Essential Updates: HER2+ Metastatic Breast Cancer

Linda Brookes, MSc

Disclosures

October 24, 2016

Editor's Note:
At the 2016 Annual Meeting of the European Society for Medical Oncology, a trio of experts—Javier Cortés, MD, PhD; Heikki Joensuu, MD, PhD; and Sherene Loi, MD, PhD—discussed the best evidence and best practices in the management of HER2-positive (HER2+) metastatic breast cancer and pointed to the most promising new agents in development.

"Prognosis for patients with HER2+ metastatic breast cancer has clearly improved following the introduction of anti-HER2 therapies, but many patients, if not the majority, will die of the disease," stressed Prof Javier Cortés, MD, PhD (Ramón y Cajal University Hospital, Madrid, and Vall d'Hebron Institute of Oncology, Medica Scientia Innovation Research, Barcelona, Spain). "In my opinion, in HER2+ breast cancer, there is still an unmet need. That is why it is important to discuss second-line and salvage therapies and new treatment options," he stated.

First-Line, Second-Line, and Salvage Therapies

Standard first-line therapy for patients with advanced HER2+ breast cancer is a combination of pertuzumab, trastuzumab, and a taxane, according to current US and European guidelines.[1,2,3] This regimen, based on evidence from randomized clinical trials (predominantly the CLEOPATRA trial[4,5]) "is effective and well tolerated, with no increase in cardiac toxic effects[6] and better health-related quality of life,[7] although there are concerns about cost,"[8] commented Prof Heikki Joensuu, MD, PhD (Department of Oncology, Helsinki University Hospital and University of Helsinki, Finland). He stressed that first-line treatment should be individualized for certain subgroups, such as patients with estrogen receptor-positive (ER+)/HER2+ disease; patients with hypersensitivity to taxanes; elderly or frail patients; patients with congestive heart failure; and patients with central nervous system metastases, which will occur in 50% of those with HER2+ metastatic breast cancer, he noted.

After first-line trastuzumab-based therapy, trastuzumab emtansine (T-DM1) is standard second-line therapy in metastatic breast cancer, according to the upcoming Advanced Breast Cancer 3 (ABC3) guidelines.[9] T-DM1 was shown to provide superior efficacy relative to other HER2-based therapies (lapatinib plus capecitabine) as second-line therapy in the EMILIA trial.[10] Beyond the second-line setting, T-DM1 was shown in the TH3RESA trial to be superior to the treatment of physician's choice in patients with two or more prior HER2-directed therapies,[11] Prof Cortés recalled.

There are no data on the use of T-DM1 after dual blockade with trastuzumab plus pertuzumab. Addition of lapatinib to trastuzumab is another option, as suggested by the EGF104900 study,[12] which showed significant benefit over lapatinib monotherapy in terms of overall survival in patients with disease progression during trastuzumab-based therapies. Lapatinib-induced accumulation of HER2 at the cell surface appears to enhance immune-mediated trastuzumab-dependent cytotoxicity, Prof Cortés explained.

Decisions on later lines of therapy should be individualized and take into account different toxicity profiles, previous exposure, patient preferences, and country availability, Prof Cortés advised. Lapatinib and/or trastuzumab regimens remain as third-line options. Prof Cortés commented that the upcoming ABC3 guidelines also recommend as third-line options combinations of trastuzumab with chemotherapeutic agents, including vinorelbine (if not given first-line), taxanes (if not given first-line), capecitabine, eribulin, liposomal anthracyclines, platinum, gemcitabine, or metronomic cyclophosphamide and methotrexate.[9]

Novel HER2-Directed Agents in Clinical Development

New anti-HER2 drugs are needed, Prof Cortés declared. Among the next generation of anti-HER2 drugs are new HER2-targeted tyrosine kinase inhibitors (TKIs).

Tyrosine kinase inhibitors. "One of the most interesting properties of neratinib is that it is a pan-HER inhibitor, binding and inhibiting HER1 (EGFR), HER2, and HER4," he noted. In a phase 2 study, single-agent neratinib produced response rates of 24% in patients previously treated with trastuzumab and 56% in patients with no prior trastuzumab.[13] An ongoing 3 trial, NALA,[14] is investigating neratinib plus capecitabine vs lapatinib plus capecitabine in patients with HER2+ metastatic breast cancer who have received two or more prior HER2-directed regimens. "I think that neratinib will be better in terms of activity," Prof Cortés predicted. A phase 2 trial is also looking at neratinib in the treatment of brain metastases.[15]

 
Tucatinib is very, very important against HER2.
 

Tucatinib (ONT-380) is "very, very important against HER2" Prof Cortés commented. "It is 500-fold more selective for HER2 compared with HER1, which might explain its lower toxicity compared with other TKIs," he suggested. Early data from two phase 1b trials showed no treatment-related grade 3 or greater diarrhea and evidence of activity in combination with capecitabine and trastuzumab,[16] in patients who very heavily treated and in patients with brain metastases.[17] A phase 2 trial is comparing progression-free survival (PFS) with tucatinib combined with capecitabine and trastuzumab in patients with pretreated disease.[18] Two trials of another TKI, afatinib,[19,20] one in patients with brain metastases,[20] showed "no improvements in anything," and "the conclusion is that afatinib is dead in breast cancer," Prof Cortes added.

 
This agent's activity seems to be much better than that of doxorubicin or trastuzumab.
 

Antibody/drug conjugates. Exciting antibody/drug conjugates are in development, said Prof Cortés. MM-302 is a novel antibody/drug conjugated liposomal doxorubicin that specifically targets cancer cells overexpressing the HER2 receptor while limiting exposure to healthy tissues, such as those of the heart. "This agent's activity seems to be much better than that of doxorubicin or trastuzumab," Prof Cortés said. "Data from a phase 1 study in heavily pretreated patients[21] suggest that further study is warranted." MM-302 at a dosage of 30 mg/m2 every 3 weeks in combination with trastuzumab is currently being evaluated in a randomized phase 2 trial (HERMIONE) in anthracycline-naïve patients previously treated with trastuzumab, pertuzumab, and T-DM1.[22]

"The other antibody/drug conjugate we have data on is DS-8201a, a humanized anti-HER2 antibody attached by a peptide linker to a novel topoisomerase I inhibitor that seems to be even more potent than T-DM1," Prof Cortes added. Phase 1 data for DS-8201a in 20 patients that were presented in Copenhagen showed an objective response rate of 35% (seven partial responses) and disease control rate of 90%, including 12 patients previously treated with T-DM1 and five with HER2 low expression.[23]

An anti-HER2 monoclonal antibody with enhanced immune properties, margetuximab, "is, in my opinion, one of the most interesting compounds," Prof Cortés said. "Like trastuzumab, it binds the tumor cell at HER2, but because of the changes in the amino acids, it has a higher affinity in favor of the activating Fcγ receptors and a decreased affinity for the inhibitory Fcγ receptors of the immune cells. So this is clearly an immune-based drug." Phase 1 research in patients heavily pretreated with prior anti-HER2 therapy showed monotherapy antitumor activity.[24] "Median PFS of approximately 5.5 months compared favorably with 3.2 months in patients who received chemotherapy plus trastuzumab in TH3RESA,[11]" Prof Cortés commented.

SOPHIA, a phase 3 clinical trial, is evaluating margetuximab plus chemotherapy against trastuzumab plus chemotherapy in patients with metastatic HER2+ breast cancer receiving third-line therapy.[25]

Other agents. The phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway is frequently activated in breast cancer, and activation of the pathway has been associated with development of resistance to HER2-directed and cytotoxic therapy in breast cancer.

The BOLERO-3 trial[26] evaluated the addition of the mTOR inhibitor everolimus vs placebo to vinorelbine plus trastuzumab in patients with trastuzumab-resistant and taxane-pretreated, HER2+ advanced breast cancer. The trial showed that everolimus improved PFS from 5.78 to 7 months (hazard ratio, 0.78), "so not very interesting"; however, subgroup analysis showed an "impressive" improvement in PFS in patients with ER- but not ER+ cancers, suggesting that ER acts as an escape pathway when HER2 but not ER is inhibited. "So we may need to block PI3K and ER simultaneously in this subset of ER+/HER2+ breast cancer patients," Prof Cortés suggested. "That is why I propose that in patients with triple-positive tumors, explore the use of these agents, but always combined with HER2-targeted and endocrine therapy."

Studies of cell cycle regulation have identified a potential therapeutic role for inhibition of cyclin-dependent kinases 4 and 6 (CDK4/6) in breast cancer.[27] A phase 1b study is looking at the CDK4/6 inhibitor palbociclib in combination with T-DM1 in patients with recurrent or metastatic HER2+ breast cancer after prior HER2-directed therapy.[28] The PATRICIA trial is an open-label trial of palbociclib plus trastuzumab with or without letrozole who have received chemotherapy and trastuzumab.[29] Another CDK4/6 inhibitor, abemaciclib, is being studied in one phase 1 and two phase 2 trials.[30,31,32]

Role of Immune Response in Treatment

HER2 has long been considered a tumor-associated antigen, and it is now known that in HER2-positive breast cancer, tumor-infiltrating lymphocytes (TILs) are clinically relevant and represent preexisting antitumor immunity, noted Sherene Loi, MD, PhD (Peter McCallum Cancer Centre, Melbourne, Victoria, Australia). The presence of TILs at diagnosis has been shown to be an independent, positive, prognostic marker in HER2-positive early breast cancer treated with neoadjuvant anti-HER2 agents and chemotherapy for both pathologic complete response (pCR) and event-free survival.[33]

There are currently no data on TILs in the advanced setting, but the results of a secondary analysis of the prognostic associations of TILs in patients from the CLEOPATRA study will be presented at the 2016 San Antonio Breast Cancer Symposium, Dr Loi revealed.[34] Because TILs are associated with responses to chemotherapy, they could potentially be used for treatment de-escalation and help in tailoring treatment decisions.[35]

"High TILs and pCR imply excellent disease-free survival," Dr Loi said. "These are the patients we know will respond well to taxane plus dual anti-HER2 therapy. These are the patients in whom we can consider leaving out the anthracycline or the taxane, depending how brave we are in our future clinical trials," she suggested. "For patients with high TILs and no pCR, we can consider targeted inhibitors, programmed cell death 1 (PD-1) blockade, or other immune agonists. Patients with low TILs and no pCR are the ones we need to focus our efforts in sequencing and understanding why they do badly."

Checkpoint blockade in combination with anti-HER2 therapy will without doubt further improve survival, particularly in patients with advanced disease.

At present, it is unclear what triggers immune infiltration in breast cancers, but the presence of TILs provides rationale for evaluation of checkpoint blockade, Dr Loi explained. "Checkpoint blockade in combination with anti-HER2 therapy will without doubt further improve survival, particularly in patients with advanced disease," she said. Dr Loi and her colleagues showed that the combination of pembrolizumab with trastuzumab was synergistic in a HER2-driven mammary mouse model,[36] and now the efficacy of the combination is being evaluated in a phase 1b/2, proof-of-concept trial (PANACEA),[37] which is expected to report in 2017.

"TILs may be a biomarker or help us understand who will respond to PD-1 blockade," Dr Loi proposed. Studies in melanoma, gastric cancer, and head and neck cancer suggest that the presence of preexisting immunity, either with TILs or CD8+[38] or interferon gamma signature,[39] predicts a better response to PD-1 blockade. This may help us identify patients who are suitable for anti-PD-1 monotherapy, Dr Loi suggested. "We are only just beginning to understand how immune influences and modulation in HER2+ disease are important, but in the future, we will be trying to incorporate this into our patient care," she predicted.

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