The annual meeting of the American Society of Clinical Oncology (ASCO) provides a fascinating glimpse at themes that capture the interest and attention of leading researchers and clinicians worldwide. We look for the oral presentations that have the potential to change practice, but there are many lessons to be learned in educational sessions and posters as well.
With my interest in the care of patients with breast cancer, I found it fascinating that ASCO devoted an educational session to issues that concern premenopausal women with breast cancer and that it covered innovation in surgical practice, fertility preservation, and use of endocrine therapies. In addition, many posters addressed important quality-of-life concerns of young women with breast cancer, and these are crucial to inform decision-making in the clinic.
I was also struck by the inclusion of two important studies on bone-modifying agents (Dr Julie Gralow's comparison of oral and intravenous bisphosphonates and Dr Michael Gnant's study of low-dose denosumab (Prolia®) for prevention of fractures related to the use of aromatase inhibitors in postmenopausal women) in the oral breast cancer sessions, because this focus shows that the research community is seriously attempting to solve many of the problems related to side effects of treatment that are so important for the community of patients.
The studies that caught my eye were primarily from among the oral presentations. Here are what I consider the take-home messages in breast cancer from ASCO 2015.
HER2-Positive Breast Cancer
Studies have shown that achieving a pathologic complete response (CR) after neoadjuvant chemotherapy is associated with improvement in event-free survival and overall survival (OS), and it is always interesting to hear long-term outcome results to see whether this relationship really "holds". At this meeting, Dr Luca Gianni presented the 5-year analysis of the phase 2 NeoSphere trial. This study randomly assigned patients with HER2-positive breast cancer to receive trastuzumab + docetaxel OR pertuzumab + trastuzumab + docetaxel OR pertuzumab + trastuzumab OR pertuzumab + docetaxel, preoperatively. After surgery, all patients (except those not receiving docetaxel) received three cycles of FEC (fluorouracil, epirubicin, cyclophosphamide) chemotherapy and completed a year of trastuzumab. Those who did not receive docetaxel preoperatively received four cycles of docetaxel before the planned chemotherapy with FEC. This was done to ensure that all patients received the same chemotherapy backbone. A planned intention-to-treat (ITT) analysis was conducted. Patients were evenly split according to hormone receptor (HR) status.
Pertuzumab + trastuzumab without chemotherapy was better tolerated, but progression-free survival (PFS) was highest in the arm that received pertuzumab + trastuzumab + docetaxel. Dr Gianni showed a Forest plot that illustrated better PFS for patients who achieved a pathologic CR.
A comparison between pertuzumab + trastuzumab and pertuzumab + trastuzumab + docetaxel favors the triplet. The benefit was more pronounced in patients with HR-negative breast cancer. In conclusion, the combination of neoadjuvant pertuzumab + trastuzumab plus the taxane improved long-term outcomes especially for those with HR-negative disease and those who achieved a pathologic CR after neoadjuvant pertuzumab, suggesting a carryover effect of the addition of the second antibody, given the fact that adjuvant therapy was identical for all patients in this study.
We finally heard 2-year follow-up data from investigators of the ExteNET study, which explored the benefit of neratinib after a year of adjuvant therapy with trastuzumab for patients with HER2-positive disease. You may remember the TEACH study presented a few years ago which looked at the possible benefit of the delayed addition of lapatinib (Tykerb®), an oral tyrosine kinase inhibitor for patients with HER2-positive disease. Patients in the earlier study had not received adjuvant trastuzumab containing chemotherapy, and the study did not show a significant benefit.
In the case of the ExteNET study, however, all patients were treated with contemporary trastuzumab-based chemotherapy and received a year of trastuzumab. The question asked was whether sequential anti-HER2 therapy with neratinib, an oral tyrosine kinase irreversible inhibitor of HER1, HER2, and HER4, could improve outcomes for a population of women at high risk for relapse.
Presenting for ExteNET investigators, Australian researcher Arlene Chan reminded the audience that this population has a 23%-26% chance for relapse or any "breast cancer event" and that the landmark HERA trial failed to show improvement by extending treatment with trastuzumab alone. In this study, HER2 was assessed by local pathologists, and all participants needed to be free of disease at the time of enrollment, following completion of adjuvant trastuzumab-based chemotherapy.
There were numerous protocol amendments that delayed the study and changed the emphasis, and finally the third sponsor restored the initial design calling for a 5-year follow-up. Since the study began, interesting data from I-SPY2 suggested that the combination of neratinib and paclitaxel is particularly effective.
The ExteNET trial enrolled 2821 patients (median age, 52 years) with stage 1-3 HER2-positive breast cancer. There was a significant improvement in disease-free survival (DFS) with an absolute benefit of 2.3% at 2 years for all patients, including a decrease in central nervous system events. Of great interest, patients with HR-positive breast cancer had even greater benefit from neratinib (4.2% absolute benefit). The major toxicity was diarrhea, with 40% of patients experiencing grade 3 diarrhea in the first 30 days of treatment. There was no protocol-mandated antidiarrheal prophylaxis in place. Studies have since shown that loperamide prophylaxis ameliorates or prevents this side effect.
With a 2-year follow-up, it appears that the late addition of neratinib decreases breast cancer-related events at the expense of considerable diarrhea, and that the latter could be managed by a structured regimen of antidiarrheal prophylaxis.
ExteNET and NeoSphere were perhaps the two most important studies presented.
Endocrine Therapy and Bone Health
Aromatase inhibitors (AIs) remain the cornerstone of adjuvant endocrine therapy for postmenopausal women and some premenopausal women considered to be at high risk for relapse (used with ovarian suppressive therapies). Michael Gnant presented results of ABCSG-18, a study designed to investigate the role of adjuvant denosumab in regard to bone density, fractures, and outcomes in women taking AIs. In this phase 3 study, 3425 women were randomly assigned to receive denosumab at a dose of 60 mg subcutaneously every 6 months or placebo, and 75% of participants received endocrine therapy alone. Investigators assessed the time to first clinical fracture. There were six endpoints, including the percentage change in bone mineral density and the incidence of vertebral fractures. Some 55% of patients had a normal bone mineral density at the time of entry into the study. Outcomes will be presented at a later date.
Investigators found that denosumab significantly delayed the time to first clinical fracture compared with placebo, without any apparent side effects (note that the incidence of osteonecrosis of the jaw and atypical femoral fractures was nil). There were 176 clinical fractures in the group that received placebo, suggesting a staggering 10% incidence of fractures at 3 years. The number of fractures only got worse with prolonged follow-up, with a 19% incidence at 6 years. Denosumab cut the fracture risk in half. The true magnitude of this finding emerges when one considers that 20% of women will experience a fracture during their time on AI therapy. Gnant noted this even in women with an apparently normal T-score at entry.
This study certainly caused considerable discussion among US oncologists who were surprised at the high incidence of reported fractures, impressed by the benefit of the drug, and frustrated at their inability to prescribe the drug due to the staggering cost.
CDK4/6 Inhibitors: Important Therapeutic Advance
Dr Nick Turner presented results of the PALOMA3 trial. This study enrolled 521 patients with metastatic HR-positive and HER2-negative breast cancer that had relapsed or progressed during prior endocrine therapy.
Growth of HR-positive breast cancer relies ion cyclin-dependent kinases 4 and 6 (CDK4 and CDK6), which promote progression from the G1 phase to the S phase of the cell cycle.
Participants were randomly assigned (2:1) to receive palbociclib (Ibrance®; an inhibitor of CDK 4 and 6) and fulvestrant (Faslodex®) or placebo and fulvestrant. Premenopausal or perimenopausal women also received goserelin (Zoladex®). Most of the patients had received prior treatment with AIs. The median PFS was 9.2 months for those treated with palbociclib + fulvestrant and 3.8 months with placebo + fulvestrant. The most common grade 3 or 4 adverse events in the palbociclib arm were neutropenia, leukopenia, anemia, and fatigue, with < 1% incidence of febrile neutropenia in both arms. The rate of discontinuation of palbociclib was 2.6% and 1.7% with placebo. Dr Turner concluded that among the group of patients whose disease had progressed on prior endocrine therapy, which typically included an AI, the combination of palbociclib with fulvestrant was well tolerated and resulted in longer PFS than with fulvestrant alone. He reminded the audience that this was the first demonstration of benefit for premenopausal women.
Commenting on the study, Dr Joseph Sparano remarked that CDK4/6 inhibitors represent an important therapeutic advance in HR-positive metastatic breast cancer. This was not the only presentation that addressed this promising group of drugs that we will see combined with other pathway inhibitors and endocrine therapy for women with advanced breast cancer and that are currently being investigated in the adjuvant setting.
Medscape Oncology © 2015 WebMD, LLC
Cite this: Lidia Schapira. Neratinib Lowers Recurrence in High-Risk HER2+ Breast Cancer - Medscape - Jun 15, 2015.