BRIEF CO‐ADMINISTRATION OF IDELALISIB MAY IMPROVE THE LONG‐TERM EFFICACY OF FRONTLINE CHEMOIMMUNOTHERAPY IN CHRONIC LYMPHOCYTIC LEUKAEMIA: 3‐YEAR FOLLOW‐UP FROM THE RIALTO TRIAL

Introduction: The Phase 3 RIAltO trial opened in December 2011 to compare ofatumumab plus chlorambucil (O+C) with ofatumumab plus bendamustine (O+B) in patients with previously untreated chronic lymphocytic leukaemia (CLL) considered unfit for FCR (fludarabine, cyclophosphamide, rituximab). The protocol was amended in September 2014 to investigate the addition of idelalisib (first-in-class inhibitor of the p110δ isoform of phosphoinositol-3 kinase) or placebo. However, all idelalisib/placebo treatment was withdrawn from the trial in March 2016 following safety analysis of idelalisib registration studies and recommendations from Gilead Sciences Ltd and regulatory authorities. Here, we present an updated ad-hoc analysis of the cohort of patients in RIAltO who received idelalisib or placebo. Methods: Patients were eligible for inclusion if they had previously untreated CLL requiring treatment by NCI/IWCLL criteria, were considered unfit for FCR and did not have any contraindications to the study drugs. Consenting patients underwent an unblinded 1:1 randomisation to ofatumumab (300mg iv day 1 and 1000mg iv day 8 of cycle 1; 1000mg iv day 1 of cycle 2 onwards) plus either chlorambucil (10mg/m2 day 1-7, repeated every 28 days for 3-12 cycles) or bendamustine (70mg/m2 iv day 1-2 for 3-6 cycles) and a double-blinded 1:1 randomisation to concurrently administered placebo or idelalisib (150mg bd for up to 3 years). Co-trimoxazole prophylaxis was recommended. Study drugs were discontinued in the event of disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). The mandatory post-treatment reporting period for serious adverse events (SAEs) was 6 months for grade ≥3 infections and 28 days for other events. Results: 145 patients received idelalisib (73) or placebo (72), the two arms being well balanced for age, gender, stage, co-morbidity, performance status and chemotherapy allocation. The median idelalisib exposure time was 3.3 months (IQR 1.2-7.3 months). As of January 2019, SAEs were reported in 79% of idelalisib-treated patients (87 grade 3-4 and 9 grade 5) compared to 50% of the placebo arm (38 grade 3-4 and 6 grade 5). The frequency of SAEs in the idelalisib arm was similar in both chemotherapy groups. After a median follow-up of 41.7 months (IQR 36.2-45.4 months), 28 PFS events have been reported in the idelalisib arm compared with 39 in the placebo arm (P = 0.070, log-rank test), while 10 and 16 deaths have been observed in the idelalisib and placebo arms, respectively (P = 0.218, log-rank test). Although 6-month mortality in the idelalisib arm was twice that of the placebo arm, only 2 deaths have been reported beyond 6 months in the idelalisib arm compared with 12 in the placebo arm. Keywords: chronic lymphocytic leukemia (CLL); idelalisib; ofatumumab. Disclosures: Pettitt, A: Research Funding: Celgene, Chugai, Gilead, GSK/Novartis, Roche, Verastem; Other Remuneration: Celgene, Gilead. Kalakonda, N: Research Funding: Celgene. Schuh, A: Consultant Advisory Role: Gilead, Abbvie, Janssen, Roche; Honoraria: Gilead, Abbvie, Janssen, Roche; Research Funding: Gilead and Janssen. Duncombe, A: Honoraria: Abbvie, Novartis, Gilead, Janssen. Paneesha, S: Honoraria: Speaker Fee Janssen, Gilead, Abbvie. Fox, C: Consultant Advisory Role: Abbvie, Adienne, Celgene, Gilead, Janssen, Roche, Takeda, Sunesis, Atarabio; Honoraria: Abbvie, Adienne, Celgene, Gilead, Janssen, Roche, Takeda, Sunesis, Atarabio; Research Funding: Abbvie, Adienne, Gilead, Roche. Hamblin, M: Honoraria: Roche. Hillmen, P: Honoraria: Janssen, Abbvie, Roche; Research Funding: Janssen, Pharmacyclics, Abbvie, Roche, Gilead.