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As distinct cancer biomarkers have been discovered in recent years, a need to reclassify tumors by more than their histology has been proposed, and therapies are now tailored to treat cancers based on specific molecular aberrations and immunologic markers. In fact, multiple histology-agnostic therapies are currently adopted in clinical practice for treating patients regardless of their tumor site of origin. In parallel with this new model for drug development, in the past few years, several novel antibody–drug conjugates (ADCs) have been approved to treat solid tumors, benefiting from engineering improvements in the conjugation process and the introduction of novel linkers and payloads. With the recognition that numerous surface targets are expressed across various cancer histologies, alongside the remarkable activity of modern ADCs, this drug class has been increasingly evaluated as suitable for a histology-agnostic expansion of indication. For illustration, the anti-HER2 ADC trastuzumab deruxtecan has demonstrated compelling activity in HER2-overexpressing breast, gastric, colorectal, and lung cancer. Examples of additional novel and potentially histology-agnostic ADC targets include trophoblast cell-surface antigen 2 (Trop-2) and nectin-4, among others. In the current review article, the authors summarize the current approvals of ADCs by the US Food and Drug Administration focusing on solid tumors and discuss the challenges and opportunities posed by the multihistological expansion of ADCs.

Anti-PD-1/PD-L1 monoclonal antibodies have substantially improved the overall survival of a subset of patients across multiple solid tumour types, but other patients can have a deterioration of their disease as a result of such therapies. This paradoxical phenomenon is defined as hyperprogression. In this Review, we present the available evidence of hyperprogressive disease following immune-checkpoint inhibition, the pathophysiological hypotheses that might explain hyperprogressive disease and the current challenges for patient management in routine clinical settings. Finally, we also discuss how the risk of hyperprogressive disease should be taken into account in clinical decisions involving immune-checkpoint inhibition.

In the wake of the success of modern immunotherapy, oncolytic viruses (OVs) are currently seen as a potential therapeutic option for patients with cancer who do not respond or fail to achieve durable responses following treatment with immune checkpoint inhibitors. OVs offer a multifaceted therapeutic platform because they preferentially replicate in tumour cells, can be engineered to express transgenes that augment their cytotoxic and immunostimulatory activities, and modulate the tumour microenvironment to optimize immune-mediated tumour eradication, both at locoregional and systemic sites of disease. Lysis of tumour cells releases tumour-specific antigens that trigger both the innate and adaptive immune systems. OVs also represent attractive combination partners with other systemically delivered agents by virtue of their highly favourable safety profiles. Rational combinations of OVs with different immune modifiers and/or antitumour agents, based on mechanisms of tumour resistance to immune-mediated attack, may benefit the large, currently underserved, population of patients who respond poorly to immune checkpoint inhibition.

Because responses of patients with cancer to immunotherapy can vary in success, innovative predictors of response to treatment are urgently needed to improve treatment outcomes. We aimed to develop and independently validate a radiomics-based biomarker of tumour-infiltrating CD8 cells in patients included in phase 1 trials of anti-programmed cell death protein (PD)-1 or anti-programmed cell death ligand 1 (PD-L1) monotherapy. We also aimed to evaluate the association between the biomarker, and tumour immune phenotype and clinical outcomes of these patients. In this retrospective multicohort study, we used four independent cohorts of patients with advanced solid tumours to develop and validate a radiomic signature predictive of immunotherapy response by combining contrast-enhanced CT images and RNA-seq genomic data from tumour biopsies to assess CD8 cell tumour infiltration. To develop the radiomic signature of CD8 cells, we used the CT images and RNA sequencing data of 135 patients with advanced solid malignant tumours who had been enrolled into the MOSCATO trial between May 1, 2012, and March 31, 2016, in France (training set). The genomic data, which are based on the CD8B gene, were used to estimate the abundance of CD8 cells in the samples and data were then aligned with the images to generate the radiomic signatures. The concordance of the radiomic signature (primary endpoint) was validated in a Cancer Genome Atlas [TGCA] database dataset including 119 patients who had available baseline preoperative imaging data and corresponding transcriptomic data on June 30, 2017. From 84 input variables used for the machine-learning method (78 radiomic features, five location variables, and one technical variable), a radiomics-based predictor of the CD8 cell expression signature was built by use of machine learning (elastic-net regularised regression method). Two other independent cohorts of patients with advanced solid tumours were used to evaluate this predictor. The immune phenotype internal cohort (n=100), were randomly selected from the Gustave Roussy Cancer Campus database of patient medical records based on previously described, extreme tumour-immune phenotypes: immune-inflamed (with dense CD8 cell infiltration) or immune-desert (with low CD8 cell infiltration), irrespective of treatment delivered; these data were used to analyse the correlation of the immune phenotype with this biomarker. Finally, the immunotherapy-treated dataset (n=137) of patients recruited from Dec 1, 2011, to Jan 31, 2014, at the Gustave Roussy Cancer Campus, who had been treated with anti-PD-1 and anti-PD-L1 monotherapy in phase 1 trials, was used to assess the predictive value of this biomarker in terms of clinical outcome. We developed a radiomic signature for CD8 cells that included eight variables, which was validated with the gene expression signature of CD8 cells in the TCGA dataset (area under the curve [AUC]=0·67; 95% CI 0·57–0·77; p=0·0019). In the cohort with assumed immune phenotypes, the signature was also able to discriminate inflamed tumours from immune-desert tumours (0·76; 0·66–0·86; p<0·0001). In patients treated with anti-PD-1 and PD-L1, a high baseline radiomic score (relative to the median) was associated with a higher proportion of patients who achieved an objective response at 3 months (vs those with progressive disease or stable disease; p=0·049) and a higher proportion of patients who had an objective response (vs those with progressive disease or stable disease; p=0·025) or stable disease (vs those with progressive disease; p=0·013) at 6 months. A high baseline radiomic score was also associated with improved overall survival in univariate (median overall survival 24·3 months in the high radiomic score group, 95% CI 18·63–42·1; vs 11·5 months in the low radiomic score group, 7·98–15·6; hazard ratio 0·58, 95% CI 0·39–0·87; p=0·0081) and multivariate analyses (0·52, 0·35–0·79; p=0·0022). The radiomic signature of CD8 cells was validated in three independent cohorts. This imaging predictor provided a promising way to predict the immune phenotype of tumours and to infer clinical outcomes for patients with cancer who had been treated with anti-PD-1 and PD-L1. Our imaging biomarker could be useful in estimating CD8 cell count and predicting clinical outcomes of patients treated with immunotherapy, when validated by further prospective randomised trials. Fondation pour la Recherche Médicale, and SIRIC-SOCRATE 2.0, French Society of Radiation Oncology.

Precision medicine focuses on DNA abnormalities, but not all tumors have tractable genomic alterations. The WINTHER trial ( NCT01856296 ) navigated patients to therapy on the basis of fresh biopsy-derived DNA sequencing (arm A; 236 gene panel) or RNA expression (arm B; comparing tumor to normal). The clinical management committee (investigators from five countries) recommended therapies, prioritizing genomic matches; physicians determined the therapy given. Matching scores were calculated post-hoc for each patient, according to drugs received: for DNA, the number of alterations matched divided by the total alteration number; for RNA, expression-matched drug ranks. Overall, 303 patients consented; 107 (35%; 69 in arm A and 38 in arm B) were evaluable for therapy. The median number of previous therapies was three. The most common diagnoses were colon, head and neck, and lung cancers. Among the 107 patients, the rate of stable disease ≥6 months and partial or complete response was 26.2% (arm A: 23.2%; arm B: 31.6% ( P  = 0.37)). The patient proportion with WINTHER versus previous therapy progression-free survival ratio of >1.5 was 22.4%, which did not meet the pre-specified primary end point. Fewer previous therapies, better performance status and higher matching score correlated with longer progression-free survival (all P  < 0.05, multivariate). Our study shows that genomic and transcriptomic profiling are both useful for improving therapy recommendations and patient outcome, and expands personalized cancer treatment. Prospective analysis of transcriptomic and genomic alterations increases the proportion of patients with solid cancer who are eligible for receiving matched therapies and shows promise in improving clinical outcomes.

Non-small-cell lung cancer is one of the leading causes of deaths from cancer worldwide. Therefore, improvements in diagnostics and treatments are urgently needed. In this review, we will discuss the evolution of lung cancer staging towards more non-invasive, endoscopy-based, and image-based methods, and the development of stage-adapted treatment. A special focus will be placed on the role of novel surgical approaches and modern radiotherapy strategies for early stages of disease, the effect of multimodal treatment in locally advanced disease, and ongoing developments in the treatment of patients with metastatic disease. In particular, we will include an emphasis on targeted therapies, which are based on the assumption that a treatable driver mutation or gene rearrangement is present within the tumour. Finally, the position of lung cancer treatment on the pathway to personalised therapy will be discussed.

Therapeutic strategies harnessing the immune system to eliminate tumour cells have been successfully used for several cancer types, including in patients with advanced-stage non-small-cell lung cancer (NSCLC). In these patients, immune-checkpoint inhibitors (ICIs) can provide durable responses and improve overall survival either as monotherapy, or combined with chemotherapy or other immunotherapeutic agents. However, the implementation of ICIs in early stage NSCLC has been hampered by the continuous struggle to develop robust end points to assess their efficacy in this setting, especially those enabling a fast and reproducible evaluation of the clinical activity of neoadjuvant strategies. Several trials are testing ICIs, alone or in combination with chemotherapy, in early stage NSCLC as an adjuvant, neoadjuvant or perioperative approach. As a novelty, most trials in the neoadjuvant setting have adopted pathological response as a primary end point. ICIs have been approved for use in the neoadjuvant and adjuvant settings on the basis of event-free survival and disease-free survival benefit, respectively; however, the correlation of these end points with overall survival remains unclear in these settings. Unresolved challenges for the optimal use of ICIs with curative intent include concerns about their applicability in daily clinical practice and about improving patient selection based on predictive biomarkers or assessment of pathological response and minimal residual disease. In this Review, we discuss the rationale, available strategies and current trial landscape for the implementation of ICIs in patients with resectable NSCLC, and we further elaborate on future approaches to optimize their clinical benefit.Several trials are testing immune-checkpoint inhibitors (ICIs), alone or in combination with chemotherapy, in patients with resectable non-small-cell lung cancer as an adjuvant, neoadjuvant or perioperative approach. However, the optimal use of ICIs with curative intent in patients with early stage non-small-cell lung cancer remains unclear. The authors of this Review discuss the current trial landscape and discuss challenges and opportunities.

Activating enhancer of zeste homolog 2 (EZH2) mutations or aberrations of the switch/sucrose non-fermentable (SWI/SNF) complex (eg, mutations or deletions of the subunits INI1 or SMARCA4) can lead to aberrant histone methylation, oncogenic transformation, and a proliferative dependency on EZH2 activity. In this first-in-human study, we aimed to investigate the safety, clinical activity, pharmacokinetics, and pharmacodynamics of tazemetostat, a first-in-class selective inhibitor of EZH2. We did an open-label, multicentre, dose-escalation, phase 1 study using a 3 + 3 design with planned cohort expansion at the two highest doses below the maximally tolerated dose. The study was done at two centres in France: Institut Gustave Roussy (Villejuif, Val de Marne) and Institut Bergonié (Bordeaux, Gironde). Eligible patients had relapsed or refractory B-cell non-Hodgkin lymphoma or an advanced solid tumour and were older than 18 years, with Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate end-organ function. Tazemetostat was administered orally from 100 mg twice daily to 1600 mg twice daily in 28-day cycles. The primary endpoint was to establish the maximum tolerated dose or recommended phase 2 dose of tazemetostat, as determined by dose-limiting toxicities, laboratory values, and other safety or pharmacokinetic measures in cycle one according to local investigator assessment. Safety was assessed in patients who received at least one dose of tazemetostat; antitumour activity was assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01897571. The phase 1 part of the study is complete, and phase 2 is ongoing. Between June 13, 2013, and Sept 21, 2016, 64 patients (21 with B-cell non-Hodgkin lymphoma, and 43 with advanced solid tumours) received doses of tazemetostat. The most common treatment-related adverse events, regardless of attribution, were asthenia (21 [33%] of 64 treatment-related events), anaemia (nine [14%]), anorexia (four [6%]), muscle spasms (nine [14%]), nausea (13 [20%]), and vomiting (six [9%]), usually grade 1 or 2 in severity. A single dose-limiting toxicity of grade 4 thrombocytopenia was identified at the highest dose of 1600 mg twice daily. No treatment-related deaths occurred; seven (11%) patients had non-treatment-related deaths (one at 200 mg twice daily, four at 400 mg twice daily, and two at 1600 mg twice daily). The recommended phase 2 dose was determined to be 800 mg twice daily. Durable objective responses, including complete responses, were observed in eight (38%) of 21 patients with B-cell non-Hodgkin lymphoma and two (5%) of 43 patients with solid tumours. Tazemetostat showed a favourable safety profile and antitumour activity in patients with refractory B-cell non-Hodgkin lymphoma and advanced solid tumours, including epithelioid sarcoma. Further clinical investigation of tazemetostat monotherapy is ongoing in phase 2 studies in adults and a phase 1 study for children, which are currently enrolling patients who have B-cell non-Hodgkin lymphoma and INI1-negative or SMARCA4-negative tumours. Epizyme and Eisai.

Few standard treatment options are available for patients with metastatic sarcomas. We did this trial to evaluate the efficacy, safety, and changes in the tumour microenvironment for durvalumab, an anti-PD-L1 drug, and tremelimumab, an anti-CTLA-4 drug, across multiple sarcoma subtypes. In this single-centre phase 2 trial, done at The University of Texas MD Anderson Cancer Center (Houston, TX USA), patients aged 18 years or older with advanced or metastatic sarcoma with an Eastern Cooperative Oncology Group performance status of 0 or 1 who had received at least one previous line of systemic therapy were enrolled in disease subtype-specific groups (liposarcoma, leiomyosarcoma, angiosarcoma, undifferentiated pleomorphic sarcoma, synovial sarcoma, osteosarcoma, alveolar soft-part sarcoma, chordoma, and other sarcomas). Patients received 1500 mg intravenous durvalumab and 75 mg intravenous tremelimumab for four cycles, followed by durvalumab alone every 4 weeks for up to 12 months. The primary endpoint was progression-free survival at 12 weeks in the intention-to-treat population (all patients who received at least one dose of treatment). Safety was also analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02815995, and is completed. Between Aug 17, 2016, and April 9, 2018, 62 patients were enrolled, of whom 57 (92%) received treatment and were included in the intention-to-treat population. With a median follow-up of 37·2 months (IQR 1·8–10·1), progression-free survival at 12 weeks was 49% (95% CI 36–61). 21 grade 3–4 treatment-related adverse events were reported, the most common of which were increased lipase (four [7%] of 57 patients), colitis (three [5%] patients), and pneumonitis (three [5%] patients). Nine (16%) patients had a treatment related serious adverse event. One patient had grade 5 pneumonitis and colitis. The combination of durvalumab and tremelimumab is an active treatment regimen for advanced or metastatic sarcoma and merits evaluation in specific subsets in future trials. AstraZeneca.

Key Points CTLA-4 regulates T-cell activation upon initiation of an immune response, in the lymphoid organs, where naive T cells are primed, and potentially in the periphery via regulatory T-cell (T REG ) depletion This diverse role of CTLA-4 in initiating and mounting immune responses might explain the plethora of immune-related adverse events (irAEs) experienced by patients receiving treatment with anti-CTLA-4 antibodies PD-1 suppresses T-cell activity, mostly within the peripheral tissues and in the tumour microenvironment, which might explain the distinct spectrum and reduced incidence of adverse effects of anti-PD-1 antibodies Thyroid disorders are more frequent adverse effects of treatment with anti-PD-1 antibodies (pembrolizumab and nivolumab) whereas colitis and hypophysitis are more frequent with anti-CTLA-4 antibodies (ipilimumab) General guidelines on the management of irAEs recommend treatment of symptoms; corticosteroids are generally indicated together with dose skipping or discontinuation in patients with persistent grade ≥2 adverse events Immune checkpoint inhibition is a novel approach to cancer treatment with enormous potential to improve the outcomes of patients with a range of malignancies. However, owing to this novel approach, a range of adverse events have emerged with different aetiologies to those of more conventional cancer treatments. In this Review, the authors describe the occurrence, and optimal management of adverse events resulting from use of immune checkpoint inhibitors. Inhibition of immune checkpoints using anti-programmed cell death-1 (PD-1) or anti cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4) monoclonal antibodies has revolutionized the management of patients with advanced-stage melanoma and is among the most promising treatment approaches for many other cancers. Use of CTLA-4 and PD-1 inhibitors, either as single agents, or in combination, has been approved by the US FDA for the treatment of metastatic melanoma. Treatment with these novel immunotherapies results in a unique and distinct spectrum of adverse events, which are mostly related to activation of the immune system and are, therefore, an unwanted consequence of their mechanisms of action. Adverse effects of CTLA-4 and/or PD-1 inhibition are most commonly observed in the skin, gastrointestinal tract, liver and endocrine systems and include pruritus, rash, nausea, diarrhoea and thyroid disorders. In this Review, the authors describe the adverse event profile of checkpoint inhibitors targeting CTLA-4 and PD-1, used both as monotherapies and in combination and aim to provide some general guidelines, based upon the mechanisms of action of these therapies and on the management of these immune-related adverse events.