Diagnosis of adenocarcinoma of the lung, a major subtype of non-small lung cancer (NSCLC), nowadays triggers mandatory testing of tumor tissue for alterations in four genes: EGFR, ALK, ROS1, and more recently, BRAF. If present, these alterations predict sensitivity to specific targeted drugs approved by the U.S. Food and Drug Administration (FDA) that work better and often longer than standard chemotherapy, and are better tolerated.
However, there are many more targetable/actionable genomic alterations (also known as “drivers”) in NSCLC. This blog post will briefly discuss most of them, with the goal of promoting molecular testing for more than the four “usual suspects” mentioned above. Some patients with these alterations may benefit from FDA-approved drugs or from enrollment in clinical trials that are testing additional drugs and drug combinations. Continue reading…
“The adjuvant treatment landscape for patients with HER2-positive breast cancer continues to grow, particularly following the recent FDA approval of pertuzumab (Perjeta) in combination with trastuzumab (Herceptin) and chemotherapy, which was based on findings from the APHINITY trial.
“In the phase III trial, the combination demonstrated a 3-year invasive disease-free survival (DFS) rate of 94.1%, which represented an 18% reduction in the risk of developing invasive disease or death. The benefit was more pronounced among higher-risk patients. The DFS rate for patients with node-positive disease was 92.0% with pertuzumab versus 90.2% with standard therapy.”
“A combination of pembrolizumab (Keytruda) and trastuzumab, tested in patients with trastuzumab-resistant advanced HER2-positive breast cancer, was well tolerated and had clinical benefit in patients whose tumors were positive for a biomarker for pembrolizumab, according to data presented from the phase Ib/II PANACEA trial at the 2017 San Antonio Breast Cancer Symposium, held Dec. 5–9.
“ ‘We wanted to investigate if immunotherapy approaches can work in patients with advanced HER2-positive breast cancer that is resistant to trastuzumab,’ said Sherene Loi, MD, PhD, associate professor at Peter MacCallum Cancer Centre in Melbourne, Australia, working with the International Breast Cancer Study Group (IBCSG).”
“Traditional neoadjuvant chemotherapy along with dual HER2-targeted blockade yielded significantly better response rates than a novel approach using HER2-targeted chemotherapy plus HER2-targeted blockade, according to a randomized phase III trial.
” ‘Despite the improvements in outcomes associated with HER2-directed therapy, approximately a quarter of patients who receive treatment for their early breast cancer remain at risk of relapse after 8–10 years, and around 15% will die within a decade,’ wrote study authors led by Sara A. Hurvitz, MD, of the David Geffen School of Medicine at the University of California, Los Angeles. A need for new strategies in this setting led the investigators to test a neoadjuvant regimen of the antibody–drug conjugate trastuzumab emtansine along with pertuzumab in comparison with traditional systemic chemotherapy along with trastuzumab plus pertuzumab.”
“A new randomized trial found that neoadjuvant trastuzumab/pertuzumab alone yields a substantially worse rate of pathologic complete response compared with trastuzumab/pertuzumab plus paclitaxel in women with early, HER2-positive, hormone receptor (HR)-negative breast cancer.
” ‘Pathologic complete response (pCR) after neoadjuvant [therapy] has strong prognostic impact in HER2 disease,’ wrote study authors led by Ulrike Nitz, MD, of the West German Study Group GmbH in Moenchengladbach, Germany. The WSG-ADAPT HER2+/HR− trial assessed whether dual blockade with trastuzumab and pertuzumab could achieve similar rates of pCR in those with strong early response to dual blockade along with chemotherapy.”
“The FDA approved abemaciclib for the treatment of women with hormone receptor-positive HER-2-negative advanced or metastatic breast cancer who progressed following endocrine therapy.
“The agency approved abemaciclib (Verzenio, Eli Lilly) — an investigational cyclin-dependent kinase 4/6 inhibitor —in combination with fulvestrant (Faslodex, AstraZeneca) following progression on endocrine therapy, and as a monotherapy for patients with metastatic disease previously treated with endocrine therapy and chemotherapy.”
Non-metastatic breast cancers are most often treated with surgery, but if the tumors are fairly large, or involve nearby lymph nodes, neoadjuvant (pre-operative) treatments with chemotherapy (NAC) are done first. NAC often reduces the tumor size and kills cancer cells in lymph nodes, if present, prior to surgery, improving the outcome. The best possible result of neoadjuvant treatment is pCR (pathologic compete response), when the tumor is no longer visible in imaging studies. Here, I review the new directions in which neoadjuvant treatments are evolving.
Today, treatments for metastatic breast cancers are tailored for specific subtypes. Starting with the introduction of the drug trastuzumab (Herceptin) for HER2-positive cancers, new, more specific treatment options were eventually developed and approved for other types as well. Estrogen deprivation endocrine therapies, lately prescribed in combination with CDK4/6 inhibitors, are used in estrogen receptor (ER)-positive cancers. Triple negative cancers (TNBC) are still treated mostly with chemotherapy, but immune checkpoint drugs and PARP inhibitors are explored in clinical trials, with some successes reported.
However, neoadjuvant treatments (except for HER2+ cancers) remain largely limited to chemotherapy regimens. This is starting to change now, with new approaches tailored to the cancer type being investigated in clinical trials.
In this regard, it is important to mention the I-SPY2 trial, NCT01042379, which started in 2010 and is for women with stage II-III breast cancer. It offers about a dozen drugs that are chosen based on particular features of the newly diagnosed cancers. This trial has a unique design and has produced some important results. Additional treatments and trials for various types of breast cancer are discussed below. Continue reading…
“The FDA granted breakthrough therapy designation to DS-8201 for the treatment of HER-2-positive locally advanced or metastatic breast cancer that progressed after treatment with other HER-2-targeting agents.
“The agency based the designation on preliminary evidence from a phase 1 study designed to evaluate the safety, tolerability and efficacy of DS-8201 (Daiichi Sankyo), an investigational HER-2-targeting antibody-drug conjugate.”
“The U.S. Food and Drug Administration today approved Nerlynx (neratinib) for the extended adjuvant treatment of early-stage, HER2-positive breast cancer. For patients with this type of cancer, Nerlynx is the first extended adjuvant therapy, a form of therapy that is taken after an initial treatment to further lower the risk of the cancer coming back. Nerlynx is indicated for adult patients who have been previously treated with a regimen that includes the drug trastuzumab.”