LOS ANGELES—Among the many industry shows and events that went virtual due to COVID-19 was the 2020 Virtual San Antonio Breast Cancer Symposium, at which Puma Biotechnology, Inc. shared efficacy data for neratinib in HER2-positive early-stage breast cancer. The results were also published in Clinical Breast Cancer.
The results came from the Phase 3 ExteNET trial, a multicenter, randomized, double-blind trial of 2,840 patients with HER2-positive early-stage breast cancer who received neratinib after neoadjuvant and/or adjuvant therapy with chemotherapy and trastuzumab. Patients were stratified by hormone receptor (HR) status and, once randomized, received either oral neratinib 240 mg/day or placebo for one year. ExteNET's primary endpoint was invasive disease-free survival (iDFS), with secondary endpoints including overall survival and cumulative incidence of central nervous system (CNS) metastases.
“Descriptive analyses suggest that neratinib may be associated with longer overall survival in subgroups of clinical interest and in the high-risk patient subgroup with residual disease after neoadjuvant therapy who are at a high risk of disease recurrence,” said Alan H. Auerbach, president and CEO of Puma Biotechnology. “Although there have been many new treatment options for patients with early-stage HER2-positive breast cancer, the risk of disease recurrence—and more specifically, CNS recurrence—remains significant, and more must be done. These newly published data demonstrate that neratinib provides a clinically meaningful reduction in the risk of recurrence and CNS recurrence, and provides a very important option for these high-risk patients.”
The trial endpoints were analyzed in three groups: (i) the intent to treat (ITT) population; (ii) patients with HR+ breast cancer who initiated treatment within one year of completing a regimen with adjuvant trastuzumab; and (iii) patients with HR+ breast cancer who initiated treatment within one year of completing a regiment with adjuvant trastuzumab and who did not achieve a pathological complete response (no pCR), and therefore were at a high risk of recurrence.
In the ITT population, 127 of 1,420 patients (8.9 percent) in the neratinib group and 137 of 1,420 patients (9.6 percent) in the placebo group died as of the analysis cut-off date (July 2019). The estimated eight-year overall survival (OS) rates were 90.1 percent in the neratinib group and 90.2 percent in the placebo group. The cumulative incidence of CNS metastases at five years was 1.3 percent for the neratinib cohort and 1.8 percent for placebo, while the estimated CNS disease-free survival at five years for the two groups was was 97.5 percent and 96.4 percent, respectively.
In the HR+/ <1 year patient population, 53 of 670 patients (7.9 percent) in the neratinib group and 68 of 664 patients (10.2 percent) in the placebo group died. Estimated eight-year OS rates were 91.5 percent in the neratinib group and 89.4 percent in the placebo group, for a 2.1-percent absolute benefit. The cumulative incidence of CNS metastases at five years was 0.7 percent in the neratinib cohort and 2.1 percent in placebo, while the estimated CNS disease-free survival at five years for the two cohorts was 98.4 percent and 95.7 percent, respectively.
In the HR+ no pCR subgroup, eight-year OS rates of 91.3 percent were seen in the neratinib group and 82.2 percent in the placebo group, for a 9.1-percent absolute benefit. In the HR+/ <1 year group with a pCR (n=38), patients in the neratinib arm saw eight-year OS rates of 93.3 percent while patients in the placebo arm saw 73.7 percent, for a 19.6-percent absolute benefit. The cumulative incidence of CNS metastases at five years was 0.8 percent in the neratinib arm and 3.6 percent in the placebo arm, with an estimated CNS disease-free survival at five years of 98.4 percent and 92.0 percent, respectively.
“These descriptive analyses in HR+ patients who received neratinib within one year of completing trastuzumab and did not achieve a pCR post-neoadjuvant therapy suggest that neratinib may be associated with improved OS in this high-risk group (HR 0.47, absolute benefit 9.1 percent). Importantly, neratinib is the first HER2-directed agent to show a trend towards improved CNS outcomes in early-stage HER2-positive breast cancer, with consistently fewer CNS events observed in the neratinib arm compared with placebo in all groups evaluated,” stated Dr. Frankie Ann Holmes of Texas Oncology Houston–US Oncology Research, an investigator of the ExteNET trial.
As many as 20 percent of breast cancer patients present with tumors that over-express the HER2 protein, and HER2-positive breast cancer is frequently more aggressive than other breast cancer types. According to a Puma Biotechnology spokesperson, “It is estimated that when there is a recurrence, an estimated 30 to 50 percent of the recurrences occur in the CNS.”
“The goal of early-stage treatment for HER2-positive early-stage breast cancer is to reduce the risk of recurrence,” the spokesperson tells DDN. “After a patient completes standard-of-care treatment with an adjuvant trastuzumab-based therapy, neratinib is the only drug that is approved in the extended adjuvant treatment of these early-stage patients to reduce the risk of recurrence. It is estimated that up to 25 percent of patients treated with trastuzumab experience recurrence within 10 years, the majority of which are metastatic recurrences.”
Beyond breast cancer, Puma Biotechnology's spokesperson also notes that the company is evaluating neratinib in patients with “cervical cancer and other solid tumors that have a HER2 mutation, as well as in patients with lung cancer who have an EGFR mutation in exon 18.”