A Phase1b Clinical Study of the Oral PI3Kδ Inhibitor, Linperlisib, in Patients with B-Cell Lymphomas

Introduction The PI3Kδ inhibitor, linperlisib, is a structurally distinctive oral agent demonstrated to be clinically efficacious with a favorable safety profile in follicular lymphoma (FL) and peripheral T-cell lymphoma (PTCL). Here we report initial results of a phase1b study (NCT04279405) evaluating the activity and safety of linperlisib across B-cell lymphoma types, namely DLBCL, MCL, MZL, FL and SLL/CLL. Methods Enrollment initiated in Jan 2020 at 11 clinical sites in China for patients (pts) of DLBCL, MCL, MZL, FL and SLL/CLL having received at least one standard anti-tumor systemic therapy and at least 2 cycles of each prior treatment. Linperlisib tablets were administered orally, 80mg once daily under fasted conditions for 28 days as a cycle, until disease progression, unacceptable toxicity or withdrawal from the study. Adverse events (AEs) were graded by NCI-CTCAE v5.0. Efficacy was evaluated every 2 cycles using the IWG 2007 criteria. Results As of Jul 22, 2021, 43 r/r lymphoma patients were enrolled, including DLBCL (20 pts), MCL (9 pts), FL (8 pts), MZL (3 pts) and SLL/CLL (3 pts). With a median of 2 prior therapies, the majority (93%) of pts previously received first line immunochemotherapy including anti-CD20 targeted therapies. One pts withdrew consent before study treatment began. Three pts withdrew consent in first cycle without post baseline imaging assessment. Forty two pts and 39 patients were evaluable for safety and efficacy, respectively. Linperlisib was well-tolerated in this study. The safety profile observed was consistent to that observed in the clinical studies with FL and PTCL patients, with no new toxicities reported. The most frequent TRAE (all Grade >10%) were neutropenia (54.8%), lymphopenia (40.5%), thrombocytopenia (28.6%), anemia (23.8%), alanine aminotransferase increased (21.4%), aspartate aminotransferase increased (21.4%), blood triglycerides increased (16.7%), blood uric acid increased (14.3%), diarrhoea (11.9%), proteinuria (11.9%) and rash (11.9%). The most frequent Grade ≥3 TRAEs were neutropenia (26.2%) and lymphopenia (9.5%). Thirteen (31.0%) pts experienced SAE considered to be drug related, including pneumonia, thrombocytopenia, pancreatitis, and febrile neutropenia. SAE leading discontinuation from study occurred in 7 pts .Three pts experienced AE that lead to dose modification. No death happened due to any TRAE. No specific associations were observed between B-cell lymphoma types and adverse events on linperlisib treatment. An overall response rate (ORR) and overall disease control rate (DCR) of 53.8% and 79.5% were observed in the evaluable patients. Table1 The 17 evaluable DLBCL pts contained 1 unconfirmed CR (GCB) and 3 PR (GCB, N-GCB, and DLBCL transformed from MZL). The DOR for the 4 DLBCL responders were 56 days, 56 days, 56 days and 196 days. The 8 evaluable FL pts were 3 unconfirmed CR plus 5 PR, and a median DOR of 112days. The 8 evaluable MCL pts contained 2 unconfirmed CR, 3 PR, and 2 SD. The median DOR of the 5 MCL responders were 56 days. The 3 evaluable MZL pts and 3 evaluable SLL/CLL pts were both consisted of 1 unconfirmed CR, 1 PR and 1 SD .The DOR for the 2 MZL responders were 196 days and 56 days, the DOR for the 2 SLL/CLL responders were both 196 days. At the data cutoff date, 16 pts were still treatment ongoing, 19 pts had received exceeding 6 months of treatment, and 1 pt had received exceeding 12 months of treatment, supporting a durable benefit of linperlisib monotherapy. Conclusions Linperlisib demonstrated broad anti-tumor activities in several r/r B -cell malignancies, including DLBC, MCL, MZL, FL and SLL/CLL. Furthermore, linperlisib showed a favorable safety profile with respect to the previously reported information from approved agents in the class of PI3K inhibitors. Further clinical studies of linperlisib in B-cell malignancies and in combination therapies are warranted. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Reasons for canakinumab initiation among patients with periodic fever syndromes: a retrospective medical chart review from the United States

Background Although canakinumab has demonstrated efficacy in multiple trials in patients with periodic fever syndromes (PFS), the evidence on initiation of canakinumab among PFS patients in real world setting is not well understood. We aimed to characterize the reasons for canakinumab initiation among patients with PFS, specifically, cryopyrin-associated periodic syndrome (CAPS), hyperimmunoglobulin D syndrome/mevalonate kinase deficiency (HIDS/MKD), TNF receptor-associated periodic syndrome (TRAPS) and familial Mediterranean fever (FMF). Methods Physicians retrospectively reviewed the medical charts of PFS patients prescribed canakinumab between 2016 and 2018. Information collected included patient clinical characteristics, reasons for previous treatment discontinuation and canakinumab initiation. The results were summarized for overall patients, and by children (< 18 years) and adults and by subtype of PFS. Results Fifty-eight physicians in the US (rheumatologists, 44.8 %; allergists/immunologists, 29.3 %; dermatologists, 25.9 %) abstracted information for 147 patients (children, 46.3 %; males, 57.1 %; CAPS, 36.7 %; TRAPS, 26.5 %; FMF, 26.5 %; HIDS/MKD, 6.8 %; Mixed, 3.4 %). Overall, most patients (90.5 %) received treatment directly preceding canakinumab (NSAIDs, 27.8 % [40.0 % in HIDS/MKD]; anakinra, 24.1 % [32.7 % in CAPS]; colchicine, 21.8 % [35.9 % in FMF]), which were discontinued due to lack of efficacy/effectiveness (39.5 %) and availability of a new treatment (36.1 %). The common reasons for canakinumab initiation were physician perceived efficacy/effectiveness (81.0 %; children, 75.0 %; adults, 86.1 %), lack of response to previous treatment (40.8 %; children, 38.2 %; adults, 43.0 %) and favorable safety profile/tolerability (40.1 %; children, 42.6 %; adults, 38.0 %). Within subtypes, efficacy/effectiveness was the most stated reason for canakinumab initiation in HIDS/MKD (90.9 %), lack of response to previous treatment in FMF (52.4 %) and convenience of administration/dosing in CAPS (27.1 %). Conclusions This study provided insights into how canakinumab is initiated in US clinical practice among PFS patients, with physician perceived efficacy/effectiveness of canakinumab, lack of response to previous treatment and favorable safety profile/tolerability of canakinumab being the dominant reasons for canakinumab initiation in all patients and in children and adults and PFS subtypes. Notably, the favorable safety profile/tolerability of canakinumab was more often the reason for initiation among children versus adults.

1% Tirbanibulin Ointment for the Treatment of Actinic Keratoses

Objective Actinic keratoses (AKs) are cutaneous lesions that arise in sun-damaged skin. AKs may transform into squamous cell carcinoma in situ. Tirbanibulin 1% ointment is a new topical treatment for AKs, recently approved by the Food and Drug Administration. Data Sources The PubMed database was searched for articles published from 1960 to March 31, 2021, using the keywords tirbanibulin and Klisyri. Data Extraction Phase 2 and phase 3 clinical trials were reviewed. Data Synthesis In phase 2 clinical trials, 43% of patients treated with tirbanibulin experienced complete clearance by day 57 (43% [95% CI = 32, 54]). Across two phase 3 clinical trials (pooled data), complete (100%) clearance occurred in 49% of patients in tirbanibulin groups and in only 9% of the vehicle groups (difference, 41% points; 95% CI = 35 to 47; P < 0.001). Although no comparative studies are available, tirbanibulin is applied for a shorter duration (5 days) compared with diclofenac 3% gel, fluorouracil 5% cream, and imiquimod 3.75% cream. Adverse events were mild and included pruritus, application site pain, and local skin reactions. Systemic adverse events such as necrosis and angioedema, observed with other AK treatments such as fluorouracil and imiquimod, were not observed with tirbanibulin, thus giving tirbanibulin a favorable safety profile. Relevance to Patient Care and Clinical Practice Tirbanibulin effectively reduces AK burden and recurrence and has a favorable safety profile with mild adverse events. In comparison, imiquimod, 5-flourouracil, and diclofenac can result in necrosis, angioedema, and arthralgias. Conclusion With a favorable safety profile and short regimen, tirbanibulin is an efficacious treatment for clinicians to utilize in their treatment toolbox when treating AKs on the face and scalp.