Summary
New emerging data from clinical trials has led to changes in the National Comprehensive Cancer Network (NCCN) guidelines on how to treat metastatic breast cancer (MBC).
At the 2020 NCCN Annual Meeting, William Gradishar, MD of Northwestern University provided an overview of changing interventions in invasive breast cancer. “Despite the era of molecular medicine, in the clinic we still to a large degree rely on pragmatic decision making based on tumor expression. Estrogen receptor (ER)-positive/Progesterone receptor (PR)-positive tumors can be appropriately treated with endocrine or targeted therapies; human epidermal growth factor receptor(HER)2-positive with endocrine therapy; and triple-negative tumors with chemotherapy or immunotherapy. BRCA-associated tumors are amenable to PARP inhibitors,” said Gradishar.
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Original Article
New Therapies Added to NCCN Guidelines on Managing Metastatic Breast Cancer
Oncology Times
By Mark L. Fuerst
New emerging data from clinical trials has led to changes in the National Comprehensive Cancer Network (NCCN) guidelines on how to treat metastatic breast cancer (MBC).
At the 2020 NCCN Annual Meeting, William Gradishar, MD of Northwestern University provided an overview of changing interventions in invasive breast cancer. “Despite the era of molecular medicine, in the clinic we still to a large degree rely on pragmatic decision making based on tumor expression. Estrogen receptor (ER)-positive/Progesterone receptor (PR)-positive tumors can be appropriately treated with endocrine or targeted therapies; human epidermal growth factor receptor(HER)2-positive with endocrine therapy; and triple-negative tumors with chemotherapy or immunotherapy. BRCA-associated tumors are amenable to PARP inhibitors,” said Gradishar.
Over the last decade most breast cancer patients have done appreciably better. “This is a reflection of identifying breast cancer in early-stage disease and to a large degree related to aggressive breast cancer screening programs and identifying small, early-stage tumors that have better prognosis. Another part is more effective adjuvant therapy to reduce the risk of disease recurrence and also the emergence of new therapies in metastatic disease setting have lengthened overall survival (OS),” he said.
Emerging new HER2-targeted therapies have shown a benefit in OS of patients with metastatic HER2-positive breast cancer. The addition of traztuzumab to chemotherapy has doubled results with chemotherapy alone. “This revolutionary dual therapy continues improvements in progression-free survival (PFS) and clearly improves OS. It leads to a remarkably effective reduction in disease recurrence in early-stage disease,” said Gradishar.
He outlined how clinicians treat HER2-positive patients, based on NCCN guidelines. First-line therapy is dual targeting with a taxane plus traztuzumab or pertuzumab. As the disease progresses, second-line therapy is the antibody drug conjugate (ADC) trastuzumab emtansine or T-DM1. After second-line therapy, “it’s a Wild West of different options. You can switch out chemotherapy and continue traztuzumab. Laparib can be used combined typically with capecitabine,” he said. For a subset of both HER2-positive and ER-positive patients, data support targeting both pathways with an endocrine agent and a HER2-directed therapy.
New trials are investigating novel agents, some of which have been approved and others that soon will be and will be added to the NCCN guidelines shortly, he said.
Gradishar went through the current NCCN guidelines algorithm for HER2-positive disease. If the patient has received HER2-directed therapy and progresses, leverage HER2 and switch to a different HER2 therapy. As long as the patient benefits, continue systemic therapy in consultation with the patient, he said.
The preferred regimen is dual targeting, such as the new dual targeted therapy of traztuzumab plus deruxtecan. “This novel ADC is uniquely designed for optimal anti-tumor effect. It has the potential for greater cell killing than T-DM1,” he said. The key feature is a novel payload with high potency, short systemic half-life, membrane permeability, a stable linker, and it is tumor selective. There is also evidence of by a stander effect, particularly in heterogeneous tumors.
Several trials led to the development of the trastuzumab plus deruxtecan combination. An early phase 1 trial found, after 10 months follow-up, about a 60 percent response with duration of 20 months and median PFS of 22 months. All patients had received previous trastuzumab.
The Destiny-Breast 01 phase 2 open-label, multicenter study of 184 patients led to the approval of this dual therapy. The patients in this study had prior T-DM1, and half of them had hormone-positive status. Those with stable treated brain metastases were allowed in the study. “In these heavily pretreated patients the vast majority responded, with a significant ORR of 61 percent,” he said. Patients developed a response within 15 months and a median PFS of 16 months. This led to accelerated FDA approval.
The majority of patients had grade 1 or 2 side effects, but 4 patients died from interstitial lung disease. This led to a black box warning to monitor and promptly investigate cough, dyspnea, fever or other respiratory symptoms. Interstitial lung disease may occur so there is a low threshold for stopping or dose-reducing the drug, he said.
The NALA phase 3 trial of neratinib for HER2-positive MBC randomized neratinib and capecitabine versus lapatinib plus capecitabine. The difference between the arms modestly favored neratinib over lapatinib, with a PFS increase of 2 months and OS increase of 1.8 months. Neratinib patients received an anti-diarrheal to counteract the known increase of diarrhea with this drug.
“Of interest, the time to intervention for CNS metastases was longer with neratinib, suggesting a benefit in CNS disease. Patients needed radiation therapy, surgery, anti-cancer medications less with neratinib, in particular radiation therapy, which reflects the central effect of the drug,” said Gradishar.
Tucatinib is an oral TKI that is highly selective and active in patients with refractory HER2-positive MBC and brain metastases. In one early trial, all patients had received trastuzumab and almost all had T-DM1. ORR was 61 percent and PFS was 7.8 months. Tucatinib appears to induce diarrhea less often than neratinib.
The HER2 CLIMB trial included 410 patients who receive tucatinib/trastuzumab/capecitabine and 202 patients who received placebo plus trastuzumab/capecitabine. Importantly, patients with brain metastases were allowed into the trial if previously treated brain metastases were stable.
Incorporation of tucatinib improved PFS by about 2 months and OS by about 4 months. ORR was clinically doubled. Those with documented brain metastases showed a PFS improvement of about 2 months. Based on these “remarkable results,” he said this drug was recently approved by the FDA and the NCCN breast cancer panel will likely incorporate it into the guidelines shortly.
There is a long list of emerging directed therapies for HER2-positive MBC. “Some will have benefit, and others will fall by the wayside. We are looking to combine agents with other targeted therapies and immunotherapies, such as CD 4/6 and PI3K inhibitors,” said Gradishar.
He highlighted one promising agent, margetuximab. This is a bioengineered trastuzumab with improved affinity for activating receptor genotypes and a lower affinity for inhibitor receptor phenotypes. Data suggest it may be more effective than trastuzumab.
The SOPHIA phase 3 trial compared margetuximab plus chemotherapy against trastuzumab plus chemotherapy. Patients with brain metastases were allowed, if treated and stable. These patients also had significant prior HER2-positive therapy.
The first and second interim analyses showed no major effect of margetuximab. But “if we look at FF and FV phenotypes, margetuximab may have an advantage over trastuzumab. This speaks to tailored, precision medicine to figure out the genotype that would be important to reap an advantage using this drug,” said Gradishar. Margetuximab is not yet FDA-approved, but will likely be considered in the coming months.
All of these drugs are expensive, he noted. “Cost associated with cancer drugs has skyrocketed and is a big driver. The cost of new anti-cancer drugs in the US is rising quickly. With new novel agents we need to be smarter about how we use these drugs and in which patients,” said Gradishar.
He noted that a number of trastuzumab biosimilars have been developed and approved. “This is reflected in the NCCN guidelines as appropriate choices where we would use trastuzumab. Clinical trials evaluating biosimilars show similar results to what we would expect with standard trastuzumab,” said Gradishar.
Mark L. Fuerst is a contributing writer.