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Entospletinib, a selective inhibitor of spleen tyrosine kinase (Syk), showed a dismal rate of progression-free survival and a high rate of adverse events in a cohort of previously treated patients with diffuse large B-cell lymphoma (DLBCL).
![Micrograph of a 'diffuse large B cell lymphoma. Lymph node FNA specimen. Field stain.(http://www.gnu.org/copyleft/fdl.html)], via Wikimedia Commons](https://cdn.mdedge.com/files/s3fs-public/Image/June-2017/DLBCL_web.jpg)
Entospletinib was evaluated in an open-label, single-agent, phase 2 trial (NCT01799889) with five relapsed/refractory patient cohorts: chronic lymphocytic leukemia (CLL), follicular lymphoma, other indolent non-Hodgkin lymphomas, mantle cell lymphoma, and DLBCL.
John M. Burke, MD, of Rocky Mountain Cancer Centers in Aurora, Colo., and his colleagues reported on the current analysis, which looked specifically at the 43 patients in the trial with previously treated DLBCL. Patients received at least one starting dose of 800 mg of entospletinib orally twice daily. The findings were published in Clinical Lymphoma, Myeloma & Leukemia.
In a previous report on the relapsed/refractory CLL cohort, the investigational agent demonstrated clinical activity with acceptable toxicity (Blood. 2015 Apr 9;125[15]:2336-43).
In the current report, the rate of progression-free survival (PFS) at 16 weeks was 3.6% and the median PFS was 1.5 months. None of the patients in the study achieved a complete or partial response to treatment, and just five patients had stable disease.
All patients in the study eventually discontinued treatment and the median treatment duration was 1 month.
“The lack of activity of Syk inhibition in patients with relapsed DLBCL is in contrast to what would have been expected from preclinical data,” the investigators wrote. “Although it is unclear why entospletinib monotherapy lacked activity in the present study, it is possible that resistance to Syk inhibition played a role. Potential mechanisms of resistance of DLBCL to Syk inhibition include transcriptional upregulation of Syk mediated by FOXO1 and PTEN depletion.”
The investigators said that Syk inhibition in combination with BCL2 inhibitors could potentially overcome this resistance. Another approach, they suggested, would be to offer entospletinib in combination with Janus kinase (JAK) 1/3 inhibition.
“Based on results of the preclinical data, the efficacy of entospletinib in combination will be evaluated in future clinical trials,” the investigators wrote.
The rate of adverse events was high in the DLBCL cohort. Forty-two patients (98%) experienced an adverse event and nearly three-quarters experienced a grade 3 event. Overall, 30% of the grade 3 adverse events were related to treatment. More than 40% of patients interrupted treatment because of adverse events, and 19% discontinued. Four patients experienced an adverse event that led to death.
While the lack of clinical activity may have surprised investigators, the safety profile was in line with other patient cohorts in the phase 2 study. In the CLL and indolent non-Hodgkin lymphoma cohorts, the rates of treatment interruption were 45% and 54%, respectively.
The study was supported by Gilead Sciences. Dr. Burke reported relationships with Gilead and other companies.
SOURCE: Burke JM et al. Clin Lymphoma Myeloma Leuk. 2018 Aug;18(8):e327-e331.
Entospletinib, a selective inhibitor of spleen tyrosine kinase (Syk), showed a dismal rate of progression-free survival and a high rate of adverse events in a cohort of previously treated patients with diffuse large B-cell lymphoma (DLBCL).
Entospletinib was evaluated in an open-label, single-agent, phase 2 trial (NCT01799889) with five relapsed/refractory patient cohorts: chronic lymphocytic leukemia (CLL), follicular lymphoma, other indolent non-Hodgkin lymphomas, mantle cell lymphoma, and DLBCL.
John M. Burke, MD, of Rocky Mountain Cancer Centers in Aurora, Colo., and his colleagues reported on the current analysis, which looked specifically at the 43 patients in the trial with previously treated DLBCL. Patients received at least one starting dose of 800 mg of entospletinib orally twice daily. The findings were published in Clinical Lymphoma, Myeloma & Leukemia.
In a previous report on the relapsed/refractory CLL cohort, the investigational agent demonstrated clinical activity with acceptable toxicity (Blood. 2015 Apr 9;125[15]:2336-43).
In the current report, the rate of progression-free survival (PFS) at 16 weeks was 3.6% and the median PFS was 1.5 months. None of the patients in the study achieved a complete or partial response to treatment, and just five patients had stable disease.
All patients in the study eventually discontinued treatment and the median treatment duration was 1 month.
“The lack of activity of Syk inhibition in patients with relapsed DLBCL is in contrast to what would have been expected from preclinical data,” the investigators wrote. “Although it is unclear why entospletinib monotherapy lacked activity in the present study, it is possible that resistance to Syk inhibition played a role. Potential mechanisms of resistance of DLBCL to Syk inhibition include transcriptional upregulation of Syk mediated by FOXO1 and PTEN depletion.”
The investigators said that Syk inhibition in combination with BCL2 inhibitors could potentially overcome this resistance. Another approach, they suggested, would be to offer entospletinib in combination with Janus kinase (JAK) 1/3 inhibition.
“Based on results of the preclinical data, the efficacy of entospletinib in combination will be evaluated in future clinical trials,” the investigators wrote.
The rate of adverse events was high in the DLBCL cohort. Forty-two patients (98%) experienced an adverse event and nearly three-quarters experienced a grade 3 event. Overall, 30% of the grade 3 adverse events were related to treatment. More than 40% of patients interrupted treatment because of adverse events, and 19% discontinued. Four patients experienced an adverse event that led to death.
While the lack of clinical activity may have surprised investigators, the safety profile was in line with other patient cohorts in the phase 2 study. In the CLL and indolent non-Hodgkin lymphoma cohorts, the rates of treatment interruption were 45% and 54%, respectively.
The study was supported by Gilead Sciences. Dr. Burke reported relationships with Gilead and other companies.
SOURCE: Burke JM et al. Clin Lymphoma Myeloma Leuk. 2018 Aug;18(8):e327-e331.
Entospletinib, a selective inhibitor of spleen tyrosine kinase (Syk), showed a dismal rate of progression-free survival and a high rate of adverse events in a cohort of previously treated patients with diffuse large B-cell lymphoma (DLBCL).
Entospletinib was evaluated in an open-label, single-agent, phase 2 trial (NCT01799889) with five relapsed/refractory patient cohorts: chronic lymphocytic leukemia (CLL), follicular lymphoma, other indolent non-Hodgkin lymphomas, mantle cell lymphoma, and DLBCL.
John M. Burke, MD, of Rocky Mountain Cancer Centers in Aurora, Colo., and his colleagues reported on the current analysis, which looked specifically at the 43 patients in the trial with previously treated DLBCL. Patients received at least one starting dose of 800 mg of entospletinib orally twice daily. The findings were published in Clinical Lymphoma, Myeloma & Leukemia.
In a previous report on the relapsed/refractory CLL cohort, the investigational agent demonstrated clinical activity with acceptable toxicity (Blood. 2015 Apr 9;125[15]:2336-43).
In the current report, the rate of progression-free survival (PFS) at 16 weeks was 3.6% and the median PFS was 1.5 months. None of the patients in the study achieved a complete or partial response to treatment, and just five patients had stable disease.
All patients in the study eventually discontinued treatment and the median treatment duration was 1 month.
“The lack of activity of Syk inhibition in patients with relapsed DLBCL is in contrast to what would have been expected from preclinical data,” the investigators wrote. “Although it is unclear why entospletinib monotherapy lacked activity in the present study, it is possible that resistance to Syk inhibition played a role. Potential mechanisms of resistance of DLBCL to Syk inhibition include transcriptional upregulation of Syk mediated by FOXO1 and PTEN depletion.”
The investigators said that Syk inhibition in combination with BCL2 inhibitors could potentially overcome this resistance. Another approach, they suggested, would be to offer entospletinib in combination with Janus kinase (JAK) 1/3 inhibition.
“Based on results of the preclinical data, the efficacy of entospletinib in combination will be evaluated in future clinical trials,” the investigators wrote.
The rate of adverse events was high in the DLBCL cohort. Forty-two patients (98%) experienced an adverse event and nearly three-quarters experienced a grade 3 event. Overall, 30% of the grade 3 adverse events were related to treatment. More than 40% of patients interrupted treatment because of adverse events, and 19% discontinued. Four patients experienced an adverse event that led to death.
While the lack of clinical activity may have surprised investigators, the safety profile was in line with other patient cohorts in the phase 2 study. In the CLL and indolent non-Hodgkin lymphoma cohorts, the rates of treatment interruption were 45% and 54%, respectively.
The study was supported by Gilead Sciences. Dr. Burke reported relationships with Gilead and other companies.
SOURCE: Burke JM et al. Clin Lymphoma Myeloma Leuk. 2018 Aug;18(8):e327-e331.
FROM CLINICAL LYMPHOMA, MYELOMA & LEUKEMIA
Key clinical point:
Major finding: The rate of progression-free survival at 16 weeks was 3.6% with a median PFS of 1.5 months.
Study details: An analysis of 43 relapsed/refractory DLBCL patients who received single-agent entospletinib.
Disclosures: The study was supported by Gilead Sciences. Dr. Burke reported relationships with Gilead and other companies.
Source: Burke JM et al. Clin Lymphoma Myeloma Leuk. 2018 Aug;18(8):e327-e331.