Safety and Effectiveness of Idelalisib in Patients with Double-Refractory Follicular Lymphoma: A Pan-European Cohort of 242 Patients

Background: Malignant lymphoid cells are characteristically dependent on signals mediated by the phosphatidylinositol 3-kinase delta isoform (PI3Kδ). Idelalisib is an oral, selective, PI3Kδ inhibitor approved by the FDA and EMA as monotherapy for the treatment of advanced follicular lymphoma (FL). The approval was based on a phase 2 trial in patients with indolent non-Hodgkin lymphoma including 72 patients with FL who were refractory to at least 2 prior regimens (NCT01282424; Study 101-09). Interim safety analysis of this large, pan-European, noninterventional study of refractory FL patients treated with idelalisib monotherapy (EUPAS19618; NCT03568929) showed that the adverse event (AE) profile in clinical practice corroborates the known safety profile of idelalisib reported from clinical trials. Herein, we report the effectiveness and updated safety analysis from this study. Methods: This was a non-interventional, retrospective, cohort study. Adult patients treated with idelalisib for FL in routine clinical practice in 10 European countries were included. Data were collected retrospectively from sites by study personnel from remotely source data-verified medical records using electronic case report forms. Safety and effectiveness data for each patient were collected from time of idelalisib initiation until 6 months post-discontinuation of idelalisib, start of next treatment, or death. For this analysis, the data cut-off date was 16 June 2021. Effectiveness of idelalisib was assessed by overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), time to next treatment (TTNT), and overall survival (OS). The overall safety profile of idelalisib was assessed by estimating the incidence of AEs, serious AEs, adverse drug reactions (ADRs), and serious ADRs. Focus was given to special health outcomes of interest (HOIs), including transaminase elevation, hepatocellular injury, severe diarrhea/colitis, pneumonitis, neutropenia, rash, Stevens-Johnson syndrome, and serious infections. Multivariate Poisson regression analyses are used to estimate rates of ADRs, serious ADRs, and HOIs, and are adjusted for potential confounders. Time-to-event data were analyzed using Kaplan-Meier methods. Results: Overall, there were 257 eligible patients in the study from 85 sites. The Full Analysis Set (FAS) consisted of 242 patients excluding those with deviations (n=10) or those without any data contribution at the cut-off date (n=5). Of the 242 patients, 183 initiated idelalisib at least 12 months prior to data cut-off date and were included in the Effectiveness Analysis Set (EAS; n=49 patients did not have effectiveness data recorded, and 10 did not meet effectiveness inclusion criteria). For the 183 patients in the EAS, median age was 67 years and 54.6% (n=100) were male (Fig. 1A). Median number of prior therapies was 3 (range 1-10) and median time since diagnosis was 5.8 years (range: 0.4-32). At treatment initiation, 64% (n=117) had Ann Arbor stage III/IV disease. Median duration of idelalisib exposure was 6.8 months (IQR 3.0-15.6); 41.5% (n=76) had dose interruptions. Patients received doses of 150 mg only (67.8%), both 150 mg and 100 mg (28.4%), or 100 mg only (3.8%). Patients were observed for a median of 9.8 months (IQR 5.2-19.3). In the EAS, 103/183 patients achieved a response with 30 patients (16.4%) achieving a complete response (CR) and 73 (39.9%) achieving a partial response (PR), yielding a best ORR of 56.3% (95% CI: 48.8-63.6; Fig. 1B). Median DOR, PFS, and TTNT were 22.5 (95% CI: 15.1-27.9), 11.1 (95% CI: 8.1-18.1) and 15.4 months (95% CI: 9.9-22.2), respectively (Fig. 1B, C). Median OS had not been reached at the time of data cut-off (Fig. 1D). Updated safety information was available from the 242 patients in the FAS. The most frequent AEs recorded were infections, diarrhea and/or colitis, and transaminase elevation. The proportion of patients in the FAS experiencing Grade 3/4, severe, common, and HOI TEAEs are presented in Fig. 1E. Conclusions: We report to our knowledge the largest cohort of FL patients treated with idelalisib outside of the clinical trial setting. Our effectiveness findings are remarkably similar to those from the registrational study 101-09 (Gopal 2014 N Engl J Med). Safety profile of idelalisib was consistent with trial experience, and no new safety signals were identified. Idelalisib remains an effective treatment option for FL patients. Figure 1 Figure 1. Disclosures Gyan: Gilead Sciences, Inc.: Consultancy; Novartis: Research Funding; Mundipharma: Research Funding; Fresenius Kabi: Research Funding; Sanofi: Honoraria; AbbVie: Other: Hospitality; AstraZeneca: Honoraria. Tisi: Incyte: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees. Merli: Takeda: Consultancy; Janssen Pharmaceuticals: Consultancy; Gilead Sciences, Inc.: Consultancy; Novartis: Consultancy. Di Raimondo: Amgen: Honoraria; AbbVie: Honoraria; Pfizer: Honoraria; Bristol Myers Squibb: Honoraria; Janssen Pharmaceuticals: Honoraria; Jazz Pharmaceutical: Honoraria. Mercadal: Gilead Sciences, Inc.: Honoraria, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Puccini: Takeda: Membership on an entity's Board of Directors or advisory committees. Vandenberghe: Janssen Pharmaceuticals: Honoraria; AbbVie: Honoraria. Boland: Gilead Sciences, Inc.: Current Employment, Current equity holder in publicly-traded company. Shah Gupta: Gilead Sciences, Inc.: Current Employment, Current equity holder in publicly-traded company. van Troostenburg: Gilead Sciences, Inc.: Current Employment, Current equity holder in publicly-traded company. Dunnill: Gilead Sciences, Inc.: Current equity holder in publicly-traded company, Other: Contractor. Ramroth: Gilead Sciences, Inc.: Current Employment, Current equity holder in publicly-traded company. Rajakumaraswamy: Gilead Sciences, Inc.: Current Employment, Current equity holder in publicly-traded company. Salles: Genentech/Roche: Consultancy; Incyte: Consultancy; Regeneron: Consultancy, Honoraria; Miltneiy: Consultancy; Genmab: Consultancy; Epizyme: Consultancy, Honoraria; Velosbio: Consultancy; Novartis: Consultancy; Ipsen: Consultancy; Morphosys: Consultancy, Honoraria; Allogene: Consultancy; Debiopharm: Consultancy; Janssen: Consultancy; Kite/Gilead: Consultancy; Loxo: Consultancy; Takeda: Consultancy; Rapt: Consultancy; BMS/Celgene: Consultancy; Beigene: Consultancy; Abbvie: Consultancy, Honoraria; Bayer: Honoraria.

A Rare Occurrence of Hyperkalemia Following Remdesivir: A Case Series

Remdesivir is a nucleoside analog with broad-spectrum antiviral activity against several viruses such as respiratory syncytial virus, Nipah virus, Ebola virus (EBOV), Middle East respiratory syndrome (MERS-CoV), and Severe Acute respiratory Syndrome Coronavirus-1 (SARS-CoV-1). Remdesivir has been used in moderate to severe COVID-19 during the pandemic. Remdesivir is associated with various adverse drug reactions like serum transaminase elevation, nausea, diarrhea, vomiting, poor appetite, gastroparesis, pneumothorax, hypotension, hematuria etc. It has been rarely associated with hyperkalemia. We have reported 3 cases of hyperkalemia following Remdesivir use. In all 3 cases, patients did not have any renal pathology or history of alcohol consumption. Patients were not taking any concurrent medication which increases serum potassium levels with such characteristics seen in our cases. Temporal association was present between hyperkalemia and initiation of Remdesivir in all cases described. Hence, it is very important to be vigilant while prescribing Remdesivir in COVID-19.

Taletrectinib (AB-106; DS-6051b) in metastatic non-small cell lung cancer (NSCLC) patients with ROS1 fusion: Preliminary results of TRUST.

9066 Background: Taletrectinib (AB-106; DS-6051b) is a potent, selective ROS1/NTRK inhibitor. In two phase I trials, NSCLC patients (pts) with ROS1 fusion who received taletrectinib as first line ROS1 TKI had an objective response rate (ORR) of 66.7% (6/9) and median progression-free survival (PFS) of 29.1 mo (Sai-Hong Ignatius Ou et al., JTO Clinical and Research Reports, 2020). TRUST (NCT04395677) is an ongoing, multicenter, phase II study of taletrectinib in Chinese NSCLC pts with ROS1 fusion. Methods: The ROS1 TKI naïve or crizotinib pre-treated NSCLC patients with ROS1 fusion were treated with taletrectinib 400 or 600 mg QD. ROS1 testing was performed in each center and confirmed by central lab using RT-PCR. The primary endpoint was ORR (complete response [CR] + partial response [PR]) by IRC assessment. Secondary endpoints were disease control rate (DCR; CR + PR + stable disease), PFS and safety, etc. The pharmacokinetics (PK) of taletrectinib following 400 or 600 mg QD regimen was also evaluated. Results: As of the data cutoff (15 Jan 2021), 22 pts had received taletrectinib treatment. Median age was 54.5 years (range, 32-77 years;); 18.2% (4/22) had central nervous system metastases; ECOG performance status was 0 in 13.6% (3/22) of pts and 1 in 86.4% (19/22) of pts. Most pts (54.5%, 12/22) had prior systematic chemotherapy; 31.8% (7/22) of pts had prior crizotinib treatment. ORR by investigator among the crizotinib naïve pts with tumor assessment (N = 11) was 100% (95% CI, 72%-100%); 81.8% (18/22) of pts had treatment-emergent adverse events (TEAEs), including nausea, vomiting, diarrhea, transaminase elevation, white blood cell count decrease/neutrophil count decrease, etc. 13.6% (3/22) were grade ≥ 3, including fatigue (4.5%, 1/22), white blood cell decrease (4.5%, 1/22) and transaminase elevation (4.5%, 1/22).TEAEs led to dose interruption in 3 pts (13.6%), including dose reduction in 2 pts (9.1%). Taletrectinib in plasma approximately reached steady state on Cycle 1 Day 8 with 2- to 3- fold accumulations of exposure, which was consistent with results observed in the phase I trials. Conclusions: Taletrectinib demonstrated promising clinical activity with high ORR and good tolerability in ROS1 fusion positive NSCLC patients. The safety and PK profiles following taletrectinib treatment was generally consistent with the phase I trials. Clinical trial information: NCT04395677. Clinical trial information: NCT04395677.

Preliminary analysis of a phase II, multicenter, randomized, active-control study to evaluate the efficacy and safety of eganelisib (IPI 549) in combination with nivolumab compared to nivolumab monotherapy in patients with advanced urothelial carcinoma.

436 Background: Inhibition of the PD-1 pathway has demonstrated clinical benefit in metastatic urothelial carcinoma (mUC); however, response rates of 15% to 29% highlight the need for more effective therapies, especially for PD-L1- patients. Eganelisib is a first-in-class, novel, oral agent which selectively inhibits PI3K-γ, with the goal of improving the immune response to checkpoint inhibitors (CPI). Methods: Eligible patients (pts) with mUC who progressed on > 1 platinum-based chemotherapy regimen and were CPI naïve were enrolled. Pts were randomized 2:1 to receive eganelisib in combination with nivolumab (EN) or placebo with nivolumab (PN). Pts were stratified by baseline circulating monocytic myeloid derived suppressor cells (mMDSC) level. The primary endpoint was objective response rate (ORR) per RECIST v1.1 in pts with high baseline mMDSC levels. Other endpoints included ORR, progression free survival (PFS) and overall survival (OS) in all pts and PD-L1 +/- pts. Results: We report preliminary data (as of 9/1/2020) for the first 49 pts with 33 randomized to receive EN and 16 PN. Preliminary ORR/PFS is presented in the table below. Except for the mMDSC high subgroup, ORR and PFS were improved in the EN arm compared to the PN arm. The duration of exposure was a median of 15 weeks for EN and 11 for PN. Most common all-Gr AEs (EN vs PN %) were pyrexia (33 vs 0), decreased appetite (30 vs 19), pruritis (24 vs 6), rash (24 vs 6), asthenia (21 vs 31), and transaminase elevation (21 vs 6). Most common Gr≥3 AEs (EN vs PN %) include hepatotoxicity (15 vs 0), transaminase elevation (12 vs 6), and rash (9 vs 0). Following an early safety review, eganelisib dose was reduced from 40 to 30 mg, resulting in a reduction of hepatic AEs. Conclusions: Preliminary data demonstrates that the combination of eganelisib, once reduced to 30 mg, and nivolumab was well tolerated with hepatic and skin-related toxicities more common in the EN arm. When compared to PN, the combination demonstrated an improved ORR and PFS, especially in the PD-L1- subset. Updated efficacy, including PFS and OS, safety and translational data will be presented. Clinical trial information: NCT03980041 . [Table: see text]

Comparison of CALGB 10403 (Alliance) and COG AALL0232 toxicity results in young adults with acute lymphoblastic leukemia

Adolescents and young adults (AYAs) with acute lymphoblastic leukemia have improved outcomes when treated with pediatric-inspired regimens. CALGB 10403 was the largest prospective study to evaluate the feasibility of using a pediatric regimen in AYAs with acute lymphoblastic leukemia up to 40 years of age. This article presents the toxicity events observed in the CALGB 10403 study and compares these toxicities vs those observed among AYAs treated on the same arm of the companion Children’s Oncology Group (COG) AALL0232 study. Toxicities in CALGB 10403 were similar to those observed in COG AALL0232. Some grade 3 to 4 adverse events were more often reported in CALGB 10403 compared with COG AALL0232 (hyperglycemia, hyperbilirubinemia, transaminase elevation, and febrile neutropenia). Adverse events correlated with body mass index ≥30 kg/m2 and some with increasing age. The mortality rate in CALGB 10403 was low (4%) and similar to that in the COG AALL0232 trial. A caveat to this analysis is that only 39% of CALGB 10403 patients completed all planned protocol treatment. In COG AALL0232, although 74% of patients aged <18 years completed treatment, only 57% of patients aged ≥18 years completed treatment. This scenario suggests that issues associated with age and treating physician may be a factor. Due to its improved survival rates compared with historical controls, the CALGB 10403 regimen is now a standard of care. The hope is that the rate of protocol completion will increase as more familiarity is gained with this regimen. These trials were registered at www.clinicaltrials.gov as #NCT00558519 (CALGB 10403) and #NCT00075725 (COG AALL0232).