2015 ASCO Annual Meeting

CHICAGO – Combining ibrutinib with standard chemoimmunotherapy extended progression-free survival in patients with relapsed chronic lymphocytic leukemia (CLL), according to interim results from the HELIOS trial.

In fact, while median progression-free survival was approximately 13 months in the placebo arm, the median progression-free survival had not been reached yet in the study’s ibrutinib arm, explained lead study author Dr. Asher Chanan-Khan.

“I believe that ibrutinib has now become the backbone of treatment of patients with relapsed CLL,” said Dr. Chanan-Khan, professor of medicine at the Mayo Clinic in Jacksonville, Fla.

In a video interview at the annual meeting of the American Society of Clinical Oncology, Dr. Chanan-Khan discussed ibrutinib’s significant impact on the risk of progression and death, even in the presence of factors associated with aggressive disease or poor outcome.

[email protected]

CHICAGO – Combining ibrutinib with standard chemoimmunotherapy extended progression-free survival in patients with relapsed chronic lymphocytic leukemia (CLL), according to interim results from the HELIOS trial.

In fact, while median progression-free survival was approximately 13 months in the placebo arm, the median progression-free survival had not been reached yet in the study’s ibrutinib arm, explained lead study author Dr. Asher Chanan-Khan.

“I believe that ibrutinib has now become the backbone of treatment of patients with relapsed CLL,” said Dr. Chanan-Khan, professor of medicine at the Mayo Clinic in Jacksonville, Fla.

In a video interview at the annual meeting of the American Society of Clinical Oncology, Dr. Chanan-Khan discussed ibrutinib’s significant impact on the risk of progression and death, even in the presence of factors associated with aggressive disease or poor outcome.

[email protected]

CHICAGO – Combining ibrutinib with standard chemoimmunotherapy extended progression-free survival in patients with relapsed chronic lymphocytic leukemia (CLL), according to interim results from the HELIOS trial.

In fact, while median progression-free survival was approximately 13 months in the placebo arm, the median progression-free survival had not been reached yet in the study’s ibrutinib arm, explained lead study author Dr. Asher Chanan-Khan.

“I believe that ibrutinib has now become the backbone of treatment of patients with relapsed CLL,” said Dr. Chanan-Khan, professor of medicine at the Mayo Clinic in Jacksonville, Fla.

In a video interview at the annual meeting of the American Society of Clinical Oncology, Dr. Chanan-Khan discussed ibrutinib’s significant impact on the risk of progression and death, even in the presence of factors associated with aggressive disease or poor outcome.

[email protected]

Crowd at ASCO 2015

©ASCO/Rodney White

CHICAGO—Combination regimens including the histone deacetylase inhibitor panobinostat can produce durable responses and prolong progression-free survival (PFS) in patients with relapsed/refractory multiple myeloma (MM), according to research presented at the 2015 ASCO Annual Meeting.

In a phase 2 trial, panobinostat plus lenalidomide and dexamethasone produced durable responses, even in high-risk, lenalidomide-refractory MM patients.

In a phase 3 trial, panobinostat in combination with bortezomib and dexamethasone led to a 7.8-month improvement in median PFS over placebo-bortezomib-dexamethasone in patients with relapsed or relapsed and refractory MM who had received 2 or more prior regimens.

Both studies were sponsored by Novartis, the company developing panobinostat.

PANORAMA-1 substudy

PANORAMA-1 was a phase 3, randomized, double-blind, placebo-controlled trial of 768 MM patients. Overall, panobinostat in combination with bortezomib and dexamethasone led to a clinically relevant and statistically significant increase in PFS of about 4 months compared to placebo-bortezomib-dexamethasone.

At ASCO, Jesús San Miguel, MD, of Clínica Universidad de Navarra in Pamplona, Spain, presented the results of an exploratory analysis of 147 patients in this trial (abstract 8526*).

The patients had relapsed or relapsed and refractory MM and had received 2 or more prior regimens, including bortezomib and an immunomodulatory agent (IMiD).

Disease and treatment characteristics were as follows:

The median PFS was 12.5 months in the panobinostat arm, compared to 4.7 months in the placebo arm. Treatment with panobinostat also led to an increase in complete/near complete response rates (21.9% vs 8.1%) and overall response rate (58.9% vs 39.2%).

Common grade 3/4 non-hematologic adverse events in the panobinostat arm and placebo arm, respectively, included diarrhea (33.3% vs 15.1%), asthenia/fatigue (26.4% vs 13.7%), and peripheral neuropathy (16.7% vs 6.8%).

The most common grade 3/4 hematologic abnormalities in the panobinostat arm and placebo arm, respectively, were thrombocytopenia (68.1% vs 44.4%), lymphopenia (48.6% vs 49.3%), and neutropenia (40.3% vs 16.4%).

The percentage of on-treatment deaths was similar between the treatment arms (6.9% vs 6.8%).

“These data provide physicians with a better understanding of the clinical use of panobinostat, an HDAC inhibitor, a promising new drug class for this difficult-to-treat patient population with a high unmet need,” Dr San Miguel said.

Phase 2 trial

Ajai Chari, MD, of Mount Sinai Medical Center in New York, presented the results of a phase 2 study of panobinostat with lenalidomide and weekly dexamethasone in patients with relapsed/refractory MM (abstract 8528*).

There were 20 evaluable patients with a median age of 64 (range, 51-75). They had received a median of 3 prior therapies (range, 1-10). Prior regimens were as follows:

For this study, patients received panobinostat (20 mg on days 1, 3, 5, 15, 17, and 19), lenalidomide (25 mg on days 1-21), and dexamethasone (40 mg on days 1, 8, and 15).

The overall response rate was 45%. This included 1 complete response, 3 very good partial responses, 5 partial responses, and 8 minimal responses. Two patients had stable disease, and 1 progressed.

Among lenalidomide-refractory patients (n=16), the overall response rate was 38%. This included 3 very good partial responses, 3 partial responses, and 7 minimal responses. Two patients had stable disease, and 1 progressed.

The median PFS was 6.5 months overall and among lenalidomide-refractory patients.

Grade 3/4 toxicities were primarily hematologic, including neutropenia (55%), thrombocytopenia (40%), and anemia (5%). Grade 3/4 non-hematologic adverse events included infections (n=4), diarrhea (n=3), pulmonary emboli (n=2), neck pain (n=1), QTc prolongation (n=1), fatigue (n=1), and weight loss (n=1).

“In relapsed/refractory MM patients, panobinostat in combination with lenalidomide and dexamethasone demonstrated durable responses comparable to other recently approved agents, even in lenalidomide-refractory patients with high-risk molecular findings,” Dr Chari said.

“In notable contrast to PANORAMA-1 results, this completely oral regimen is well-tolerated, with no grade 3/4 [gastrointestinal] toxicities and primarily expected hematologic toxicities.”

*Information in the abstract differs from that presented at the meeting.

Crowd at ASCO 2015

©ASCO/Rodney White

CHICAGO—Combination regimens including the histone deacetylase inhibitor panobinostat can produce durable responses and prolong progression-free survival (PFS) in patients with relapsed/refractory multiple myeloma (MM), according to research presented at the 2015 ASCO Annual Meeting.

In a phase 2 trial, panobinostat plus lenalidomide and dexamethasone produced durable responses, even in high-risk, lenalidomide-refractory MM patients.

In a phase 3 trial, panobinostat in combination with bortezomib and dexamethasone led to a 7.8-month improvement in median PFS over placebo-bortezomib-dexamethasone in patients with relapsed or relapsed and refractory MM who had received 2 or more prior regimens.

Both studies were sponsored by Novartis, the company developing panobinostat.

PANORAMA-1 substudy

PANORAMA-1 was a phase 3, randomized, double-blind, placebo-controlled trial of 768 MM patients. Overall, panobinostat in combination with bortezomib and dexamethasone led to a clinically relevant and statistically significant increase in PFS of about 4 months compared to placebo-bortezomib-dexamethasone.

At ASCO, Jesús San Miguel, MD, of Clínica Universidad de Navarra in Pamplona, Spain, presented the results of an exploratory analysis of 147 patients in this trial (abstract 8526*).

The patients had relapsed or relapsed and refractory MM and had received 2 or more prior regimens, including bortezomib and an immunomodulatory agent (IMiD).

Disease and treatment characteristics were as follows:

The median PFS was 12.5 months in the panobinostat arm, compared to 4.7 months in the placebo arm. Treatment with panobinostat also led to an increase in complete/near complete response rates (21.9% vs 8.1%) and overall response rate (58.9% vs 39.2%).

Common grade 3/4 non-hematologic adverse events in the panobinostat arm and placebo arm, respectively, included diarrhea (33.3% vs 15.1%), asthenia/fatigue (26.4% vs 13.7%), and peripheral neuropathy (16.7% vs 6.8%).

The most common grade 3/4 hematologic abnormalities in the panobinostat arm and placebo arm, respectively, were thrombocytopenia (68.1% vs 44.4%), lymphopenia (48.6% vs 49.3%), and neutropenia (40.3% vs 16.4%).

The percentage of on-treatment deaths was similar between the treatment arms (6.9% vs 6.8%).

“These data provide physicians with a better understanding of the clinical use of panobinostat, an HDAC inhibitor, a promising new drug class for this difficult-to-treat patient population with a high unmet need,” Dr San Miguel said.

Phase 2 trial

Ajai Chari, MD, of Mount Sinai Medical Center in New York, presented the results of a phase 2 study of panobinostat with lenalidomide and weekly dexamethasone in patients with relapsed/refractory MM (abstract 8528*).

There were 20 evaluable patients with a median age of 64 (range, 51-75). They had received a median of 3 prior therapies (range, 1-10). Prior regimens were as follows:

For this study, patients received panobinostat (20 mg on days 1, 3, 5, 15, 17, and 19), lenalidomide (25 mg on days 1-21), and dexamethasone (40 mg on days 1, 8, and 15).

The overall response rate was 45%. This included 1 complete response, 3 very good partial responses, 5 partial responses, and 8 minimal responses. Two patients had stable disease, and 1 progressed.

Among lenalidomide-refractory patients (n=16), the overall response rate was 38%. This included 3 very good partial responses, 3 partial responses, and 7 minimal responses. Two patients had stable disease, and 1 progressed.

The median PFS was 6.5 months overall and among lenalidomide-refractory patients.

Grade 3/4 toxicities were primarily hematologic, including neutropenia (55%), thrombocytopenia (40%), and anemia (5%). Grade 3/4 non-hematologic adverse events included infections (n=4), diarrhea (n=3), pulmonary emboli (n=2), neck pain (n=1), QTc prolongation (n=1), fatigue (n=1), and weight loss (n=1).

“In relapsed/refractory MM patients, panobinostat in combination with lenalidomide and dexamethasone demonstrated durable responses comparable to other recently approved agents, even in lenalidomide-refractory patients with high-risk molecular findings,” Dr Chari said.

“In notable contrast to PANORAMA-1 results, this completely oral regimen is well-tolerated, with no grade 3/4 [gastrointestinal] toxicities and primarily expected hematologic toxicities.”

*Information in the abstract differs from that presented at the meeting.

Crowd at ASCO 2015

©ASCO/Rodney White

CHICAGO—Combination regimens including the histone deacetylase inhibitor panobinostat can produce durable responses and prolong progression-free survival (PFS) in patients with relapsed/refractory multiple myeloma (MM), according to research presented at the 2015 ASCO Annual Meeting.

In a phase 2 trial, panobinostat plus lenalidomide and dexamethasone produced durable responses, even in high-risk, lenalidomide-refractory MM patients.

In a phase 3 trial, panobinostat in combination with bortezomib and dexamethasone led to a 7.8-month improvement in median PFS over placebo-bortezomib-dexamethasone in patients with relapsed or relapsed and refractory MM who had received 2 or more prior regimens.

Both studies were sponsored by Novartis, the company developing panobinostat.

PANORAMA-1 substudy

PANORAMA-1 was a phase 3, randomized, double-blind, placebo-controlled trial of 768 MM patients. Overall, panobinostat in combination with bortezomib and dexamethasone led to a clinically relevant and statistically significant increase in PFS of about 4 months compared to placebo-bortezomib-dexamethasone.

At ASCO, Jesús San Miguel, MD, of Clínica Universidad de Navarra in Pamplona, Spain, presented the results of an exploratory analysis of 147 patients in this trial (abstract 8526*).

The patients had relapsed or relapsed and refractory MM and had received 2 or more prior regimens, including bortezomib and an immunomodulatory agent (IMiD).

Disease and treatment characteristics were as follows:

The median PFS was 12.5 months in the panobinostat arm, compared to 4.7 months in the placebo arm. Treatment with panobinostat also led to an increase in complete/near complete response rates (21.9% vs 8.1%) and overall response rate (58.9% vs 39.2%).

Common grade 3/4 non-hematologic adverse events in the panobinostat arm and placebo arm, respectively, included diarrhea (33.3% vs 15.1%), asthenia/fatigue (26.4% vs 13.7%), and peripheral neuropathy (16.7% vs 6.8%).

The most common grade 3/4 hematologic abnormalities in the panobinostat arm and placebo arm, respectively, were thrombocytopenia (68.1% vs 44.4%), lymphopenia (48.6% vs 49.3%), and neutropenia (40.3% vs 16.4%).

The percentage of on-treatment deaths was similar between the treatment arms (6.9% vs 6.8%).

“These data provide physicians with a better understanding of the clinical use of panobinostat, an HDAC inhibitor, a promising new drug class for this difficult-to-treat patient population with a high unmet need,” Dr San Miguel said.

Phase 2 trial

Ajai Chari, MD, of Mount Sinai Medical Center in New York, presented the results of a phase 2 study of panobinostat with lenalidomide and weekly dexamethasone in patients with relapsed/refractory MM (abstract 8528*).

There were 20 evaluable patients with a median age of 64 (range, 51-75). They had received a median of 3 prior therapies (range, 1-10). Prior regimens were as follows:

For this study, patients received panobinostat (20 mg on days 1, 3, 5, 15, 17, and 19), lenalidomide (25 mg on days 1-21), and dexamethasone (40 mg on days 1, 8, and 15).

The overall response rate was 45%. This included 1 complete response, 3 very good partial responses, 5 partial responses, and 8 minimal responses. Two patients had stable disease, and 1 progressed.

Among lenalidomide-refractory patients (n=16), the overall response rate was 38%. This included 3 very good partial responses, 3 partial responses, and 7 minimal responses. Two patients had stable disease, and 1 progressed.

The median PFS was 6.5 months overall and among lenalidomide-refractory patients.

Grade 3/4 toxicities were primarily hematologic, including neutropenia (55%), thrombocytopenia (40%), and anemia (5%). Grade 3/4 non-hematologic adverse events included infections (n=4), diarrhea (n=3), pulmonary emboli (n=2), neck pain (n=1), QTc prolongation (n=1), fatigue (n=1), and weight loss (n=1).

“In relapsed/refractory MM patients, panobinostat in combination with lenalidomide and dexamethasone demonstrated durable responses comparable to other recently approved agents, even in lenalidomide-refractory patients with high-risk molecular findings,” Dr Chari said.

“In notable contrast to PANORAMA-1 results, this completely oral regimen is well-tolerated, with no grade 3/4 [gastrointestinal] toxicities and primarily expected hematologic toxicities.”

*Information in the abstract differs from that presented at the meeting.

 

 

Attendees at ASCO 2015

©ASCO/Rodney White

 

CHICAGO—The CD19-directed chimeric antigen receptor (CAR) T-cell therapy CTL019 has shown promise for treating non-Hodgkin lymphoma (NHL) and may be a feasible treatment option for multiple myeloma (MM) as well, according to researchers.

In an ongoing phase 2 trial, CTL019 has produced durable responses in patients with relapsed or refractory NHL.

And early results of a phase 1 trial suggest CTL019 can provide clinical benefit in heavily pretreated patients with MM.

Both studies were presented at the 2015 ASCO Annual Meeting. The University of Pennsylvania and Novartis have an exclusive global collaboration to research, develop, and commercialize CTL019.

CTL019 in NHL

Stephen Schuster, MD, of the Abramson Cancer Center of the University of Pennsylvania in Philadelphia, presented results of the phase 2 NHL trial (abstract 8516*).

The trial included 20 evaluable patients, 13 with diffuse large B-cell lymphoma (DLBCL) and 7 with follicular lymphoma (FL). At the time of presentation, the median follow-up was 274 days for the patients with DLBCL and 290 days for those with FL.

The overall response rate was 100% in patients with FL and 50% in those with DLBCL. Thirteen patients responded to the therapy, including 11 who achieved a complete response and 2 who experienced a partial response.

Six patients with a partial response to treatment at 3 months achieved a complete response by 6 months. Two patients with a partial response experienced disease progression at 6 and 12 months after treatment.

The researchers said toxicity appeared to be acceptable, with primarily grade 2 cytokine release syndrome (CRS). Two patients developed CRS of grade 3 or higher at peak T-cell expansion. There were no deaths from CRS.

“The results from this ongoing study of CTL019 are encouraging, as we now have data through 6 months showing that patients may have achieved durable overall response rates,” Dr Schuster said. “These data support our ongoing efforts to determine the potential role of CTL019 in improving outcomes for patients with certain types of B-cell lymphomas.”

CTL019 in MM

Alfred Garfall, MD, of the Abramson Cancer Center, presented preliminary results of an ongoing phase 1 study investigating CTL019 in patients with MM (abstract 8517*).

Dr Garfall and his colleagues hypothesized that CTL019 would exhibit efficacy in MM due to low-level CD19 expression on MM plasma cells or CD19 expression in drug-resistant, disease-propagating subsets of the MM clone.

The study included 5 patients who experienced disease progression within a year of a prior autologous stem cell transplant and were medically fit to undergo a second autologous transplant. The patients had received a median of 7.5 prior lines of therapy.

“We found potential evidence of clinical benefit in 3 of 4 patients with more than 100 days of follow-up,” Dr Garfall said.

Two patients experienced longer, deeper responses, and 1 patient experienced CRS.

The data suggest “it is safe and feasible to manufacture and administered CTL019 to refractory multiple myeloma patients,” Dr Garfall said.

*Information in the abstract differs from that presented at the meeting.

 

 

Attendees at ASCO 2015

©ASCO/Rodney White

 

CHICAGO—The CD19-directed chimeric antigen receptor (CAR) T-cell therapy CTL019 has shown promise for treating non-Hodgkin lymphoma (NHL) and may be a feasible treatment option for multiple myeloma (MM) as well, according to researchers.

In an ongoing phase 2 trial, CTL019 has produced durable responses in patients with relapsed or refractory NHL.

And early results of a phase 1 trial suggest CTL019 can provide clinical benefit in heavily pretreated patients with MM.

Both studies were presented at the 2015 ASCO Annual Meeting. The University of Pennsylvania and Novartis have an exclusive global collaboration to research, develop, and commercialize CTL019.

CTL019 in NHL

Stephen Schuster, MD, of the Abramson Cancer Center of the University of Pennsylvania in Philadelphia, presented results of the phase 2 NHL trial (abstract 8516*).

The trial included 20 evaluable patients, 13 with diffuse large B-cell lymphoma (DLBCL) and 7 with follicular lymphoma (FL). At the time of presentation, the median follow-up was 274 days for the patients with DLBCL and 290 days for those with FL.

The overall response rate was 100% in patients with FL and 50% in those with DLBCL. Thirteen patients responded to the therapy, including 11 who achieved a complete response and 2 who experienced a partial response.

Six patients with a partial response to treatment at 3 months achieved a complete response by 6 months. Two patients with a partial response experienced disease progression at 6 and 12 months after treatment.

The researchers said toxicity appeared to be acceptable, with primarily grade 2 cytokine release syndrome (CRS). Two patients developed CRS of grade 3 or higher at peak T-cell expansion. There were no deaths from CRS.

“The results from this ongoing study of CTL019 are encouraging, as we now have data through 6 months showing that patients may have achieved durable overall response rates,” Dr Schuster said. “These data support our ongoing efforts to determine the potential role of CTL019 in improving outcomes for patients with certain types of B-cell lymphomas.”

CTL019 in MM

Alfred Garfall, MD, of the Abramson Cancer Center, presented preliminary results of an ongoing phase 1 study investigating CTL019 in patients with MM (abstract 8517*).

Dr Garfall and his colleagues hypothesized that CTL019 would exhibit efficacy in MM due to low-level CD19 expression on MM plasma cells or CD19 expression in drug-resistant, disease-propagating subsets of the MM clone.

The study included 5 patients who experienced disease progression within a year of a prior autologous stem cell transplant and were medically fit to undergo a second autologous transplant. The patients had received a median of 7.5 prior lines of therapy.

“We found potential evidence of clinical benefit in 3 of 4 patients with more than 100 days of follow-up,” Dr Garfall said.

Two patients experienced longer, deeper responses, and 1 patient experienced CRS.

The data suggest “it is safe and feasible to manufacture and administered CTL019 to refractory multiple myeloma patients,” Dr Garfall said.

*Information in the abstract differs from that presented at the meeting.

 

 

Attendees at ASCO 2015

©ASCO/Rodney White

 

CHICAGO—The CD19-directed chimeric antigen receptor (CAR) T-cell therapy CTL019 has shown promise for treating non-Hodgkin lymphoma (NHL) and may be a feasible treatment option for multiple myeloma (MM) as well, according to researchers.

In an ongoing phase 2 trial, CTL019 has produced durable responses in patients with relapsed or refractory NHL.

And early results of a phase 1 trial suggest CTL019 can provide clinical benefit in heavily pretreated patients with MM.

Both studies were presented at the 2015 ASCO Annual Meeting. The University of Pennsylvania and Novartis have an exclusive global collaboration to research, develop, and commercialize CTL019.

CTL019 in NHL

Stephen Schuster, MD, of the Abramson Cancer Center of the University of Pennsylvania in Philadelphia, presented results of the phase 2 NHL trial (abstract 8516*).

The trial included 20 evaluable patients, 13 with diffuse large B-cell lymphoma (DLBCL) and 7 with follicular lymphoma (FL). At the time of presentation, the median follow-up was 274 days for the patients with DLBCL and 290 days for those with FL.

The overall response rate was 100% in patients with FL and 50% in those with DLBCL. Thirteen patients responded to the therapy, including 11 who achieved a complete response and 2 who experienced a partial response.

Six patients with a partial response to treatment at 3 months achieved a complete response by 6 months. Two patients with a partial response experienced disease progression at 6 and 12 months after treatment.

The researchers said toxicity appeared to be acceptable, with primarily grade 2 cytokine release syndrome (CRS). Two patients developed CRS of grade 3 or higher at peak T-cell expansion. There were no deaths from CRS.

“The results from this ongoing study of CTL019 are encouraging, as we now have data through 6 months showing that patients may have achieved durable overall response rates,” Dr Schuster said. “These data support our ongoing efforts to determine the potential role of CTL019 in improving outcomes for patients with certain types of B-cell lymphomas.”

CTL019 in MM

Alfred Garfall, MD, of the Abramson Cancer Center, presented preliminary results of an ongoing phase 1 study investigating CTL019 in patients with MM (abstract 8517*).

Dr Garfall and his colleagues hypothesized that CTL019 would exhibit efficacy in MM due to low-level CD19 expression on MM plasma cells or CD19 expression in drug-resistant, disease-propagating subsets of the MM clone.

The study included 5 patients who experienced disease progression within a year of a prior autologous stem cell transplant and were medically fit to undergo a second autologous transplant. The patients had received a median of 7.5 prior lines of therapy.

“We found potential evidence of clinical benefit in 3 of 4 patients with more than 100 days of follow-up,” Dr Garfall said.

Two patients experienced longer, deeper responses, and 1 patient experienced CRS.

The data suggest “it is safe and feasible to manufacture and administered CTL019 to refractory multiple myeloma patients,” Dr Garfall said.

*Information in the abstract differs from that presented at the meeting.

CHICAGO – Adjuvant denosumab is efficacious and safe for reducing fracture risk among women taking aromatase inhibitors (AIs) as part of their treatment for early breast cancer, finds the Austrian Breast & Colorectal Cancer Study Group’s study 18 (ABCSG-18).

Compared with peers randomized to placebo in the phase III trial, women randomized to the antiresorptive monoclonal antibody at the dose typically used to treat osteoporosis were half as likely to experience a first clinical fracture, first author Dr. Michael Gnant reported at the annual meeting of the American Society of Clinical Oncology. The benefit was similar whether women had normal bone mineral density at baseline or already had osteopenia.

Courtesy MeduniWien/Matern

Patients in the denosumab group did not have a significantly higher rate of adverse events, including the much-feared complication of osteonecrosis of the jaw.

“The actual fracture risk of postmenopausal breast cancer patients on AIs is substantial and may have been underestimated until today,” commented Dr. Gnant, professor of surgery at the Medical University of Vienna. “In these patients with only a modest risk of disease recurrence, adjuvant denosumab significantly reduced the bone side effects of AI treatment. We therefore believe that denosumab 60 mg every 6 months should be considered for clinical practice.”

“Today, several clinical practice guidelines advocate the use of bisphosphonates for breast cancer patients receiving AIs, however, only if they are at high risk for fractures,” he further noted. However, “patients with normal baseline bone mineral density showed a similar fracture risk but also similar benefit from denosumab as compared to patients with baseline T scores below –1, indicating that DEXA scans may be an insufficient way to assess the individual patient’s fracture risk. In view of the benefits in this particular patient subgroup, we may have to rediscuss our current clinical practice guidelines.”

Invited discussant Dr. Robert E. Coleman of the University of Sheffield and Weston Park Hospital in England, said, “It’s very important to dissect out fractures related to subsequent recurrence from fractures due to poor bone health.” Most of the reduction in fracture risk in ABCSG-18 appeared to be because of prevention of fractures before any recurrence, whereas most of that in the AZURE trial (Adjuvant Zoledronic Acid to Reduce Recurrence) of an adjuvant bisphosphonate, another type of antiresorptive agent, appeared to be because of prevention of fractures from bone metastases. “So I think we are seeing something very different with denosumab to what we’ve seen to date with a bisphosphonate,” he said.

“As oncologists, we are somewhat wedded to measuring bone mineral density as the reason for giving bone-targeted therapy to protect [against] bone loss, but there are much better ways of predicting fracture with online algorithms such as FRAX [Fracture Risk Assessment Tool] and others,” Dr. Coleman further commented. “And bone mineral density is a pretty poor predictor of fracture, so it’s perhaps not surprising that the risk reductions were fairly similar” across bone mineral density subgroups.

During a question and answer period, session attendee Dr. Toru Watanabe, Hamamatsu (Japan) Oncology Center, said, “It is really clear that the osteoporosis-related fracture is prevented by denosumab at the dose usually used for the treatment of osteoporosis. That part is very clear. My question is, the same dose is being tested for modifying overall survival or progression-free survival. Don’t you think it’s necessary to conduct some kind of dose-finding trial?”

Two studies are addressing the impact of denosumab on breast cancer outcomes, according to Dr. Gnant: the investigators’ ABCSG-18 study and the Study of Denosumab as Adjuvant Treatment for Women With High-Risk Early Breast Cancer Receiving Neoadjuvant or Adjuvant Therapy (D-CARE), which is using a higher initial dose and tapering after 1 year. “So we will have that indirect comparison at least. My personal expectation would be that there is a trade-off potentially between efficacy and tolerability,” he commented.

The 3,425 postmenopausal breast cancer patients in ABCSG-18 were randomized evenly to receive 60 mg of denosumab or placebo every 6 months. Denosumab is approved by the Food and Drug Administration for the prevention and treatment of fractures due to bone metastases (brand name Xgeva) and osteoporosis after menopause (brand name Prolia), as well as other indications. The study used the dose for postmenopausal osteoporosis, which is much lower than that typically used for bone metastases (120 mg every 4 weeks), Dr. Gnant noted.

Main results showed that denosumab was highly efficacious in reducing the risk of first clinical fractures, meaning those that were clinically evident and causing symptoms (hazard ratio, 0.50; P less than .0001), according to data presented at the meeting and simultaneously published (Lancet 2015 May 31).

The estimated 6-year fracture rate was about 10% in the denosumab group and 20% in the placebo group. “Please note that the frequency of clinical fractures reported in this trial that is focusing on bone health is markedly higher than fracture rates reported in previous large AI trials. Obviously, we had a tendency to underreport them in those trials,” Dr. Gnant commented. “The true magnitude of the problem in clinical practice is likely reflected in the placebo group … with approximately one out of five patients experiencing a new clinical fracture within 5-6 years of adjuvant AI treatment.”

Benefit was similar across numerous patient subgroups studied, including the subgroups of women who had a baseline bone mineral density T-score of less than –1 and women who had a baseline bone mineral density T-score of –1 or greater.

Additionally, the denosumab group had improvements from baseline in bone mineral density of the lumbar spine, total hip, and femoral neck, whereas the placebo group had worsening at all sites (P less than .0001 between groups for each site). And at 36 months, the denosumab group had significantly lower risks of both new vertebral fractures and new or worsening vertebral fractures.

“Adjuvant denosumab at this dose and schedule is safe,” Dr. Gnant maintained. The two groups had similar rates of various adverse events, with musculoskeletal disorders and vascular disorders (including hot flashes) predominating. “This means that we are in essence reporting the side effects of the underlying adjuvant AI treatment,” he noted.

There were 31 cases of dental issues, but none met diagnostic criteria for osteonecrosis of the jaw. “We can safely say that at this dose of denosumab, 60 mg twice yearly, ONJ is not an issue,” Dr. Gnant commented. Additionally, none of the women experienced atypical fractures.

Dr. Gnant disclosed employment of an immediate family member with Sandoz; receipt of honoraria from Amgen, AstraZeneca, GlaxoSmithKline, NanoString Technologies, Novartis, and Roche Pharma AG; a consulting or advisory role with Accelsiors, AstraZeneca, and Novartis; and receipt of research funding from GlaxoSmithKline, Novartis, Pfizer, Roche Pharma AG, Sanofi, and Smiths Medical. The trial was sponsored by Amgen.

CHICAGO – Adjuvant denosumab is efficacious and safe for reducing fracture risk among women taking aromatase inhibitors (AIs) as part of their treatment for early breast cancer, finds the Austrian Breast & Colorectal Cancer Study Group’s study 18 (ABCSG-18).

Compared with peers randomized to placebo in the phase III trial, women randomized to the antiresorptive monoclonal antibody at the dose typically used to treat osteoporosis were half as likely to experience a first clinical fracture, first author Dr. Michael Gnant reported at the annual meeting of the American Society of Clinical Oncology. The benefit was similar whether women had normal bone mineral density at baseline or already had osteopenia.

Courtesy MeduniWien/Matern

Patients in the denosumab group did not have a significantly higher rate of adverse events, including the much-feared complication of osteonecrosis of the jaw.

“The actual fracture risk of postmenopausal breast cancer patients on AIs is substantial and may have been underestimated until today,” commented Dr. Gnant, professor of surgery at the Medical University of Vienna. “In these patients with only a modest risk of disease recurrence, adjuvant denosumab significantly reduced the bone side effects of AI treatment. We therefore believe that denosumab 60 mg every 6 months should be considered for clinical practice.”

“Today, several clinical practice guidelines advocate the use of bisphosphonates for breast cancer patients receiving AIs, however, only if they are at high risk for fractures,” he further noted. However, “patients with normal baseline bone mineral density showed a similar fracture risk but also similar benefit from denosumab as compared to patients with baseline T scores below –1, indicating that DEXA scans may be an insufficient way to assess the individual patient’s fracture risk. In view of the benefits in this particular patient subgroup, we may have to rediscuss our current clinical practice guidelines.”

Invited discussant Dr. Robert E. Coleman of the University of Sheffield and Weston Park Hospital in England, said, “It’s very important to dissect out fractures related to subsequent recurrence from fractures due to poor bone health.” Most of the reduction in fracture risk in ABCSG-18 appeared to be because of prevention of fractures before any recurrence, whereas most of that in the AZURE trial (Adjuvant Zoledronic Acid to Reduce Recurrence) of an adjuvant bisphosphonate, another type of antiresorptive agent, appeared to be because of prevention of fractures from bone metastases. “So I think we are seeing something very different with denosumab to what we’ve seen to date with a bisphosphonate,” he said.

“As oncologists, we are somewhat wedded to measuring bone mineral density as the reason for giving bone-targeted therapy to protect [against] bone loss, but there are much better ways of predicting fracture with online algorithms such as FRAX [Fracture Risk Assessment Tool] and others,” Dr. Coleman further commented. “And bone mineral density is a pretty poor predictor of fracture, so it’s perhaps not surprising that the risk reductions were fairly similar” across bone mineral density subgroups.

During a question and answer period, session attendee Dr. Toru Watanabe, Hamamatsu (Japan) Oncology Center, said, “It is really clear that the osteoporosis-related fracture is prevented by denosumab at the dose usually used for the treatment of osteoporosis. That part is very clear. My question is, the same dose is being tested for modifying overall survival or progression-free survival. Don’t you think it’s necessary to conduct some kind of dose-finding trial?”

Two studies are addressing the impact of denosumab on breast cancer outcomes, according to Dr. Gnant: the investigators’ ABCSG-18 study and the Study of Denosumab as Adjuvant Treatment for Women With High-Risk Early Breast Cancer Receiving Neoadjuvant or Adjuvant Therapy (D-CARE), which is using a higher initial dose and tapering after 1 year. “So we will have that indirect comparison at least. My personal expectation would be that there is a trade-off potentially between efficacy and tolerability,” he commented.

The 3,425 postmenopausal breast cancer patients in ABCSG-18 were randomized evenly to receive 60 mg of denosumab or placebo every 6 months. Denosumab is approved by the Food and Drug Administration for the prevention and treatment of fractures due to bone metastases (brand name Xgeva) and osteoporosis after menopause (brand name Prolia), as well as other indications. The study used the dose for postmenopausal osteoporosis, which is much lower than that typically used for bone metastases (120 mg every 4 weeks), Dr. Gnant noted.

Main results showed that denosumab was highly efficacious in reducing the risk of first clinical fractures, meaning those that were clinically evident and causing symptoms (hazard ratio, 0.50; P less than .0001), according to data presented at the meeting and simultaneously published (Lancet 2015 May 31).

The estimated 6-year fracture rate was about 10% in the denosumab group and 20% in the placebo group. “Please note that the frequency of clinical fractures reported in this trial that is focusing on bone health is markedly higher than fracture rates reported in previous large AI trials. Obviously, we had a tendency to underreport them in those trials,” Dr. Gnant commented. “The true magnitude of the problem in clinical practice is likely reflected in the placebo group … with approximately one out of five patients experiencing a new clinical fracture within 5-6 years of adjuvant AI treatment.”

Benefit was similar across numerous patient subgroups studied, including the subgroups of women who had a baseline bone mineral density T-score of less than –1 and women who had a baseline bone mineral density T-score of –1 or greater.

Additionally, the denosumab group had improvements from baseline in bone mineral density of the lumbar spine, total hip, and femoral neck, whereas the placebo group had worsening at all sites (P less than .0001 between groups for each site). And at 36 months, the denosumab group had significantly lower risks of both new vertebral fractures and new or worsening vertebral fractures.

“Adjuvant denosumab at this dose and schedule is safe,” Dr. Gnant maintained. The two groups had similar rates of various adverse events, with musculoskeletal disorders and vascular disorders (including hot flashes) predominating. “This means that we are in essence reporting the side effects of the underlying adjuvant AI treatment,” he noted.

There were 31 cases of dental issues, but none met diagnostic criteria for osteonecrosis of the jaw. “We can safely say that at this dose of denosumab, 60 mg twice yearly, ONJ is not an issue,” Dr. Gnant commented. Additionally, none of the women experienced atypical fractures.

Dr. Gnant disclosed employment of an immediate family member with Sandoz; receipt of honoraria from Amgen, AstraZeneca, GlaxoSmithKline, NanoString Technologies, Novartis, and Roche Pharma AG; a consulting or advisory role with Accelsiors, AstraZeneca, and Novartis; and receipt of research funding from GlaxoSmithKline, Novartis, Pfizer, Roche Pharma AG, Sanofi, and Smiths Medical. The trial was sponsored by Amgen.

CHICAGO – Adjuvant denosumab is efficacious and safe for reducing fracture risk among women taking aromatase inhibitors (AIs) as part of their treatment for early breast cancer, finds the Austrian Breast & Colorectal Cancer Study Group’s study 18 (ABCSG-18).

Compared with peers randomized to placebo in the phase III trial, women randomized to the antiresorptive monoclonal antibody at the dose typically used to treat osteoporosis were half as likely to experience a first clinical fracture, first author Dr. Michael Gnant reported at the annual meeting of the American Society of Clinical Oncology. The benefit was similar whether women had normal bone mineral density at baseline or already had osteopenia.

Courtesy MeduniWien/Matern

Patients in the denosumab group did not have a significantly higher rate of adverse events, including the much-feared complication of osteonecrosis of the jaw.

“The actual fracture risk of postmenopausal breast cancer patients on AIs is substantial and may have been underestimated until today,” commented Dr. Gnant, professor of surgery at the Medical University of Vienna. “In these patients with only a modest risk of disease recurrence, adjuvant denosumab significantly reduced the bone side effects of AI treatment. We therefore believe that denosumab 60 mg every 6 months should be considered for clinical practice.”

“Today, several clinical practice guidelines advocate the use of bisphosphonates for breast cancer patients receiving AIs, however, only if they are at high risk for fractures,” he further noted. However, “patients with normal baseline bone mineral density showed a similar fracture risk but also similar benefit from denosumab as compared to patients with baseline T scores below –1, indicating that DEXA scans may be an insufficient way to assess the individual patient’s fracture risk. In view of the benefits in this particular patient subgroup, we may have to rediscuss our current clinical practice guidelines.”

Invited discussant Dr. Robert E. Coleman of the University of Sheffield and Weston Park Hospital in England, said, “It’s very important to dissect out fractures related to subsequent recurrence from fractures due to poor bone health.” Most of the reduction in fracture risk in ABCSG-18 appeared to be because of prevention of fractures before any recurrence, whereas most of that in the AZURE trial (Adjuvant Zoledronic Acid to Reduce Recurrence) of an adjuvant bisphosphonate, another type of antiresorptive agent, appeared to be because of prevention of fractures from bone metastases. “So I think we are seeing something very different with denosumab to what we’ve seen to date with a bisphosphonate,” he said.

“As oncologists, we are somewhat wedded to measuring bone mineral density as the reason for giving bone-targeted therapy to protect [against] bone loss, but there are much better ways of predicting fracture with online algorithms such as FRAX [Fracture Risk Assessment Tool] and others,” Dr. Coleman further commented. “And bone mineral density is a pretty poor predictor of fracture, so it’s perhaps not surprising that the risk reductions were fairly similar” across bone mineral density subgroups.

During a question and answer period, session attendee Dr. Toru Watanabe, Hamamatsu (Japan) Oncology Center, said, “It is really clear that the osteoporosis-related fracture is prevented by denosumab at the dose usually used for the treatment of osteoporosis. That part is very clear. My question is, the same dose is being tested for modifying overall survival or progression-free survival. Don’t you think it’s necessary to conduct some kind of dose-finding trial?”

Two studies are addressing the impact of denosumab on breast cancer outcomes, according to Dr. Gnant: the investigators’ ABCSG-18 study and the Study of Denosumab as Adjuvant Treatment for Women With High-Risk Early Breast Cancer Receiving Neoadjuvant or Adjuvant Therapy (D-CARE), which is using a higher initial dose and tapering after 1 year. “So we will have that indirect comparison at least. My personal expectation would be that there is a trade-off potentially between efficacy and tolerability,” he commented.

The 3,425 postmenopausal breast cancer patients in ABCSG-18 were randomized evenly to receive 60 mg of denosumab or placebo every 6 months. Denosumab is approved by the Food and Drug Administration for the prevention and treatment of fractures due to bone metastases (brand name Xgeva) and osteoporosis after menopause (brand name Prolia), as well as other indications. The study used the dose for postmenopausal osteoporosis, which is much lower than that typically used for bone metastases (120 mg every 4 weeks), Dr. Gnant noted.

Main results showed that denosumab was highly efficacious in reducing the risk of first clinical fractures, meaning those that were clinically evident and causing symptoms (hazard ratio, 0.50; P less than .0001), according to data presented at the meeting and simultaneously published (Lancet 2015 May 31).

The estimated 6-year fracture rate was about 10% in the denosumab group and 20% in the placebo group. “Please note that the frequency of clinical fractures reported in this trial that is focusing on bone health is markedly higher than fracture rates reported in previous large AI trials. Obviously, we had a tendency to underreport them in those trials,” Dr. Gnant commented. “The true magnitude of the problem in clinical practice is likely reflected in the placebo group … with approximately one out of five patients experiencing a new clinical fracture within 5-6 years of adjuvant AI treatment.”

Benefit was similar across numerous patient subgroups studied, including the subgroups of women who had a baseline bone mineral density T-score of less than –1 and women who had a baseline bone mineral density T-score of –1 or greater.

Additionally, the denosumab group had improvements from baseline in bone mineral density of the lumbar spine, total hip, and femoral neck, whereas the placebo group had worsening at all sites (P less than .0001 between groups for each site). And at 36 months, the denosumab group had significantly lower risks of both new vertebral fractures and new or worsening vertebral fractures.

“Adjuvant denosumab at this dose and schedule is safe,” Dr. Gnant maintained. The two groups had similar rates of various adverse events, with musculoskeletal disorders and vascular disorders (including hot flashes) predominating. “This means that we are in essence reporting the side effects of the underlying adjuvant AI treatment,” he noted.

There were 31 cases of dental issues, but none met diagnostic criteria for osteonecrosis of the jaw. “We can safely say that at this dose of denosumab, 60 mg twice yearly, ONJ is not an issue,” Dr. Gnant commented. Additionally, none of the women experienced atypical fractures.

Dr. Gnant disclosed employment of an immediate family member with Sandoz; receipt of honoraria from Amgen, AstraZeneca, GlaxoSmithKline, NanoString Technologies, Novartis, and Roche Pharma AG; a consulting or advisory role with Accelsiors, AstraZeneca, and Novartis; and receipt of research funding from GlaxoSmithKline, Novartis, Pfizer, Roche Pharma AG, Sanofi, and Smiths Medical. The trial was sponsored by Amgen.

Attendees at ASCO 2015

© ASCO/Scott Morgan

CHICAGO—A dual inhibitor of FLT3 and Axl may produce more durable responses than other FLT3 inhibitors and improve survival in patients with FLT3-positive, relapsed or refractory acute myeloid leukemia (AML), according to a speaker at the 2015 ASCO Annual Meeting.

The FLT3/Axl inhibitor, ASP2215, has not been compared against other FLT3 inhibitors directly, and the data presented were from a phase 1/2 study.

However, the speaker said ASP2215 provided “potent and sustained” inhibition of FLT3 and produced an overall response rate (ORR) of 52% among FLT3-positive patients.

The median duration of response for these patients was 18 weeks, and their median overall survival was about 27 weeks.

Mark J. Levis, MD, PhD, of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore, Maryland, presented these results at ASCO as abstract 7003.*

“We’ve been studying FLT3 inhibitors for a number of years now,” Dr Levis began, “and we think they show significant clinical promise, [but] they also have problems.”

He noted that some of these drugs haven’t been particularly safe or well-tolerated. They can cause gastrointestinal toxicity, hand-foot syndrome, QT prolongation, and myelosuppression.

However, the most intriguing problem with FLT3 inhibitors, according to Dr Levis, is the emergence of resistance-conferring point mutations observed in studies of some of the newer drugs, such as sorafenib and quizartinib.

“So in that context, here we have ASP2215,” Dr Levis said. “This is a type 1 FLT3 tyrosine kinase inhibitor, and, as such, it has activity against not only wild-type and ITD-mutated FLT3 but also against those resistance-conferring point mutations typically found in the activation loop at the so-called gatekeeper residue (F691L).”

With this in mind, he and his colleagues conducted a phase 1/2 trial of ASP2215. The study was sponsored by Astellas Pharma Global Development, Inc., the company developing ASP2215.

The trial was open to patients with relapsed or refractory AML, irrespective of their FLT3 mutation status. The researchers’ goal was to identify a safe, tolerable dose of ASP2215 that fully inhibited FLT3.

The team used a standard 3+3 design, with dose levels ranging from 20 mg to 450 mg once daily. They expanded every cohort until they reached a dose-limiting toxicity.

In all, the trial enrolled 198 patients, 24 in the dose-escalation cohorts and 174 in the dose-expansion cohorts. The patients’ median age was 62 (range, 21-90), and 53.1% were male.

Nearly 66% of patients had FLT3 mutations, 29.4% were FLT3-negative, and 5.2% had unknown FLT3 status. About 35% of patients had received 1 prior line of therapy, 26.3% had 2, 33.5% had 3 or more, and 5.7% had an unknown number of prior therapies.

Safety results

In the 194 patients who were evaluable for safety, treatment-emergent adverse events included diarrhea (13.4%), fatigue (12.4%), AST increase (11.3%), ALT increase (9.3%), thrombocytopenia (7.7%), anemia (7.2%), peripheral edema (7.2%), constipation (6.7%), nausea (6.7%), dizziness (6.2%), vomiting (5.7%), and dysgeusia (5.2%).

Serious adverse events included febrile neutropenia (27.3%), sepsis (11.9%), disease progression (10.3%), pneumonia (8.8%), hypotension (5.7%), and respiratory failure (5.7%).

“The kinds of side effects we saw were typical for a relapsed/refractory AML population,” Dr Levis said. “Nothing really stood out. Any trial of relapsed/refractory AML is going to have febrile neutropenia and sepsis, and those were our dominant, serious adverse events. There was no real safety signal here that was unique to the drug, we felt.”

The researchers said the maximum-tolerated dose of ASP2215 was 300 mg, as 2 patients who received the 450 mg dose experienced dose-limiting toxicities. One was grade 3 diarrhea, and the other was grade 3 AST elevation.

Response and survival

Among the 127 patients who were FLT3-positive, the ORR was 52% (n=66). The complete response (CR) rate was 6.3% (n=8). The composite CR rate, which includes CRs with incomplete hematologic recovery (CRi) and incomplete platelet recovery (CRp), was 40.9% (n=52). And the partial response (PR) rate was 11% (n=14).

“As we scale up the dose, the PRs shift on over to CRis, and the dominant response is, in fact, a complete response with incomplete count recovery,” Dr Levis said. “The categories where we had the largest number of responses were the 120 mg and 200 mg categories. We didn’t really have enough patients in the 300 mg category to comment on it. ”

For the FLT3-positive patients, the median duration of response was 126 days.

“The duration of response really stood out here,” Dr Levis said. “It’s over 4 months. That is something we really didn’t see with the other drugs, and I suspect that is a reflection of the suppression of the outgrowth of these resistance mutations.”

Unfortunately, FLT3-wild-type patients did not fare as well. The ORR among these patients was 8.8%. None of the patients achieved a CR, 3 had a composite CR (5.3%), and 2 had a PR (3.5%).

Among the FLT3-positive patients, the median overall survival was about 27 weeks. It was 128 days in the 20 mg dose cohort (n=13), 105.5 days in the 40 mg cohort (n=8), 201 days in the 80 mg cohort (n=12), 199 days in the 120 mg cohort (n=40), and 161 days in the 200 mg cohort (n=45). Dr Levis did not present survival data for the 300 mg or 450 mg cohorts, which included 7 and 2 patients, respectively.

“[Relapsed/refractory AML] is a population that has a median survival of about 3 months with conventional therapy, at least by historical publications,” Dr Levis noted. “If you look at survival in this trial, patients treated at the FLT3-inhibitory doses [had a] greater than 6-month median survival.”

He added that studies of ASP2215 in combination with other agents are ongoing in patients with newly diagnosed AML. And phase 3 trials of ASP2215 at the 120 mg dose, with the option of scaling up to 200 mg, are planned.

*Information in the abstract differs from that presented at the meeting.

Attendees at ASCO 2015

© ASCO/Scott Morgan

CHICAGO—A dual inhibitor of FLT3 and Axl may produce more durable responses than other FLT3 inhibitors and improve survival in patients with FLT3-positive, relapsed or refractory acute myeloid leukemia (AML), according to a speaker at the 2015 ASCO Annual Meeting.

The FLT3/Axl inhibitor, ASP2215, has not been compared against other FLT3 inhibitors directly, and the data presented were from a phase 1/2 study.

However, the speaker said ASP2215 provided “potent and sustained” inhibition of FLT3 and produced an overall response rate (ORR) of 52% among FLT3-positive patients.

The median duration of response for these patients was 18 weeks, and their median overall survival was about 27 weeks.

Mark J. Levis, MD, PhD, of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore, Maryland, presented these results at ASCO as abstract 7003.*

“We’ve been studying FLT3 inhibitors for a number of years now,” Dr Levis began, “and we think they show significant clinical promise, [but] they also have problems.”

He noted that some of these drugs haven’t been particularly safe or well-tolerated. They can cause gastrointestinal toxicity, hand-foot syndrome, QT prolongation, and myelosuppression.

However, the most intriguing problem with FLT3 inhibitors, according to Dr Levis, is the emergence of resistance-conferring point mutations observed in studies of some of the newer drugs, such as sorafenib and quizartinib.

“So in that context, here we have ASP2215,” Dr Levis said. “This is a type 1 FLT3 tyrosine kinase inhibitor, and, as such, it has activity against not only wild-type and ITD-mutated FLT3 but also against those resistance-conferring point mutations typically found in the activation loop at the so-called gatekeeper residue (F691L).”

With this in mind, he and his colleagues conducted a phase 1/2 trial of ASP2215. The study was sponsored by Astellas Pharma Global Development, Inc., the company developing ASP2215.

The trial was open to patients with relapsed or refractory AML, irrespective of their FLT3 mutation status. The researchers’ goal was to identify a safe, tolerable dose of ASP2215 that fully inhibited FLT3.

The team used a standard 3+3 design, with dose levels ranging from 20 mg to 450 mg once daily. They expanded every cohort until they reached a dose-limiting toxicity.

In all, the trial enrolled 198 patients, 24 in the dose-escalation cohorts and 174 in the dose-expansion cohorts. The patients’ median age was 62 (range, 21-90), and 53.1% were male.

Nearly 66% of patients had FLT3 mutations, 29.4% were FLT3-negative, and 5.2% had unknown FLT3 status. About 35% of patients had received 1 prior line of therapy, 26.3% had 2, 33.5% had 3 or more, and 5.7% had an unknown number of prior therapies.

Safety results

In the 194 patients who were evaluable for safety, treatment-emergent adverse events included diarrhea (13.4%), fatigue (12.4%), AST increase (11.3%), ALT increase (9.3%), thrombocytopenia (7.7%), anemia (7.2%), peripheral edema (7.2%), constipation (6.7%), nausea (6.7%), dizziness (6.2%), vomiting (5.7%), and dysgeusia (5.2%).

Serious adverse events included febrile neutropenia (27.3%), sepsis (11.9%), disease progression (10.3%), pneumonia (8.8%), hypotension (5.7%), and respiratory failure (5.7%).

“The kinds of side effects we saw were typical for a relapsed/refractory AML population,” Dr Levis said. “Nothing really stood out. Any trial of relapsed/refractory AML is going to have febrile neutropenia and sepsis, and those were our dominant, serious adverse events. There was no real safety signal here that was unique to the drug, we felt.”

The researchers said the maximum-tolerated dose of ASP2215 was 300 mg, as 2 patients who received the 450 mg dose experienced dose-limiting toxicities. One was grade 3 diarrhea, and the other was grade 3 AST elevation.

Response and survival

Among the 127 patients who were FLT3-positive, the ORR was 52% (n=66). The complete response (CR) rate was 6.3% (n=8). The composite CR rate, which includes CRs with incomplete hematologic recovery (CRi) and incomplete platelet recovery (CRp), was 40.9% (n=52). And the partial response (PR) rate was 11% (n=14).

“As we scale up the dose, the PRs shift on over to CRis, and the dominant response is, in fact, a complete response with incomplete count recovery,” Dr Levis said. “The categories where we had the largest number of responses were the 120 mg and 200 mg categories. We didn’t really have enough patients in the 300 mg category to comment on it. ”

For the FLT3-positive patients, the median duration of response was 126 days.

“The duration of response really stood out here,” Dr Levis said. “It’s over 4 months. That is something we really didn’t see with the other drugs, and I suspect that is a reflection of the suppression of the outgrowth of these resistance mutations.”

Unfortunately, FLT3-wild-type patients did not fare as well. The ORR among these patients was 8.8%. None of the patients achieved a CR, 3 had a composite CR (5.3%), and 2 had a PR (3.5%).

Among the FLT3-positive patients, the median overall survival was about 27 weeks. It was 128 days in the 20 mg dose cohort (n=13), 105.5 days in the 40 mg cohort (n=8), 201 days in the 80 mg cohort (n=12), 199 days in the 120 mg cohort (n=40), and 161 days in the 200 mg cohort (n=45). Dr Levis did not present survival data for the 300 mg or 450 mg cohorts, which included 7 and 2 patients, respectively.

“[Relapsed/refractory AML] is a population that has a median survival of about 3 months with conventional therapy, at least by historical publications,” Dr Levis noted. “If you look at survival in this trial, patients treated at the FLT3-inhibitory doses [had a] greater than 6-month median survival.”

He added that studies of ASP2215 in combination with other agents are ongoing in patients with newly diagnosed AML. And phase 3 trials of ASP2215 at the 120 mg dose, with the option of scaling up to 200 mg, are planned.

*Information in the abstract differs from that presented at the meeting.

Attendees at ASCO 2015

© ASCO/Scott Morgan

CHICAGO—A dual inhibitor of FLT3 and Axl may produce more durable responses than other FLT3 inhibitors and improve survival in patients with FLT3-positive, relapsed or refractory acute myeloid leukemia (AML), according to a speaker at the 2015 ASCO Annual Meeting.

The FLT3/Axl inhibitor, ASP2215, has not been compared against other FLT3 inhibitors directly, and the data presented were from a phase 1/2 study.

However, the speaker said ASP2215 provided “potent and sustained” inhibition of FLT3 and produced an overall response rate (ORR) of 52% among FLT3-positive patients.

The median duration of response for these patients was 18 weeks, and their median overall survival was about 27 weeks.

Mark J. Levis, MD, PhD, of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore, Maryland, presented these results at ASCO as abstract 7003.*

“We’ve been studying FLT3 inhibitors for a number of years now,” Dr Levis began, “and we think they show significant clinical promise, [but] they also have problems.”

He noted that some of these drugs haven’t been particularly safe or well-tolerated. They can cause gastrointestinal toxicity, hand-foot syndrome, QT prolongation, and myelosuppression.

However, the most intriguing problem with FLT3 inhibitors, according to Dr Levis, is the emergence of resistance-conferring point mutations observed in studies of some of the newer drugs, such as sorafenib and quizartinib.

“So in that context, here we have ASP2215,” Dr Levis said. “This is a type 1 FLT3 tyrosine kinase inhibitor, and, as such, it has activity against not only wild-type and ITD-mutated FLT3 but also against those resistance-conferring point mutations typically found in the activation loop at the so-called gatekeeper residue (F691L).”

With this in mind, he and his colleagues conducted a phase 1/2 trial of ASP2215. The study was sponsored by Astellas Pharma Global Development, Inc., the company developing ASP2215.

The trial was open to patients with relapsed or refractory AML, irrespective of their FLT3 mutation status. The researchers’ goal was to identify a safe, tolerable dose of ASP2215 that fully inhibited FLT3.

The team used a standard 3+3 design, with dose levels ranging from 20 mg to 450 mg once daily. They expanded every cohort until they reached a dose-limiting toxicity.

In all, the trial enrolled 198 patients, 24 in the dose-escalation cohorts and 174 in the dose-expansion cohorts. The patients’ median age was 62 (range, 21-90), and 53.1% were male.

Nearly 66% of patients had FLT3 mutations, 29.4% were FLT3-negative, and 5.2% had unknown FLT3 status. About 35% of patients had received 1 prior line of therapy, 26.3% had 2, 33.5% had 3 or more, and 5.7% had an unknown number of prior therapies.

Safety results

In the 194 patients who were evaluable for safety, treatment-emergent adverse events included diarrhea (13.4%), fatigue (12.4%), AST increase (11.3%), ALT increase (9.3%), thrombocytopenia (7.7%), anemia (7.2%), peripheral edema (7.2%), constipation (6.7%), nausea (6.7%), dizziness (6.2%), vomiting (5.7%), and dysgeusia (5.2%).

Serious adverse events included febrile neutropenia (27.3%), sepsis (11.9%), disease progression (10.3%), pneumonia (8.8%), hypotension (5.7%), and respiratory failure (5.7%).

“The kinds of side effects we saw were typical for a relapsed/refractory AML population,” Dr Levis said. “Nothing really stood out. Any trial of relapsed/refractory AML is going to have febrile neutropenia and sepsis, and those were our dominant, serious adverse events. There was no real safety signal here that was unique to the drug, we felt.”

The researchers said the maximum-tolerated dose of ASP2215 was 300 mg, as 2 patients who received the 450 mg dose experienced dose-limiting toxicities. One was grade 3 diarrhea, and the other was grade 3 AST elevation.

Response and survival

Among the 127 patients who were FLT3-positive, the ORR was 52% (n=66). The complete response (CR) rate was 6.3% (n=8). The composite CR rate, which includes CRs with incomplete hematologic recovery (CRi) and incomplete platelet recovery (CRp), was 40.9% (n=52). And the partial response (PR) rate was 11% (n=14).

“As we scale up the dose, the PRs shift on over to CRis, and the dominant response is, in fact, a complete response with incomplete count recovery,” Dr Levis said. “The categories where we had the largest number of responses were the 120 mg and 200 mg categories. We didn’t really have enough patients in the 300 mg category to comment on it. ”

For the FLT3-positive patients, the median duration of response was 126 days.

“The duration of response really stood out here,” Dr Levis said. “It’s over 4 months. That is something we really didn’t see with the other drugs, and I suspect that is a reflection of the suppression of the outgrowth of these resistance mutations.”

Unfortunately, FLT3-wild-type patients did not fare as well. The ORR among these patients was 8.8%. None of the patients achieved a CR, 3 had a composite CR (5.3%), and 2 had a PR (3.5%).

Among the FLT3-positive patients, the median overall survival was about 27 weeks. It was 128 days in the 20 mg dose cohort (n=13), 105.5 days in the 40 mg cohort (n=8), 201 days in the 80 mg cohort (n=12), 199 days in the 120 mg cohort (n=40), and 161 days in the 200 mg cohort (n=45). Dr Levis did not present survival data for the 300 mg or 450 mg cohorts, which included 7 and 2 patients, respectively.

“[Relapsed/refractory AML] is a population that has a median survival of about 3 months with conventional therapy, at least by historical publications,” Dr Levis noted. “If you look at survival in this trial, patients treated at the FLT3-inhibitory doses [had a] greater than 6-month median survival.”

He added that studies of ASP2215 in combination with other agents are ongoing in patients with newly diagnosed AML. And phase 3 trials of ASP2215 at the 120 mg dose, with the option of scaling up to 200 mg, are planned.

*Information in the abstract differs from that presented at the meeting.