Epidermal growth factor receptor (EGFR) mutations are the most common oncogenic drivers in non-small-cell lung cancer (NSCLC). Significant developments have taken place which highlight the differences in tumor biology that exist between the mutant and wild-type subtypes of NSCLC. Patients with advanced EGFR-mutant NSCLC have a variety of EGFR-targeting agents available proven to treat their disease. This has led to superior patient outcomes when used as a monotherapy over traditional cytotoxic systemic therapy. Attempts at combining EGFR agents with other anticancer systemic treatment options, such as chemotherapy, antiangiogenic agents, and immunotherapy, have shown varied outcomes. Currently, no specific combination stands out to cause a shift away from the use of single-agent EGFR inhibitors in the first-line setting. Similarly, adjuvant EGFR inhibitors, are yet to significantly add to patient overall survival if used at earlier timepoints in the disease course. Liquid biopsy is an evolving technology with potential promise of being incorporated into the management paradigm of this disease. Data are emerging to suggest that this technique may be capable of identifying early resistance mechanisms and consequential disease progression on the basis of the analysis of blood-based circulating tumor cells.

The management of non-small cell lung cancer (NSCLC) has changed significantly with the discovery of specific drug targets. These drugs have helped transform patient care and outcomes. BRAF mutated NSCLC is now recognised as a rare form of lung cancer. Data has begun to emerge supporting the use of BRAF/MEK inhibitors that target BRAF^V600E mutations in the mitogen-activated protein kinase (MAPK) pathway. Multiple phase 2 studies have been performed assessing the effectiveness of single agent BRAF inhibition and combination BRAF/MEK inhibition in pretreated and untreated patient populations. Consistently overall response rate (ORR) and progression free survival (PFS) are improved with the addition of a MEK inhibitor. A 2-cohort phase 2 study demonstrated an ORR of 33% vs. 67% and PFS of 5.5 vs. 10.2 months in those treated with single agent dabrafenib vs. dabrafenib and trametinib respectively. A similar ORR of 63% and PFS of 10.9 months was seen in a separate phase 2 study in patients treated with Dabrafenib and Trametinib in the first line setting. Immunotherapy is beginning to show promise as an active therapy in BRAF mutated NSCLC in both V600E and non-V600E subtypes; however, this requires further study and clarification. BRAF^V600E mutated NSCLC treated with chemotherapy have been widely reported to be associated with worse outcomes when compared to those without a mutation. With efficacy of combination BRAF/MEK established and early evidence of immune checkpoint inhibitor activity careful consideration should be given when choosing the most appropriate therapy in this select patient cohort.

Profiling the tumour microenvironment (TME) has been informative in understanding the underlying tumour–immune interactions. Multiplex immunohistochemistry (mIHC) coupled with molecular barcoding technologies have revealed greater insights into the TME. In this study, we utilised the Nanostring GeoMX Digital Spatial Profiler (DSP) platform to profile a non-small-cell lung cancer (NSCLC) tissue microarray for protein markers across immune cell profiling, immuno-oncology (IO) drug targets, immune activation status, immune cell typing, and pan-tumour protein modules. Regions of interest (ROIs) were selected that described tumour, TME, and normal adjacent tissue (NAT) compartments. Our data revealed that paired analysis (n = 18) of matched patient compartments indicate that the TME was significantly enriched in CD27, CD3, CD4, CD44, CD45, CD45RO, CD68, CD163, and VISTA relative to the tumour. Unmatched analysis indicated that the NAT (n = 19) was significantly enriched in CD34, fibronectin, IDO1, LAG3, ARG1, and PTEN when compared to the TME (n = 32). Univariate Cox proportional hazards indicated that the presence of cells expressing CD3 (hazard ratio (HR): 0.5, p = 0.018), CD34 (HR: 0.53, p = 0.004), and ICOS (HR: 0.6, p = 0.047) in tumour compartments were significantly associated with improved overall survival (OS). We implemented both high-plex and high-throughput methodologies to the discovery of protein biomarkers and molecular phenotypes within biopsy samples, and demonstrate the power of such tools for a new generation of pathology research.

Identifying and targeting specific oncogenic drivers has become standard of care in the routine management of patients with lung cancer. Research is ongoing to expand the number of drug targets that can offer clinically meaningful outcomes. Rearranged during transfection (RET) fusions are the latest oncogenic driver alterations that show potential as a drug target. RET fusions occur in 1–2% of non-small cell lung cancer (NSCLC) cases. They are more commonly associated with younger age, female gender, non-smokers and Asian ethnicity. The RET kinase is abnormally activated through fusion with a partner protein such as KIF5B, CCDC6 or NCOA4. This leads to downstream intracellular signalling and enhancement of gene transcription and cell proliferation. The effectiveness of multi-kinase inhibitors in RET positive NSCLC has been explored in early phase and retrospective studies. From these studies, the most effective agents identified include cabozantanib and vandetanib. Overall response rates (ORR) vary from 18–47% across studies. In general, these agents have a manageable toxicity profile, although there are a number of off-target toxicities. Similar to the increased activity in ALK rearranged disease, pemetrexed has demonstrated superior response rates in this patient group and should be considered. Selective RET inhibitors, including LOXO-292 and BLU-667, are progressing in clinical trials. LOXO-292 has demonstrated an impressive ORR of 77% in RET positive solid tumours. It is anticipated this agent will be an effective targeted therapeutic option for patients with RET positive lung cancer.

A 63-year-old man with metastatic lung adenocarcinoma presented with biopsy confirmed toxic epidermal necrolysis (TEN). Symptoms commenced following 3 cycles of carboplatin, pemetrexed and pembrolizumab, with the first cycle given ~9.5 weeks prior to presentation. The patient was managed with immunosuppressive therapy including high dose methylprednisolone, cyclosporine, intravenous immunoglobulin, antibiotics and optimal skin care, and achieved excellent recovery of the skin lesions with minimal sequelae. This rare occurrence of pembrolizumab-induced TEN has only been reported previously in a few cases with limited evidence on management. Given the increasing use of immune checkpoint inhibitors and the long half-life of these agents, our case highlights the importance of recognizing this complication and of a multidisciplinary approach to management.

Background: Circulating tumour DNA (ctDNA) has emerged as a promising biomarker for monitoring non-small-cell lung cancer (NSCLC). This has enabled the monitoring of clinically actionable mutations over the course of therapy. Case presentation: We present the case of a 74-year-old female who was treated with EGFR inhibitors for NSCLC which later transformed to SCLC. The kinetics of ctDNA was monitored by measuring the EGFR Exon 19 mutant L747–A750 > P and PIK3CA E545K over the course of therapy. Stabilisation of the PIK3CA mutation was found in response to therapy, however there appeared to be increasing levels of the EGFR mutant, potentially reflective of untreated EGFR-driven disease. Conclusion: The key finding described here, revealed by mutational tracking of mutations from the blood, is that clinically actionable mutations are assessable and may demonstrate clinical utility in measuring disease burden, multiple clones and progression non-invasively for lung cancer.