Experimental voxtalisib shows mixed results in phase 2 study

Voxtalisib, an investigational agent that targets both mTOR and multiple isoforms of PI3K, showed “promising” efficacy with acceptable safety in patients with relapsed or refractory follicular lymphoma (FL), results of a phase 2 trial indicate.

Among 46 patients with FL, the overall response rate was 41.3%, including five (10.9%) complete responses. The median progression-free survival in this group was 58 weeks, reported Jennifer R. Brown, MD, PhD, of the Dana-Farber Cancer Institute in Boston, and her colleagues.

“The observed activity of voxtalisib in relapsed or refractory follicular lymphoma, notable for inducing complete responses in 10.9% of patients, warrants further study,” the investigators wrote in a study published in the Lancet Haematology.

Efficacy of the drug was limited, however, against aggressive malignancies, including mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), or chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).

Voxtalisib (XL765) is a potent inhibitor of all four class I PI3Ks, as well as a less robust inhibitor of the mammalian target of rapamycin (mTOR). In contrast, idelalisib (Zydelig) – which is approved by the Food and Drug Administration for treatment of relapsed/refractory FL or for CLL, in combination with rituximab – inhibits only the delta isoform of PI3K, and does not have marked anti–mTOR properties.

The investigators conducted an open-label, nonrandomized trial of voxtalisib in 30 centers in the United States, Belgium, France, Germany, the Netherlands, and Australia.

Adults 18 years or older with relapsed or refractory MCL, FL, DLBCL or CLL/SLL with Eastern Cooperative Oncology Group performance status of 2 or less were enrolled. All patients received voxtalisib 50 mg orally twice daily in 28-day continuous dosing cycles until progression or unacceptable toxicity.

All patients who received more the 4 weeks of treatment and had both a baseline and one or more on-treatment tumor assessments were included in the efficacy analysis. Patients with lymphoma had received a median of three prior lines of therapy, and those with CLL had received a median of four prior lines.

The overall response rate in the entire study population was 18.3% (30 patients), including 22 partial and 8 complete responses. ORR rates were as follows:

• FL: 41.3% (19 of 46 patients).
• MCL: 11.9% (5 of 42 patients).
• DLBCL: 4.9% (2 of 41 patients).
• CLL/SLL: 11.4% (4 of 35 patients).

The safety analysis, which included all 167 patients enrolled, was consistent with that of previous studies of voxtalisib, the investigators said. The most frequently reported adverse events of any grade or type were diarrhea in 35% of patients, fatigue in 32%, nausea in 27%, pyrexia in 26%, cough 24%, and decreased appetite in 21%.

Grade 3 or greater adverse events include anemia in 12%, and pneumonia and thrombocytopenia in 8% each. Slightly more than half of all patients (58.1%) had a serious adverse event.

The investigators noted that voxtalisib’s short plasma half-life may explain the drug’s lack of efficacy against the aggressive lymphomas and CLL/SLL. Longer-acting formulations of the drug or more frequent dosing might address this problem, although the latter solution could be challenging for patients to follow, the investigators acknowledged.

In light of the results, no further studies of voxtalisib in CLL are planned, thought investigation of the drug alone or in combination with chemoimmunotherapy is warranted for patients with follicular lymphoma, the investigators wrote.

The study was funded by Sanofi. Dr. Brown reported consulting for Janssen, Gilead, Celgene, Sun BioPharma, Novartis, AbbVie, Pfizer, AstraZeneca, Astellas, RedX, Pharmacyclics, Genentech/Roche, Verastem, and TG Therapeutics, and grants from Gilead and Sun BioPharma.

SOURCE: Brown J et al. Lancet Haematol. 2018 Mar 14. doi: 10.1016/S2352-3026(18)30030-9.
 

Voxtalisib, an investigational agent that targets both mTOR and multiple isoforms of PI3K, showed “promising” efficacy with acceptable safety in patients with relapsed or refractory follicular lymphoma (FL), results of a phase 2 trial indicate.

Among 46 patients with FL, the overall response rate was 41.3%, including five (10.9%) complete responses. The median progression-free survival in this group was 58 weeks, reported Jennifer R. Brown, MD, PhD, of the Dana-Farber Cancer Institute in Boston, and her colleagues.

“The observed activity of voxtalisib in relapsed or refractory follicular lymphoma, notable for inducing complete responses in 10.9% of patients, warrants further study,” the investigators wrote in a study published in the Lancet Haematology.

Efficacy of the drug was limited, however, against aggressive malignancies, including mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), or chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).

Voxtalisib (XL765) is a potent inhibitor of all four class I PI3Ks, as well as a less robust inhibitor of the mammalian target of rapamycin (mTOR). In contrast, idelalisib (Zydelig) – which is approved by the Food and Drug Administration for treatment of relapsed/refractory FL or for CLL, in combination with rituximab – inhibits only the delta isoform of PI3K, and does not have marked anti–mTOR properties.

The investigators conducted an open-label, nonrandomized trial of voxtalisib in 30 centers in the United States, Belgium, France, Germany, the Netherlands, and Australia.

Adults 18 years or older with relapsed or refractory MCL, FL, DLBCL or CLL/SLL with Eastern Cooperative Oncology Group performance status of 2 or less were enrolled. All patients received voxtalisib 50 mg orally twice daily in 28-day continuous dosing cycles until progression or unacceptable toxicity.

All patients who received more the 4 weeks of treatment and had both a baseline and one or more on-treatment tumor assessments were included in the efficacy analysis. Patients with lymphoma had received a median of three prior lines of therapy, and those with CLL had received a median of four prior lines.

The overall response rate in the entire study population was 18.3% (30 patients), including 22 partial and 8 complete responses. ORR rates were as follows:

• FL: 41.3% (19 of 46 patients).
• MCL: 11.9% (5 of 42 patients).
• DLBCL: 4.9% (2 of 41 patients).
• CLL/SLL: 11.4% (4 of 35 patients).

The safety analysis, which included all 167 patients enrolled, was consistent with that of previous studies of voxtalisib, the investigators said. The most frequently reported adverse events of any grade or type were diarrhea in 35% of patients, fatigue in 32%, nausea in 27%, pyrexia in 26%, cough 24%, and decreased appetite in 21%.

Grade 3 or greater adverse events include anemia in 12%, and pneumonia and thrombocytopenia in 8% each. Slightly more than half of all patients (58.1%) had a serious adverse event.

The investigators noted that voxtalisib’s short plasma half-life may explain the drug’s lack of efficacy against the aggressive lymphomas and CLL/SLL. Longer-acting formulations of the drug or more frequent dosing might address this problem, although the latter solution could be challenging for patients to follow, the investigators acknowledged.

In light of the results, no further studies of voxtalisib in CLL are planned, thought investigation of the drug alone or in combination with chemoimmunotherapy is warranted for patients with follicular lymphoma, the investigators wrote.

The study was funded by Sanofi. Dr. Brown reported consulting for Janssen, Gilead, Celgene, Sun BioPharma, Novartis, AbbVie, Pfizer, AstraZeneca, Astellas, RedX, Pharmacyclics, Genentech/Roche, Verastem, and TG Therapeutics, and grants from Gilead and Sun BioPharma.

SOURCE: Brown J et al. Lancet Haematol. 2018 Mar 14. doi: 10.1016/S2352-3026(18)30030-9.
 

Voxtalisib, an investigational agent that targets both mTOR and multiple isoforms of PI3K, showed “promising” efficacy with acceptable safety in patients with relapsed or refractory follicular lymphoma (FL), results of a phase 2 trial indicate.

Among 46 patients with FL, the overall response rate was 41.3%, including five (10.9%) complete responses. The median progression-free survival in this group was 58 weeks, reported Jennifer R. Brown, MD, PhD, of the Dana-Farber Cancer Institute in Boston, and her colleagues.

“The observed activity of voxtalisib in relapsed or refractory follicular lymphoma, notable for inducing complete responses in 10.9% of patients, warrants further study,” the investigators wrote in a study published in the Lancet Haematology.

Efficacy of the drug was limited, however, against aggressive malignancies, including mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), or chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).

Voxtalisib (XL765) is a potent inhibitor of all four class I PI3Ks, as well as a less robust inhibitor of the mammalian target of rapamycin (mTOR). In contrast, idelalisib (Zydelig) – which is approved by the Food and Drug Administration for treatment of relapsed/refractory FL or for CLL, in combination with rituximab – inhibits only the delta isoform of PI3K, and does not have marked anti–mTOR properties.

The investigators conducted an open-label, nonrandomized trial of voxtalisib in 30 centers in the United States, Belgium, France, Germany, the Netherlands, and Australia.

Adults 18 years or older with relapsed or refractory MCL, FL, DLBCL or CLL/SLL with Eastern Cooperative Oncology Group performance status of 2 or less were enrolled. All patients received voxtalisib 50 mg orally twice daily in 28-day continuous dosing cycles until progression or unacceptable toxicity.

All patients who received more the 4 weeks of treatment and had both a baseline and one or more on-treatment tumor assessments were included in the efficacy analysis. Patients with lymphoma had received a median of three prior lines of therapy, and those with CLL had received a median of four prior lines.

The overall response rate in the entire study population was 18.3% (30 patients), including 22 partial and 8 complete responses. ORR rates were as follows:

• FL: 41.3% (19 of 46 patients).
• MCL: 11.9% (5 of 42 patients).
• DLBCL: 4.9% (2 of 41 patients).
• CLL/SLL: 11.4% (4 of 35 patients).

The safety analysis, which included all 167 patients enrolled, was consistent with that of previous studies of voxtalisib, the investigators said. The most frequently reported adverse events of any grade or type were diarrhea in 35% of patients, fatigue in 32%, nausea in 27%, pyrexia in 26%, cough 24%, and decreased appetite in 21%.

Grade 3 or greater adverse events include anemia in 12%, and pneumonia and thrombocytopenia in 8% each. Slightly more than half of all patients (58.1%) had a serious adverse event.

The investigators noted that voxtalisib’s short plasma half-life may explain the drug’s lack of efficacy against the aggressive lymphomas and CLL/SLL. Longer-acting formulations of the drug or more frequent dosing might address this problem, although the latter solution could be challenging for patients to follow, the investigators acknowledged.

In light of the results, no further studies of voxtalisib in CLL are planned, thought investigation of the drug alone or in combination with chemoimmunotherapy is warranted for patients with follicular lymphoma, the investigators wrote.

The study was funded by Sanofi. Dr. Brown reported consulting for Janssen, Gilead, Celgene, Sun BioPharma, Novartis, AbbVie, Pfizer, AstraZeneca, Astellas, RedX, Pharmacyclics, Genentech/Roche, Verastem, and TG Therapeutics, and grants from Gilead and Sun BioPharma.

SOURCE: Brown J et al. Lancet Haematol. 2018 Mar 14. doi: 10.1016/S2352-3026(18)30030-9.