Hitting BTK, PI3K pays off in B-cell malignancies

 

LUGANO, SWITZERLAND – A combination of ibrutinib and umbralisib, an investigational inhibitor of phosphatidylinostiol 3-kinase (PI3K), induced high response rates in patients with relapsed/refractory B-cell malignancies, with no dose-limiting toxicities, based on updated early efficacy results from a phase I/IB dose-escalation study.

One-year progression-free survival (PFS) was 88% for patients with chronic lymphocytic leukemia (CLL), and 1-year overall survival (OS) was 94%, reported Matthew S. Davids, MD, MMSc, of the Dana-Farber Cancer Institute in Boston.

For patients with mantle cell lymphoma (MCL), the respective PFS and OS rates were 8.4 and 11.6 months.

Single-agent ibrutinib (Imbruvica), an inhibitor of Bruton’s tyrosine kinase, is effective in patients with high-risk CLL or MCL, but the depth and durability of response are limited, he said. Umbralisib (TGR-1202) is a second-generation PI3K inhibitor with a high degree of specificity for the delta isoform of the kinase. It was designed to have a better safety profile than the first-in-class agent idelalisib (Zydelig).

“We hypothesized that inhibiting multiple BCR [B-cell receptor] pathways with kinase inhibitors may both deepen and prolong response and potentially overcome resistance mutations,” he said at the International Conference on Malignant Lymphoma.

In an ongoing, investigator-initiated phase I/IB trial, Dr. Davids and his colleagues enrolled 14 patients with MCL and 18 with CLL into parallel dose-escalation arms. Data were insufficient for the preliminary efficacy analysis.

Among patients with CLL, the objective response rate was 94% (16 of 17 patients). Of the 17 patients, 15 had a partial response or a partial response with lymphocytosis. One patient had a complete response, and three had radiographic complete responses, but these were not included in the objective response rate.

All three patients who had prior exposure to a PI3K inhibitor had responses, as did one of two patients with prior ibrutinib exposure.

For the patients with MCL, the objective response rate was 79% (11 of 14 patients); 10 had a partial response and 1 had a complete response. One other patient with a radiographic complete response was not included in the objective response rate.

Median follow-up among survivors was 14 months. As noted, the 1-year PFS and OS for patients with CLL were 88% and 94%, and the median PFS and OS for patients with MCL were 8.4 and 11.6 months.

One patient with CLL and five with MCL died of disease progression. A sixth patient with MCL did not have an adequate response to ibrutinib/umbralisib and died of toxicities related to the next line of therapy.

The safety analysis showed no dose-limiting toxicities, and the maximum tolerated dose was not identified with umbralisib at doses of 400 mg, 600 mg, or 800 mg daily in patients with either CLL or MCL.

The most common hematologic adverse events were grade 3/4 neutropenia in approximately 37% of patients in each arm, thrombocytopenia in 11% of CLL patients and 36% of MCL patients, and anemia in 15% and 29%, respectively.

The MCL arm of the study is still accruing patients, and correlative studies are in progress, Dr. Davids said.

The study is supported by TG Therapeutics, BCRP/LLS TAP, and grants from ASCO and the National Institutes of Health. Dr. Davids disclosed honoraria from Janssen and research funding to his institution from Phamarcyclics.

 

LUGANO, SWITZERLAND – A combination of ibrutinib and umbralisib, an investigational inhibitor of phosphatidylinostiol 3-kinase (PI3K), induced high response rates in patients with relapsed/refractory B-cell malignancies, with no dose-limiting toxicities, based on updated early efficacy results from a phase I/IB dose-escalation study.

One-year progression-free survival (PFS) was 88% for patients with chronic lymphocytic leukemia (CLL), and 1-year overall survival (OS) was 94%, reported Matthew S. Davids, MD, MMSc, of the Dana-Farber Cancer Institute in Boston.

For patients with mantle cell lymphoma (MCL), the respective PFS and OS rates were 8.4 and 11.6 months.

Single-agent ibrutinib (Imbruvica), an inhibitor of Bruton’s tyrosine kinase, is effective in patients with high-risk CLL or MCL, but the depth and durability of response are limited, he said. Umbralisib (TGR-1202) is a second-generation PI3K inhibitor with a high degree of specificity for the delta isoform of the kinase. It was designed to have a better safety profile than the first-in-class agent idelalisib (Zydelig).

“We hypothesized that inhibiting multiple BCR [B-cell receptor] pathways with kinase inhibitors may both deepen and prolong response and potentially overcome resistance mutations,” he said at the International Conference on Malignant Lymphoma.

In an ongoing, investigator-initiated phase I/IB trial, Dr. Davids and his colleagues enrolled 14 patients with MCL and 18 with CLL into parallel dose-escalation arms. Data were insufficient for the preliminary efficacy analysis.

Among patients with CLL, the objective response rate was 94% (16 of 17 patients). Of the 17 patients, 15 had a partial response or a partial response with lymphocytosis. One patient had a complete response, and three had radiographic complete responses, but these were not included in the objective response rate.

All three patients who had prior exposure to a PI3K inhibitor had responses, as did one of two patients with prior ibrutinib exposure.

For the patients with MCL, the objective response rate was 79% (11 of 14 patients); 10 had a partial response and 1 had a complete response. One other patient with a radiographic complete response was not included in the objective response rate.

Median follow-up among survivors was 14 months. As noted, the 1-year PFS and OS for patients with CLL were 88% and 94%, and the median PFS and OS for patients with MCL were 8.4 and 11.6 months.

One patient with CLL and five with MCL died of disease progression. A sixth patient with MCL did not have an adequate response to ibrutinib/umbralisib and died of toxicities related to the next line of therapy.

The safety analysis showed no dose-limiting toxicities, and the maximum tolerated dose was not identified with umbralisib at doses of 400 mg, 600 mg, or 800 mg daily in patients with either CLL or MCL.

The most common hematologic adverse events were grade 3/4 neutropenia in approximately 37% of patients in each arm, thrombocytopenia in 11% of CLL patients and 36% of MCL patients, and anemia in 15% and 29%, respectively.

The MCL arm of the study is still accruing patients, and correlative studies are in progress, Dr. Davids said.

The study is supported by TG Therapeutics, BCRP/LLS TAP, and grants from ASCO and the National Institutes of Health. Dr. Davids disclosed honoraria from Janssen and research funding to his institution from Phamarcyclics.

 

LUGANO, SWITZERLAND – A combination of ibrutinib and umbralisib, an investigational inhibitor of phosphatidylinostiol 3-kinase (PI3K), induced high response rates in patients with relapsed/refractory B-cell malignancies, with no dose-limiting toxicities, based on updated early efficacy results from a phase I/IB dose-escalation study.

One-year progression-free survival (PFS) was 88% for patients with chronic lymphocytic leukemia (CLL), and 1-year overall survival (OS) was 94%, reported Matthew S. Davids, MD, MMSc, of the Dana-Farber Cancer Institute in Boston.

For patients with mantle cell lymphoma (MCL), the respective PFS and OS rates were 8.4 and 11.6 months.

Single-agent ibrutinib (Imbruvica), an inhibitor of Bruton’s tyrosine kinase, is effective in patients with high-risk CLL or MCL, but the depth and durability of response are limited, he said. Umbralisib (TGR-1202) is a second-generation PI3K inhibitor with a high degree of specificity for the delta isoform of the kinase. It was designed to have a better safety profile than the first-in-class agent idelalisib (Zydelig).

“We hypothesized that inhibiting multiple BCR [B-cell receptor] pathways with kinase inhibitors may both deepen and prolong response and potentially overcome resistance mutations,” he said at the International Conference on Malignant Lymphoma.

In an ongoing, investigator-initiated phase I/IB trial, Dr. Davids and his colleagues enrolled 14 patients with MCL and 18 with CLL into parallel dose-escalation arms. Data were insufficient for the preliminary efficacy analysis.

Among patients with CLL, the objective response rate was 94% (16 of 17 patients). Of the 17 patients, 15 had a partial response or a partial response with lymphocytosis. One patient had a complete response, and three had radiographic complete responses, but these were not included in the objective response rate.

All three patients who had prior exposure to a PI3K inhibitor had responses, as did one of two patients with prior ibrutinib exposure.

For the patients with MCL, the objective response rate was 79% (11 of 14 patients); 10 had a partial response and 1 had a complete response. One other patient with a radiographic complete response was not included in the objective response rate.

Median follow-up among survivors was 14 months. As noted, the 1-year PFS and OS for patients with CLL were 88% and 94%, and the median PFS and OS for patients with MCL were 8.4 and 11.6 months.

One patient with CLL and five with MCL died of disease progression. A sixth patient with MCL did not have an adequate response to ibrutinib/umbralisib and died of toxicities related to the next line of therapy.

The safety analysis showed no dose-limiting toxicities, and the maximum tolerated dose was not identified with umbralisib at doses of 400 mg, 600 mg, or 800 mg daily in patients with either CLL or MCL.

The most common hematologic adverse events were grade 3/4 neutropenia in approximately 37% of patients in each arm, thrombocytopenia in 11% of CLL patients and 36% of MCL patients, and anemia in 15% and 29%, respectively.

The MCL arm of the study is still accruing patients, and correlative studies are in progress, Dr. Davids said.

The study is supported by TG Therapeutics, BCRP/LLS TAP, and grants from ASCO and the National Institutes of Health. Dr. Davids disclosed honoraria from Janssen and research funding to his institution from Phamarcyclics.