Topline results from Phase III trial of NKTR 102 (etirinotecan pegol) in Breast Cancer-Nektar Therapeutics

Nektar Therapeutics has announced topline results from its Phase III BEACON study evaluating single-agent NKTR 102 (etirinotecan pegol) 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 vs 10.3 months for patients receiving TPC). The results 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 vs 4.8 months). 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). 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.

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%).

Comment: Unlike first generation topo I inhibitors that exhibit a high initial peak concentration and short half-life, etirinotecan pegol's unique pro-drug design results in a lowered initial peak concentration of active topo I inhibitor in the blood. The large etirinotecan pegol molecule is inactive when administered. Over time, the body's natural enzymatic processes slowly metabolize the linkers within the molecule, continuously freeing active drug that then works to stop tumor cell division through inhibition of topo I.