ASCO 2017 Report — Breast Cancer
ASCO 2017 Report — Breast Cancer
- William J. Gradishar, MD
Highlights of the latest treatments
- William J. Gradishar, MD
At this year's annual meeting of the American Society of Clinical Oncology (ASCO 2017), held June 3 to 7 in Chicago, investigators discussed the latest findings in cancer research. The editors of NEJM Journal Watch Oncology and Hematology were on hand to report highlights of the conference. Here, Editor-in-Chief William J. Gradishar, MD, reviews key presentations on new breast cancer treatments. All meeting abstracts can be viewed in the ASCO meeting library.
Abemaciclib for HR-positive/HER2-Negative Metastatic Breast Cancer
The approach to treating patients with ER-positive metastatic breast cancer has changed in the last couple of years with adoption of strategies partnering endocrine therapy with targeted therapy, such as an mTOR inhibitor or CDK4/6 inhibitors. The approved CDK4/6 inhibitors, palbociclib and ribociclib, extend progression free-survival (PFS) for patients when combined with endocrine therapy versus endocrine therapy alone. These two CDK4/6 inhibitors are generally well tolerated, with asymptomatic neutropenia being the most adverse event.
Now, in the MONARCH 2 study (abstract 1000), Sledge and colleagues have evaluated the efficacy and safety of a third CDK4/6 inhibitor, abemaciclib, in patients with HR-positive, HER2-negative metastatic breast cancer who had disease progression on first-line endocrine therapy and who had not received chemotherapy. Patients were randomized to receive fulvestrant with or without abemaciclib.
PFS was prolonged with abemaciclib plus fulvestrant versus fulvestrant alone (16.4 vs. 9.3 months; P<0.0000001). The combination was generally well tolerated, but gastrointestinal symptoms were more common with abemaciclib than what was observed with palbociclib and ribociclib in other trials. Abemaciclib is likely to be the third CDK inhibitor approved in the near future, posing the challenge of how to optimally use these drugs.
Neoadjuvant Pembrolizumab for HER2-Negative Breast Cancer
Checkpoint inhibitors have demonstrated an anti-tumor signal in breast cancer in recent trials, but they have not been approved for breast cancer treatment despite being approved to treat other diseases, such as melanoma and lung cancer. Part of the challenge may be that breast cancer has a “middling” mutational load or expression of neo-antigens, compared with other malignancies.
The I-SPY platform incorporates an adaptive design in the neoadjuvant setting to quickly drop compounds that would appear to have limited success in a larger trial and to proceed with more promising drugs. This approach was used by Nanda and colleagues (abstract 506) to evaluate the role of the immune checkpoint inhibitor pembrolizumab combined with weekly paclitaxel versus paclitaxel alone prior to doxorubicin and cyclophosphamide in the neoadjuvant setting for patients with HER2-negative disease.
The pathological complete response (pCR) rate was higher for patients receiving pembrolizumab than for patients receiving paclitaxel alone (controls) among those with HER2-negative disease (46% and 16%, respectively) as well as among those with HER2-negative/ER-negative disease (60% and 20%) and HER2-negative/ER-positive disease (34% and 13%).
These results signal the promise of checkpoint inhibitors in patients with breast cancer in both the metastatic and adjuvant setting. Numerous trials with a variety of agents in the metastatic disease setting and the adjuvant setting are ongoing. All that remains to complete the story are the data.
Adjuvant Pertuzumab plus Trastuzumab for HER2-Positive Early Disease
The provisional approval of pertuzumab (along with trastuzumab and chemotherapy) by the FDA in the neoadjuvant setting for patients with HER2-positive disease was based on a high pCR rate that was observed in clinical trials. To provide a definitive randomized clinical trial in the adjuvant setting, von Minckwitz and colleagues conducted the long awaited APHINITY trial (abstract LBA500 and NEJM JW Oncol Hematol Aug 2017), in which patients with early stage breast cancer were randomized postoperatively to chemotherapy with trastuzumab for 1 year or chemotherapy with both trastuzumab and pertuzumab for 1 year.
With follow-up of <4 years, patients receiving dual HER2 targeting with trastuzumab and pertuzumab had a superior PFS compared with those receiving trastuzumab (difference, 1.7%; P=0.045). The benefit of pertuzumab was observed across subgroups, but was greatest in patients with node-positive disease (difference, 3.2%) and in those with ER-negative disease (difference, 2.3%).
The addition of pertuzumab to adjuvant chemotherapy and trastuzumab may offer the greatest benefit for those with high-risk disease, whereas those with lower risk disease could avoid the addition of pertuzumab to their adjuvant regimen.
Olaparib for Patients with HER2-Negative BRCA-Mutated Disease
PARP (poly ADP-ribose polymerase) inhibitors have been in development for several years and offer the prospect of a significant anti-tumor effect, particularly in BRCA-mutated tumors. PARPs bind to areas of DNA damage and set up the “scaffolding” to recruit other DNA repair enzymes. In tumor cells that already have DNA repair limitations due to a BRCA mutation, affecting other mechanisms of DNA repair with a PARP inhibitor can lead to cell death. The oral PARP inhibitor olaparib was reported in a small study (Lancet 2010; 376:235) to have anti-tumor activity as a single agent in BRCA-mutated, metastatic breast cancer (objective response rate, 41%).
Now, in the OlympiAD trial (abstract LBA4 and NEJM JW Oncol Hematol Aug 2017), Robson and colleagues evaluated the use of olaparib versus standard chemotherapy in patients with HER2-negative (ER-positive or triple-negative) breast cancer and a known or suspected BRCA mutation. Patients were required to have received prior anthracyclines and taxane therapy and up to two lines of prior chemotherapy in the metastatic disease setting.
PFS (the primary endpoint) favored olaparib versus chemotherapy (7.0 vs. 4.2 months; P<0.009). PFS also seemed to be better in patients who had not received prior platinum therapy. The objective response rate also favored olaparib (69% vs. 31%), but survival was similar with either treatment. Adverse effects of any grade with olaparib were manageable, with nausea, anemia, vomiting, fatigue, and neutropenia being most common. Based on these data, olaparib stands a good chance to be approved as the first PARP inhibitor for treatment of BRCA-mutated disease. Many other PARP inhibitors are also being developed as breast cancer therapies.
Editor Disclosures at Time of Publication
Disclosures for William J. Gradishar, MD at time of publication Editorial boards Clinical Breast Cancer; Oncology Leadership positions in professional societies National Comprehensive Cancer Network (Chair, Breast Cancer Panel)