By Ana Espino | Published on October 23, 2025 | 3 min readBrain metastases are a frequent and severe
complication of advanced cancers, particularly non–small cell lung cancer
(NSCLC) and metastatic breast cancer (MBC). They significantly
worsen prognosis and quality of life, while remaining difficult to manage due
to the blood–brain barrier (BBB), which limits the penetration of
conventional chemotherapies into brain tissue.
Current therapeutic options rely primarily on local
treatments (surgery, radiotherapy), but these are often exhausted in
patients with active or progressive brain disease. Therefore, finding
chemotherapeutic agents that can effectively cross the BBB remains a
critical — and largely unresolved — challenge.
Against this backdrop, this study was designed
to evaluate the intracranial efficacy and tolerability of etirinotecan
pegol (EP) — a long-acting formulation of irinotecan — in patients with active
brain metastases resistant to local treatments.
Etirinotecan: hope or cerebral illusion?
A total of 27 patients were enrolled in
the study: 12 with NSCLC, 12 with metastatic breast cancer, and 3
with small cell lung cancer (SCLC). All participants had active brain
metastases and had previously undergone local treatments (radiotherapy and/or
surgery).
Etirinotecan pegol was administered every three
weeks at a fixed dose, with radiological evaluations every six weeks.
The primary endpoint was the 12-week
intracranial disease control rate (including partial response, complete
response, or stable disease). This rate was low — 17% in both the
NSCLC and MBC cohorts (2 patients per group), and 0% in the SCLC group.
No prolonged benefit or complete intracranial response was observed.
Regarding progression-free survival (PFS),
outcomes were modest : 2.6 months for NSCLC patients,
1.4 months for MBC patients.
Median overall survival (OS) was 7
months (NSCLC) and 8.5 months (MBC) — roughly comparable to current
standards of care.
In terms of tolerability, treatment was
associated with frequent adverse effects, including diarrhea (48%), nausea
(48%), and fatigue (26%), along with serious toxicities such as sepsis
and dehydration. There were six deaths during the study, three of which were
considered possibly treatment-related — raising concerns about the
safety profile of etirinotecan pegol in an already vulnerable patient
population.
Too toxic to convince?
Brain metastases in advanced cancers represent
a major therapeutic challenge, especially after failure of local
treatments. This study sought to explore a systemic solution using
etirinotecan pegol, targeting a patient population with few effective
therapeutic options.
However, results indicate limited
intracranial activity, notable toxicity, and no clear clinical
benefit. The low disease control rate, combined with the severity of
adverse events, suggests that this treatment cannot currently be recommended
for this indication.
Nonetheless, the study underscores the urgent
need to develop chemotherapeutic agents capable of crossing the BBB more
selectively and safely. Future research should focus on novel
formulations, innovative drug combinations, and targeted
therapeutic approaches to improve management of active brain metastases
in breast and lung cancer.
Read next: TNBC after chemotherapy: can immunotherapy change the game?
About the author – Ana EspinoPhD in Immunology, specialized in Virology
