NEWS & PERSPECTIVE
First immunotherapy in PD-L1 positive metastatic triple-negative breast cancer
Atezolizumab plus the chemotherapy nab-paclitaxel has been granted accelerated approval for the first-line treatment of unresectable locally advanced or metastatic, PD-L1-positive triple-negative breast cancer (TNBC) by the United States Food and Drug Administration (FDA).1 The approval was based on the results of the clinical trial IMpassion130 (NCT02425891), which was presented at the European Society for Medical Oncology (ESMO) 2018 congress and subsequently published in The New England Journal of Medicine.2,3
The characteristic feature of TNBC is that it lacks the three most common types of receptors known to fuel the growth of breast cancer-oestrogen, progesterone and the human epidermal growth factor receptor 2 (HER2).4 Therefore, common treatments like hormone therapy and drugs that target oestrogen, progesterone and HER2 are ineffective. The clinical outcome of TNBC patients is poor and the overall median survival varies with 18 months as an approximate.4 Chemotherapy remains the primary systemic treatment at present and guidelines in general support the use of single-agent taxanes or anthracyclines as first-line therapy.4,5 In TNBC, the expression of programmed death ligand-1 (PD-L1) occurs mainly in tumor-infiltrating immune cells rather than in tumor cells inhibiting anti-cancer tumor response.6 Thereby inhibiting the PD-L1 may subsequently reinstate the anti-cancer immune responses.6
Atezolizumab, the new addition to TNBC therapy, is an immune checkpoint inhibitor.7 It targets PD-L1 selectively to prevent interaction with the receptors, programmed death-1 (PD-1) and B7-1 (a costimulatory cell-surface protein), reversing T-cell suppression.7 Furthermore, nab-paclitaxel, the standard-of-care for TNBC, a taxane, enhances tumor-antigen release and antitumor responses to immune checkpoint inhibition.5 Also, taxanes activate the toll-like receptor activity and promote dendritic cell activity.5 Thus, the simultaneous action of atezolizumab and nab-paclitaxel have the potential to expedite the antitumor response towards TNBC.5
The new approval of the combination is based on the safety and efficacy results from IMpassion130, which is an international, randomized, double bind and placebo-controlled trial.2 The trial randomly assigned equal number of patients (n=451) with locally advanced or metastatic TNBC to two groups, atezolizumab and placebo respectively.2 Both groups received the nab-paclitaxel chemotherapy.2 In this intention-to-treat population, atezolizumab plus nab-paclitaxel significantly reduced the risk of disease progression or death (Progression-free survival: PFS) compared with placebo with nab-paclitaxel (HR=0.80; 95% CI: 0.69-0.92; p=0.0025).2
In the subgroup analysis, patients whose tumors expressed PD-L1, median PFS was 7.5 months for patients receiving atezolizumab with nab-paclitaxel and 5 months for those receiving placebo with nab-paclitaxel (HR=0.62; 95% CI: 0.49-0.78; p<0.0001).2 Objective response rate in patients with confirmed responses was 53% compared to 33% of the atezolizumab and the placebo-containing arms.2
Presenting the overall survival results, at ESMO congress 2018, lead study author Peter Schmid, MD, PhD, St. Bartholomew’s Breast Cancer Centre, Barts Health NHS Trust, London, United Kingdom, commented “In the PD-L1 positive (+) subgroup, we see a nearly 10-month overall survival difference with atezolizumab plus nab-paclitaxel, which I think is a key encouragement to see this drug as a new standard”.8
The investigators have further reported that the adverse events were consistent with the known safety profiles of each agent.2 According to the FDA announcement, the most common adverse effects of atezolizumab with nab-paclitaxel were alopecia, peripheral neuropathies, fatigue, nausea, diarrhea, anemia, constipation, cough, headache, neutropenia, vomiting and decreased appetite.1 The recommended atezolizumab dose for patients with TNBC whose tumors express PD-L1 is 840 mg administered as an intravenous infusion over 60 minutes, followed by 100mg/m2 nab-paclitaxel. For each 28-day cycle, atezolizumab is administered on days 1 and 15, and nab-paclitaxel is administered on days 1,8, and 15 until disease progression or unacceptable toxicity.1,2
In conclusion, atezolizumab is the first immunotherapy to be approved for PD-L1 positive metastatic TNBC. In combination with nab-paclitaxel, it has prolonged the PFS among patients with TNBC in both the intention-to-treat population and the PD-L1 + subgroup. This could pave the way for a new era in the management of TNBC.
- FDA approves atezolizumab for PD-L1 positive unresectable locally advanced or metastatic triple-negative breast cancer: US Food and Drug Administration. (Accessed March 14 2019, at https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm633065.htm).
- Schmid P, Adams S, Rugo HS, et al. Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative Breast Cancer. N Engl J Med. 2018;379(22):2108-21.
- Liobl S, Lucas PC, Nekljudova V. Abstract. A randomized double-blind phase III clinical trial of neoadjuvant chemotherapy with atezolizumab or placebo in patients with triple negative breast cancer (TNBC) followed by adjuvant atezolizumab or placebo. B 59, European Society for Medical Oncology (ESMO) 2018 Munich, Germany.
- den Brok WD, Speers CH, Gondara L, et al. Survival with metastatic breast cancer based on initial presentation, de novo versus relapsed. Breast Cancer Res Treat. 2017;161(3):549-56.
- Cardoso F, Senkus E, Costa A, et al. 4th ESO-ESMO International Consensus Guidelines for Advanced Breast Cancer (ABC 4)dagger. Ann Oncol. 2018;29(8):1634-57.
- Herbst RS, Soria JC, Kowanetz M, et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature. 2014;515(7528):563-7.
- Tecentriq (atezolizumab): summary of product characteristics. Roche Registration, Welwyn Garden City, United Kingdom; 2018.
- FDA Approves First Immunotherapy for Breast Cancer, Medscape Medical News. (Accessed March 15 2019, at https://www.medscape.com/viewarticle/910121).
Results of DESTINY-Breast04: Trastuzumab deruxtecan vs. TPC for HER2-low unresectable and/or mBC
Glossary: BICR: Blinded independent central review; CI: Confidence interval; ECOG: Eastern Cooperation Oncology Group; HER2-: Human epidermal growth factor receptor 2-negative; HR: Hazard ratio; HR+: Hormone receptor-positive; HR-: Hormone receptor-negative; IHC: Immunohistochemistry; ISH: In situ
MAINTAIN: ET with or without ribociclibafter progression on AET + CDK4/6i in patients with unresectable or HR+, HER2- mBC
Glossary: AEs: Adverse events; AI: Aromatase inhibitor; CBR: Clinical benefit rate; CDK4/6i: Cyclin-dependent kinase 4/6 inhibitor; CI: Confidence interval; CR: Complete response; ECOG: Eastern Cooperation Oncology Group; ER+: Estrogen receptor-positive; ET: Endocrine therapy; GnRH: Gonadotropin-r
MONALEESA-2: Impact of ribociclib dose modifications on OS in HR+/HER2- ABC patients
Glossary: 1L: First-line; ABC: Advanced breast cancer; AE: Adverse event; CBR: Clinical benefit rate; CI: Confidence interval; CKD4/6i: Cyclin-dependent kinase 4/6 inhibotor; HER2-: Human epidermal growth factor receptor 2-negative; HR: Hazard ratio; HR+: Hormone receptor-positive; NR: Not reached
Ribociclib plus fulvestratnt has the longest mOS OF over 67 months in postmenopausal breast cancer patients
Cancer is a leading cause of death globally, claiming almost 10 million deaths in 2020.1 Breast cancer is one of the most common cancers in women, with nearly 2.3 million new breast cancer diagnoses in 2020 worldwide.1 Gene-expression profiling has identified distinct subtypes of cancer, among which there are subpopulations expressing specific markers.2 According to the National Institutes of Health (NIH), hormone receptor-positive/human epidermal growth factor 2-negative (HR+/HER2-) is the most prevalent breast cancer.3 Cyclin-dependent kinase 4 and 6 (CDK4/6) are good drug targets for cancer, owing to their role in cell cycle progression.4 Ribociclib is one of the 3 inhibitors of CDK4/6 approved in combination with fulvestrant for treating HR+/HER2- advanced breast cancers in adults, based on a series of phase 3 clinical trials called MONALEESA, which tested ribociclib along with different drug partners in HR+/HER2- cancer patients.4-7 The MONALEESA-2 study showed that progression-free survival (PFS) was significantly longer with first-line ribociclib + letrozole than with placebo + letrozole.7 The MONALEESA-7 trial also showed significantly longer median overall survival (mOS) in ribociclib in combination with the endocrine therapy (ET) vs. the placebo arm in postmenopausal HR+/HER2- cancer patients.6 Similarly, the primary MONALEESA-3 trial and its subsequent analysis Demonstrated that ribociclib + fulvestrant had significant OS benefit as compared with placebo in HR+/HER2- patients advanced breast cancer patients.5,6 In a recently held European Society of Medical Oncology (ESMO) Breast Cancer Congress, Neven, et al. presented an updated exploratory mOS analysis result with the longest follow-up of the MONALEESA 3 study to date.8
Optimal breast cancer screening approaches for women with ATM, CHEK2, and PALB2 PVs
Recently, a group of non-BRCA1/2, moderate- to high-risk breast cancer susceptibility genes, have been observed. Among them, the most prevalent ones are ATM, CHEK2 and PALB2.1-3 These pathogenic variants (PVs) can increase the risk of breast cancer by at least 2-fold, thus indicating an obvious and urgent need for screening them.1,3 However, optimal strategies for screening in women carrying these PVs have yet to be well established.1 In a recent study published in the Journal of the American Medical Association (JAMA), Lowry K P and his colleagues conducted a comparative simulation modeling analysis to determine whether screening using mammography and magnetic resonance imaging (MRI) could benefit breast cancer patients with ATM, CHEK2 and PALB2 PVs at various age intervals, which may increase the survival rate in these female patients.1
Poorer survival outcomes in breast cancer patients with chronic stress
The allostatic load, which results from lifelong exposure to social and environmental stressors such as discrimination and poverty, provides with us a way to evaluate the eftects of chronic stress on a patient's physiology.1 Chronic stress has been shown to be associated with various health problems, including hypertension, kidney disease, inflammation, and other conditions.1 According to a recent ECOG-ACRIN E5103 phase 3 clinical trial, Dr. Samilia Obeng-Gysai, a surgical oncologist at The Ohio State University Comprehensive Cancer Center, analyzed the data from the trial on the relationship between allostatic load and clinical outcomes in breast cancer patients, the elevated allostatic load was found to be linked with a lover likelihood of chemotherapy completion and a higher risk of death among breast cancer patients.1
Overcoming the clinical challenges of breast cancer management: From identifying prognostic factors to achieving personalized treatment
Breast cancer is the most common cancer among females in Hong Kong and accounted for 27.2% and 12.4% of all cancer incidences and deaths in 2018, respectively.1 Over the past decade, the incidence and death rate of breast cancer continued to increase while the challenges of managing the disease rema
Updates on the latest immunotherapeutic options
The field of immunotherapy has been rapidly evolving and is increasingly utilized in the management of lymphomas.1 Currently, various immunotherapeutic modalities have been pursued including monoclonal antibodies, bispecific T-cell engagers (BiTEs), checkpoint inhibitors and chimeric antigen recepto
Neoadjuvant singular immunotherapy versus perioperative chemoimmunotherapy for early-stage lung cancer
Dr. Mariano Provencio, Hospital Universitario Puerta de Hierro, Spain, explained that options to improve poor lung cancer survival include adjuvant treatment for stage I and II and neoadjuvant treatment for stage III disease. Where both neoadjuvant and adjuvant treatments provide a clinically signif