In the phase III BEACON trial, etirinotecan pegol missed the primary endpoint of significantly extending overall survival versus physician's choice of therapy.
Javier Cortes, MD
In the phase III BEACON trial, etirinotecan pegol (NKTR-102) missed the primary endpoint of significantly extending overall survival (OS) versus physician’s choice of therapy in patients with breast cancer, according to Nektar Therapeutics, the company developing the drug. In a silver lining, Nektar reported that NKTR-102 significantly improved OS among patient subgroups with either brain or liver metastases.
Among the overall patient population, there was a nonstatistically significant 2.1-month (P = .08) OS improvement for patients receiving NKTR-102. In patient subgroups with brain and liver metastases, there was a significant OS benefit of 5.2 months (P <.01) and 2.6 months (P <.002), respectively.
“In BEACON, NKTR-102 provided a clinically meaningful benefit with a greater than 2-month survival advantage in these late-stage breast cancer patients, many who were refractory to existing therapies,” said Javier Cortes, MD, director of the Breast Cancer Program at Vall d'Hebron University Hospital in Spain, in a statement.
“Of particular significance, median survival in patients with brain metastases was more than double on NKTR-102,” added Cortes, who served as co-principal investigator of the study, along with Edith A. Perez, MD, deputy director of the Mayo Clinic Cancer Center.
The topoisomerase inhibitor polymer conjugate NKTR-102 is an improved formulation of irinotecan. NKTR-102 has an extended half-life compared with irinotecan, with a lower peak initial concentration and higher trough level, which suggests improved consistency in exposure to active drug.
“Given the frequency of cross-resistance and overlapping toxicities observed with many available agents, NKTR-102 would offer a new mechanism of action for physicians and patients in the fight against advanced breast cancer,” said Joyce O'Shaughnessy, MD, a lead BEACON investigator and steering committee member in the United States.
“The results in the subgroups of patients with both liver and brain metastases are noteworthy because NKTR-102 is designed to enhance concentration of its active metabolite in highly vascular tumor environments. From a clinician’s perspective, the combination of NKTR-102’s clinical benefit and improved tolerability supports its value as a potential new treatment option in late-stage breast cancer,” added O’Shaughnessy, who is chair, Breast Cancer Research, The US Oncology Network and the Baylor Sammons Cancer Center, Texas Oncology.
The open-label, multicenter, international phase III BEACON trial randomized 852 women with recurrent or metastatic breast cancer to NKTR-102 or physician’s choice of therapy. All patients had disease progression after receiving an anthracycline, a taxane, and capecitabine.
Patients in the NKTR-102 arm received 145 mg/m2 of the drug as a 90-minute IV infusion on day 1 of continuous 3-week cycles. Physician’s choice of standard therapy in the control arm included single-agent eribulin, ixabepilone, vinorelbine, gemcitabine, paclitaxel, docetaxel, or nab-paclitaxel.
OS was the primary outcome measure for the study. Secondary outcome measures included progression-free survival (PFS) and overall response rate (ORR).
The median OS in the overall study population was 12.4 months for the NKTR-102 arm, compared with 10.3 months in the control group. The HR for survival of 0.87 was not statistically significant.
The study also did reach its secondary endpoint of a significant PFS benefit with NKTR-102, according to Nektar.
Among 67 patients with a history of brain metastases, treatment with NKTR-102 improved OS by 49% compared with standard care (10.0 vs 4.8 months; HR = 0.51). Twelve-month OS rates were 44.4% and 19.4%, respectively, for the treatment and control arms.
In patients with liver metastases at baseline (n = 456), OS was 10.9 months with NKTR-102 versus 8.3 months with physician’s choice of care (HR = 0.73). Twelve-month OS rates were 46.9% and 33.3% in the two arms, respectively.
Grade ≥3 adverse event (AE) rates were lower in the NKTR-102 arm versus the control arm at 48% versus 63%.
The most frequently observed grade ≥3 AEs in the NKTR-102 arm included neutropenia (9.6%), diarrhea (9.6%), anemia (4.7%) and fatigue (4.5%). No incidents of grade 4 diarrhea were reported with NKTR-102.
In the control arm, the most commonly reported AEs ≥ grade 3 were neutropenia, anemia, and dyspnea, at 30.8%, 4.7%, and 4.4%, respectively.
Rates of grade 1/2 alopecia and grade ≥3 neuropathy were lower in the NKTR-102 group versus the control group at 10% versus 23% and 0.5% versus 3.7%, respectively.
“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,” said Cortes.
The BEACON trial was launched following positive results from a phase II study reported at the 2011 ASCO Annual Meeting, in which NKTR-102 had an ORR of 29% in 70 patients with metastatic breast cancer who had received at least two prior treatment regimens.
Nektar reported that it intends to submit the full data from the BEACON trial for presentation at an upcoming scientific meeting. The company also plans to continue to examine and interpret the results.
“It is clear from our BEACON study that NKTR-102 has potential as an important anticancer agent when compared to the best available treatment options today for women with advanced breast cancer,” said Howard W. Robin, president and CEO 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.”