Reviews & Analysis

Cell-based immunotherapies are showing great promise in the treatment of even the most treatment-refractory of haematological malignancies. Herein, Jennifer Brudno and James Kochenderfer review the results obtained to date with CAR-T-cell therapies for lymphoma. They also discuss what has been learned regarding the limitations of CAR-T-cell therapies and areas for improvement relating to toxicity management, the design of CAR-T-cell products, conditioning regimens, and combination therapies.

A wide range of gene fusions have been detected in solid tumours, and the products of these fusions, some of which result in constitutive activation of kinase signalling, can be targeted using tyrosine-kinase inhibitors. However, the development of acquired resistance is almost inevitable. In this Review, the authors describe strategies used to diagnose and treat patients with fusion-positive cancers.

Updated results from the EMILIA and TH3RESA trials in patients with advanced-stage HER2-positive breast cancer confirm the overall survival benefit and favourable safety profile of T-DM1 after prolonged follow-up durations. The efficacy of T-DM1 as a second or later line of treatment indicates that HER2 is a relevant therapeutic target throughout the course of the disease.

Potential strategies for improving the outcomes of patients with early stage HER2-positive (HER2+) breast cancer have included dual anti-HER2 therapy. Recent results from the APHINITY trial show a statistically significant, but clinically modest, benefit from the addition of pertuzumab to trastuzumab and chemotherapy. Subsequent trials should focus on biomarkers to identify patients with HER2+ breast cancer who require more-intensive or less-intensive therapy.

First-line, potent androgen blockade for patients with newly diagnosed, advanced-stage, castration-sensitive prostate cancer is confirmed as an effective strategy by data from the STAMPEDE and LATITUDE trials. Herein, we highlight the benefits, discuss caveats and consider the clinical care implications of these findings.

Patients with metastatic soft-tissue sarcoma can benefit from systemic therapy, but the best drug combinations for the different disease subtypes remain to be established. Recently, great emphasis has been placed on histology-based chemotherapy regimens. Herein, we discuss the results of a recently published study demonstrating that some of these regimens are not superior to standard-of-care chemotherapy in the neoadjuvant setting.

Important biological questions can be addressed by interrogating the transcriptomes of cancer cells. In a recently published landmark study, Giustacchini and collaborators used a single-cell approach to analyse mRNA of cancer cells derived from patients with chronic myeloid leukaemia. Herein, we discuss how this approach could be used to address relevant clinical questions.

The development of predictive biomarkers is complex and the non-systematic approach to biomarker development in HER2-positive breast cancer challenges the way translational research is performed. Women with very favourable prognostic features will likely prefer shorter courses of treatment and might enquire about the possibility to forego aggressive chemotherapy. Considering these legitimate needs, Gingras et al. review the results of more than a decade of translational research efforts in this disease.

Virtually all successful treatments of cancer either create, restore or enhance the antitumour immune response. Therefore, the specific features of the immune microenvironment, both before and after treatment, are important determinants of patients' outcomes. In this Review, the authors describe the influence of the immunological characteristics of the tumour microenvironment on responses to treatment in patients with a variety of cancers.

In 2016, results of an important randomized trial demonstrated that patients undergoing chemotherapy who reported symptoms electronically have a better quality of life than those receiving usual care. Now, a significant survival improvement for patients in the experimental arm of this study has been reported. The emphasis of this survival benefit is 'culturally' positive, promoting the adoption of patient-reported outcomes in clinical practice.

Regorafenib is only the second agent approved by the FDA for the treatment of patients with advanced-stage hepatocellular carcinoma. Herein, we discuss the evidence that led to the approval of this agent. Examination of this process reveals important challenges associated with drug regulation, relating to trial design, treatment toxicity, and real-world clinical benefit.

Few therapeutic options are currently available for patients with glioblastoma, which are associated with a poor prognosis. Therapies with monoclonal antibodies, alone or linked to cytotoxic payloads, are currently being explored in these patients. Herein, the authors summarize therapeutic strategies based on antibody–drug conjugates (ADCs), targeted against EGFR, and discuss key aspects such as the blood–brain barrier, resistance mechanisms, and the development of specific biomarkers.

The identification of the tissue of origin in patients with cancer of unknown primary (CUP) is an example of how epigenomics can be incorporated in clinical settings. Epigenetic and other molecularly-based diagnostic strategies have emerged to complement traditional diagnostic procedures, thereby improving the clinical management of patients with CUP. Herein, the authors present the latest data on strategies using epigenetics and other molecular biomarkers to guide therapeutic decisions involving patients with CUP, addressing a previously unmet need.

Patients receiving anticancer therapies based on immune-checkpoint blockade (ICB) often experience clinical benefits from such treatments, but unconventional patterns of response can be observed, emphasizing the importance of using a specific approach to evaluating responses to immunotherapy. Herein, the authors review the biological mechanisms underlying the response patterns associated with ICB, describe strategies for the assessments of such responses, and highlight the ongoing efforts to identify biomarkers to guide treatment with ICB.

Response criteria for disease assessment have important therapeutic and prognostic implications in clinical trials and in routine clinical practice. The Lugano classification has been used widely for evaluation of the response of patients with lymphoma to treatment, although the alternative Response Evaluation Criteria In Lymphoma 2017 (RECIL 2017) classification was recently proposed; these criteria are compared herein.

The current standard-of-care therapy for patients with multiple myeloma is autologous stem-cell transplantation; however, whether this approach should be enhanced or displaced by triplet combination therapy is the subject of ongoing debate. We discuss the latest trial that has attempted to address this question and the impact of transplantation and triplet therapy assessment and surrogate end points in future trial design.

Accurate detection and monitoring of treatment responses is an essential element of the management of patients with lymphoma. In this Perspectives, the authors describe the evolution of lymphoma staging criteria and highlight unaddressed questions, which, if answered, will substantially improve the management of patients with lymphoma.

Patients with early stage breast cancer have traditionally been assigned adjuvant systemic therapies on the basis of the clinical and histological characteristics of their disease. However, this approach often leads to overtreatment. In this Review, the authors describe the use of gene-expression signatures, some of which are already in clinical use, for determining the risks of recurrence and progression, and the most appropriate form of adjuvant therapy.

For three decades, the treatment of small-cell lung cancer (SCLC) has remained essentially unchanged, and patient outcomes remain dismal. In the past 5 years, however, advances in our understanding of the disease, at the molecular level, have resulted in the development of new therapeutic strategies, encompassing immunotherapies and novel molecularly targeted agents. Herein, authors review the breakthroughs that hold the promise to improve SCLC outcomes.

Precision medicine has dramatically changed the landscape of drug development in oncology, but this paradigm shift remains to be adopted in early phase clinical trials of molecularly targeted agents and immunotherapeutic agents in children with cancer. The authors, members of the Innovative Therapies for Children with Cancer (ITCC) Consortium, describe trial design strategies to enable drugs with promising activity to progress rapidly to randomized studies and, therefore, substantially accelerate drug development for children and adolescents with cancer.