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
“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
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.