Investigational CDK4/6 inhibitor shows activity, less toxicity

Abemaciclib, a CDK4/6 inhibitor, showed durable clinical activity when given as continuous single-agent therapy to patients with advanced cancer, including breast cancer and non–small-cell lung cancer, according to investigators.

Neutropenia was rarely observed in patients treated with abemaciclib, the toxicity observed in some patients who receive the only Food and Drug Administration–approved CDK4/6 inhibitor, palbociclib.

“Abemaciclib is a small-molecule inhibitor of CDK4 and CDK6 that is structurally distinct from other dual inhibitors (such as palbociclib and ribociclib) and notably exhibits greater selectivity for CDK4 compared with CDK6,” wrote Dr. Amita Patnaik of South Texas Accelerated Research Therapeutics and her associates (Cancer Discov. 2016 May 23. doi: 10.1158/2159-8290.CD-16-0095).

Furthermore, preclinical models indicate that the drug can cross the blood-brain barrier, suggesting potential efficacy against primary and metastatic tumors involving the central nervous system, they said.

A total of 225 patients with various types of advanced cancers were enrolled in this multicohort phase I study (dose escalation, n = 33; single-agent abemaciclib therapy for breast cancer, n = 47; non–small-cell lung cancer, n = 68; glioblastoma, n = 17; melanoma, n = 26; colorectal cancer, n = 15; abemaciclib plus fulvestrant combination therapy for hormone receptor–positive breast cancer, n = 19). Abemaciclib was given orally to all patients.

Neither dose-limiting toxicity nor maximum tolerated dose was reached in patients treated at levels of 50 mg, 100 mg, 150 mg, or 225 mg once daily. The maximum tolerated dose was 200 mg for patients treated with abemaciclib twice daily.

In the single-agent breast cancer cohort, the disease control rate was 81% for hormone receptor–positive (HR-positive) tumors, 33% for HR-negative tumors, 100% for HR-positive HER2-positive tumors, 72% for HR-positive HER2-negative tumors, and 70% overall. The response rate was 31% for HR-positive tumors, 0% for HR-negative tumors, 36% for HR-positive HER2-positive tumors, 28% for HR-positive HER2-negative tumors, and 23% overall.

The overall response rate was 21% for breast cancer patients receiving abemaciclib plus fulvestrant.

Among the 68 patients with non–small-cell lung cancer, 2 had a partial response and 31 had stable disease. Of the 26 patients with melanoma, 1 had a partial response and 6 had stable disease. Of the 17 patients with glioblastoma, 3 had stable disease.

Overall, there were no study-related deaths. Diarrhea, nausea, and fatigue were the most common adverse events; all were reversible.

Neutropenia was observed in 39 patients (23% of 173 patients in the single-agent tumor-specific cohort) – 2 were grade 4 events. Grade 3 neutropenia occurred in 6 patients (32% of 19 patients with HR-positive breast cancer receiving combination therapy with abemaciclib plus fulvestrant).

“Previous reports have identified neutropenia as an adverse event associated with dual inhibition of CDK4 and CDK6. However, abemaciclib given as a single agent on a continuous schedule in the tumor-specific cohorts was associated with an acceptable incidence of investigator-reported grade 3 (9%, 16 of 173 patients) or grade 4 (1%, 2 of 173 patients) neutropenia,” wrote the investigators.

“In summary, the results of this clinical trial demonstrate the safety and antitumor activity of abemaciclib as a single agent and support its further development both as monotherapy and in rational combinations. Furthermore, these findings validate CDK4 and CDK6 as anticancer drug targets and translate preclinical predictions regarding therapeutic targeting of cell-cycle derangements in cancer into clinical efficacy,”they wrote.

Eli Lilly funded the study. Eight investigators reported serving in advisory roles, having ownership or stock interest in, or receiving financial compensation from multiple companies including Eli Lilly.

[email protected]

On Twitter @JessCraig_OP

Abemaciclib, a CDK4/6 inhibitor, showed durable clinical activity when given as continuous single-agent therapy to patients with advanced cancer, including breast cancer and non–small-cell lung cancer, according to investigators.

Neutropenia was rarely observed in patients treated with abemaciclib, the toxicity observed in some patients who receive the only Food and Drug Administration–approved CDK4/6 inhibitor, palbociclib.

“Abemaciclib is a small-molecule inhibitor of CDK4 and CDK6 that is structurally distinct from other dual inhibitors (such as palbociclib and ribociclib) and notably exhibits greater selectivity for CDK4 compared with CDK6,” wrote Dr. Amita Patnaik of South Texas Accelerated Research Therapeutics and her associates (Cancer Discov. 2016 May 23. doi: 10.1158/2159-8290.CD-16-0095).

Furthermore, preclinical models indicate that the drug can cross the blood-brain barrier, suggesting potential efficacy against primary and metastatic tumors involving the central nervous system, they said.

A total of 225 patients with various types of advanced cancers were enrolled in this multicohort phase I study (dose escalation, n = 33; single-agent abemaciclib therapy for breast cancer, n = 47; non–small-cell lung cancer, n = 68; glioblastoma, n = 17; melanoma, n = 26; colorectal cancer, n = 15; abemaciclib plus fulvestrant combination therapy for hormone receptor–positive breast cancer, n = 19). Abemaciclib was given orally to all patients.

Neither dose-limiting toxicity nor maximum tolerated dose was reached in patients treated at levels of 50 mg, 100 mg, 150 mg, or 225 mg once daily. The maximum tolerated dose was 200 mg for patients treated with abemaciclib twice daily.

In the single-agent breast cancer cohort, the disease control rate was 81% for hormone receptor–positive (HR-positive) tumors, 33% for HR-negative tumors, 100% for HR-positive HER2-positive tumors, 72% for HR-positive HER2-negative tumors, and 70% overall. The response rate was 31% for HR-positive tumors, 0% for HR-negative tumors, 36% for HR-positive HER2-positive tumors, 28% for HR-positive HER2-negative tumors, and 23% overall.

The overall response rate was 21% for breast cancer patients receiving abemaciclib plus fulvestrant.

Among the 68 patients with non–small-cell lung cancer, 2 had a partial response and 31 had stable disease. Of the 26 patients with melanoma, 1 had a partial response and 6 had stable disease. Of the 17 patients with glioblastoma, 3 had stable disease.

Overall, there were no study-related deaths. Diarrhea, nausea, and fatigue were the most common adverse events; all were reversible.

Neutropenia was observed in 39 patients (23% of 173 patients in the single-agent tumor-specific cohort) – 2 were grade 4 events. Grade 3 neutropenia occurred in 6 patients (32% of 19 patients with HR-positive breast cancer receiving combination therapy with abemaciclib plus fulvestrant).

“Previous reports have identified neutropenia as an adverse event associated with dual inhibition of CDK4 and CDK6. However, abemaciclib given as a single agent on a continuous schedule in the tumor-specific cohorts was associated with an acceptable incidence of investigator-reported grade 3 (9%, 16 of 173 patients) or grade 4 (1%, 2 of 173 patients) neutropenia,” wrote the investigators.

“In summary, the results of this clinical trial demonstrate the safety and antitumor activity of abemaciclib as a single agent and support its further development both as monotherapy and in rational combinations. Furthermore, these findings validate CDK4 and CDK6 as anticancer drug targets and translate preclinical predictions regarding therapeutic targeting of cell-cycle derangements in cancer into clinical efficacy,”they wrote.

Eli Lilly funded the study. Eight investigators reported serving in advisory roles, having ownership or stock interest in, or receiving financial compensation from multiple companies including Eli Lilly.

[email protected]

On Twitter @JessCraig_OP

Abemaciclib, a CDK4/6 inhibitor, showed durable clinical activity when given as continuous single-agent therapy to patients with advanced cancer, including breast cancer and non–small-cell lung cancer, according to investigators.

Neutropenia was rarely observed in patients treated with abemaciclib, the toxicity observed in some patients who receive the only Food and Drug Administration–approved CDK4/6 inhibitor, palbociclib.

“Abemaciclib is a small-molecule inhibitor of CDK4 and CDK6 that is structurally distinct from other dual inhibitors (such as palbociclib and ribociclib) and notably exhibits greater selectivity for CDK4 compared with CDK6,” wrote Dr. Amita Patnaik of South Texas Accelerated Research Therapeutics and her associates (Cancer Discov. 2016 May 23. doi: 10.1158/2159-8290.CD-16-0095).

Furthermore, preclinical models indicate that the drug can cross the blood-brain barrier, suggesting potential efficacy against primary and metastatic tumors involving the central nervous system, they said.

A total of 225 patients with various types of advanced cancers were enrolled in this multicohort phase I study (dose escalation, n = 33; single-agent abemaciclib therapy for breast cancer, n = 47; non–small-cell lung cancer, n = 68; glioblastoma, n = 17; melanoma, n = 26; colorectal cancer, n = 15; abemaciclib plus fulvestrant combination therapy for hormone receptor–positive breast cancer, n = 19). Abemaciclib was given orally to all patients.

Neither dose-limiting toxicity nor maximum tolerated dose was reached in patients treated at levels of 50 mg, 100 mg, 150 mg, or 225 mg once daily. The maximum tolerated dose was 200 mg for patients treated with abemaciclib twice daily.

In the single-agent breast cancer cohort, the disease control rate was 81% for hormone receptor–positive (HR-positive) tumors, 33% for HR-negative tumors, 100% for HR-positive HER2-positive tumors, 72% for HR-positive HER2-negative tumors, and 70% overall. The response rate was 31% for HR-positive tumors, 0% for HR-negative tumors, 36% for HR-positive HER2-positive tumors, 28% for HR-positive HER2-negative tumors, and 23% overall.

The overall response rate was 21% for breast cancer patients receiving abemaciclib plus fulvestrant.

Among the 68 patients with non–small-cell lung cancer, 2 had a partial response and 31 had stable disease. Of the 26 patients with melanoma, 1 had a partial response and 6 had stable disease. Of the 17 patients with glioblastoma, 3 had stable disease.

Overall, there were no study-related deaths. Diarrhea, nausea, and fatigue were the most common adverse events; all were reversible.

Neutropenia was observed in 39 patients (23% of 173 patients in the single-agent tumor-specific cohort) – 2 were grade 4 events. Grade 3 neutropenia occurred in 6 patients (32% of 19 patients with HR-positive breast cancer receiving combination therapy with abemaciclib plus fulvestrant).

“Previous reports have identified neutropenia as an adverse event associated with dual inhibition of CDK4 and CDK6. However, abemaciclib given as a single agent on a continuous schedule in the tumor-specific cohorts was associated with an acceptable incidence of investigator-reported grade 3 (9%, 16 of 173 patients) or grade 4 (1%, 2 of 173 patients) neutropenia,” wrote the investigators.

“In summary, the results of this clinical trial demonstrate the safety and antitumor activity of abemaciclib as a single agent and support its further development both as monotherapy and in rational combinations. Furthermore, these findings validate CDK4 and CDK6 as anticancer drug targets and translate preclinical predictions regarding therapeutic targeting of cell-cycle derangements in cancer into clinical efficacy,”they wrote.

Eli Lilly funded the study. Eight investigators reported serving in advisory roles, having ownership or stock interest in, or receiving financial compensation from multiple companies including Eli Lilly.

[email protected]

On Twitter @JessCraig_OP