Mantle Cell Lymphoma: BTK Inhibitor Scores Again

SAN DIEGO – Even before it has earned a name, the novel targeted agent designated PCI-32765 is earning an impressive reputation, first for its mettle against chronic lymphocytic leukemia, and now for its potent action against relapsed or refractory mantle cell lymphoma in early clinical data, reported investigators at the annual meeting of the American Society of Hematology.

Preliminary results of a phase II trial of PCI-32765, an inhibitor of Bruton’s tyrosine kinase (BTK) expressed in several hematologic malignancies, show that the agent induced complete responses in 16% of 51 patients with relapsed/refractory mantle cell lymphoma (MCL) and partial responses in 53%, for a combined overall response rate of 69%, said Dr. Luhua (Michael) Wang from the division of lymphoma and myeloma at the University of Texas M.D. Anderson Cancer Center in Houston.

"We think, as a single oral agent in the relapse setting of mantle cell lymphoma, this is a high response rate so far. The efficacy is also observed in patients with bulky disease, and also in refractive disease. Most importantly, the efficacy is independent, so far, from the MIPI [MCL International Prognostic Index] score," he said.

Patients with a high-risk MIPI score had a 75% response rate, the same as that for patients with a low-risk score; intermediate-risk patients had a 65% response rate.

An additional 18% of patients overall had stable disease; only 14% experienced disease progression.

In an earlier presentation at the ASH meeting, Dr. Susan O’Brien, also from M.D. Anderson, reported that PCI-32765 was associated with an overall response rate of 70% at 10.2 months’ follow-up in patients with relapsed/refractory CLL.

In the mantle cell lymphoma study, the BTK-inhibitor induced good responses both in patients who had previously been treated with the proteasome inhibitor bortezomib (Velcade), with rates of 15% for complete responses and 50% for partial responses, and in those who were bortezomib naive, with a 16% complete response rate and 55% partial response rate.

"People are very interested in this agent," commented Dr. Mitchell R. Smith from the Fox Chase Cancer Center in Philadelphia, in an interview.

"It looks very active, but we don’t know a lot about long-term effects and how long responses will last. But when you think about hitting specific pathways, that’s our goal in treating these diseases. This hits a specific pathway, does it well, and there have been responses in many B-cell disorders," he said. Dr. Smith comoderated the session at which the data were presented, but was not involved in the study.

PCI-32765 is an oral inhibitor of BTK, an essential element of the B-cell antigen receptor-signaling pathway. It blocks receptor signaling and induces apoptosis, as well as mantle cell migration and adhesion, and has been shown in in vitro studies to block pERK, pJNK, and NF-kappaB pathways in MCL cell lines.

The trial, designated PCYC-1104-CA, is a multicenter open-label phase II study of PCI-32765 in 68 patients. Dr. Wang presented data from an efficacy analysis of 51 patients who had at least one post-baseline tumor assessment. The patients were divided into two groups: bortezomib-exposed (27 patients) and bortezomib naive (41 patients, 34 of whom had never received bortezomib, and 7 who had received less than 2 cycles).

The patients were treated with 560 mg PCI-32765 daily until disease progression.

Median time on study was 3.7 months among all patients. At the most recent follow-up, 71% of bortezomib-naive and 70% of bortezomib-exposed patients were still on study. Discontinuations were primarily for disease progression, and there was one on-study death, a patient who had previously received bortezomib.

Non-hematologic adverse events were generally mild, with the only grade 4 toxicity being abdominal pain in about 2% of patients.

Grade 3 neutropenia occurred in 2% overall of 61 patients available for a safety analysis, and grade 4 neutropenia was seen 3%. Grade 3 febrile neutropenia, anemia, and thrombocytopenias were each seen in 3% of patients (no grade 4), and grade 4 pancytopenia was seen in 2%.

The investigators saw a 57% overall response rate in patients with bulky disease, 67% in those with refractory disease, 77% among those who had received fewer than 3 prior lines of therapy, and 57% among those who had received 3 or more. In addition, the overall response rate was 71% in patients who had received high-intensity prior therapy, and 65% in those who had received standard-dose therapy.

Additional follow-up will be required before the investigators can determine duration of response and progression-free survival, and more clinical trials with PCI-32765 are in the planning stages, Dr. Wang said.

Pharmacyclics sponsored the study. Dr. Wang disclosed consulting, having equity ownership in, and receiving research funding from, Pharmacyclics. He also disclosed relationships with Celgene, Millennium, Novartis, and Onyx. Dr. Smith disclosed board membership and receiving research funding from Cephalon, and being on the speakers bureau for Celgene, Genentech, Spectrum, and Allos.

SAN DIEGO – Even before it has earned a name, the novel targeted agent designated PCI-32765 is earning an impressive reputation, first for its mettle against chronic lymphocytic leukemia, and now for its potent action against relapsed or refractory mantle cell lymphoma in early clinical data, reported investigators at the annual meeting of the American Society of Hematology.

Preliminary results of a phase II trial of PCI-32765, an inhibitor of Bruton’s tyrosine kinase (BTK) expressed in several hematologic malignancies, show that the agent induced complete responses in 16% of 51 patients with relapsed/refractory mantle cell lymphoma (MCL) and partial responses in 53%, for a combined overall response rate of 69%, said Dr. Luhua (Michael) Wang from the division of lymphoma and myeloma at the University of Texas M.D. Anderson Cancer Center in Houston.

"We think, as a single oral agent in the relapse setting of mantle cell lymphoma, this is a high response rate so far. The efficacy is also observed in patients with bulky disease, and also in refractive disease. Most importantly, the efficacy is independent, so far, from the MIPI [MCL International Prognostic Index] score," he said.

Patients with a high-risk MIPI score had a 75% response rate, the same as that for patients with a low-risk score; intermediate-risk patients had a 65% response rate.

An additional 18% of patients overall had stable disease; only 14% experienced disease progression.

In an earlier presentation at the ASH meeting, Dr. Susan O’Brien, also from M.D. Anderson, reported that PCI-32765 was associated with an overall response rate of 70% at 10.2 months’ follow-up in patients with relapsed/refractory CLL.

In the mantle cell lymphoma study, the BTK-inhibitor induced good responses both in patients who had previously been treated with the proteasome inhibitor bortezomib (Velcade), with rates of 15% for complete responses and 50% for partial responses, and in those who were bortezomib naive, with a 16% complete response rate and 55% partial response rate.

"People are very interested in this agent," commented Dr. Mitchell R. Smith from the Fox Chase Cancer Center in Philadelphia, in an interview.

"It looks very active, but we don’t know a lot about long-term effects and how long responses will last. But when you think about hitting specific pathways, that’s our goal in treating these diseases. This hits a specific pathway, does it well, and there have been responses in many B-cell disorders," he said. Dr. Smith comoderated the session at which the data were presented, but was not involved in the study.

PCI-32765 is an oral inhibitor of BTK, an essential element of the B-cell antigen receptor-signaling pathway. It blocks receptor signaling and induces apoptosis, as well as mantle cell migration and adhesion, and has been shown in in vitro studies to block pERK, pJNK, and NF-kappaB pathways in MCL cell lines.

The trial, designated PCYC-1104-CA, is a multicenter open-label phase II study of PCI-32765 in 68 patients. Dr. Wang presented data from an efficacy analysis of 51 patients who had at least one post-baseline tumor assessment. The patients were divided into two groups: bortezomib-exposed (27 patients) and bortezomib naive (41 patients, 34 of whom had never received bortezomib, and 7 who had received less than 2 cycles).

The patients were treated with 560 mg PCI-32765 daily until disease progression.

Median time on study was 3.7 months among all patients. At the most recent follow-up, 71% of bortezomib-naive and 70% of bortezomib-exposed patients were still on study. Discontinuations were primarily for disease progression, and there was one on-study death, a patient who had previously received bortezomib.

Non-hematologic adverse events were generally mild, with the only grade 4 toxicity being abdominal pain in about 2% of patients.

Grade 3 neutropenia occurred in 2% overall of 61 patients available for a safety analysis, and grade 4 neutropenia was seen 3%. Grade 3 febrile neutropenia, anemia, and thrombocytopenias were each seen in 3% of patients (no grade 4), and grade 4 pancytopenia was seen in 2%.

The investigators saw a 57% overall response rate in patients with bulky disease, 67% in those with refractory disease, 77% among those who had received fewer than 3 prior lines of therapy, and 57% among those who had received 3 or more. In addition, the overall response rate was 71% in patients who had received high-intensity prior therapy, and 65% in those who had received standard-dose therapy.

Additional follow-up will be required before the investigators can determine duration of response and progression-free survival, and more clinical trials with PCI-32765 are in the planning stages, Dr. Wang said.

Pharmacyclics sponsored the study. Dr. Wang disclosed consulting, having equity ownership in, and receiving research funding from, Pharmacyclics. He also disclosed relationships with Celgene, Millennium, Novartis, and Onyx. Dr. Smith disclosed board membership and receiving research funding from Cephalon, and being on the speakers bureau for Celgene, Genentech, Spectrum, and Allos.

SAN DIEGO – Even before it has earned a name, the novel targeted agent designated PCI-32765 is earning an impressive reputation, first for its mettle against chronic lymphocytic leukemia, and now for its potent action against relapsed or refractory mantle cell lymphoma in early clinical data, reported investigators at the annual meeting of the American Society of Hematology.

Preliminary results of a phase II trial of PCI-32765, an inhibitor of Bruton’s tyrosine kinase (BTK) expressed in several hematologic malignancies, show that the agent induced complete responses in 16% of 51 patients with relapsed/refractory mantle cell lymphoma (MCL) and partial responses in 53%, for a combined overall response rate of 69%, said Dr. Luhua (Michael) Wang from the division of lymphoma and myeloma at the University of Texas M.D. Anderson Cancer Center in Houston.

"We think, as a single oral agent in the relapse setting of mantle cell lymphoma, this is a high response rate so far. The efficacy is also observed in patients with bulky disease, and also in refractive disease. Most importantly, the efficacy is independent, so far, from the MIPI [MCL International Prognostic Index] score," he said.

Patients with a high-risk MIPI score had a 75% response rate, the same as that for patients with a low-risk score; intermediate-risk patients had a 65% response rate.

An additional 18% of patients overall had stable disease; only 14% experienced disease progression.

In an earlier presentation at the ASH meeting, Dr. Susan O’Brien, also from M.D. Anderson, reported that PCI-32765 was associated with an overall response rate of 70% at 10.2 months’ follow-up in patients with relapsed/refractory CLL.

In the mantle cell lymphoma study, the BTK-inhibitor induced good responses both in patients who had previously been treated with the proteasome inhibitor bortezomib (Velcade), with rates of 15% for complete responses and 50% for partial responses, and in those who were bortezomib naive, with a 16% complete response rate and 55% partial response rate.

"People are very interested in this agent," commented Dr. Mitchell R. Smith from the Fox Chase Cancer Center in Philadelphia, in an interview.

"It looks very active, but we don’t know a lot about long-term effects and how long responses will last. But when you think about hitting specific pathways, that’s our goal in treating these diseases. This hits a specific pathway, does it well, and there have been responses in many B-cell disorders," he said. Dr. Smith comoderated the session at which the data were presented, but was not involved in the study.

PCI-32765 is an oral inhibitor of BTK, an essential element of the B-cell antigen receptor-signaling pathway. It blocks receptor signaling and induces apoptosis, as well as mantle cell migration and adhesion, and has been shown in in vitro studies to block pERK, pJNK, and NF-kappaB pathways in MCL cell lines.

The trial, designated PCYC-1104-CA, is a multicenter open-label phase II study of PCI-32765 in 68 patients. Dr. Wang presented data from an efficacy analysis of 51 patients who had at least one post-baseline tumor assessment. The patients were divided into two groups: bortezomib-exposed (27 patients) and bortezomib naive (41 patients, 34 of whom had never received bortezomib, and 7 who had received less than 2 cycles).

The patients were treated with 560 mg PCI-32765 daily until disease progression.

Median time on study was 3.7 months among all patients. At the most recent follow-up, 71% of bortezomib-naive and 70% of bortezomib-exposed patients were still on study. Discontinuations were primarily for disease progression, and there was one on-study death, a patient who had previously received bortezomib.

Non-hematologic adverse events were generally mild, with the only grade 4 toxicity being abdominal pain in about 2% of patients.

Grade 3 neutropenia occurred in 2% overall of 61 patients available for a safety analysis, and grade 4 neutropenia was seen 3%. Grade 3 febrile neutropenia, anemia, and thrombocytopenias were each seen in 3% of patients (no grade 4), and grade 4 pancytopenia was seen in 2%.

The investigators saw a 57% overall response rate in patients with bulky disease, 67% in those with refractory disease, 77% among those who had received fewer than 3 prior lines of therapy, and 57% among those who had received 3 or more. In addition, the overall response rate was 71% in patients who had received high-intensity prior therapy, and 65% in those who had received standard-dose therapy.

Additional follow-up will be required before the investigators can determine duration of response and progression-free survival, and more clinical trials with PCI-32765 are in the planning stages, Dr. Wang said.

Pharmacyclics sponsored the study. Dr. Wang disclosed consulting, having equity ownership in, and receiving research funding from, Pharmacyclics. He also disclosed relationships with Celgene, Millennium, Novartis, and Onyx. Dr. Smith disclosed board membership and receiving research funding from Cephalon, and being on the speakers bureau for Celgene, Genentech, Spectrum, and Allos.