Combination offers ‘important new option’ for CLL, team says

Attendees meet in Orlando

Photo courtesy of ASH

ORLANDO, FL—Idelalisib, the first-in-class PI3Kδ inhibitor, combined with bendamustine and rituximab (BR) for relapsed/refractory chronic

lymphocytic leukemia (CLL) offers “an important new option over the standard of care,” according to Andrew Zelenetz, MD, a member of the

international research team that conducted the phase 3 study of this combination.

Patients who received idelalisib plus BR experienced a much longer progression-free survival (PFS) than those who received BR alone, 23.1

months versus 11.1 months, respectively.

“And the benefit was seen across risk groups,” Dr Zelenetz said.

He pointed out that the trial was stopped early in October because of the “overwhelming benefit” of idelalisib compared to the conventional therapy arm.

Dr Zelenetz, of Memorial Sloan Kettering Cancer Center in New York, New York, presented the findings at the 2015 ASH Annual Meeting as LBA-5.

Idelalisib had already been approved by the US Food and Drug Administration for the treatment of relapsed/refractory CLL.

“Many people refer to this [idelalisib] as a B-cell receptor drug,” Dr Zelenetz said, “but it is more than that. It is involved in signaling of very key pathways in cell survival and migration.”

The investigators hoped that by combining idelalisib with BR, they would be able to improve PFS and maintain tolerable toxicity. So they conducted Study 115 to find out.

Study 115 design and population

Study 115 was a double-blind, placebo-controlled phase 3 study.

The idelalisib arm consisted of 207 patients randomized to receive bendamustine at 70 mg/m² on days 1 and 2 every 4 weeks for 6 cycles, rituximab at 375 mg/m² during cycle 1 and 500 mg/m² cycles 2 through 6, and idelalisib at 150 mg twice daily until progression.

The BR arm consisted of 209 patients randomized to the same BR regimen plus placebo twice daily until progression.

Investigators stratified patients according to 17p deletion and/or TP52 mutation, IGHV mutation status, and refractory versus relapsed disease.

The primary endpoint was PFS and the secondary endpoints were overall response rate (ORR), nodal response, overall survival (OS), and complete response (CR) rate.

Patients had to have disease progression within less than 36 months from their last therapy, measurable disease, and no history of CLL transformation. They could not have progressed in less than 6 months from their last bendamustine treatment and they could not have had any prior inhibitors of BTK, PI3Kδ, or SYK.

Patient disposition and demographics

One hundred fifteen patients (56%) in the idelalisib arm are still on study, and 52% are on treatment. In the BR arm, 63 patients (30%) are still on study, and 29% are on treatment.

Patient characteristics were well balanced between the arms. Most patients (76%) were male, 58% were younger than 65 years and 42% were 65 or older. About half were Rai stage III/IV and the median number of prior regimens was 2 (range, 1–13).

The most common prior regimens in both arms were fludarabine/cyclophosphamide/rituximab, fludarabine/cyclophosphamide, and chlorambucil. Fifteen percent of patients in the idelalisib arm and 8% in the BR arm had prior BR.

A third of patients in each arm had either 17p deletion or TP53 mutation, and two-thirds had neither. Most patients did not have IGHV mutation—84% in the idelalisib group and 83% in the BR group.

Thirty-one percent of the idelalisib-treated patients and 29% of the placebo patients had refractory disease, and 69% and 71%, respectively, had relapsed disease.

Efficacy

Median PFS, as assessed by independent review committee, “was highly statistically significant,” Dr Zelenetz said,  at 23.1 months for idelalisib and 11.1 for BR (P<0.0001).

In addition, all subgroups analyzed favored idelalisib—refractory or relapsed disease, mutation status, cytogenetics, gender, age, and race.

Patients with neither deletion 17p nor TP53 had a hazard ratio of 0.22 favoring the idelalisib group, and patients with either one or the other of those mutations had a hazard ratio of 0.50 favoring idelalisib.

ORR was 68% and 45% for idelalisib and placebo, respectively, with 5% in the idelalisib arm and none in the placebo arm achieving a CR.

Dr Zelenetz pointed out that the CR rate was low largely due to missing confirmatory biopsies.

Ninety-six percent of patients in the idelalisib arm experienced 50% or more reduction in lymph nodes, compared with 61% in the placebo arm.

Patients in the idelalisib arm also experienced a significant improvement in OS of P=0.008 when stratified and P=0.023 when unstratified. Median OS has not been reached in either arm.

There was no difference in survival benefit in patients with refractory disease.

Safety

All patients in the idelalisib arm and 97% in the BR arm experienced an adverse event (AE), with 93% and 76% grade 3 or higher in the idelalisib and BR arms, respectively.

Serious AEs occurred in 66% of idelalisib-treated patients and 44% of placebo patients.

Fifty-four patients (26%) in the idelalisib arm discontinued the study drug due to AEs, and 22 (11%) required a study drug dose reduction. This was compared with 28 patients (13%) discontinuing and 13 patients requiring dose reductions in the placebo arm.

The most frequent AE occurring in more than 10% of patients was neutropenia. Grade 3 or higher neutropenia occurred in 60% of idelalisib patients and 46% of placebo patients.

Most AEs were higher in the idelalisib arm compared with the BR arm, including grade 3 or higher events, such as febrile neutropenia (20%, 6%), anemia (15%, 12%), thrombocytopenia (13%, 12%), pneumonia (11%, 6%), ALT increase (11%, <1%), pyrexia (7%, 3%), diarrhea (7%, 2%), and rash (3%, 0), among others.

Serious AEs occurring in more than 2% of patients were also higher in the idelalisib arm than the BR arm, and included febrile neutropenia (18%, 5%), pneumonia (14%, 6%), pyrexia (12%, 6%), neutropenia (4%, 1%), sepsis (4%, 1%), anemia (2%, 2%), lower respiratory tract infection (2%, 2%), diarrhea (4%, <1%), and neutropenic sepsis (1%, 3%).

The remainder of the serious AEs—urinary tract infection, bronchitis, septic shock, and squamous cell carcinoma—occurred in 2% or fewer patients in either arm.

Dr Zelenetz pointed out that the safety profile is consistent with previously reported studies.

Gilead Sciences developed idelalisib and funded Study 115.

*Data in the abstract differ slightly from data presented at the meeting.

Attendees meet in Orlando

Photo courtesy of ASH

ORLANDO, FL—Idelalisib, the first-in-class PI3Kδ inhibitor, combined with bendamustine and rituximab (BR) for relapsed/refractory chronic

lymphocytic leukemia (CLL) offers “an important new option over the standard of care,” according to Andrew Zelenetz, MD, a member of the

international research team that conducted the phase 3 study of this combination.

Patients who received idelalisib plus BR experienced a much longer progression-free survival (PFS) than those who received BR alone, 23.1

months versus 11.1 months, respectively.

“And the benefit was seen across risk groups,” Dr Zelenetz said.

He pointed out that the trial was stopped early in October because of the “overwhelming benefit” of idelalisib compared to the conventional therapy arm.

Dr Zelenetz, of Memorial Sloan Kettering Cancer Center in New York, New York, presented the findings at the 2015 ASH Annual Meeting as LBA-5.

Idelalisib had already been approved by the US Food and Drug Administration for the treatment of relapsed/refractory CLL.

“Many people refer to this [idelalisib] as a B-cell receptor drug,” Dr Zelenetz said, “but it is more than that. It is involved in signaling of very key pathways in cell survival and migration.”

The investigators hoped that by combining idelalisib with BR, they would be able to improve PFS and maintain tolerable toxicity. So they conducted Study 115 to find out.

Study 115 design and population

Study 115 was a double-blind, placebo-controlled phase 3 study.

The idelalisib arm consisted of 207 patients randomized to receive bendamustine at 70 mg/m² on days 1 and 2 every 4 weeks for 6 cycles, rituximab at 375 mg/m² during cycle 1 and 500 mg/m² cycles 2 through 6, and idelalisib at 150 mg twice daily until progression.

The BR arm consisted of 209 patients randomized to the same BR regimen plus placebo twice daily until progression.

Investigators stratified patients according to 17p deletion and/or TP52 mutation, IGHV mutation status, and refractory versus relapsed disease.

The primary endpoint was PFS and the secondary endpoints were overall response rate (ORR), nodal response, overall survival (OS), and complete response (CR) rate.

Patients had to have disease progression within less than 36 months from their last therapy, measurable disease, and no history of CLL transformation. They could not have progressed in less than 6 months from their last bendamustine treatment and they could not have had any prior inhibitors of BTK, PI3Kδ, or SYK.

Patient disposition and demographics

One hundred fifteen patients (56%) in the idelalisib arm are still on study, and 52% are on treatment. In the BR arm, 63 patients (30%) are still on study, and 29% are on treatment.

Patient characteristics were well balanced between the arms. Most patients (76%) were male, 58% were younger than 65 years and 42% were 65 or older. About half were Rai stage III/IV and the median number of prior regimens was 2 (range, 1–13).

The most common prior regimens in both arms were fludarabine/cyclophosphamide/rituximab, fludarabine/cyclophosphamide, and chlorambucil. Fifteen percent of patients in the idelalisib arm and 8% in the BR arm had prior BR.

A third of patients in each arm had either 17p deletion or TP53 mutation, and two-thirds had neither. Most patients did not have IGHV mutation—84% in the idelalisib group and 83% in the BR group.

Thirty-one percent of the idelalisib-treated patients and 29% of the placebo patients had refractory disease, and 69% and 71%, respectively, had relapsed disease.

Efficacy

Median PFS, as assessed by independent review committee, “was highly statistically significant,” Dr Zelenetz said,  at 23.1 months for idelalisib and 11.1 for BR (P<0.0001).

In addition, all subgroups analyzed favored idelalisib—refractory or relapsed disease, mutation status, cytogenetics, gender, age, and race.

Patients with neither deletion 17p nor TP53 had a hazard ratio of 0.22 favoring the idelalisib group, and patients with either one or the other of those mutations had a hazard ratio of 0.50 favoring idelalisib.

ORR was 68% and 45% for idelalisib and placebo, respectively, with 5% in the idelalisib arm and none in the placebo arm achieving a CR.

Dr Zelenetz pointed out that the CR rate was low largely due to missing confirmatory biopsies.

Ninety-six percent of patients in the idelalisib arm experienced 50% or more reduction in lymph nodes, compared with 61% in the placebo arm.

Patients in the idelalisib arm also experienced a significant improvement in OS of P=0.008 when stratified and P=0.023 when unstratified. Median OS has not been reached in either arm.

There was no difference in survival benefit in patients with refractory disease.

Safety

All patients in the idelalisib arm and 97% in the BR arm experienced an adverse event (AE), with 93% and 76% grade 3 or higher in the idelalisib and BR arms, respectively.

Serious AEs occurred in 66% of idelalisib-treated patients and 44% of placebo patients.

Fifty-four patients (26%) in the idelalisib arm discontinued the study drug due to AEs, and 22 (11%) required a study drug dose reduction. This was compared with 28 patients (13%) discontinuing and 13 patients requiring dose reductions in the placebo arm.

The most frequent AE occurring in more than 10% of patients was neutropenia. Grade 3 or higher neutropenia occurred in 60% of idelalisib patients and 46% of placebo patients.

Most AEs were higher in the idelalisib arm compared with the BR arm, including grade 3 or higher events, such as febrile neutropenia (20%, 6%), anemia (15%, 12%), thrombocytopenia (13%, 12%), pneumonia (11%, 6%), ALT increase (11%, <1%), pyrexia (7%, 3%), diarrhea (7%, 2%), and rash (3%, 0), among others.

Serious AEs occurring in more than 2% of patients were also higher in the idelalisib arm than the BR arm, and included febrile neutropenia (18%, 5%), pneumonia (14%, 6%), pyrexia (12%, 6%), neutropenia (4%, 1%), sepsis (4%, 1%), anemia (2%, 2%), lower respiratory tract infection (2%, 2%), diarrhea (4%, <1%), and neutropenic sepsis (1%, 3%).

The remainder of the serious AEs—urinary tract infection, bronchitis, septic shock, and squamous cell carcinoma—occurred in 2% or fewer patients in either arm.

Dr Zelenetz pointed out that the safety profile is consistent with previously reported studies.

Gilead Sciences developed idelalisib and funded Study 115.

*Data in the abstract differ slightly from data presented at the meeting.

Attendees meet in Orlando

Photo courtesy of ASH

ORLANDO, FL—Idelalisib, the first-in-class PI3Kδ inhibitor, combined with bendamustine and rituximab (BR) for relapsed/refractory chronic

lymphocytic leukemia (CLL) offers “an important new option over the standard of care,” according to Andrew Zelenetz, MD, a member of the

international research team that conducted the phase 3 study of this combination.

Patients who received idelalisib plus BR experienced a much longer progression-free survival (PFS) than those who received BR alone, 23.1

months versus 11.1 months, respectively.

“And the benefit was seen across risk groups,” Dr Zelenetz said.

He pointed out that the trial was stopped early in October because of the “overwhelming benefit” of idelalisib compared to the conventional therapy arm.

Dr Zelenetz, of Memorial Sloan Kettering Cancer Center in New York, New York, presented the findings at the 2015 ASH Annual Meeting as LBA-5.

Idelalisib had already been approved by the US Food and Drug Administration for the treatment of relapsed/refractory CLL.

“Many people refer to this [idelalisib] as a B-cell receptor drug,” Dr Zelenetz said, “but it is more than that. It is involved in signaling of very key pathways in cell survival and migration.”

The investigators hoped that by combining idelalisib with BR, they would be able to improve PFS and maintain tolerable toxicity. So they conducted Study 115 to find out.

Study 115 design and population

Study 115 was a double-blind, placebo-controlled phase 3 study.

The idelalisib arm consisted of 207 patients randomized to receive bendamustine at 70 mg/m² on days 1 and 2 every 4 weeks for 6 cycles, rituximab at 375 mg/m² during cycle 1 and 500 mg/m² cycles 2 through 6, and idelalisib at 150 mg twice daily until progression.

The BR arm consisted of 209 patients randomized to the same BR regimen plus placebo twice daily until progression.

Investigators stratified patients according to 17p deletion and/or TP52 mutation, IGHV mutation status, and refractory versus relapsed disease.

The primary endpoint was PFS and the secondary endpoints were overall response rate (ORR), nodal response, overall survival (OS), and complete response (CR) rate.

Patients had to have disease progression within less than 36 months from their last therapy, measurable disease, and no history of CLL transformation. They could not have progressed in less than 6 months from their last bendamustine treatment and they could not have had any prior inhibitors of BTK, PI3Kδ, or SYK.

Patient disposition and demographics

One hundred fifteen patients (56%) in the idelalisib arm are still on study, and 52% are on treatment. In the BR arm, 63 patients (30%) are still on study, and 29% are on treatment.

Patient characteristics were well balanced between the arms. Most patients (76%) were male, 58% were younger than 65 years and 42% were 65 or older. About half were Rai stage III/IV and the median number of prior regimens was 2 (range, 1–13).

The most common prior regimens in both arms were fludarabine/cyclophosphamide/rituximab, fludarabine/cyclophosphamide, and chlorambucil. Fifteen percent of patients in the idelalisib arm and 8% in the BR arm had prior BR.

A third of patients in each arm had either 17p deletion or TP53 mutation, and two-thirds had neither. Most patients did not have IGHV mutation—84% in the idelalisib group and 83% in the BR group.

Thirty-one percent of the idelalisib-treated patients and 29% of the placebo patients had refractory disease, and 69% and 71%, respectively, had relapsed disease.

Efficacy

Median PFS, as assessed by independent review committee, “was highly statistically significant,” Dr Zelenetz said,  at 23.1 months for idelalisib and 11.1 for BR (P<0.0001).

In addition, all subgroups analyzed favored idelalisib—refractory or relapsed disease, mutation status, cytogenetics, gender, age, and race.

Patients with neither deletion 17p nor TP53 had a hazard ratio of 0.22 favoring the idelalisib group, and patients with either one or the other of those mutations had a hazard ratio of 0.50 favoring idelalisib.

ORR was 68% and 45% for idelalisib and placebo, respectively, with 5% in the idelalisib arm and none in the placebo arm achieving a CR.

Dr Zelenetz pointed out that the CR rate was low largely due to missing confirmatory biopsies.

Ninety-six percent of patients in the idelalisib arm experienced 50% or more reduction in lymph nodes, compared with 61% in the placebo arm.

Patients in the idelalisib arm also experienced a significant improvement in OS of P=0.008 when stratified and P=0.023 when unstratified. Median OS has not been reached in either arm.

There was no difference in survival benefit in patients with refractory disease.

Safety

All patients in the idelalisib arm and 97% in the BR arm experienced an adverse event (AE), with 93% and 76% grade 3 or higher in the idelalisib and BR arms, respectively.

Serious AEs occurred in 66% of idelalisib-treated patients and 44% of placebo patients.

Fifty-four patients (26%) in the idelalisib arm discontinued the study drug due to AEs, and 22 (11%) required a study drug dose reduction. This was compared with 28 patients (13%) discontinuing and 13 patients requiring dose reductions in the placebo arm.

The most frequent AE occurring in more than 10% of patients was neutropenia. Grade 3 or higher neutropenia occurred in 60% of idelalisib patients and 46% of placebo patients.

Most AEs were higher in the idelalisib arm compared with the BR arm, including grade 3 or higher events, such as febrile neutropenia (20%, 6%), anemia (15%, 12%), thrombocytopenia (13%, 12%), pneumonia (11%, 6%), ALT increase (11%, <1%), pyrexia (7%, 3%), diarrhea (7%, 2%), and rash (3%, 0), among others.

Serious AEs occurring in more than 2% of patients were also higher in the idelalisib arm than the BR arm, and included febrile neutropenia (18%, 5%), pneumonia (14%, 6%), pyrexia (12%, 6%), neutropenia (4%, 1%), sepsis (4%, 1%), anemia (2%, 2%), lower respiratory tract infection (2%, 2%), diarrhea (4%, <1%), and neutropenic sepsis (1%, 3%).

The remainder of the serious AEs—urinary tract infection, bronchitis, septic shock, and squamous cell carcinoma—occurred in 2% or fewer patients in either arm.

Dr Zelenetz pointed out that the safety profile is consistent with previously reported studies.

Gilead Sciences developed idelalisib and funded Study 115.

*Data in the abstract differ slightly from data presented at the meeting.