	The novel first-in-class agent CPX-351 liposome injection improved response rates and eventfree survival (EFS) in elderly patients with newly diagnosed acute myeloid leukemia (AML). Lead author Jeffrey E. Lancet, MD, H. Lee Moffitt Cancer Center, Tampa, Florida, who presented interim data from the phase II study, said responses were even more robust in high-risk patients.

	CPX-351 targets and inhibits the CK2 kinase, an enzyme that contributes to the regulation of several proteins essential to cell proliferation and differentiation. CPX-351 encapsulates cytarabine and daunorubicin at a 5:1 ratio; it is designed to maximize the synergy between these 2 cytotoxic agents to induce apoptosis. Both drugs are commonly used in treating AML in a standard “7 3” regimen, said Lancet.

	The phase II study compared CPX-351 with the conventional “7 3” regimen of cytarabine and daunorubicin in 126 patients aged 60 to 75 years with newly diagnosed AML. The primary endpoint of this ongoing study is the rate of complete remission (CR); secondary endpoints include 1-year overall survival (OS), duration of response, EFS, and 30- and 60-day mortality. Study arms were well balanced for demographics and disease characteristics. Patients aged >70 years, or those with secondary AML, or who had ≥3 chromosomal abnormalities were stratified as high risk, and all others were classified as standard risk.

	At an approximately 2:1 ratio, patients were randomized to receive 10 units/m2 of CPX-351 on days 1, 3, and 5; or 100 mg/m2 of cytarabine daily for 7 days by continuous infusion combined with 60 mg/m2 of daunorubicin on days 1, 2, and 3. Follow-up was 1 year.

	The experimental drug produced a better rate of remission (CR plus CR with incomplete neutrophil/ platelet recovery) than standard therapy (66.7% vs 51.2%, respectively). The CPX-351 arm also had a higher aplasia rate than the control arm (87.7% vs 71.1%, respectively). EFS reached a median of 5 months in the CPX-351 arm compared with 2 months in the control arm. No significant difference in OS was observed between the groups at 1 year, with a median OS of 14.7 months for the 85 patients receiving CPX-351 versus 12.9 months for the 41 patients assigned to standard therapy.

	High-risk patients did much better on the experimental drug. For example, in patients with secondary AML, median EFS was 3.8 months and OS was 12.1 months for those taking CPX-351 CPX-351 Improves Response in Elderly Patients With Newly Diagnosed Acute Myeloid Leukemia compared with EFS of 1.4 months and OS of 6.1 months for those receiving standard therapy.

	The CPX-351 arm had a higher rate of cytopeniaassociated adverse events, including febrile neutropenia, infections (all grades), bacteremia, petechiae, and ecchymoses. The groups had similarly low rates of cardiac events. Median time to platelet count recovery following induction was longer with CPX-351, which Lancet attributed to the drug’s preferential uptake in the bone marrow. No statistically significant difference in early deaths was observed between the treatment arms. All induction deaths (ie, deaths at 30 and 60 days) occurred among the high-risk subgroups. “Our findings suggest that CPX-351 may provide a long-sought opportunity to improve clinical outcomes over ‘7 3’ in previously untreated AML,” said Lancet. Based on these results, investigators are planning to conduct a phase II trial. Lancet JE, Cortes JE, Hogge DE, et al. Phase 2B randomized study of CPX-351 vs cytarabine daunorubicin in newly diagnosed AML patients aged 60-75. Presented at: 52nd ASH Annual Meeting and Exposition; December 4-7, 2010; Orlando, Florida.

Articles

The novel first-in-class agent CPX-351 liposome injection improved response rates and eventfree survival in elderly patients with newly diagnosed acute myeloid leukemia.

ASH 2010: CPX-351 Improves Response in Elderly Patients With Newly Diagnosed Acute Myeloid Leukemia

	The novel agent elotuzumab, when administered with lenalidomide (Revlimid) and dexamethasone, produced responses in 81% of previously treated myeloma patients, according to interim phase II study data presented at ASH 2010. Paul G. Richardson, MD, of Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, reported the findings.

	Elotuzumab is a humanized monoclonal immunoglobin G1 antibody that targets CS1, a glycoprotein heavily expressed on the surface of multiple myeloma cells but with limited expression on normal cells. Phase I studies had demonstrated a high rate of response in patients with advanced disease, providing the rationale for the current phase II study. The primary objective of the open-label, multicenter trial is to select the maximum-tolerated dose.

	The study included 63 patients whose disease had relapsed after or was refractory to 1 to 3 prior therapies; patients previously treated with lenalidomide were ineligible for the study. Richardson said 61% of patients had received ≥2 prior therapies, usually including bortezomib (Velcade) and/ or thalidomide, and more than three-quarters had undergone autologous transplantation.

	Investigators randomized the patients to 28-day cycles of elotuzumab at a 10-mg/kg or 20-mg/kg dose, administered intravenously on days 1, 8, 15, and 22 of a 28-day cycle for the first 2 cycles Elotuzumab Highly Active in Patients With Advanced Myeloma and then on days 1 and 15 for subsequent cycles. Patients given both doses of elotuzumab received 25 mg of oral lenalidomide daily on days 1-21 and 40 mg of oral dexamethasone weekly. Treatment continued until disease progression or unacceptable toxicity. To mitigate possible infusion reactions, patients were pretreated with methylprednisolone, diphenhydramine or its equivalent; ranitidine or its equivalent; and acetaminophen. This regimen was administered 30 to 60 minutes prior to an elotuzumab infusion.

	Among the 63 patients, a partial response or greater was observed in 51 (81%) patients, including 90% of those taking the lower, 10-mg dose. As a result of the response trend favoring the 10-mg dose, Richardson said the investigators selected this as the therapeutic dose for future evaluations. Overall, 5% of patients experienced complete response, which included 7% of patients in the 10-mg dosing arm. Nearly one-third (29%) of patients in the study had a very good partial response, and this increased to 32% of patients taking the 10-mg dose. In addition, 16% of patients study-wide achieved stable disease.

	Prior treatment with thalidomide or bortezomib was not associated with weaker responses. In the 10-mg/kg dosing arm, the overall response rate was 90% for patients treated previously with thalidomide compared with an 83% overall response rate for patients who had taken bortezomib.

	“The quality of the responses was very impressive as well,” said Richardson. “We saw a consistent signal in patients with prior thalidomide or bortezomib [use].” At a median follow-up of 4.9 months, the median progressionfree survival has not yet been reached.

	Grade 3/4 toxicities were observed in 56% of patients, consisting primarily of muscle spasms, constipation, fatigue, pyrexia, and nausea. Richardson said toxicities were easily managed for most patients. Grade 3/4 hematologic toxicities were rare; 14% of patients developed neutropenia, another 14% experienced lymphopenia, and 13% experienced thrombocytopenia.

	While 49% of patients had infusion reactions, only 1 patient had a grade 3 reaction. Richardson credited this to the effectiveness of the premedication regimen.

	Richardson concluded that elotuzumab produced “robust and durable responses” in a population of patients who were highly refractory to existing therapies. He said the investigative drug will be further evaluated in a phase II trial expected to start in 2011.

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Richardson PG, Moreau P, Jakubowiak J, et al. Elotuzumab in combination with lenalidomide and dexamethasone in patients with relapsed multiple myeloma: interim results of a phase 2 study. Presented at: 52nd ASH Annual Meeting and Exposition; December 4-7, 2010; Orlando, Florida.

The novel agent elotuzumab, when administered with lenalidomide (Revlimid) and dexamethasone, produced responses in 81% of previously treated myeloma patients.

ASH 2010: Elotuzumab Highly Active in Patients With Advanced Myeloma

	In patients with newly diagnosed multiple myeloma who are candidates for transplant, bortezomib (Velcade) achieved high complete response (CR) rates during induction, delayed disease progression, and improved overall survival (OS). The final analysis of the HOVON-65/GMMGHD4 phase II trial (conducted in Germany, the Netherlands, and Belgium) also found that bortezomib maintenance therapy produced higher rates of CR and near CR at all treatment stages and improved outcomes for patients having a poor prognosis due to genetic abnormalities. Data were presented by Pieter Sonneveld, MD, PhD, Erasmus Medical Center, Rotterdam, the Netherlands.

	The HOVON-65/GMMG-HD4 study enrolled 744 patients with newly diagnosed, symptomatic multiple myeloma who were candidates for highdose therapy. Patients were randomized to 3 cycles of vincristine, doxorubicin, and dexamethasone (VAD; Arm A) or bortezomib, doxorubicin, and dexamethasone (PAD; Arm B). Allogeneic stem cell transplant (ASCT) was offered to patients in both study arms who had a human leukocyte antigen— identical donor. The intent of the trial was to evaluate the efficacy of bortezomib used as part of an induction regimen and a maintenance regimen.

	Patients in the PAD arm received 1.3 mg/m

 of bortezomib on days 1, 4, 8, and 11; 9 mg/m

 of doxorubicin on days 1-4, and 40 mg of dexamethasone on days 1-4, 9-12, and 17-20. Transplant-eligible patients received 1 or 2 administrations of high-dose melphalan (HDM) with ASCT. The maintenance protocol consisted of 50 mg of thalidomide daily for 2 years for patients assigned to Arm A and 1.3 mg/m2 of bortezomib twice weekly for patients in Arm B. The protocolspecified analysis was intent-to-treat and was censored for the 58 patients who received ASCT after a single course of HDM1.

	At a median follow-up of 40 months, 90% of patients had completed induction and 84% had completed HDM. Of the 239 patients in the VAD arm who began thalidomide maintenance therapy, 55% were still taking it at 12 months’ follow-up and 29% were receiving it at 24 months’ followup. A total of 205 patients in the PAD arm initiated bortezomib-based maintenance therapy; 76% were taking it at 12 months’ follow-up and 49% were receiving it at 24 months’ follow-up. “At any stage of treatment, more patients remained on the bortezomib-based regimen,” Sonneveld noted, adding that responses at each stage were higher with PAD (

). Both maintenance regimens led to additional response in the majority of patients.

	Patients treated with the PAD regimen were significantly less likely than patients taking VAD to experience disease progression. In patients on a bortezomib-based regimen, progressionfree survival (PFS) increased from a median of 27 months with standard treatment to 36 months, said Sonneveld. At 36 months, the risk of progression overall was 21% lower for patients on the PAD regimen than for those on the VAD regimen (

= .01); excluding transplant patients, the risk of progression for patients in the PAD group at 36 months was 25% lower (

= .001) than it was for patients in the VAD group. Sonneveld reported that bortezomib was also associated with significant improvement in OS, with a 27% lower risk of mortality for patients in the PAD cohort than for those in the VAD group (

	“Subgroup analyses by cytogenetic abnormalities clearly showed the standard arm to be less effective,” he said (

). “Bortezomib treatment overcame the poor risk caused by these abnormalities.”

	In the VAD cohort, only 29% of patients with the -13/13q- mutation had PFS ≥36 months, and the rate of 36-month OS for this subgroup was 58%; for those patients with the t(4:14) translocation, only 20% had PFS ≥36 months, with a 36-month OS rate of 40%; in patients with a 17p deletion, 16% experienced PFS ≥36 months and these patients had a 36-month OS rate of 17%.

	Assignment to PAD conveyed much better outcomes for patients with these genetic mutations, with 40% of patients with the -13/13qmutation experiencing PFS ≥36 months and having a 36-month OS rate of 79%. Looking at the subgroup of patients receiving PAD who had the t(4:14) translocation, 28% had PFS ≥36 months, with a 36-month OS rate of 60%; 22% of patients with a 17p deletion experienced PFS ≥36 months and the 36-month OS rate for patients with this abnormality was 61%.

	During the 2 years of maintenance therapy, peripheral neuropathy was observed in 41% of patients in the VAD arm, with 15% experiencing grades 3/4 neuropathy. In the PAD arm, the rate of peripheral neuropathy reached 23%, with 9% experiencing a grade 3/4 level of this adverse effect. More patients in the VAD arm than in the PAD arm discontinued treatment because of toxicity (31% vs 9%, respectively).

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Sonneveld P, Schmidt-Wolf I, van deer Holt B, et al. HOVON-65/GMMG-HD4 randomized phase III trial comparing bortezomib, doxorubicin, dexamethasone (PAD) vs VAD followed by high-dose melphalan (HDM) and maintenance with bortezomib or thalidomide in patients with newly diagnosed multiple myeloma. Presented at: 52nd ASH Annual Meeting and Exposition; December 4-7, 2010; Orlando, Florida.

In patients with newly diagnosed multiple myeloma who are candidates for transplant, bortezomib (Velcade) achieved high complete response (CR) rates during induction, delayed disease progression, and improved overall survival (OS).

ASH 2010: Multiple Benefits Observed for Bortezomib in Newly Diagnosed Myeloma Patients

	Exemestane (Aromasin) was no better than anastrozole (Arimidex) at reducing cancer recurrence in postmenopausal women with hormone receptor-positive primary breast cancer, according to final data from the NCIC CTG MA.27 trial presented at the San Antonio Breast Cancer Symposium. MA.27 is the first definitive early breast cancer trial comparing a nonsteroidal and a steroidal aromatase inhibitor as adjuvant therapy. Anastrozole, the nonsteroidal aromatase inhibitor, is approved as single-agent adjuvant therapy; exemestane, the steroidal aromatase inhibitor, is approved as sequential therapy in women who have received 2 to 3 years of tamoxifen.

	"MA.27 tested the hypothesis that exemestane would have greater efficacy and better end-organ safety than anastrozole for several reasons," said principal investigator Paul E. Goss, MD, Massachusetts General Hospital, Boston. He noted that exemestane is an irreversible and more potent aromatase inhibitor than anastrozole and does not induce intratumoral aromatase. "Through its mild androgenic activity, [exemestane] may exert a second anti-tumor effect and [produce] a more favorable bone and lipid metabolism profile than anastrozole."

	The investigators for MA.27 randomized 7576 women with breast cancer to treatment for 5 years with 1 mg of anastrozole or 25 mg of exemestane daily. Initially, the study also tested the role of the cyclooxygenase (COX)-2 inhibitor celecoxib (Celebrex) in combination with an aromatase inhibitor, but Goss said they discontinued this arm early on during the trial after other studies and clinical evidence associated COX-2 inhibitors with cardiovascular toxicity.

	"Exemestane was not superior to anastrozole, which was the primary objective of the trial," said Goss. "There were no significant differences in any outcome variables. The event-free survival curves were superimposable at 4.1 years of follow-up," he added.

	The disease-free survival rate was 91% in both arms of the study. Events--recurrence, new breast cancer, and deaths--were observed in 9.2% of patients taking exemestane versus 9.1% of patients randomized to anastrozole (

= .85). Nearly 4% of patients in each arm developed distant recurrence. By 3 years, approximately one-fourth of patients in each arm had discontinued treatment.

	In subset analyses, the curves were again superimposable, with nonsignificant P values, said Goss. This was also true for a comparison between women who had prior adjuvant chemotherapy and women who did not. Rather than viewing the trial as a failure for not demonstrating superiority for one regimen or another, Goss said, "We see this as providing a new option for 5 years of upfront adjuvant therapy."

	Both arms had similar rates of menopauselike symptoms, although vaginal bleeding was less frequent in women taking exemestane. Cardiovascular events were infrequent and occurred at similar rates and with similar intensity in both arms. Hypertriglyceridemia and hypercholesterolemia were less likely to occur in patients receiving exemestane, and patients taking exemestane were less likely to report a new diagnosis of osteoporosis. Clinical fracture rates were similar in both study arms, however.

	"In keeping with its steroidal structure, exemestane may cause mild androgenic effects and lower rates of osteoporosis,"Goss said. "Event rates were low in both arms. At 4 years, 91% of women were diseasefree, probably reflecting the low-risk population and improvements in breast cancer care," he said. "Endorgan effects were slightly different between the drugs, and that may be clinically important."

	"The aromatase inhibitors are coming off patent soon, and generic versions are appearing around the world. We believe this result provides patients with additional choices, depending on local access to care and cost," said Goss. "Because the side effect profiles are somewhat different, if patients have symptoms on one drug they can try another one without doing harm," he added. Exemestane is not currently approved in the United States as initial adjuvant treatment in this patient population. 

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Goss PE, Ingle JN, Chapman, J-AW, et al. Final analysis of NCIC CTG MA.27: A randomized phase III trial of exemestane versus anastrozole in postmenopausal women with hormone receptor positive primary breast cancer. Paper presented at: 33rd Annual San Antonio Breast Cancer Symposium; December 8-12, 2010; San Antonio, TX.

Exemestane (Aromasin) was no better than anastrozole (Arimidex) at reducing cancer recurrence in postmenopausal women with hormone receptor-positive primary breast cancer

Audrey Andrews

Articles

ASH 2010: CPX-351 Improves Response in Elderly Patients With Newly Diagnosed Acute Myeloid Leukemia

ASH 2010: Elotuzumab Highly Active in Patients With Advanced Myeloma

ASH 2010: Multiple Benefits Observed for Bortezomib in Newly Diagnosed Myeloma Patients

SABCS Coverage: MA.27 Study Finds Exemestane and Anastrozole Comparable