TGR-1202

TGR-1202 is a novel, next-generation, once-daily PI3Kδ inhibitor. According to findings presented at the American Society of Hematology (ASH) 57th Annual Meeting & Exposition in Orlando, Florida, 94% of 16 patients with relapsed/refractory CLL treated with TGR-1202 monotherapy achieved a nodal partial response, and 63% achieved a partial response per Hallek 2008 criteria.4


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In a study evaluating the activity and tolerability of TGR-1202 in conjunction with ublituximab, a novel anti-CD20 monoclonal antibody, 5 of 7 evaluable patients with CLL treated with higher doses of TGR-1202 achieved a response. No patients with CLL had progressed as of the first efficacy assessment, despite 4 patients having high-risk cytogenetics.5

“Efficacy-wise, TGR-1202 looks comparable to idelalisib, and the once-daily dosing of TGR-1202 is beneficial for patients,” said Dr Davids.

TGR-1202 monotherapy resulted in no grade 3 or higher adverse events in 10% or more of patients. General tolerability and the incidence of hepatotoxicity and colitis appeared to be significantly less than that reported with other agents in this class, such as idelalisib.4

“What is really exciting about TGR-1202, at least from the early data we have seen, is that even though it is a delta-specific PI3K kinase inhibitor, we are not seeing the same toxicities that we see with idelalisib, particularly, the colitis, hepatotoxicity, and pneumonitis,” Dr Davids said.

TGR-1202 is also being studied in combination with obinutuzumab plus chlorambucil for the treatment of CLL, as well with ibrutinib in relapsed/refractory CLL.6

“If we put idelalisib with ibrutinib, we are certainly worried about the diarrhea we see with both drugs, but when we put TGR-1202 with ibrutinib, we are hopeful we won’t see prohibitive rates of diarrhea or colitis,” Dr Davids noted.

Duvelisib

Duvelisib is a novel PI3K inhibitor that targets both PI3K delta and gamma. In a phase 1 study presented at the ASH 55th Annual Meeting & Exposition in San Francisco, California, the objective response rate was 57% with duvelisib 25 mg twice daily in patients with relapsed/refractory CLL. For patients who achieved a partial response with lymphocytosis, the overall response rate was approximately 80%.7

With the 25-mg twice daily dose of duvelisib, median progression-free survival had not yet been reached, compared with 15.7 months among all duvelisib-treated patients. The 2-year progression-free survival rate was 59% with the 25-mg twice daily dose.7

“So far, the efficacy data of duvelisib looks great, though there is no head-to-head data with idelalisib,” Dr Davids noted.

Duvelisib had a similar safety profile to idelalisib. Most treatment-emergent adverse events were grade 1 to 2, and the most frequently reported grade 3 or worse adverse events were transient cytoepnias, febrile neutropenia, and pneumonia.7

Duvelisib is being studied as monotherapy, in combination with fludarabine, cyclophosphamide, rituximab, and with obinutuzumab. The phase 3 DUO trial is evaluating the efficacy and safety of duvelisib with ofatumumab.

GDC-0853

GDC-0853 is another novel inhibitor of Bruton’s tyrosine kinase, which does not rely upon the C481 site of Bruton’s tyrosine kinase and lacks ITK inhibition, unlike ibrutinib. ITK inhibition limits antibody-dependent cytotoxicity (ADCC) and the efficacy of antibody therapy.8

In an in vitro study presented at the ASCO Annual Meeting 2016, researchers at The Ohio State University Comprehensive Cancer Center in Columbus used freshly purified B cells from primary CLL samples treated with a Bruton’s tyrosine kinase inhibitor. Results showed that GDC-0853 reduced the activation of Bruton’s tyrosine kinase and its downstream targets, and modestly reduced CLL viability.8

The study also demonstrated that, unlike ibrutinib, GDC-0853 inhibited signaling of both wild-type and C481S mutated Bruton’s tyrosine kinase, and preserved natural killer cell ADCC with clinical αCD20 antibodies.8