Groundbreaking findings reported in 2017 at oncology conferences and published in prestige scientific journals are summarized in a series of articles published in February 2018 issue of the Nature Reviews Clinical Oncology. Distinguished researchers in the fields of acute lymphoblastic leukaemia (ALL), non-small cell lung cancer (NSCLC), urothelial cancer, melanoma, colorectal and breast cancers contextualize important practice messages emerged from clinical trials data.
2017 advances in ALL
David T. Teachey and Stephen P. Hunger of the Department of Pediatrics, The Center for Childhood Cancer Research, Children's Hospital of Philadelphia, and the Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA, wrote that in 2017, three novel and distinct immunotherapeutics, inotuzumab ozogamicin, blinatumomab, and tisagenlecleucel, were approved for the treatment of relapsed and/or refractory B-cell ALL based on compelling results from international clinical trials.
INO-VATE studied anti-CD22 antibody-drug conjugate, inotuzumab ozogamicin in adults with relapsed and/or refractory B-cell ALL. Inotuzumab ozogamicin received positive opinion from the European Medicines Agency (EMA) in 2017. The outcome that served for approval is complete remission rate of 35.8% with inotuzumab ozogamicin (89.7% in case of minimal residual disease negative status) versus 17.4% (31.6% in case of minimal residual disease negative status) with chemotherapy.
TOWER studied anti-CD19/CD3 bi-specific T-cell engager, blinatumomab in children and adults with relapsed and/or refractory B-cell ALL. Blinatumomab received accelerated approval by the US Food and Drug Administration (FDA) in 2015 and full approval in 2017, and was recommended by EMA in 2015. The outcome that served for approval is a median overall survival (OS) of 7.7 months with blinatumomab versus 4.0 months with chemotherapy.
ELIANA studies anti-CD19 chimeric antigen receptor T cells, tisagenlecleucel in patients aged ≤ 25 years with relapsed and/or refractory B-cell ALL. Tisagenlecleucel is currently approved by the FDA only. The outcome that served for regulatory approval is overall remission rate of 82.5% (63% CR, 19% CR with incomplete haematological recovery (100% with minimal residual disease negative status).
Additional breakthroughs included seminal research into ALL genomics (comprehensive genomic profiling of a large cohort of patients with T-cell ALL enabled the identification of novel driver genes and dysregulated pathways that are potential therapeutic targets) and the importance of adherence to chemotherapy.
2017 advances in NSCLC
David F. Heigener and Martin Reck of the Department of Thoracic Oncology, LungenClinic Grosshansdorf, Airway Research Centre North, German Center for Lung Research, Grosshansdorf, Germany wrote that in 2017 in term of molecular targeted therapy, new drugs with improved efficacy and reduced toxicity entered the clinic. Furthermore immune-checkpoint inhibition proved efficacious after chemoradiotherapy for stage III disease.
Key phase III trials in patients with NSCLC with results reported in 2017 are AURA3, ALEX, CheckMate 026 and PACIFIC.
Osimertinib became a new standard of care for patients with NSCLC who develop EGFRT790M-mediated resistance to a first-generation or second-generation EGFR inhibitor, and might soon supplant these agents in the frontline treatment.
In patients with ALK-positive NSCLC, alectinib has been shown to be superior to frontline crizotinib, with impressive efficacy against CNS metastases. The results of the ALEX study together with the findings of the J-ALEX trial in Japan, established the efficacy of alectinib in untreated patients with NSCLC.
Immune-checkpoint inhibition with the anti-PD-1 antibody nivolumab was not found to be superior to first-line chemotherapy in patients with PD-L1-positive NSCLC; however, tumour mutational burden was identified as a potential biomarker for predicting efficacy in this context. Further prospective trials are needed to clarify the role of tumour mutational burden as a predictive biomarker.
The anti-PD-L1 antibody durvalumab became the first immune-checkpoint inhibitor with proven efficacy in the consolidation treatment of stage III NSCLC, following chemoradiotherapy based on results from PACIFIC study.
2017 advances in urothelial cancer
Joaquim Bellmunt of the Dana-Farber Cancer Institute and IMIM-PSMAR Medical Research Institute, Boston, Massachusetts, and Rosa Nadal of the National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA wrote that 2017 saw the publication of clinical trials data and the approval of new treatment approaches for metastatic urothelial carcinoma.
They featured the results of the KEYNOTE-045 and RANGE trials in second-line setting and beyond in patients treated with platinum-based therapy, as well as data from the IMvigor 210 (cohort 1) and KEYNOTE-052 studies in first-line setting in cisplatin ineligible patients.
Pembrolizumab is associated with longer overall survival, better quality of life, and fewer adverse events than chemotherapy in patients with metastatic urothelial carcinoma with disease progression following cisplatin-based chemotherapy.
Atezolizumab and pembrolizumab substantially improve response rates and overall survival outcomes in patients with metastatic urothelial carcinoma who are not eligible for treatment with cisplatin.
Tumour angiogenesis presents clear therapeutic opportunities in patients with metastatic urothelial carcinoma; however, they emphasized that the addition of ramucirumab to docetaxel offers only a modest level of benefit.
2017 advances in melanoma
Michael A. Davies of the Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, and Keith T. Flahertyofthe Henri and Belinda Termeer Center for Targeted Therapies, Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA wrote that in 2017, results from phase III trials demonstrated the impressive safety and efficacy of adjuvant targeted and immune therapies in patients with resectable stage III–IV melanoma. In that regards, they featured the results of CheckMate 238 and COMBI-AD studies. Data from these phase III trials suggest that changes in the management of melanoma patients with resectable regional metastases are imminent, with both anti-PD-1 immunotherapy and combined BRAF and MEK inhibition showing promising efficacy in the adjuvant setting.
However, the results of MSLT-II study raised questions about the surgical management of patients with microscopic sentinel lymph node metastases. The study findings indicate that immediate completion lymph node dissection provided no benefit compared with surveillance in patients with resectable, sentinel lymph node positive melanoma.
New overall survival data published in 2017, add to the debate about the relative benefits of single-agent anti-PD-1 versus combined anti-PD-1 and anti-CTLA-4 immunotherapy. The CheckMate 067 study informs the continuing discussion of the relative risks and benefits of single-agent versus combination of immune checkpoint inhibitors for patients with unresectable disease.
2017 advances in colorectal cancer
Alberto Puccini and Heinz-Josef Lenz of the Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, USA point out to new discoveries that will influence the treatment of colorectal cancer.
On the basis of results of The International Duration Evaluation of Adjuvant Chemotherapy collaboration, 3 months, compared with the current standard-of-care 6 months, of adjuvant chemotherapy for patients with stage III colon cancer decreases the risk of neurotoxicities without compromising overall efficacy. The editorialists concluded that 3-months of oxaliplatin-based chemotherapy should be considered the standard of care for patients with T1-3 N1 stage III colon cancer, however in patients with T4 or N2 disease, who have a higher risk for disease relapse, medical oncologists should continue to plan 6 months of adjuvant chemotherapy.
Immune-checkpoint inhibitors targeting PD-1 (pembrolizumab and nivolumab) were approved in 2017 by the FDA for microsatellite instability-high DNA mismatch repair deficient metastatic colorectal cancer, thus providing further treatment options for these patients.
Tumour sidedness is an emerging and promising biomarker with both prognostic and predictive value that can influence the choice of biologic agent (anti-VEGF versus anti-EGFR antibodies) for first-line treatment of patients with RAS-wild-type metastatic colorectal cancer.
2017 advances in breast cancer
Jose Perez-Garcia of the Baselga Oncological Institute and Medica Scientia Innovation Research, Barcelona and Javier Cortes of the Ramon y Cajal University Hospital, Madrid, Vall d´Hebron Institute of Oncology, Barcelona and Medica Scientia Innovation Research, Barcelona, Spain wrote that data published in 2017 underscore the benefit of optimizing anti-HER2 therapy in early stage high-risk HER2-positive disease. In the AFINITY trial addition of pertuzumab to adjuvant trastuzumab plus chemotherapy improved invasive disease-free survival outcomes in patients with resected high-risk HER2-positive breast cancer.
In patients with a poor prognosis and no response to neoadjuvant therapy, the addition of capecitabine to standard adjuvant chemotherapy in CREATE-X trial was associated with improved outcomes. Despite some concerns regarding the increased sensitivity of patients of Asian ethnicity to fluoropyrimidines, the use of adjuvant capecitabine has been adopted worldwide.
In patients with metastatic breast cancer, the addition of cyclin-dependent kinase (CDK) 4/6 inhibitors to endocrine therapy improves progression-free survival outcomes. In that regard the editorialists featured the outcomes of practice changing trials conducted in first-line setting, namely of PALOMA-2 with letrozole plus palbociclib versus letrozole plus placebo, MONALEESA-2 with letrozole plus ribociclib versus letrozole plus placebo, and MONARCH 3 with non-steroidal aromatase inhibitor (NSAI) plus abemaciclib versus NSAI plus placebo. In term of endocrine-resistant disease, they featured the results of the PALOMA-3 study with fulvestrant plus palbociclib versus fulvestrant plus placebo and MONARCH 2 with fulvestrant plus abemaciclib versus fulvestrant plus placebo.
In OlympiAD study, in patients with metastatic breast cancer harbouring germline BRCA mutations, treatment with olaparib was associated with better progression-free survival than standard chemotherapy.
Trastuzumab biosimilars are becoming a realistic option for HER2-positive breast cancer.
- Teachey DT, Hunger SP. Acute lymphoblastic leukaemia in 2017: Immunotherapy for ALL takes the world by storm. Nature Reviews Clinical Oncology 2018; 15:69–70. DOI doi:10.1038/nrclinonc.2017.176
- Heigener DF, Reck M. Lung cancer in 2017: Giant steps and stumbling blocks. Nature Reviews Clinical Oncology 2018;15:71–72. doi:10.1038/nrclinonc.2017.178
- Bellmunt J, Nadal R. Urothelial cancer in 2017: Changes in expectations for metastatic urothelial carcinoma. Nature Reviews Clinical Oncology 2018; 15:73–74. doi:10.1038/nrclinonc.2017.184
- Davies MA, Flaherty KT. Melanoma in 2017: Moving treatments earlier to move further forwards. Nature Reviews Clinical Oncology 2018; 15:75–76. doi:10.1038/nrclinonc.2017.183
- Puccini A, Lenz H-J. Colorectal cancer in 2017: Practice-changing updates in the adjuvant and metastatic setting. Nature Reviews Clinical Oncology 2018; 15:77–78. doi:10.1038/nrclinonc.2017.185
- Perez-Garcia J, Cortes J. Breast cancer in 2017: Spurring science, marking progress, and influencing history. Nature Reviews Clinical Oncology 2018; 15:79–80. doi:10.1038/nrclinonc.2017.191