BTK, mTOR Inhibitor Combination Lacks Efficacy in Patients With Relapsed, Refractory DLBCL

By Cameron Kelsall, MD /alert Contributor
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The addition of vistusertib to acalabrutinib, a covalent Bruton’s tyrosine kinase inhibitor approved for the treatment of patients with B-cell lymphomas, did not increase the clinical activity when the two agents were administered as a combined treatment for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), according to the results of a phase 1/2 study published in Leukemia & Lymphoma.

The most common newly diagnosed lymphoma, DLBCL usually carries a favorable 5-year survival rate, although up to 50% of patients relapse or become refractory to treatment. Bruton’s tyrosine kinase inhibitors, which inhibit B-cell growth, are frequently used to treat patients with relapsed or refractory DLBCL.

The US Food and Drug Administration approved acalabrutinib for the treatment of patients with certain relapsed or refractory lymphoma, including mantle cell lymphoma and chronic lymphocytic leukemia/small cell lymphoma, and it has demonstrated activity in patients with DLBCL. Vistusertib is a mammalian target of rapamycin (mTOR) inhibitor that dually inhibits mTOR complex 1 and complex 2. 

Ian W. Flinn, MD, director of lymphoma research at Sarah Cannon Research Institute (Nashville, TN), and colleagues sought to determine whether the combination of acalabrutinib and vistusertib would result in a greater clinical benefit than a single-agent treatment for patients with relapsed or refractory DLBCL.

In the phase 1/2 parallel-group study, patients were enrolled to determine an appropriate dose of vistusertib that would be used in an expansion cohort. However, the study was closed prior to the expansion.

The study included data from 25 patients (median age, 69 years; range, 27-85; 76% men), all of whom received acalabrutinib at a dose of 100 mg twice-daily. Across two levels, patients either received intermittent or continuous vistusertib: 100 mg intermittent (n = 6) or 35 mg continuous (n = 7) in level 1, and 125 mg intermittent (n = 6) or 50 mg continuous (n = 5) in level 2.

At the time of reporting, all patients had ceased treatment due to progressive disease, adverse events or investigator withdrawal. In level 1, the median duration of acalabrutinib treatment was 1.9 months for the intermediate cohort and 1.4 months for the continuous cohort; in level 2, treatment durations were 3.6 months and 1.6 months, respectively.

The median duration of vistusertib treatment was 1.7 months in the level 1 intermediate cohort and 1 month in the level 1 continuous cohort; in level 2, the median durations were 3.3 months and 1.2 months, respectively.

All patients experienced treatment-emergent adverse events, the most common of which included fatigue (52%), blood creatinine increase (48%), nausea (36%), hyperglycemia (32%), diarrhea (32%) and anemia (28%). In addition, 36% of patients (n = 9) experienced serious adverse events, including anemia (n = 2), pneumonia (n = 2) and pyrexia (n = 2).

Dose-limiting toxicities included grade 3 alanine aminotransferase/aspartate aminotransferase increase related to both agents, causing the patient to discontinue treatment; and grade 3 hyperglycemia related to vistusertib, causing the patient to discontinue vistusertib only. No maximum tolerated dose for the combination was reached.

One patient, enrolled in the level 1 intermittent cohort, achieved a complete response to treatment that lasted 20.5 months. Two patients achieved partial responses, both in the level 2 intermittent cohort. The overall response rate was 12%, with no patients in other cohorts achieving a response.

Pharmacodynamics analysis revealed strong binding of acalabrutinib to C481 in all patients, with a median occupancy of 95%. These results were consistent with rates seen in other studies of acalabrutinib monotherapy. However, for vistusertib, the researchers observed greater levels of divergence with regard to biomarkers for mTOR complex 1 (p4EBP1) and mTOR complex 1 (pAKT). In particular, p4EBP1 inhibition did not seem related to dose and schedule, and the researchers saw no clear inhibition of pAKT.

“Within the observed concentration range, higher vistusertib concentrations are associated with increased p4EBP1 inhibition (R2 = 0.6), but not with pAKT inhibition (R2 = 0.059),” they wrote.

Similarly, the researchers noted that they did not identify a subset of patients who would benefit from the combination of acalabrutinib and vistusertib through next-generation sequencing or cell-of-origin subtyping. 

However, in monitoring circulating tumor DNA, they detected correlations between clearances in somatic alterations and duration of response in the two patients who achieved a partial response. They also found that a patient with progressive disease continued to exhibit mutations during treatment.

“The data from this clinical trial assessing the combination of acalabrutinib and vistusertib suggest that greater target occupancy of the mTOR pathway is required to improve clinical responses,” the researchers concluded. “Based on these data, vistusertib in combination with acalabrutinib under the dose and schedules investigated did not sufficiently inhibit the mTOR pathway in [patients with relapsed or refractory DLBCL] to provide clinical benefit.”

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