Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN): a phase 1/2 study.

BACKGROUND: Covalent Bruton's tyrosine kinase (BTK) inhibitors are efficacious in multiple B-cell malignancies, but patients discontinue these agents due to resistance and intolerance. We evaluated the safety and efficacy of pirtobrutinib (working name; formerly known as LOXO-305), a highly selective, reversible BTK inhibitor, in these patients. METHODS: Patients with previously treated B-cell malignancies were enrolled in a first-in-human, multicentre, open-label, phase 1/2 trial of the BTK inhibitor pirtobrutinib. The primary endpoint was the maximum tolerated dose (phase 1) and overall response rate (ORR; phase 2). This trial is registered with ClinicalTrials.gov, NCT03740529. FINDINGS: 323 patients were treated with pirtobrutinib across seven dose levels (25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, and 300 mg once per day) with linear dose-proportional exposures. No dose-limiting toxicities were observed and the maximum tolerated dose was not reached. The recommended phase 2 dose was 200 mg daily. Adverse events in at least 10% of 323 patients were fatigue (65 [20%]), diarrhoea (55 [17%]), and contusion (42 [13%]). The most common adverse event of grade 3 or higher was neutropenia (32 [10%]). There was no correlation between pirtobrutinib exposure and the frequency of grade 3 treatment-related adverse events. Grade 3 atrial fibrillation or flutter was not observed, and grade 3 haemorrhage was observed in one patient in the setting of mechanical trauma. Five (1%) patients discontinued treatment due to a treatment-related adverse event. In 121 efficacy evaluable patients with chronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma (SLL) treated with a previous covalent BTK inhibitor (median previous lines of treatment 4), the ORR with pirtobrutinib was 62% (95% CI 53-71). The ORR was similar in CLL patients with previous covalent BTK inhibitor resistance (53 [67%] of 79), covalent BTK inhibitor intolerance (22 [52%] of 42), BTK C481-mutant (17 [71%] of 24) and BTK wild-type (43 [66%] of 65) disease. In 52 efficacy evaluable patients with mantle cell lymphoma (MCL) previously treated with covalent BTK inhibitors, the ORR was 52% (95% CI 38-66). Of 117 patients with CLL, SLL, or MCL who responded, all but eight remain progression-free to date. INTERPRETATION: Pirtobrutinib was safe and active in multiple B-cell malignancies, including patients previously treated with covalent BTK inhibitors. Pirtobrutinib might address a growing unmet need for alternative therapies for these patients. FUNDING: Loxo Oncology.

Ibrutinib: a first in class covalent inhibitor of Bruton's tyrosine kinase.

Ibrutinib (formerly PCI-32765) is a potent, covalent inhibitor of Bruton's tyrosine kinase, a kinase downstream of the B-cell receptor that is critical for B-cell survival and proliferation. In preclinical studies, ibrutinib bound to Bruton's tyrosine kinase with high affinity, leading to inhibition of B-cell receptor signaling, decreased B-cell activation and induction of apoptosis. In clinical studies, ibrutinib has been well-tolerated and has demonstrated profound anti-tumor activity in a variety of hematologic malignancies, most notably chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), leading to US FDA approval for relapsed CLL and MCL. Ongoing studies are evaluating ibrutinib in other types of non-Hodgkin's lymphoma, such as diffuse large B-cell lymphoma and Waldenström's macrogobulinemia, in larger Phase III studies in CLL and MCL, and in combination studies with monoclonal antibodies and chemotherapy. Future studies will combine ibrutinib with other promising novel agents currently in development in hematologic malignancies.

Overcoming stroma-mediated treatment resistance in chronic lymphocytic leukemia through BCL-2 inhibition.

Despite recent advances in the treatment of chronic lymphocytic leukemia (CLL) with chemoimmunotherapy, many patients with CLL are older or frail and cannot tolerate aggressive chemotherapy. Even those who can inevitably develop resistance due to factors such as deletion of pro-apoptotic factors like TP53 or the support of pro-survival signals from the stromal microenvironment. Using BH3 profiling, we found that CLL cells co-cultured with stroma are less primed to undergo apoptosis in response to BCL-2 inhibition. Currently, several approaches to BCL-2 inhibition with well-tolerated oral agents are in development in the clinic. Dosing of navitoclax (ABT-263) was complicated by thrombocytopenia due to BCL-XL inhibition, but the BCL-2 specific inhibitor ABT-199 (GDC-0199) should avoid this issue, and may overcome stroma-mediated resistance to apoptosis. We are developing BH3 profiling as a biomarker to predict response to novel therapies such as ABT-199, and to identify resistance mechanisms to new agents being studied in CLL.

Quality of care for older patients with cancer in the Veterans Health Administration versus the private sector: a cohort study.

BACKGROUND: The Veterans Health Administration (VHA) is the largest integrated health care system in the United States. Studies suggest that the VHA provides better preventive care and care for some chronic illnesses than does the private sector. OBJECTIVE: To assess the quality of cancer care for older patients provided by the VHA versus fee-for-service Medicare. DESIGN: Observational study of patients with cancer that was diagnosed between 2001 and 2004 who were followed through 2005. SETTING: VHA and non-VHA hospitals and office-based practices. PATIENTS: Men older than 65 years with incident colorectal, lung, or prostate cancer; lymphoma; or multiple myeloma. MEASUREMENTS: Rates of processes of care for colorectal, lung, or prostate cancer; lymphoma; or multiple myeloma. Rates were adjusted by using propensity score weighting. RESULTS: Compared with the fee-for-service Medicare population, the VHA population received diagnoses of colon (P < 0.001) and rectal (P = 0.007) cancer at earlier stages and had higher adjusted rates of curative surgery for colon cancer (92.7% vs. 90.5%; P < 0.010), standard chemotherapy for diffuse large B-cell non-Hodgkin lymphoma (71.1% vs. 59.3%; P < 0.001), and bisphosphonate therapy for multiple myeloma (62.1% vs. 50.4%; P < 0.001). The VHA population had lower adjusted rates of 3-dimensional conformal or intensity-modulated radiation therapy for prostate cancer treated with external-beam radiation therapy (61.6% vs. 86.0%; P < 0.001). Adjusted rates were similar for 9 other measures. Sensitivity analyses suggest that if patients with cancer in the VHA system have more severe comorbid illness than other patients, rates for most indicators would be higher in the VHA population than in the fee-for-service Medicare population. LIMITATION: This study included only older men and did not include information about performance status, severity of comorbid illness, or patient preferences. CONCLUSION: Care for older men with cancer in the VHA system was generally similar to or better than care for fee-for-service Medicare beneficiaries, although adoption of some expensive new technologies may be delayed in the VHA system. PRIMARY FUNDING SOURCE: Department of Veterans Affairs.