Zydelig (idelalisib)

P2, N=150, Active, not recruiting, Calluna Pharma AS | Recruiting --> Active, not recruiting

In patients with cBTKi-pretreated relapsed/refractory (R/R) CLL, the BRUIN-CLL-321 trial demonstrated improved progression-free survival (PFS) and time to next treatment (TTNT) compared with idelalisib/rituximab or bendamustine/rituximab, accompanied by a favorable tolerability profile. Data from randomized phase III BRUIN-CLL-313 and BRUIN-CLL-314 trials demonstrate the superiority of pirtobrutinib over chemoimmunotherapy in untreated patients and non-inferiority to ibrutinib in untreated patients or in patients with R/R disease who had no prior exposure to cBTKis. These data are not sufficient to justify a change in clinical practice; however, they lay the groundwork for a potential future repositioning of pirtobrutinib from the treatment of R/R CLL to earlier lines of therapy. In this review, we address a range of current and prospective aspects of pirtobrutinib-based therapies: (1) the strengths and limitations of the trial datasets; (2) the biological rationale for frontline noncovalent BTK inhibition; (3) sequencing trade-offs; and (4) prospective scenarios, including combination strategies and time-limited regimens.

Fifty-three patients received treatment after venetoclax: 29/53 (54.7%) received inhibitors (13 cBTKi, 11 idelalisib, 2 BCL2i, 3 non-covalent BTKi), 19/53 (35.8%) received chemoimmunotherapy (CT: 16 intensive, 3 palliative), 5/53 (9.4%) received hematopoietic stem cell transplantation (HSCT). Despite its limitations, this real-world study provides additional insights into double-exposed patients, who still pose a clinical challenge, demonstrating the superior efficacy of inhibitors over alternative treatment options. Enrollment in clinical trial and treatments with novel molecules, if available, may help address this unmet clinical need.

Tamoxifen promotes IPF via miR-432-3p-mediated EGFR suppression, establishing it as a pulmonary toxicant. Integrated network toxicology identifies EGFR as a diagnostic biomarker, highlighting environmental and clinical risks of tamoxifen exposure.

P2/3, N=55, Recruiting, Dizal (Jiangsu) Pharmaceutical Co. Ltd.

Chronic lymphocytic leukemia (CLL) is the most common leukemia in Western countries, and B-cell receptor (BCR) pathway inhibitors such as idelalisib and ibrutinib are currently established therapies for CLL. We conclude that BCR pathway inhibitors enhance AID mutational activity in CLL, but this does not appear to be directly involved in driving drug resistance. AID-targeted loci may nonetheless serve as biomarkers for monitoring genomic instability during treatment and inform further study.

Furthermore, idelalisib treatment promoted differentiation of conventional CD4+ T cells into Th1, Th2, and Th17 subsets-a response not observed with roginolisib. In summary, roginolisib functions as an effective PI3K inhibitor on leukemic cells while preserving T-cell functions, posing it as an alternative to current PI3K inhibitors.

In the syngeneic CT26 model, dual PI3Kδ/γ inhibition (BR101801 or duvelisib), unlike selective PI3Kδ inhibition (idelalisib), synergized with RT (7.5 Gy) to suppress tumor growth and induce durable immune memory. Furthermore, blockade of the IFN-I receptor abolished CD8+ T cell infiltration and M2-like macrophage suppression, abrogating antitumor efficacy and confirming the requirement for IFN-I signaling. These findings identify macrophage-driven activation of the cGAS-STING-IFN-I axis as a key mechanism by which dual PI3Kδ/γ inhibition potentiates RT, providing a strong scientific rationale for its development as an immunomodulatory radiosensitizer.

Comparative analysis with idelalisib revealed similar toxicity profiles to Qona11, distinct from vincristine. In vivo studies in NOD/SCID mice bearing Jurkat xenografts showed that Qona11 (100 mg.kg-1) was well tolerated with no systemic toxicity, although it did not inhibit leukemia cell proliferation in immune-independent models. Overall, Qona11 exhibits promising anticancer activity and low systemic toxicity, warranting further preclinical investigation in solid tumor models and combination therapies.

P3, N=250, Recruiting, Dizal (Jiangsu) Pharmaceutical Co., Ltd. | Not yet recruiting --> Recruiting

We present a case of invasive cutaneous mucormycosis in an elderly man with chronic lymphocytic leukemia (CLL), who was receiving a Bruton tyrosine kinase (BTK)-targeted protein degrader trial drug (BGB-16673), obinutuzumab, a newer anti-CD20 monoclonal therapy, and idelalisib, a phosphoinositide 3-kinase inhibitor. Clinical cure was achieved with limb amputation, given the extent of disease. This case underscores the necessity of a low index of suspicion for mucormycosis on presentation, critical appraisal of the patient's risk factors, and a multimodal approach to diagnosis.

P4, N=150, Not yet recruiting, Eli Lilly and Company