Combining Puma Biotechnology’s candidate therapy PB272, also known as neratinib, with the chemotherapy drug Xeloda (capecitabine) appears to have therapeutic potential for patients with advanced HER2-positive breast cancer and brain metastasis, who were not previously treated with Tykerb (lapatinib), a clinical study reports.

Results from the ongoing, multicenter Phase 2 trial (NCT01494662) found this combo therapy effectively shrank metastatic brain tumors in nearly half of treated patients, and did so with tolerable toxicity. These positive results support further research into the use of neratinib to treat breast cancer patients with brain metastases.

The findings were featured in an oral presentation, “TBCRC 022: Phase II trial of neratinib + capecitabine for patients (Pts) with human epidermal growth factor receptor 2 (HER2+) breast cancer brain metastases (BCBM),” given at the recent 2017 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago. The presentation is also available on Puma’s website.

“As a small molecule that can cross the blood brain barrier, neratinib potentially offers patients with HER2-positive metastatic breast cancer that has metastasized to the CNS a novel HER2 targeted treatment option,” Alan Auerbach, CEO and president of Puma Biotechnology, said in a press release.

Lead by investigators at Dana-Farber Cancer Institute, in collaboration with the Translational Breast Cancer Research Consortium (TBCRC), the Phase 2 trial includes three cohorts of patients with breast cancer and brain metastasis larger than 1 cm.

In the first cohort, a total of 40 patients were given neratinib as a stand-alone therapy. Results were published in the Journal of Clinical Oncology, in the study “Translational Breast Cancer Research Consortium (TBCRC) 022: A Phase II Trial of Neratinib for Patients With Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer and Brain Metastases.” They showed that neratinib alone failed to produce treatment response in at least four patients, the primary objective for this group, and did not demonstrate active therapeutic potential.

The second cohort consists of five patients with brain metastasis who are suitable candidates for surgery to remove the tumor. These patients are receiving neratinib monotherapy before and after surgical treatment. Results on this cohort will be presented at a future medical meeting.

To improve neratinib’s activity in the central nervous system (CNS), researchers are also testing its efficacy in combination with chemotherapy. In the third cohort, so far comprising 39 patients and expected to reach a total of 60, all patients received once-daily, oral neratinib, with additional twice-daily Xeloda, for 14 days followed by seven days off-treatment.

Results from this cohort, presented at the ASCO 2017 meeting, focused on those patients who had not received prior treatment with ‎Tykerb, a targeted chemical therapy. About 30 percent of patients had undergone surgery, 65 percent had received prior whole brain radiotherapy, and 35 percent had been given stereotactic radiosurgery to the brain. Stereotactic radiosurgery is a type of focused radiation beam therapy to lessen the impact on surrounding healthy tissue.

The combination of neratinib plus Xeloda was seen to promote a CNS objective response, using a combination of measurements, in about 49 percent of the patients. Under a secondary trial measure that reported response according to criteria known as RANO-BM (response assessment in neuro-oncology-brain metastasis), 24 percent showed a CNS objective response.

Patients had a median time to CNS progression of 5.5 months, and median overall survival was 13.5 months, but survival data are still immature, the researchers said.

The combo therapy was well-tolerated, with the most common treatment-related adverse event being treatable diarrhea.

“Neratinib given in combination with capecitabine showed promising activity in patients with heavily pre-treated HER2-positive disease metastatic to the CNS,” said Rachel Freedman, MD, with the Dana-Farber Cancer Institute.

“Despite the introduction of several new treatments for patients with HER2-positive metastatic breast cancer, CNS progression events remain a major source of patient morbidity and mortality. Based on the results from TBCRC-022 [the clinical trial], we look forward to additional trials with neratinib-based regimens for HER2-positive CNS disease,” Freedman added.