This section considers how recent advances in the treatment of advanced/metastatic non-small cell lung cancer (NSCLC) may affect clinical decision making for patients with this disease.
Despite the recent increase in the number of treatment options, lung cancer remains the most common cause of cancer death worldwide for men, and the second most common for women.1 Globally, the number of cases of lung cancer is estimated to rise from 2.1 million in 2018 to 3.6 million in 2040.2 Although patient outcomes are better if the disease is diagnosed in its early stages, the 5-year survival rate for metastatic disease remains at approximately 5%.3 NSCLC is the most common tumor type, accounting for approximately 85% of lung cancers.4
Future perspectives in EGFR mutation-positive lung cancer
Future perspectives in EGFR mutation-positive lung cancer
Dr Barbara Melosky, MD, FRCP(C) discusses the impact of first-, second- and third-generation EGFR TKIs for the treatment of patients with advanced NSCLC, and how the future treatment landscape might evolve. Filmed in November 2019.
Recent advances in treatments for advanced/metastatic NSCLC
Targeting driver mutations in NSCLC
One of the most significant advances in the treatment of advanced/metastatic NSCLC has been the introduction of personalised medicine through the identification and targeting of driver mutations.5,6 Several molecular drivers have been identified that represent strong predictive biomarkers and serve as therapeutic targets. Guidelines suggest that all patients with advanced adenocarcinoma should be tested for the presence of: epidermal growth factor receptor (EGFR) mutations (occurring in 10–20% of Caucasian patients and with a higher prevalence in Asian patients); rearrangements involving anaplastic lymphoma kinase (ALK; 2–5%); and rearrangements of ROS1 (1–4%). Testing for these biomarkers is now considered mandatory in many European countries. 5,6 Molecular testing for the BRAF V600E mutation (found in approximately 2% of cases) is becoming more widespread, as BRAF/MEK inhibitors are approved for selected patient populations. 5,6 NTRK1 has also emerged as a target with approved treatments in many European countries. 5,6 Mutations in human epidermal growth factor receptor 2 (HER2) and MET, and fusions involving RET are evolving targets.5,6
Tyrosine kinase inhibitors (TKIs) that target EGFR mutations or ALK rearrangement are considered the standard of care in the first-line treatment of patients whose tumors bear these mutations, which occur most frequently in non-squamous NSCLC.5,6 Acquired resistance to first- and second-generation EGFR TKIs has been reported, of which the most common mechanism is T790M mutation. The availability of third-generation TKIs targeting the EGFR T790M resistance mutation supports their use as front-line treatment (based on clinical trial data); or supports molecular re-testing after disease progression on a first- or second-generation EGFR TKI. 5,6 More information about treatment sequencing with EGFR TKIs can be found here.
Patients with NSCLC lacking targetable driver mutations
For patients with NSCLC tumors that do not exhibit driver mutations, recent advances in various treatment lines have included agents that inhibit angiogenesis, as well as immunotherapies that target the programmed cell death receptor 1 (PD-1) or programmed cell death ligand 1 (PD-L1). 5,6
Personalized treatments for patients with NSCLC
Tailoring treatment algorithms to individual patients
The number of treatment options for patients with advanced/metastatic NSCLC has increased, and patients may now receive multiple, sequential lines of therapy at this stage of disease.7
With the increasing number of treatment options has come the need to tailor treatment to ensure that the best therapy is chosen for each individual patient at the right time: treatment algorithms must balance the benefit of offering the most effective therapies first with the need to reserve efficacious options for later lines.7 As well as the genetic profile of the tumor, many other factors need to be considered, such as the patient’s age, their overall health status, the presence or absence of brain metastases, and their treatment preferences. An increasing amount of evidence is now available to support clinical decision making in subgroups of patients with NSCLC, such as elderly patients5,6,8 and patients with brain metastases.5,6,9
With regard to a patient’s overall health status, for those with an Eastern Cooperative Oncology Group performance status (ECOG PS) of 2, chemotherapy increases survival and improves health-related quality of life compared with best supportive care (BSC).7 Poor ECOG PS (3 or 4) can be caused by high tumor burden and may improve with treatment, or be a result of comorbidities. For these patients, BSC is the preferred first-line option in the absence of documented sensitising alterations, such as EGFR mutations, ALK or ROS1 rearrangements, BRAF V600 mutations, or RET or NTRK fusions.5,6
The future of tailored treatment in NSCLC
Despite the advances in treatment options and the fact that treatment can be tailored to the individual patient to some extent, there is still much room for improvement. Although EGFR- and ALK-targeted therapies are effective, a proportion of patients with adenocarcinoma and the large majority of patients with squamous disease do not have tumors that bear these driver mutations.5,6 In addition, while immunotherapy has been hailed as practice changing, not all tumors respond to this class of treatment and almost all patients eventually relapse.10 Further research is needed to clearly identify which patient subgroups will benefit most from novel treatments such as immunotherapies, and what the optimal treatment options are when these novel treatments fail.
The future of molecular diagnostics in NSCLC
Alongside treatments targeted to specific mutations, we also need to develop diagnostic techniques to identify these mutations in patients. Ideally, a diagnostic test should be sensitive, non-invasive and fast enough to inform a treatment decision. Liquid biopsy is one such technique: plasma samples, rather than tumor samples, can be analysed for the presence of mutations based on innovative new techniques like next-generation sequencing and digital droplet polymerase chain reaction (ddPCR).11
Dr Patrick Pauwels, MD, PhD explains how ddPCR can be used as a diagnostic tool to detect known hot-spot EGFR mutations in patients with NSCLC. Filmed in October 2019.
Key factors in clinical decision making in advanced/metastatic NSCLC
According to established guidelines, treatment decisions for patients with advanced NSCLC should be based on tumor histology and the presence or absence of key genetic alterations.5,6
Molecular testing for targetable driver mutations
The most frequently occurring driver alterations for which targeted treatments are available (EGFR mutations, ALK and ROS1 translocation, and BRAF V600 mutations) are often mutually exclusive, which has resulted in a well-defined treatment algorithm for these patients.5,6
Tumor histology and lifestyle factors
Histology may play a part in the decision to offer molecular testing: for example, although EGFR testing is required for patients with adenocarcinoma, it is not considered beneficial for patients with squamous cell carcinoma unless they are never-smokers or former/light smokers.5,6 Similarly, testing for ALK rearrangements is only recommended for patients with non-squamous NSCLC.5,6
Considerations for immunotherapies
With regard to immunotherapy, since not all patients respond to PD-1/PD-L1 inhibitors, the use of a validated predictive biomarker would be invaluable to aid treatment decisions. 5,6 However, a universal PD-L1 immunohistochemistry (IHC) test for selecting patients for PD-1/PD-L1 therapy is not yet available, and negative test results are not always considered to be sufficient for excluding patients from immunotherapies. 5,6 Levels of PD-L1 expression associated with clinical benefit vary among the different approved immune checkpoint inhibitors, and between treatment lines; different IHC antibody clones, staining protocols, scoring systems and cut-off values have been used across the pivotal trials for immunotherapies.12
Questions remain on how to select patients who would derive the most benefit from immunotherapy and how to accurately and consistently assess response.12 Regardless, guidelines recommend that all patients with newly diagnosed advanced NSCLC are tested for PD-L1 status by IHC; although, testing may not be required for second-line treatment with certain regimens.5,6 Various measures of tumor mutational burden, which has been validated in a prospective clinical trial, are being explored, and assessment of tumor inflammation is also of interest.5,6
Further research on biomarkers will help clinicians establish the optimal sequence of therapies (particularly in the post-immunotherapy setting).5,6
Bray F, et al. CA Cancer J Clin 2018;68(6):394–424.
Ferlay J, et al. Global Cancer Observatory: Cancer Tomorrow. 2020. https://gco.iarc.fr/tomorrow/home (Accessed: November 2020).
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Molina JR, et al. Mayo Clin Proc 2008;83(5):584–94.
Planchard D, et al. Ann Oncol 2018;29(Suppl. 4):iv192–iv237.
European Society for Medical Oncology Clinical Practice Living Guidelines – Metastatic Non-Small-Cell Lung Cancer. https://www.esmo.org/guidelines/lung-and-chest-tumours/clinical-practice-living-guidelines-metastatic-non-small-cell-lung-cancer (Accessed: November 2020).
Melosky B. Front Oncol 2017;7:38.
Takayuki N, et al. Biomed Res Int 2018;2018:8202971.
Remon J, Besse B. Front Oncol 2018;8:88.
Doroshow DB, et al. Clin Cancer Res 2019;25(15):4592–602.
Bordi P, et al. Lung Cancer 2019;131:78-85
Schvartsman G, et al. Ther Adv Med Oncol 2016;8(6):460–73.
*Afatinib is approved in more than 80 markets including the EU, Japan, Taiwan, and Canada under the brand name GIOTRIF®, in the US under the brand name GILOTRIF® and in India under the brand name Xovoltib®; for the full list please see here. Registration conditions differ internationally; please refer to locally approved prescribing information.
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Last updated: December 2020
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