Phase 2

In the phase 2 study of single-agent voxtalisib, 167 patients were enrolled and treated with 50 mg twice-daily in 28-day cycles. There were 42 patients with mantle cell lymphoma, 47 with follicular lymphoma, 42 with diffuse large B-cell lymphoma, and 36 with CLL/SLL.

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Of patients evaluable for efficacy, 18.3% had an overall response, including 8 patients with a complete response and 22 with a partial response. Of patients with follicular lymphoma, 41.3% had a response compared with 11.9% of patients with mantle cell lymphoma, 11.4% of patient with CLL/SLL, and only 4.9% of patients with diffuse large B-cell lymphoma.

“These findings are similar, particularly for the proportion of patients who achieved a complete response, to those reported with the PI3Kδ inhibitor idelalisib, which received accelerated approval from the FDA on the basis of 57% of patients showing an overall response, 6% achieving complete response, and progression-free survival of 11 months in a phase 2 study in patients with indolent B-cell non-Hodgkin lymphoma who were refractory to both rituximab and alkylating agents, although such cross-trial comparisons must be made with caution, given the different study populations,” the researchers wrote.

The safety profile was consistent with earlier studies, with the most common grade 3 or worse adverse events being anemia, pneumonia, and thrombocytopenia.

Status of PI3K Inhibitors

In an editorial that accompanied the phase 2 study, Wataru Munakata and Kensei Tobinai, of the National Cancer Center Hospital in Toyko, Japan, noted that the FDA-approved pan-PI3K inhibitor copanlisib, which also has predominant activity against PI3Kα and PI3Kδ, had clinical activity against B-cell malignancies, including CLL and SLL.8

“These data suggest that the antitumour mechanisms of PI3K inhibitors are more complicated than previously thought,” Munakata and Tobinai wrote. “Although PI3K inhibitors are anticipated to be one of the key agents for future treatment of non-Hodgkin lymphoma, further elucidation of their antitumour mechanisms, toxicity and efficacy profiles, and effectiveness in combination with other key drugs are needed.”


  1. Brown JR, Hamandani M, Hayslip J, et al. Voxtalisib (XL765) in patients with relapsed or refractory non-Hodgkin lymphoma or chronic lymphocytic leukemia: an open-label, phase 2 trial. Lancet Haematol. 2018 Mar 14. doi: 10.1016/S2352-3026(18)30030-9 [Epub ahead of print]
  2. FDA approval for idelalisib. National Cancer Institute website. Published July 29, 2014. Accessed March 2018.
  3. FDA alerts healthcare professionals about clinical trials with Zydelig (idelalisib) in combination with other cancer medicines. US Food and Drug Administration website. Updated March 14, 2016. Accessed March 2018.
  4. Thijssen R, Ter Burg J, van Bochove GG, et al. The pan phosphoinositide 3-kinase/mammalian target of rapamycin inhibitor SAR245409 (voxtalisib/XL765) blocks survival, adhesion and proliferation of primary chronic lymphocytic leukemia cells. Leukemia. 2016;30:337-45.
  5. Papadopoulos K, Tabernero J, Markman B, et al. Phase I safety, pharmacokinetic and pharmacodynamic study of SAR245409 (XL765), a novel, orally administered PI3K/mTOR inhibitor in patients with advanced solid tumors. Clin Cancer Res. 2014;20:2445-56.
  6. Papadopoulos KP, Egile C, Ruiz-Soto R, et al. Efficacy, safety, pharmacokinetics and pharmacodynamics of SAR245409 (voxtalisib, XL765), an orally administered phosphoinositide 3-kinase/mammalian target of rapamycin inhibitor: a phase 1 expansion cohort in patients with relapsed or refractory lymphoma. Leuk Lymphoma. 2015;56:1763-70.
  7. Awan FT, Gore L, Gao L, Sharma J, Lager J, Costa LJ. Phase Ib trial of the PI3K/mTOR inhibitor voxtalisib (SAR245409) in combination with chemoimmunotherapy in patients with relapsed or refractory B-cell malignancies. Br J Haematol. 2016;175:55-65.
  8. Munakata W, Tobinai K. Clinical development of voxtalisib: a pan-PI3K/mTOR inhibitor. Lancet Haematol. 2018 Mar 14. doi: 10.1016/S2352-3026(18)30034-6 [Epub ahead of print]