Date: 2015-10-15
Type of information: Publication of results in a medical journal
phase: 3
Announcement: publication of results in The Lancet Oncology
Company: Nektar Therapeutics (USA - CA)
Product: etirinotecan pegol (NKTR-102)
Action
mechanism: enzyme inhibitor/topoisomerase I inhibitor. Etirinotecan pegol is the first long-acting topoisomerase I inhibitor with an extended half-life and a unique structure that is designed to concentrate the drug in tumors. In patients, Onzeald® leads to greatly prolonged plasma SN38 exposure compared with irinotecan (elimination half-life of 37 days compared with 2 days) yet peak SN38 concentrations are at least 5- to 10-times less, which may also result in a favorable tolerability profile. Onzeald® was evaluated in a Phase 3, open-label, randomized, multicenter study (the BEACON study) that enrolled 852 women with locally recurrent or metastatic breast cancer, who have previously been treated with an anthracycline, taxane and capecitabine therapies.
Disease: advanced breast cancer
Therapeutic area: Cancer - Oncology
Country: Belgium, Canada, France, Germany, Italy, Republic of Korea, The Netherlands, Russian Federation, Spain, UK, USA
Trial
details: The BEACON (Breast Cancer Outcomes With NKTR-102) study is designed as an open-label, randomized, parallel, two arm, multicenter, international Phase 3 study in patients with recurrent or metastatic breast cancer previously treated with cytotoxic chemotherapy regimens. The primary study objective is to compare overall survival of patients who receive NKTR-102 given once every 21 days to patients who receive treatment of Physician's Choice selected from a list of seven single-agent intravenous therapies. The study enrolled 852 women with locally recurrent or metastatic breast cancer who previously had been treated with ATC and had progressed following treatment. The study was conducted at 135 sites worldwide including in North America, Europe and the Republic of Korea. Nearly half of the patients enrolled in BEACON were located in North America. Patients were randomized on a 1:1 basis to receive 145 mg/m2 of single-agent NKTR-102 once every three weeks or a single agent of the physician's choice, including ixabepilone, vinorelbine, gemcitabine, eribulin or a taxane. Randomization was stratified by geographic region, prior use of eribulin and receptor status. (NCT01492101)
Latest
news: * On October 15, 2015, results of the BEACON (BrEAst Cancer Outcomes with NKTR-102) study have been published online in The Lancet Oncology. This trial did not demonstrate an improvement in overall survival for etirinotecan pegol compared to treatment of physician's choice in patients with heavily pre-treated advanced breast cancer. The toxicity profile noted in the etirinotecan pegol group differed from that in the control group. In view of the frequency of cross-resistance and overlapping toxicities noted with many available drugs and the need for effective drugs in highly refractory disease, etirinotecan pegol may warrant further research in some subgroups of patients. * On March 17, 2015, Nektar Therapeutics announced results from its Phase 3 BEACON study evaluating single-agent NKTR-102 in patients with advanced breast cancer. BEACON compared NKTR-102 to an active control arm comprised of a single chemotherapy agent of physician's choice (TPC) in patients who were heavily pre-treated with a median of three prior therapies for metastatic disease. In a topline analysis of 852 patients from the trial, NKTR-102 provided a 2.1 month improvement in median overall survival (OS) over TPC (12.4 months for patients receiving NKTR-102 compared to 10.3 months for patients receiving TPC). Based on a stratified log-rank analysis, the primary endpoint measuring the Hazard Ratio (HR) for survival in the NKTR-102 group compared to the active control arm was 0.87 with a p-value of 0.08, which did not achieve statistical significance. In a pre-specified subgroup of patients with a history of brain metastases, NKTR-102 showed an improvement of 5.2 months in median OS (10.0 months compared to 4.8 months, n=67, HR 0.51, p-value < 0.01). The proportion of patients with brain metastases with 12-month survival was 44.4% in the NKTR-102 arm as compared to 19.4% in the control arm. In a pre-specified subgroup of patients with baseline liver metastases at study entry, NKTR-102 showed an improvement of 2.6 months in median OS (10.9 months versus 8.3 months, n=456, HR 0.73, p-value < 0.002). In these patients with baseline liver metastases, the proportion of patients with 12-month survival was 46.9% in the NKTR-102 arm as compared to 33.3% in the control arm. "In BEACON, NKTR-102 provided a clinically meaningful benefit with a greater than two month survival advantage in these late-stage breast cancer patients, many who were refractory to existing therapies," said Dr. Cortes. "NKTR-102 exhibited a lower rate of high grade adverse events including a reduced rate of neutropenia as compared to active control, which dramatically decreased the need for growth factor support in the NKTR-102 arm of the study. Of particular significance, median survival in patients with brain metastases was more than double on NKTR-102 and the 12-month survival rate for this sub-group was impressive at 44% compared to 19% with other active agents." Dr. Edith Perez, Deputy Director of the Mayo Clinic Cancer Center and Dr. Javier Cortes, Director of the Breast Cancer Program at Vall d'Hebron University Hospital in Spain, served as co-principal investigators of the global, multi-center study. BEACON enrolled 852 patients with advanced breast cancer whose disease had progressed following treatment with anthracycline, taxane and capecitabine (ATC). Secondary endpoints in the BEACON study included objective response rate (ORR) and progression-free survival (PFS), which did not achieve statistical significance in the study. The incidence of Grade 3 and higher adverse events (AEs) was lower in the NKTR-102 arm (48%) compared to the TPC arm (63%). The most common Grade 3 and above AEs observed with NKTR-102 were diarrhea (9.6%), neutropenia (9.6%), anemia (4.7%) and fatigue (4.5%). There was no Grade 4 diarrhea reported with NKTR-102 in the trial. The most common Grade 3 and above AEs observed with TPC were neutropenia (30.8%), anemia (4.7%), and dyspnea (4.4%). Severe neuropathy (G3 or higher) was seen in 3.7% of patients on TPC versus 0.5% of patients in the NKTR-102 arm. Rates of G1/G2 alopecia in the NKTR-102 arm were also lower (10%) than in the TPC arm (23%). "It is clear from our BEACON study that NKTR-102 has potential as an important anti-cancer agent when compared to the best available treatment options today for women with advanced breast cancer," said Howard W. Robin, president and chief executive officer of Nektar Therapeutics. "Given the significant need for new drugs to treat patients with this devastating disease, we will be exploring potential paths forward for NKTR-102 in metastatic breast cancer with regulatory agencies." NKTR-102 was designed to be the first topoisomerase I inhibitor with a novel molecular structure that concentrates the drug in vascularized tumors and extends its circulation time in the plasma. In 2012, the FDA designated NKTR-102 as a Fast Track development program for the treatment of patients with locally recurrent or metastatic breast cancer progressing after treatment with ATC. Nektar will continue to review and analyze the data from the BEACON study. Data from the BEACON study will be submitted for presentation at an upcoming medical meeting. Etirinotecan Pegol (NKTR-102) Passes Interim Efficacy Analysis for BEACON Pivotal Phase 3 Clinical Study in Patients with Metastatic Breast Cancer * On January 14, 2014, Nektar Therapeutics announced that the Independent Data Monitoring Committee (DMC) created to provide safety oversight for the Company's pivotal clinical study for etirinotecan pegol (NKTR-102) has recommended continuation of the BEACON phase 3 trial, based upon the completion of a planned interim efficacy analysis in accordance with the DMC charter. The independent DMC performed the pre-defined interim efficacy analysis, which consisted of a review of ongoing efficacy and safety data, including 50% of patient events necessary to evaluate the primary endpoint of overall survival. In August 2013, the BEACON study completed enrollment of 852 patients with advanced breast cancer whose disease has progressed following treatment with anthracycline, taxane and capecitabine therapies (ATC). * On July 30, 2013, Nektar Therapeutics announced that enrollment is complete in the pivotal clinical study of etirinotecan pegol (NKTR-102) in patients with metastatic breast cancer. The Phase 3 study, also known as the BEACON trial, is evaluating etirinotecan pegol versus a single-agent treatment of physician's choice for the treatment of locally recurrent or metastatic breast cancer. Positive Phase 2 data for etirinotecan pegol was previously announced and presented at the ASCO 2011 Breast Cancer Symposium (Garcia et. al., ASCO 2011). Etirinotecan pegol achieved a confirmed objective response rate by RECIST of 29 percent. In addition, 71 percent of patients in the study had no tumor progression, defined as complete response (CR), partial response (PR) and stable disease (SD), as measured by RECIST criteria. Etirinotecan pegol also demonstrated a high clinical benefit rate (CR+PR+SD greater than six months) of 46 percent (30 of 66). Six patients experienced 100 percent resolution of all target lesions, with two complete RECIST responses and four near-complete responses. Patients treated exhibited minimal alopecia, neuropathy and neutropenia, which are significant adverse events associated with existing breast cancer therapies. Side effects were generally manageable; the most common Grade 3 toxicity was diarrhea (17-23%) typically occurring after three months of therapy for both schedules.
