Immunotherapy in non-small cell lung cancer : shifting prognostic paradigms

Immune checkpoint inhibitors have shown efficacy in the treatment of non-small cell lung cancer (NSCLC) in the adjuvant, first- and subsequent-line settings. In metastatic disease, they provide hope of durable response where best-case scenario has long been inadequate. This progress has highlighted the immunogenic nature of NSCLC and invigorated research into immunotherapy in the field. In this review we consider the foundations of immunotherapy in NSCLC, canvass the current research and summarise the evidence guiding clinical practice

Biomarkers that predict response to immunotherapy : no magic bullet

Immunotherapeutic agents have shown impressive clinical efficacy in a broad range of tumour types, particularly in non-small cell lung cancer and melanoma. An effective predictive biomarker is needed to provide patients with the most effective available treatments, avoid unnecessary toxicity and improve cost effectiveness. While it has been an area of very active research in recent years, the ideal biomarker for predicting response to immune check point inhibitor therapy has not yet been universally agreed upon. Approaches to date have focussed on assessment of tumour related factors such as immunohistochemical expression of programmed death ligand-1 (PD-L1), mutational load and DNA mismatch repair gene or protein status. Alternatively, assessment of the immune microenvironment by techniques such as gene expression profiling or measurement of tumour infiltrating lymphocytes can also be informative. Identifying and validating effective biomarkers is particularly challenging for immunotherapy because the dynamic and multifactorial nature of the interaction between tumours and host immunity. In this review, we discuss the relative advantages and disadvantages of different biomarker approaches in the quest to identify a clinically effective predictive biomarker that can improve the overall utility for immune checkpoint inhibitors

Pseudoprogression associated with clinical deterioration and worsening quality of life in malignant pleural mesothelioma

Malignant pleural mesothelioma (MPM) is an aggressive asbestos-related malignancy with limited treatment options. Immune checkpoint inhibition has demonstrated promising activity in MPM with the use of single-agent pembrolizumab in a mostly chemotherapy-resistant population.1 Here we report significant responses to pembrolizumab after pseudoprogression in two patients with MPM and corresponding patient-reported outcomes (PROs) related to quality of life

Understanding immune tolerance of cancer : re-purposing insights from fetal allografts and microbes

Cancer cells seem to exploit mechanisms that evolves as part of physiological tolerance, which is a complementary and often beneficial form of defense. The study of physiological systems of tolerance can therefore provide insights into the development of a state of host tolerance of cancer, and how to break it. Analysis of these models has the potential to improve our understanding of existing immunological therapeutic targets, and help to identify future targets and rational therapeutic combinations. The treatment of cancer with immune checkpoint inhibitors aims to reverse the progression to tolerance of cancer, and achieve an immunogenic, rather than tolerogenic, homeostasis. Broadening the efficacy and durability of checkpoint inhibitors focuses on reversing tolerance and stimulating immunogenicity in the cancer, host, and environment. Two examples of important physiological states of tolerance that may inform tolerance of cancer are microbial infection and placental reproduction. These states of tolerance result from bilateral shaping of host and non-self, akin to immunoediting in cancer, and offer reliable models to study the immune tolerance paradigm

EGFR–co-mutated advanced NSCLC and response to EGFR tyrosine kinase inhibitors

Objectives The evolution of EGFR tyrosine kinase inhibitors (TKIs) has changed the landscape of disease for a subset of patients with NSCLC. Most patients with an EGFR mutation respond to these drugs; however, a proportion show limited or no tumor response. We explored the impact of co-mutation (double or multiple mutation), compared with a single mutation, of the EGFR gene on response to TKIs in a series of patients with metastatic NSCLC. Methods We retrospectively analyzed the mutation profiles of nonsquamous NSCLC tested at Royal Prince Alfred Hospital between 2012 and 2015 by MassArray using the OncoCarta v1.0 panel. Patients with metastatic disease whose tumors had sensitizing EGFR mutation(s) were included. The primary end point was progression-free survival (PFS). We used the Kaplan-Meier method for PFS and overall survival; the log rank test was used to compare groups with and without co-mutation. Multivariable analysis was done for PFS; response rate was assessed using chi-square and logistic regression analysis. Results A total of 62 patients were included, and of these, eight (12.9%) had a co-mutation. The median PFS and overall survival times were 11.5 and 26.3 months, respectively. Patients with EGFR co-mutation had a significantly shorter median PFS than those with a single mutation (5.7 months versus 12.3 months, p = 0.02). The response rate to TKIs was significantly worse in those with co-mutation compared with in those without co-mutation (38% versus 89%, p < 0.001). Conclusions Taking into account the small number of patients in this study, PFS in patients with EGFR co-mutation appeared significantly shorter, and response rate significantly lower, than in patients with a single mutation. Data from multipanel testing may identify subgroups of patients who are likely to respond poorly to standard treatment. Clarification of these subgroups may improve patient care