Rashmi K. Murthy, MD
HER2-positive breast cancer accounts for 20% of all invasive breast cancers, and was, for several decades, the subtype of breast cancer with the poorest prognosis. With the options available today, a HER2-positive diagnosis can still mean a long and healthy future for a patient, according to Rashmi K. Murthy, MD.
The monoclonal antibody trastuzumab (Herceptin) has had a journey in the breast cancer space that has spanned several decades. The FDA approved the agent in 1998 for the treatment of patients with HER2-positive metastatic breast cancer, and then gained an indication for HER2-positive early-stage breast cancer in the adjuvant setting in 2006. The pivotal trials that established the agent as a standard option for early-stage HER2-positive breast cancer were HERA, NSABP B-31/NCCTG, BCIRG-006, FinHer, and PACS 04.
In a presentation during the 2018 OncLive®
State of the Science Summit™ on Breast Cancer, Murthy, an assistant professor, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, discussed selecting therapy for patients with HER2-positive breast cancer in the curative setting.
Murthy detailed the roles of dual HER2-targeting, extended adjuvant therapy, targeting high-risk patients, shorter duration of trastuzumab, and less toxic regimens for patients with HER2-positive breast cancer.
Despite these advances in HER2-positive breast cancer treatment, about one-third of patients still have a recurrence, said Murthy.
“There has been a need to look at strategies, [such as in] the neoadjuvant setting. There were trials done around the same time that showed that patients who received neoadjuvant trastuzumab had higher rates of pathological complete response (pCR),” said Murthy. “A neoadjuvant approach is nice in that it has several unique advantages from downstaging the patient for surgery, earlier treatment of micrometastatic disease, and also serving as a tool for estimation of prognosis as well as selection of patients who are higher risk for clinical trials.”
It has been discovered that patients who have residual disease following neoadjuvant trastuzumab plus chemotherapy are at a much higher risk of recurrence, added Murthy. This has caused investigators to develop strategies to escalate therapy and to develop additional drugs.
Neoadjuvant and Adjuvant Dual HER2-Targeting
Patients who receive 2 HER2-targeted drugs in the neoadjuvant setting have better pCR compared with receiving a single HER2-targeting agent, according to Murthy. The first partner for trastuzumab in this space was lapatinib (Tykerb).
The NeoALTTO and ALTTO studies, in the neoadjuvant and adjuvant settings, respectively, evaluated the use of lapatinib and trastuzumab; neither trial showed a connection between pCR improvement and overall survival.
NeoALTTO specifically explored the combination of paclitaxel plus trastuzumab and lapatinib. Neoadjuvant therapy with dual HER2 inhibition significantly improved the odds of pCR in patients with early disease, though patients who received a single HER2-targeted agent had similar rates of pCR.1
ALTTO evaluated adjuvant lapatinib plus trastuzumab; results showed that it did not produce a statistically significant advantage over single-agent trastuzumab.2
Due to the toxicity of lapatinib and lack of improvement in long-term outcomes in ALTTO, this regimen was not approved in the adjuvant setting.
The next candidate for combination with trastuzumab was pertuzumab (Perjeta).
In September 2013, the FDA approved pertuzumab in combination with trastuzumab and chemotherapy for the neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory, or early-stage breast cancer. This approval was based on phase II findings from the NeoSphere trial, which showed an improvement in pCR. Data from the phase II TRYPHAENA study and the phase III CLEOPATRA study were also considered in this approval.
In the adjuvant setting, findings from the phase III APHINITY trial of patients with HER2-positive early breast cancer at high risk for recurrence showed that the combination demonstrated a 3-year invasive disease-free survival (iDFS) rate of 94.1% versus 93.2% for those who received trastuzumab plus chemotherapy and placebo at 3 years, representing a 18% reduction in the risk of developing invasive disease or death (HR, 0.82; 95% CI, 0.67-1.00; P
At 4 years, the iDFS rates was 92.3% for the combination. These results supported the FDA's decision to approve the combination for this adjuvant indication in December 2017.