Pan-PI3K Inhibitor Voxtalisib Active in FL but Less So in CLL, DLBCL

In a phase II study, voxtalisib, which targets all four class I PI3Ks, had efficacy in FL but limited clinical effect in MCL, DLBCL, and CLL/SLL.

The pan–phosphoinositase 3-kinase (PI3K) inhibitor voxtalisib has promising efficacy for patients with follicular lymphoma (FL), but limited clinical effect on other B-cell malignancies such as mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), and chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), a phase II study has shown.

“Voxtalisib was associated with an acceptable safety profile in relapsed or refractory lymphoma and in chronic lymphocytic leukemia/small lymphocytic lymphoma, with promising efficacy in the follicular lymphoma group,” wrote Jennifer R. Brown, MD, of Dana-Farber Cancer Institute, and colleagues in Lancet Haematology. “Investigation of voxtalisib either alone or in combination with chemoimmunotherapy is warranted in patients with follicular lymphoma.”

According to the study, evidence has suggested a role for targeting more than one isoform of PI3K to increase antitumor activity in B-cell lymphoma and CLL. Voxtalisib targets all four class I PI3Ks and is a weaker inhibitor of mammalian target of rapamycin. Because phase I studies suggested some clinical activity of voxtalisib in B-cell malignancies, the researchers conducted this phase II study to assess its safety and efficacy in patients with relapsed or refractory disease.

The nonrandomized study included 167 patients aged 18 years or older. Included patients had MCL (n = 42), FL (n = 47), DLBCL (n = 42), or CLL/SLL (n = 36). Patients were treated with voxtalisib at 50-mg twice daily in 28-day continuous dosing cycles until progression or unacceptable toxicity.

Of 164 patients evaluated for efficacy, 18.3% achieved an overall response. This included 22 patients with partial response and 8 with complete response. Patients with FL had the greatest response rate, with 41.3% of patients responding. Of the 5 patients with FL who achieved complete response, the median duration of response was 85 weeks. In contrast, only 11.9% of patients with MCL, 11.4% of those with CLL/SLL, and 4.9% of those with DLBCL responded.

The overall median progression-free survival (PFS) was 14.4 weeks. Patients with FL had a median PFS of 58 weeks, whereas the median PFS was 8.9 weeks, 7.1 weeks, and 24.1 weeks for patients with MCL, DLBCL, and CLL/SLL, respectively.

“Voxtalisib showed no pharmacodynamic effects on cytokine and chemokine concentrations in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma, despite its strong pro-apoptotic activity in vitro,” the researchers wrote. “Insufficient exposure of voxtalisib might have led to limited PI3Kδ inhibition in patients with chronic lymphocytic leukemia, which might explain the low antitumor activity observed in this subgroup and in the mantle cell lymphoma and diffuse large B-cell lymphoma subgroups.”

Among the commonly reported adverse events were diarrhea, fatigue, nausea, pyrexia, cough, and decreased appetite. Grade 3 or worse adverse events included anemia (12%), pneumonia (8%), and thrombocytopenia (8%). Overall, more than half of the patients in the study experienced a serious adverse event. About one-third (32%) of the patients died, with 43 of 53 deaths attributed to disease progression and 8 deaths due to adverse events.