During the past 2 years, there have been a number of advancements in the treatment of metastatic breast cancer that include the development of novel agents and new strategies in several disease settings, resulting in improved outcomes for patients.
Erika P. Hamilton, MD
Director, Breast and Gynecologic Cancer Research Program
During the past 2 years, there have been a number of advancements in the treatment of metastatic breast cancer (MBC) that include the development of novel agents and new strategies in several disease settings, resulting in improved outcomes for patients. The following is an overview of recent milestones in MBC research and highlights of research going forward:The clinical development of targeted therapies for breast cancer has been driven by both molecular classification and the identification of alterations in cellular signaling pathways within this disease.
Most recently, on February 19, 2016, the FDA extended the approval of palbociclib, a CDK 4/6 inhibitor, to women in combination with fulvestrant based on results from the PALOMA3 trial. In this study, women with aromatase inhibitor (AI)—resistant, hormone receptor (HR)–positive MBC were randomized 2:1 to receive fulvestrant plus palbociclib or placebo. There was an observed doubling in progression-free survival (PFS) with palbociclib compared with the control regimen (9.5 months vs 4.6 months; HR 0.461, P <.001).1,2
The earliest targeted therapies for breast cancer, tamoxifen and AIs, inhibited estrogen production and the estrogen receptor (ER), which led to improved outcomes for women with HR-positive MBC. Resistance mechanisms such as activation of the PI3K/Akt/mTOR pathway have now been recognized.
BOLERO-2 demonstrated that the combination of an mTOR inhibitor and an AI improves PFS in postmenopausal women with hormone-resistant advanced breast cancer, resulting in the first mTOR inhibitor approved for this population, everolimus. Inhibitors of this pathway have met with mixed success. The FERGI trial evaluated pictilisib, a pan-PI3K inhibitor, in combination with fulvestrant in HR-positive MBC resistant to AIs. No improvement was seen in either PI3K-mutant or wild-type (WT) tumors;3 however, in subset analysis, there was benefit for patients whose tumors were both ER-positive and progesterone-positive.
More recently, results from the BELLE-2 trial revealed a modest improvement in PFS when buparlisib, a pan-PI3K inhibitor, was added to fulvestrant compared with fulvestrant alone (6.9 months vs 5.0 months, respectively; P <.001).4
In contrast to FERGI, subset analysis of BELLE-2 data demonstrated improvement in PFS only for patients with PIK3CA mutations detected in circulating tumor DNA, and not for those with wild-type PIK3CA (7.0 months vs 3.2 months, respectively; P <.001). Phase III trials with alpha-specific PI3K inhibitors are underway (NCT02437318, NCT02340221).
ER itself has been implicated in the development of endocrine resistance, and selective ER down regulators (SERDs) such as fulvestrant have been successful here. Resistance to endocrine therapy is also mediated by mutations in ESR1, the gene encoding ER. Recent data using cell-free DNA isolated from blood samples from patients enrolled on BOLERO-2 revealed a 29% ESR1 mutation rate in essentially first- and second-line metastatic patients.5
The presence of ESR1 mutations led to a shorter median overall survival (OS) of 32.1 months in wildtype disease versus 20.7 months in ESR1 mutants; HR 1.40, P = .000037). Also noted was the increased frequency of ESR1 mutations in patients who had already been treated with AIs in the metastatic setting.
HER2-Amplified Breast Cancer
The novel SERDs GDC-0810 and AZD9496, which are orally bioavailable and have demonstrated activity in ESR1-mutant cell lines, are now being evaluated in clinical trials (NCT02569801; NCT02248090).Single-agent trastuzumab emtansine (T-DM1), the first antibody—drug conjugate approved for the treatment of breast cancer, was found to prolong OS in patients with HER2-positive MBC. The median OS was 22.7 months with T-DM1 versus 15.8 months for patients assigned to physician’s choice (HR 0.68; P = .0007).6
Trials are underway with T-DM1 in both the neoadjuvant and adjuvant settings, and it remains to be determined whether we will soon be using it in the early disease setting as modeled by pertuzumab.
Monoclonal antibodies like trastuzumab and pertuzumab and small molecule tyrosine kinase inhibitors (TKIs) like lapatinib are effective therapies for the treatment of breast cancer overexpressing HER2, but resistance to anti-HER2 therapies is inevitable.
Further, more than 50% of patients with HER2-positive MBC will develop central nervous system (CNS) metastases, as many of our very effective systemic agents do not cross the blood-brain barrier (BBB) well.
Novel TKIs like ONT-380, which crosses the BBB well, are being evaluated. ONT-380 is a potent oral inhibitor of HER2 that is more than 500- fold selective for HER2 over EGFR, resulting in reduced potential for EGFR-mediated side effects such as diarrhea and rash.
Phase I trials have evaluated ONT-380 in combination with trastuzumab plus capecitabine, and with T-DM1 in heavily pretreated HER2-positive MBC patients. Both have shown encouraging activity systemically and in patients with CNS metastases.7,8 Based on these results, a randomized phase II trial evaluating ONT-380/placebo in combination with capecitabine plus trastuzumab is underway (NCT02614794).Immunotherapy is now being explored in breast cancer after impressive results in melanoma, lung cancer, and renal cell carcinoma. At the 2015 San Antonio Breast Cancer Symposium, we saw reports of three agents’ activity in MBC.
JAVELIN evaluated the anti-PD-L1 antibody avelumab in heavily pretreated patients with patients unselected for PD-L1 and HR or HER2 status. Response rates were 2.8% in HR-positive patients, 3.8% in HER2-positive patients, and 8.6% in patients with triple-negative breast cancer (TNBC).9 The overall response rate (ORR) was 33.3% in patients with PD-L1—positive tumors (4/12 patients) versus 2.4% in participants with PD-L1-negative tumors (3/124 patients).
Preliminary results from another anti-PD-L1 antibody, atezolizumab, were reported in combination with nab-paclitaxel in 24 patients with mTNBC. The combination was well tolerated and confirmed ORR was 42%.10
Finally, pembrolizumab, an anti-PD-1 antibody, was evaluated in PD-L1—positive, HR-positive MBC in the KEYNOTE-028 trial and demonstrated an ORR of 12% and a clinical benefit rate of 20%.11
It remains to be determined whether immunotherapy would prove to be more efficacious in a subset of breast cancer such as TNBC, where we see both a high mutation rate that may result in increased immunogenic neoantigens and high levels of tumor-infiltrating lymphocytes whose presence has been associated with improved outcomes.
Another question is whether we can predict which patients are most likely to respond to immunotherapy strategies such as tumor or immune cell testing for PD-L1/PD-1 expression. Finally, we may be able to improve our response rates and the durability of responses by combining immunotherapeutic strategies, and many of these combination studies are underway.