Is Voxtalisib Effective in Cancers Other Than Follicular Lymphoma?

Data from a Phase 2 study (NCT01403636) suggest that voxtalisib has a promising safety profile, but might not be as effective in patients with aggressive malignancies as it is in patients with follicular lymphoma (FL).

The data was published in an article titled “Voxtalisib (XL765) in patients with relapsed or refractory non-Hodgkin lymphoma or chronic lymphocytic leukemia: an open-label, phase 2 trial” and recently in The Lancet Hematology.

The drug is developed by Exelixis and Sanofi, and it is approved by the Food and Drug Administration (FDA) for treatment of relapsed/refractory FL or for chronic lymphocytic leukemia (CLL), in combination with rituximab.

Voxtalisib, an investigational agent that targets both mammalian target of rapamycin (mTOR) and multiple isoforms of phosphoinositide-3 kinase (PI3K), showed “promising” efficacy with acceptable safety in patients with relapsed or refractory follicular lymphoma, results of a phase 2 trial indicate. Among 46 patients with FL, the overall response rate was 41.3%, including 5 (10.9%) complete responses.

Historical data has led scientists to believe that therapies targeting more than one isoform of PI3K and mTOR could potentially increase antitumor activity, so a team of researchers led by Jennifer R. Brown, M.D. of the Dana-Farber Cancer Institute at Harvard Medical School aimed to investigate the safety and efficacy of voxtalisib in patients with relapsed or refractory lymphoma and chronic lymphocytic leukemia/small lymphocytic lymphoma.

Between October 19, 2011 and July 24, 2013, 167 patients (42 with mantle cell lymphoma [MCL], 47 with FL, 42 with diffuse large B-cell lymphoma [DLBCL], and 36 with chronic lymphocytic leukemia/small lymphocytic leukemia [CLL/SLL]) were enrolled into a non-randomized, open-label, phase 2 trial at 30 oncology clinics across the United States, Belgium Germany, France, the Netherlands, and Australia. Each patient was aged 18 years or older and had an Eastern Cooperative Oncology Group (EGOG) performance status score of 2 or lower, and was treated with voxtalisib 50 mg orally twice daily in 28-day continuous dosing cycles until progression or unacceptable toxicity.

Efficacy served as the primary endpoint in the trial, and was defined as the objective response rate (ORR) in patients with 1 of the lymphoma or leukemia subtypes. Additional secondary endpoints included: duration of response, progression free survival (PFS), and proportion of patients with PFS at 6 months; safety and tolerability; and characterization of plasma pharmacokinetics (PK).

The median number of previous anticancer regimens was 3 and 4 for patients with lymphoma and patients with chronic lymphocytic leukemia/small lymphocytic lymphoma, respectively.

Efficacy was limited against aggressive malignancies, as the study reported the following ORR rates in MCL, DLBCL, and CLL/SLL: 11.9%, 4.9%, and 11.4%.

The most frequently reported adverse events (AEs) were diarrhea in 59 (35% of all 167 patients, fatigue in 53 (32%), nausea in 45 (27%), pyrexia in 44 (26%), cough in 40 (24%), and decreased appetite in 35 (21%). The most common AEs that were grade 3 or worse were anemia in 20 (12%) of 167 patients, pneumonia in 14 (8%), and thrombocytopenia in 13 (8%). Serious AEs occurred in 97 (58.1%) of all patients.

With this data, it was concluded that voxtalisib 50 mg given orally twice daily had an acceptable safety profile with promising efficacy in patients with FL. Patients with MCL, DLBCL, or CLL/SLL, however, experienced a similar safety profile but limited efficacy.

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