Significant developments in research and treatment for HER2-positive breast cancer have emerged over the past year. Those advances include a growing number of studies measuring the effectiveness of dual agents.
Lisa A. Carey, MD
Significant developments in research and treatment for HER2-positive breast cancer have emerged over the past year. Those advances include the introduction of a potentially powerful new tool to prevent recurrence in high-risk, early-stage patients, approval of a new therapy for metastatic disease, and a growing number of studies measuring the effectiveness of dual agents.
At the same time, an increasing awareness of the disease’s heterogeneity and the implications for treatment are furthering discussions among clinicians about new approaches to therapy, such as better tailoring the medication they prescribe to patients with different subtypes of the disease.
“With breast cancer, more can be less for some patients, and for others, less can be more. Increasingly, we are looking for tailor-made treatments rather than a layer-upon-layer approach,” said Lisa A. Carey, MD, medical director of the University of North Carolina Breast Center and associate director for clinical science at UNC Lineberger Comprehensive Cancer Center at the university.
As part of these advances, the FDA has recently approved two widely anticipated new treatments for patients with breast cancer.
In the fall of 2013, the FDA granted accelerated approval to pertuzumab (Perjeta) to treat patients with early-stage cancer prior to surgery, making it the first FDA-approved drug for the neoadjuvant treatment of breast cancer. The drug won approval in 2012 as a therapy for patients with advanced or late-stage cancer, but it can now be deployed against HER2-positive, locally advanced, inflammatory or early-stage breast cancer that is at high risk of returning or spreading. In both settings, pertuzumab is used in combination with trastuzumab and chemotherapy.1
In announcing the decision, FDA officials heralded the new indication as a paradigm shift in the treatment of early-stage breast cancer and expressed the hope that it will delay or even prevent recurrence in high-risk patients. The agency’s decision was also striking for its use of pathologic complete response (pCR)the absence of invasive cancer in the breast and lymph nodes—as the endpoint for the drug’s approval. Regulators based their decision on results from the NeoSphere trial, in which about 39% of participants who received pertuzumab plus trastuzumab and docetaxel achieved pCR, compared with about 21% who received trastuzumab plus docetaxel.2
“This was a precedent-setting trial. This approval is a big story,” Carey stated.
Going forward, the FDA will seek further data on efficacy, safety, and long-term outcomes from the confirmatory APHINITY trial, which includes more than 4800 patients who have had surgery and are deemed at high risk of recurrence. The results of that study, a comparison of chemotherapy plus trastuzumab versus chemotherapy plus trastuzumab and pertuzumab as adjuvant therapy, are expected in 2016.3
The most common side effects reported from the Neo- Sphere trial were hair loss, diarrhea, nausea, and a decrease in infection-fighting white blood cells. Other significant side effects included decreased cardiac function, infusion-related reactions, hypersensitivity reactions, and anaphylaxis.2
Earlier in the year, the FDA approved another new therapy, T-DM1 (ado-trastuzumab emtansine, Kadcyla), for patients with HER2-positive, metastatic breast cancer who have been treated with trastuzumab and chemotherapy either separately or together. Evaluated under the agency’s expedited review program, T-DM1 was the fourth drug approved to treat HER2, the others being trastuzumab in 1998, lapatinib in 2007, and pertuzumab in 2012.
The agency’s approval was based on results from the EMILIA trial, whose endpoints were progression-free survival (PFS) and tolerability. The study showed, among other findings, that patients treated with T-DM1 had a median PFS of 9.6 months, compared with 6.4 months in patients treated with lapatinib plus capecitabine. The median overall survival was 30.9 months in the group receiving T-DM1 and 25.1 months in the group receiving lapatinib plus capecitabine.4
The drug is an antibody-drug conjugate (ADC), a new kind of anticancer medicine that targets cell surface antigens as a way of delivering cytotoxins directly to cancer cells, sparing normal tissue. T-DM1, which joins the antibody trastuzumab with the chemotherapy DM1, combines the mechanisms of action of both drugs. It is the first FDA-approved ADC for treating HER2-positive metastatic disease.5
The FDA included a boxed warning in the approval, however, alerting patients and physicians that the drug can cause liver toxicity, cardiac toxicity, and fatality. The most common side effects reported in patients treated with the drug were nausea, fatigue, pain in the muscles or joints, thrombocytopenia, increased levels of liver enzymes, headache, and constipation.6
At the San Antonio Breast Cancer Symposium in December 2013, Martine Piccart-Gebhart, MD, PhD, section head in Breast Diseases at the Free University of Brussels in Belgium and chair of the Breast International Group, presented follow-up results from the NeoALTTO trial, confirming that pCR in HER2-positive cancer treatment translates into improved survival outcomes. The follow-up analysis after 4 years also confirmed the primary outcome of NeoALTTO, that dual HER2 blockade with trastuzumab and lapatinib led to a significantly higher pCR rate than did either drug alone.
“We will be looking for results from the related ALTTO trial for the effectiveness of dual targets versus single target in the adjuvant setting, as well as from the APHINITY trial,” Carey said.
In other developments within the last year, Carey reported potentially important new findings about the molecular heterogeneity of HER2 cancers that may help shape future treatment.
In the CALGB 40601 study,7 for which she was principal investigator, Carey compared the combination of paclitaxel, trastuzumab, and lapatinib with the combination of paclitaxel and trastuzumab in the neoadjuvant setting to determine whether or not pCR in the breast in the dual-agent arm would be 20% greater than pCR in the single-agent group. She found only a 10-point difference, however56% compared to 46%—which did not meet the prespecified improvement required for statistical significance. Nevertheless, the trial, designed to study pCR following neoadjuvant therapy with two HER2-targeted therapies versus one, yielded a wealth of information about the response of various cancer subtypes to both treatment regimens.
“We found that the response rate varied among subsets. The hormone receptor-negative subset of HER2-positive patients did better than the hormone receptor-positive subset with the same treatment. We also looked at more subtle differences, finding, for example, that the subset of HER2-enriched patients within the hormone receptor-negative group did the best,” she said, adding that pCR rate regardless of the treatment arm was different by subtype.
“If our main findingthat the HER2-enriched molecular subtype had much higher pCR rate—is confirmed in other similar trials, we will need to take it into account in therapy considerations,” she said. “If there is a subtype that is exquisitely sensitive to a given treatment, we would not need to use as much, or multiple HER2-targeted agents necessarily. Being more judicious—using less—saves costs and minimizes side effects. As with all breast cancer subtypes, the more we know about the biology, the more tailored we can be in our treatment,” Carey explained.
Patients in CALGB 40601 were required to submit to tumor biopsies as a condition of participation, and Carey has argued that mandatory tissue-based studies should be an element of all future HER2 trials.
“We always planned to look at the biology in our trial from the outset, to better understand not just what happened, but why,” she said, noting that other investigators are planning to conduct molecular examinations following their trials, including NeoALTTO, and then pool their data to verify whether or not her findings are confirmed. “There will be active discussions among investigators looking at this question. Together, we should have about 1000 patients or more,” Carey said.
She noted that a related question may be answered by the ATEMPT trial, which is evaluating whether T-DM1 will have fewer side effects than the traditional HER2-positive breast cancer therapy of trastuzumab and paclitaxel in the treatment of stage 1 patients.
“The idea is to choose a low-risk group and treat those patients with a minimalist approach. Most HER2 adjuvant treatment regimens are complex and aggressive, and this trial will examine whether T-DM1 has a role to play,” she said.