials have compared available treatment options; hence, there is a lack of consensus about best practices. Idelalisib demonstrated considerable anti-tumor activity in patients with relapsed/refractory indolent non-Hodgkin Lymphoma (iNHL) in phase 1 (P1) Study 101-02 (NCT00710528), and refractory iNHL in phase 2 (P2) Study 101-09 (NCT01282424; Gopal et al. NEJM. 2014;370:1008-1018). This post hoc analysis evaluated efficacy and safety in 21 patients in the MZL subset.
Methods: The P1 and P2 studies were single-arm monotherapy trials assessing the safety and efficacy of idelalisib in relapsed/refractory hematologic malignancies (P1) or B-cell non-Hodgkin lymphoma (P2). Eligible patients included those with relapsed/refractory splenic, nodal, or extranodal MZL (P1) and MZL that was refractory to both rituximab and an alkylating agent (P2). In the P1 study (a dose escalation study), idelalisib was administered at doses of 50-350 mg BID over a period of 28 days (21 days on, 7 days off) until progression of disease (PD), death, or intolerable toxicity. In the P2 study, patients received idelalisib 150 mg BID until PD, death, or intolerable toxicity. MZL response was assessed with the use of standard criteria for lymphoma (Cheson et al, J Clin Oncol. 2007; 25:579-586).
Results: TheP1 study enrolled 6 patients with MZL (n=3 MALT, n=2 NMZL, n=1 SMZL) who received 150 mg BID (n=3), 200 mg BID (n=1), or 350 mg BID (n=2). The P2 study enrolled 15 patients with MZL (n=9 MALT, n=5 NMZL, n=1 SMZL). Patients had a median age of 74 and 72 years and 50% and 80% were male, in P1 and P2 respectively. Patients had received a median of 4.5 prior regimens in the P1 study [range 1-10] and 2 prior regimens in the P2 study [range 2-9]. Grade ≥3 adverse events in the P1 study included thrombocytopenia 3/6, and anemia, neutropenia, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) increases each 2/6. Grade ≥3 adverse events in the P2 study included diarrhea 3/15, neutropenia 3/15, and ALT increase 2/15. In the P1 study, partial response (PR) was reported in 2 patients who received 350 mg BID (NMZL [n=1] and SMZL [n=1]), stable disease [(SD) in 3 patients who received 150 mg BID (n=2) or 200 mg BID (n=1) (MALT [n=2] and NMZL [n=1]), and PD in 1 patient with MALT who received 150 mg BID. In the P2 study, the overall response rate was 7/15 [(47%), including complete response in 1 patient with MALT, PR in 6 patients (SMZL [n=1], NMZL [n=1], MALT [n=4])], SD in 7 patients (NMZL [n=3], MALT [n=4]), and PD in 1 patient with NMZL (Table). Median times to first response in the P1 and P2 studies were 1 month and 3.5 months, respectively. In the P1 study, duration of response (DOR) in the 2 patients with PR was 1 and 11.9 months, respectively, and in the P2 study the median DOR was 18.4 months. In the P1 study, with median follow-up time of 3.1 months, median progression free survival (PFS) was 7.4 months; in the P2 study, with median follow-up time of 5.5 months, median PFS was 6.6 months.
Conclusions: P1 and P2 studies suggest idelalisib, with a small patient population, has activity in patients with relapsed/refractory MZL. Idelalisib was well tolerated, with a safety profile that was as expected in patients with relapsed/refractory lymphoma MZL. There were no apparent disease specific safety signals. Phase 3 clinical trials of idelalisib with combination therapy are in progress for iNHL patients, including MZL patients.
Table 1. Phase 1 [Study 02] (n=6) Phase 2 [Study 09] (n=15)* IRC ORR, n (%) [95% CI] 33% [4-78] 47% [21-73] CR 0 7% PR 33% 40% SD 50% 47% PD 17% 7% DOR (months) 1 and 11.9 18.4 PFS (months) 7.4 6.6

Disclosures
Martin: Janssen: Consultancy, Honoraria; Acerta: Consultancy; Gilead: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Bayer: Consultancy. Armas:Gilead: Research Funding. Gopal:Gilead, Spectrum, Pfizer, Janssen, Seattle Genetics: Consultancy; Millennium, Seattle Genetics, Sanofi-Aventis: Honoraria; Spectrum, Pfizer, BioMarin, Cephalon/Teva, Emergent/Abbott. Gilead, Janssen., Merck, Milennium, Piramal, Seattle Genetics, Giogen Idec, BMS: Research Funding. Wagner-Johnston:Gilead: Consultancy; Celgene: Research Funding. Walewski:Mundipharma; Roche; Takeda: Honoraria, Other: Travel expenses; Amgen; Boehringer Ingelheim; Celgene; Janssen-Cilag; Mundipharma; Roche; Takeda; Teva: Consultancy; Bayer (Inst); Bayer/Onyx (Inst); Boehringer Ingelheim (Inst); Celgene (Inst); Celltrion (Inst); Gilead Sciences (Inst); GlaxoSmithKline (Inst); GlaxoSmithKline (Inst); Mundipharma (Inst); Pfizer (Inst); Roche (Inst); Roche/Genentech (Inst); Seattle Geneti: Research Funding. Abella:Gilead: Employment. Ye:Gilead: Employment. Philip:Gilead: Employment. Sorenson:Gilead: Employment.