Lung cancer is still a global public health problem and the first cause of cancer-related mortality everywhere in the world. Nowadays, this has particular implications for elderly patients considering the generally increasing life expectancy in conjunction with the rising cancer incidence with age. At the time of diagnosis, the median age of patients with lung cancer is 70 years in the USA and 65 to 70 years in Europe.

Effective treatment options are called for in patients with resectable non-small-cell lung cancer (NSCLC), as more than half of those with stage I to III disease experience relapses [1]. Chen et al. demonstrated in their animal model that tumor PD-L1 upregulation is critical for the spread and survival of metastases [2]. Based on these considerations, several clinical trials are investigating the potential benefits of immunotherapies in the neoadjuvant setting.

Although treatment with EGFR TKIs is generally efficient in patients with EGFR-mutant lung cancer, resistance inevitably develops within 8 to 12 months of the initiation of therapy, leading to treatment failure. Therefore, there is an unmet need for options that extend the activity of EGFR-targeted therapies. Dual blockade of the VEGF and EGFR signaling pathways represents a potential approach in this respect.

KEYNOTE-001 was the first trial to demonstrate the activity of the PD-1 inhibitor pembrolizumab in patients with treatment-naïve or previously treated advanced NSCLC. Notably, in this multi­cohort phase IB study, pembrolizumab showed greater activity with increasing PD-L1 tumor proportion score (TPS). Between May 2012 and July 2014, 550 patients with advanced NSCLC had been enrolled across 4 non-randomized and 2 randomized cohorts.

What can we expect from circulating free DNA (cfDNA) as a biomarker in the setting of lung cancer diagnosis and treatment today?

MET exon 14 skipping mutations (MET­ex14) have been reported in 3 % to 4 % of NSCLC patients. They confer poor prognosis and poor responses to standard therapies including immunotherapy. Moreover, patients with MET alterations are generally older, which implies that tolerable strategies are called for. Capmatinib has been developed as a highly selective, potent MET inhibitor with in vitro and in vivo activity against preclinical cancer models harboring MET activation.

Only limited therapeutic options are available for patients with relapsing small-cell lung cancer (SCLC). Topotecan is the only FDA-approved treatment for platinum-sensitive disease in the second-line setting. However, it induces merely modest clinical benefits, while at the same time giving rise to significant hematological toxicity.

In 2017, the American Society of Clinical Oncology and the non-profit organization Friends of Cancer Research noted in their joint statement that trial enrollment criteria should strive for inclusiveness to make trial populations more representative and to maximize generalizability of findings. Also, this would enable more patients to participate and accelerate accrual, resulting in expedited availability of new therapies.

As physicians and researchers, we are fortunate to be part of the dramatic innovation in cancer research and treatment brought about by precision medicine. Although the success of precision medicine may seem like an overnight success, it has actually been a thoughtful, strategic approach based upon decades of hard, disciplined work by dedicated scientists from around the world.

Monotherapy with the anti-PD-1 monoclonal antibody pembrolizumab has significantly improved clinical endpoints compared to chemotherapy in patients with metastatic non–small-cell lung cancer (NSCLC). KEYNOTE-024 showed overall survival (OS) improvement in addition to a progression-free survival (PFS) benefit; moreover, patients treated with pembrolizumab had a better safety profile than those receiving chemotherapy.

Various clinical factors beyond PD-L1 expression have been explored as predictors of response to immune checkpoint inhibition. Specifically, analyses have associated lack of tobacco exposure with diminished responsiveness to PD-1 pathway blockade in NSCLC. One possible explanation for this is that lung cancers arising in never or minimal smokers generally show low TMB.

EGFR TKI treatment has become a standard first-line strategy for patients with advanced, EGFR-mutation–positive NSCLC. Established agents include the first-generation drugs gefitinib and erlotinib, the second-generation agents afatinib and dacomitinib, and the third-generation TKI osimertinib. Combinations of EGFR TKIs with other drug classes might lead to outcome optimisation, for instance the additional administration of anti-angiogenic drugs, such as bevacizumab and ramucirumab.

Afatinib has been licensed for the second-line treatment of patients with squamous-cell carcinoma of the lung. A combination trial is ongoing that is testing afatinib plus pembrolizumab. What can we expect from this regimen?

Standard treatment for patients with ALK-positive, advanced NSCLC includes the first-generation ALK inhibitor crizotinib and, more recently, second-generation ALK TKIs such as ceritinib and alectinib. The global, phase III ALEX trial tested the highly selective, CNS-active ALK inhibitor alectinib as first-line agent compared to crizotinib in patients with stage IIIB/IV ALK-positive NSCLC. Asymptomatic brain metastases were allowed in this study.

Extensive-disease small-cell lung cancer (ED-SCLC) is highly responsive to first-line therapy, but early relapses commonly occur, and prognosis is poor. To date, no biomarker-driven therapies have been established. Based on the involvement of the immune system in the pathophysiology of SCLC and the high mutational burden of this disease, immunotherapy has potential as a novel treatment option.

Early detection of lung cancer is a highly unmet medical need. Even though low-dose computed tomography (LDCT) has been shown to improve lung cancer mortality in high-risk individuals, the rate of clinical adoption remains low at 1.9 %. Cell-free DNA (cfDNA) testing might substitute LDCT as a screening tool, according to preliminary results of the Circulating Cell-free Genome Atlas (CCGA) Study presented at the ASCO Congress.

Lung cancer in young adults is relatively rare, but it is considered a unique subgroup with distinct biology. In patients aged ≤ 40 years, the incidence of lung cancer has been found to be 4 %, and in those aged ≤ 45 years, 5.3 %. Characteristically, women are more often affected than men; adenocarcinoma prevails, and the stage of disease is frequently advanced at the time of the diagnosis.

From the point of view of thoracic oncology, the 2017 ASCO Congress that took place from 2nd to 6th June, 2017, in Chicago, Illinois, offered no major highlights, but a range of interesting news. You will find a summary of selected presentations and posters in this issue of memo – inOncology that covers various targeted approaches as well as immunotherapy and mesothelioma.

Approximately 20 % to 25 % of non–small-cell lung cancer (NSCLC) patients are eligible for surgical resection with curative intent. To date, cisplatin-based chemotherapy constitutes the adjuvant standard of care for patients with stage II-IIIA completely resected NSCLC. The first-generation EGFR tyrosine kinase inhibitor (TKI) gefitinib is used as standard first-line treatment in patients with advanced EGFR-mutant  NSCLC.

The first-generation ALK inhibitor  crizotinib is the current standard option  for patients with newly diagnosed,  advanced ALK-positive NSCLC.  However, patients invariably relapse on  crizotinib treatment, with the central  nervous system (CNS) being one of the  most common and challenging sites of  relapse. The second-generation ALK  inhibitor alectinib is more potent than  crizotinib and shows clinical  activity in crizotinib-resistant NSCLC.

Brain metastases and leptomeningeal disease represent major clinical challenges in the management of patients with NSCLC. They are generally associated with poor prognosis, and their treatment is difficult due to the paucity of effective therapeutic options. Moreover, patients with CNS lesions are frequently excluded from clinical trials. Progress in this area is therefore slow, and more treatments are urgently needed.

The clinical relevance of additional genetic alterations in advanced EGFR-mutant NSCLC is not clear. Blakely et al. hypothesised that co-occurring genomic alterations in cancer-related genes can cooperate with the mutant EGFR to drive de-novo resistance to EGFR TKI treatments. The investigators performed targeted exome sequencing of plasma cell-free DNA (cfDNA) in 86 samples collected from 81 patients with known clinical history.

HER2 aberrations in lung cancer are being increasingly identified due to the use of sensitive testing procedures, such as multiplexed testing and next-generation sequencing. Mutations of the HER2 gene need to be distinguished from HER2 amplifications and HER2 protein overexpression. In contrast to breast and gastric cancer, HER2 overexpression in NSCLC does not always occur with HER2 amplification, while amplifications and HER2 mutations are generally mutually exclusive.

As the anti-PD-1 antibody nivolumab is known to induce deep and durable responses in a subset of lung cancer patients, this agent was investigated in the neoadjuvant setting, which is an area of unmet need. There have been no advances in systemic treatment of resectable lung cancer since 2004. Chaft et al. hypothesised that neoadjuvant nivolumab treatment might induce immunity against micrometastases.

Liquid biopsy for plasma circulating tumour DNA (ctDNA) next generation sequencing (NGS) is a rapidly evolving science. Plasma ctDNA assays are now commercially available, and are increasingly adopted in the community with a paucity of evidence-based guidance on timing and value of this test. Sabari et al. sought to determine the feasibility and utility of plasma ctDNA NGS to identify matched targeted therapy in a real-world clinical setting.

Lung cancer is a considerable issue in China. Every year, we have 700,000 new cases. There is a need to perform clinical trials and to launch innovative drugs. With regard to the introduction of targeted therapies, China lags 3 to 4 years behind when compared to the western countries. Two months ago, the EGFR TKI afatinib was launched, offering Chinese patients with EGFR-mutant lung cancer an effective treatment option.

Malignant pleural mesothelioma (MPM) is a rare tumour that is often diagnosed at an advanced stage. Limited efficacy of the available therapies contributes to the generally poor prognosis for MPM patients. Since 2003, the only approved regimen for MPM treatment has been chemotherapy with pemetrexed and cisplatin, with median survival of approximately 12 months.

KRAS mutations constitute the largest subset of oncogene-driven lung adenocarcinomas, at approximately 30 %. Patients with KRAS-mutant metastatic lung cancer have heterogeneous clinical outcomes depending on the mutation subtype and associated co-mutations. El Osta et al. analysed the Lung Cancer Mutation Consortium (LCMC) database to evaluate the characteristics of these patients and the effect of KRAS mutation features on their outcomes.

Lung cancer mortality rates for both men and women have been declining in recent years. Early detection, refined understanding of tumour biology, and a variety of novel treatment options have made these advances possible. Nevertheless, lung cancer is still the leading cause of cancer death in the United States and worldwide, prompting the scientific community to persevere in their research efforts and to extend them to areas that have traditionally been marked by little progress, such as small-cell lung cancer (SCLC).

Besides targeted drugs for driver mutations, immunotherapies represent one of the two recent major advancements of the past decade for the treatment of metastatic non–small-cell lung cancer (NSCLC). Nivolumab and ipilimumab enhance T-cell antitumour activity through distinct and complementary mechanisms.

ALK gene rearrangements occur in approximately 4 %to 5 % of all Caucasian and Asian patients with advanced NSCLC. Crizotinib was the first approved ALK inhibitor and is the current front-line standard treatment for ALK-positive NSCLC. However, despite initial responses to TKI treatment, all of these patients relapse in the long run.

It is important to understand that Latin America is a large continent with approximately 600 million inhabitants. The four most-populated cities are Mexico City, Rio de Janeiro, São Paulo, and Buenos Aires, where the number of people living in just these four cities is equal to the total number of inhabitants of France.

The phase IIb LUX-Lung 7 trial was a head-to-head comparison of the second- generation ErbB family blocker afatinib and the first-generation reversible EGFR TKI gefitinib in patients with treatment-naïve, EGFR-mutation-positive, advanced (stage IIIB/IV) adenocarcinoma of the lung.According to the primary analysis, patients treated with afatinib derived significant PFS, ORR and time-to-treatment-failure benefits compared to those who received gefitinib.

Which parameters should be taken into consideration regarding the choice of EGFR TKIs in a lung cancer patient with an activating EGFR mutation? When EGFR mutations are diagnosed in the first-line setting, we have the luxury of having three options today. However, it is important to discriminate between the different types.

The Lung Cancer Mutation Consortium (LCMC) is a multi-institutional consortium for the study of driver mutations of lung adenocarcinoma. The cooperating sites enable the identification of relatively large numbers of patients with uncommon and rare alterations, facilitate the analysis of their clinical characteristics, and lay the ground for targeted therapy trials.

Only minor progress has been made over the past 30 to 40 years in the treatment of small-cell lung cancer (SCLC), which accounts for 10 % to 15 % of lung cancer cases. SCLC is radiosensitive, but approximately 70 % of patients present with extended disease that cannot be included within one radiotherapy field. The majority of patients respond to first-line chemotherapy.

As chemotherapy in the second-line or third-line settings of NSCLC shows limited efficacy, the phase III, randomised ULTIMATE trial tested the combination of chemotherapy and bevacizumab in patients with advanced NSCLC of non-squamous histology, who had progressed after one or two lines of treatment.

The randomised, multicentre, open-label, phase II RENO trial was conducted with the objective of establishing a standard chemotherapy regimen in the setting of chemo-radiotherapy of locally advanced NSCLC. A total of 134 patients with inoperable stage III NSCLC received either oral vinorelbine plus cisplatin or etoposide plus cisplatin.

Evidence suggests the existence of a ,limited metastatic’ NSCLC phenotype. However, the type of optimal treatment and the role of aggressive local therapy in these patients remain controversial. Gomez et al. presented the first prospective, randomised trial to address this question. Patients had stage IV disease without RECIST progression and a maximum of three metastases after front-line systemic therapy (FLST).

The phase III E1505 trial was designed to investigate the addition of bevacizumab to adjuvant chemotherapy in patients with early-stage, completely resected NSCLC. It was based on the rationale that the benefit of adjuvant cisplatin-based chemotherapy is modest in this population. E1505 included 1,501 patients with completely resected, stage IB NSCLC.

As for many other oncological diseases, the management of lung cancer has undergone major changes in the last few years with the rise of targeted therapies, and more lately, of immunotherapy. These advances are reflected in the results of experimental research and clinical trials that were presented at the Annual Meeting of the American Society of Clinical Oncology that took place in Chicago, from 29th May to 2nd June, 2015.

Tumours with squamous histology account for 20 % to 30 % of cases of non–small-cell lung cancer (NSCLC). Despite this substantial proportion, only limited progress has been made in the treatment of advanced squamous-cell carcinoma (SCC) compared to non-squamous NSCLC, and thus SCC of the lung is a disease with a high unmet medical need.

Which of the recent advances in the field of NSCLC would you deem most important from the clinical point of view?

EGFR mutations and ALK rearrangements are well-established therapeutic targets in NSCLC, with EGFR TKIs and ALK TKIs representing the first-line standard of care for these molecular subsets of patients. However, resistance to first-generation inhibitors invariably develops, which calls for strategies to improve upon the durability of any response.

At this ASCO Congress, the biggest news in the field of NSCLC was the effects of the checkpoint inhibitors in the treatment of this disease. This applies especially to the results of the CheckMate 057 trial. The PD-1 inhibitor nivolumab is one of the first checkpoint inhibitors to be approved in lung cancer; it was approved in the United States for the treatment of squamous NSCLC early in 2015.

Small-cell lung cancer (SCLC) accounts for approximately 15 % of all lung cancers, and it is associated with poor outcomes. 70 % of these patients present with extensive disease. Their treatment remains a significant challenge for oncologists. The median survival in the extensive disease stage is 7 months to 9 months, and only 2 % of patients survive for 5 years

Immune checkpoint inhibitors have become established as standard therapy for certain subsets of NSCLC patients. Efforts are ongoing to optimise the benefits gained through these drugs, by identification of reliable prognostic and predictive biomarkers, such as PD-L1 expression in tumour cells or infiltrating immune cells, CD8-positive tumour-infiltrating lymphocytes, smoking status, and mutation burden.

Will findings presented here at ASCO change the future of NSCLC therapy?

The standard-of-care for inoperable stage III NSCLC is concurrent chemoradiotherapy. However, the role of consolidation chemotherapy remains controversial. The multi-targeted antifolate pemetrexed shows selective activity in non-squamous NSCLC.