2025-10-23
Brain under pressure: the ultimate frontier?
Oncology
By Ana Espino | Published on october 23, 2025 | 3 min read
Brain 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.
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.
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.
About the author – Ana Espino
As a scientific writer, Ana is passionate about bridging the gap between research and real-world impact. With expertise in immunology, virology, oncology, and clinical studies, she makes complex science clear and accessible. Her mission: to accelerate knowledge sharing and empower evidence-based decisions through impactful communication.
Brain 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 Espino
PhD in Immunology, specialized in Virology
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