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Novel agent crosses blood-brain barrier to treat CNS metastases from breast cancer
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COPENHAGEN, Denmark — ANG1005, a novel peptide–paclitaxel conjugate, demonstrated activity and crossed the blood-brain barrier in women with recurrent brain metastases from breast cancer, according to results of an open-label, phase 2 study presented at the European Society for Medical Oncology Congress.
ANG1005 (Angiochem) is a novel taxane derivative that consists of three paclitaxel molecules that are covalently linked to Angiopep-2, a peptide designed to use the LRP-1 transport system to cross the blood-brain barrier and attack tumor cells.
“Breast cancer is very sensitive to paclitaxel, which is the chemotherapy base for this novel agent,” Shou-Ching Tang, MD, PhD, FACP, FRCPC, professor of medicine and leader of the breast cancer multidisciplinary team at Augusta University Cancer Center, told HemOnc Today. “Therefore, the drug conjugate should be effective against these metastases if it can be delivered intracranially.”
Tang and colleagues evaluated 600 mg/m3 IV ANG1005 in 130 women (median age, 47.5 years, range, 26-76) with measurable brain metastases, 32% of whom had newly diagnosed leptomeningeal carcinomatosis. Seventy-two women were included in the safety population and 58 were included in the efficacy population.
Patients received a median of six (range, 1-29) prior therapies for breast cancer, and 84% had received prior taxane treatment. Eighty-seven percent of women underwent cranial surgery and 19% had received systemic therapies for brain metastases.
Overall, the best intracranial response in the efficacy population included ten women (17%) with partial responses — with a 7% partial response rate confirmed by MRI 6 weeks later — and 31 (54%) with stable disease. This included a 21% partial response rate in women with HER–2-positive disease, 13% in women with HER–2-negative disease and 17% with triple-negative disease.
Among 34 patients evaluable for extracranial tumor responses — 93% of whom had previously received a taxane — one (3%) achieved a complete response, two (6%) achieved a partial response and 27 (79%) demonstrated stable disease. These data equated to a clinical benefit rate of 88%. Further, 93% of patients with HER–2-positive disease achieved stable disease.
There was a concordance between intracranial and extracranial tumor response in evaluable patients, Tang said. Twenty-two patients achieved stable disease as best response in both the peripheral and central nervous system, whereas three patients had progressive intracranial and extracranial disease, equating to a concordance rate of 54%.
Among patients with leptomeningeal carcinomatosis, the rate of 6-month OS was 63.6 % (95% CI, 42.9-78.5) and estimated median OS was 34.6 weeks (95% CI, 24.1-40.9), or approximately 8 months from first ANG1005 treatment.
Conversely, historical median OS for leptomeningeal carcinomatosis is 1 to 2 months without treatment, and 3 to 4 months with treatment, Tang said.
“Patients with leptomeningeal carcinomatosis or metastasis were originally excluded from the phase 2 trial,” Tang said. “When the trial was changed to allow them to enroll, the survival in those patients was greatly improved over historical expectations. This has led to additional study in this subgroup of patients with recurrent brain metastasis because they have a very poor prognosis.”
After treatment, patients — including those with leptomeningeal carcinomatosis — demonstrated improved CNS clinical symptoms.
Researchers noted that adverse events that occurred were comparable with those that occur with single-agent paclitaxel. Myelosuppression was the most common toxicity.
“Patients with brain metastases are not treated with paclitaxel for their brain metastases because the drug does not cross the blood-brain barrier,” Tang said. “But breast cancer is very sensitive to paclitaxel outside the brain. Therefore, to use this drug conjugate to cross the blood-brain barrier provides the intracranial space with a very active drug against the metastatic tumors in the brain and the meninges.”
Based on these data, a randomized pivotal study in patients with breast cancer with brain metastases and leptomeningeal carcinomatosis is planned to compare ANG1005 vs. physician’s best choice, Tang said. – by Alexandra Todak
Reference:
Tang S-C, et al. Abstract 324O. Presented at: European Society for Medical Oncology Congress; Oct. 7-11, 2016; Copenhagen, Denmark.
For more information:
Shou-Ching Tang, MD, PhD, FACP, FRCPC, can be reached at Medical College of Georgia, Augusta University, 1411 Laney Walker Blvd., Augusta, GA; email: stang@augusta.edu.
Disclosure: Tang reports no relevant financial disclosures. One researchers reports research funding from or uncompensated advisory roles with Angiochem, Genentech, Geron, Kadmon, Lilly, Merck, Merrimack, Nektar, Novartis, Oncothyreon, PUMA, Sanofi and toBBB.