Disease condition and impact on patients Lung cancer is the most commonly diagnosed cancer worldwide and is a major cause of cancer-related morbidity, disability and mortality, with an estimated 2 million new cases and 1.8 million related deaths in 2018 (1). The most commonly diagnosed histology type is non-small cell lung carcinoma (NSCLC), followed by small-cell lung carcinoma (SCLC). Various molecular alterations have been detected in NSCLC, which are known to drive tumour progression and clinical pattern. NSCLC can occur in either oncogene-addicted or non-addicted forms, according to the presence of specific genetic mutations driving tumorigenesis and their pharmacological targetability. The molecular characteristics of NSCLC generally orient therapeutic approaches, especially in the advanced setting. The EGFR gene can present a somatic acquired pathogenetic mutation in a significant portion of NSCLC. EGFR-addicted NSCLC, given its incidence, comprises a high burden and leads to a high death rate. But advances in cancer oncoprotein-directed treatments means survival and quality of life have both improved. The use of anti-EGFR treatments, including tyrosine kinase inhibitors (TKIs) doubles objective response rates (ORRs) compared with chemotherapy and improves progression-free survival (PFS). The median survival time is nearly 3 years if the patient receives both targeted medicines and chemotherapy, compared with a median survival time of around 10 months for patients receiving chemotherapy alone (2). Does the test meet a medical need? The main international guidelines for treating advanced NSCLC confirm that testing EGFR to assess its mutational status has crucial therapeutic implications because patients with mEGFR NSCLC can derive significant benefit from treatment with an anti-EGFR TKI. ESMO (2) recommends using EGFR TKIs as the standard of care for first-line treatment of advanced EGFR-mutated NSCLC (level of evidence: I; grade of recommendation: A). EGFR mutation as an oncogenic target has proven a predictive role in NSCLC from multiple phase 3 trials of EGFR-TKIs versus platinum-based chemotherapy. The improvement in ORR and PFS is consistent across all age groups, genders, smoking status and performance status. According to the WHO cancer medicines working group, the ESMO Magnitude of Clinical Benefit Scale (MCBS) is a useful tool for selecting medicines that are eligible for priority screening in the WHO EML. Based on the results of the LUX-Lung 3 study (3), afatinib scores 4/5 on the MCBS v 1.1 for first-line use in metastatic mEGFR-positive NSCLC. The OPTIMAL (4) and EURTAC (5) studies give erlotinib an MCBS v 1.1 score of 4/5; and the IPASS study (6) similarly gives gefitinib an MCBS v 1.1 score of 4/5 for first-line use in metastatic mEGFR NSCLC. The US National Comprehensive Cancer Network (NCCN) guidelines also recognize the value of the EGFR TKIs gefitinib, erlotinib and afatinib, giving these TKIs scores of 3/5 for efficacy, 3/5 for safety, 5/5 for quality and consistency of evidence, and 2/5 for affordability. In 2019, based on data of clinical benefit, the WHO Expert Committee on the Selection and Use of Essential Medicines added erlotinib to the complementary list of the EML for first-line treatment of mEGFR advanced NSCLC, identifying afatinib and gefitinib as therapeutically equivalent alternatives (7). The committee noted that these medicines show relevant survival benefits for patients and have better toxicity profiles and quality of life compared with chemotherapy. The committee also noted that since these medicines were considered for inclusion on the EML in 2015, generic versions of these medicines are more widely available, as are quality-assured diagnostic molecular tests for EGFR mutations. How the test is used The test (EGFR PCR) is used as a stand-alone test, in patients diagnosed with NSCLC, adenocarcinoma or mixed histology with adenocarcinoma components (non-squamous NSCLC). There is currently no role for a pre-screening test with EGFR immunohistochemistry (IHC); nor can EGFR IHC substitute for the molecular assay. Although novel applications of PCR and next-generation sequencing methods can have various applications in this setting, this submission addresses EGFR testing in tumour tissue samples, and not cell-free DNA or other types of “liquid biopsies”; the test can be performed either from samples of the primary tumour or from metastatic sites, as clinically appropriate. Although some clinical-pathologic features can enrich the population more likely to harbour mEGFR (e.g. women, non- or light smokers), EGFR molecular testing should be offered to all-comer advanced non-squamous NSCLC patients to indicate EGFR-targeted TKI therapy, regardless of specific clinical characteristics (8, 2). According to ESMO, routine EGFR somatic mutation testing is recommended for all non-squamous tumours in patients with advanced/recurrent disease (level of evidence:1; grade of recommendation: A). ESMO encourages a wide coverage of mutations in exons 18–21, as some are associated with sensitivity to therapies. At a minimum, when resources or material are limited, the most common activating mutations (Exon19del, L858R) should be determined (level of evidence:1; grade of recommendation: A) (9). In 2018, the College of American Pathologists (CAP), the International Association for the Study of Lung Cancer (IASCL), and the Association for Molecular Pathology updated their joint standards for the molecular analysis of lung cancers to guide treatment decisions with targeted inhibitors (10). The panel recommends that pathologists use cell blocks or other cytologic preparations as specimens for lung cancer EGFR molecular testing. It further recommends laboratories to use, or to have available at an external reference laboratory, clinical lung cancer biomarker molecular testing assays that can detect molecular alterations in specimens with as little as 20% cancer cells. It clarifies that laboratories should not use total EGFR expression by IHC testing to select patients for mEGFR-targeted TKI therapy as there is no role for IHC against total EGFR protein as a determinant of treatment with an EGFR kinase inhibitor in NSCLC. Mechanistically, the targetable mutations lead to constitutive and uncontrolled activation of the protein kinase EGFR; however, these molecular alterations have no bearing on the extent of expression at the cell surface of EGFR, which is what is detected by the total EGFR immuno-stain. Although EGFR expression by IHC has been performed in some early studies of EGFR TKI, clinical responses were observed across a wide range of EGFR IHC expression, including in NSCLC with absent/weak IHC expression. The joint standards also make clear that while early studies showed that EGFR-mutated lung cancers responded to treatment with EGFR inhibitors using unmodified Sanger sequencing with a sensitivity limit of 50% tumour cellularity, in practice this is insufficient because many lung cancer samples are small and mostly comprise benign stromal cells. Most of the larger phase 3 clinical trials that confirmed the clinical utility of mEGFR testing used PCR-based methods that were more sensitive than unmodified Sanger sequencing. Given the widespread availability of technology capable of reliably detecting lower-frequency mutational events in small samples, it is no longer appropriate to offer a low-sensitivity test that cannot test tumours with 20–50% tumour content and requires patients to undergo more invasive procedures to procure a suitable tissue sample (11).

Prevalence and socioeconomic impact Lung cancer is the most commonly diagnosed cancer worldwide; and NSCLC is the most commonly diagnosed histology type. The disease has a huge economic impact, estimated at around US$ 8 billion in lost productivity in Brazil, Russia, India, China and South Africa (12). The absence of effective screening programmes combined with the large number of tobacco smokers means that lung cancer diagnoses are made at the advanced stage in nearly two-thirds of cases (13). The mutational pattern of NSCLC relative to EGFR varies across regions, with the highest prevalence in the Asia-Pacific region, where up to 76% of patients present with mEGFR, and the lowest prevalence in Oceania (12%). Africa, Europe and North America registered the same rate of EGFR-mutated NSCLC, at around 20%. Regardless of geographic region, prevalence is higher among never-smokers, women, and the adenocarcinoma subtype (8). The recognition of a pathogenetic mutation of EGFR in lung cancer patients implicates a possible change in the algorithm of treatment of 15–75% of patients, according to the region of origin. Implementing EGFR testing in Asia, where the incidence of mEGFR in lung tumours is highest, could considerably address the health issues of 500 000 to a million patients. Enhancing access to TKI could substantially improve the quality of life and increase life expectancy in patients with generally poor outcomes.

The EGFR molecular test is recommended in the clinical algorithm for NSCLC in the WHO 21st EML (14). It is also mentioned in 2015 WHO Classification of Tumors of the Lung, Pleura, Thymus and Heart (15). International guidelines for treating advanced NSCLC have been issued by the American Society of Clinical Oncology (ASCO) (11), CAP (10), ESMO (9) and NCCN (16). All recommend testing EGFR to assess its mutational status (see “Does the test meet a medical need?” and “How the test is used” in Section D for details).

The panel of experts behind the 2018 CAP/IASCL/AMP guidelines (10) confirmed the clinical utility of mEGFR testing methods. The joint panel, endorsed by ASCO and aligned with ESMO and other national and international societies of oncology, also developed a systematic revision of EGFR testing to address clinical validity, utility, diagnostic performance and quality assurance (10, 11). An FDA non-clinical performance evaluation from one of the commercially available EGFR PCR tests (17) showed that the test could detect mutations in EGFR exons 18, 19, 20 and 21 with at least 5% mutation level using the standard input of 50 ng per reaction well. Rosell et al. (5) assessed the clinical performance of the test by comparing it to two reference methods (bidirectional Sanger sequencing and quantitative next-generation sequencing), using 487 specimens from patients with advanced NSCLC. The positive percentage agreement between the test and Sanger sequencing was 96.6% (95% CI: 91.5–98.7); the negative percentage agreement was 88.3% (95% CI: 84.1–91.5), in the detection of exon 19 deletions and L858R mutations in aggregate as presented. The FDA (18) has presented similar clinical studies for other commercially available tests.

A systematic review was performed and published in 2015 by the Italian medical oncology team of the National Cancer Institute and the Mario Negri Institute for Pharmacological Research IRCCS (19). The authors analysed reports of randomized controlled trials in the peer-reviewed literature and found that all treatments with TKIs had similar efficacy, but differing toxicity. PFS was better for patients receiving TKI compared with chemotherapy; although data on overall survival were inconclusive and no gain was demonstrated for the extensive patients crossing over into the experimental arm. The role of EGFR TKI first (erlotinib, gefitinib), second (afatinib) and third generation (osimertinib) has been demonstrated in several phase 3 randomized clinical trials, with consistent results. Gefitinib has been tested against platinum-based chemotherapy in four randomized clinical trials (6, 20–22); erlotinib in two trials (4, 5) and afatinib in one trial (3) and six studies (23). The trials enrolled both Asian and non-Asian populations, providing consistent results across different ethnicities. The use of TKI in the controlled trials was associated with improved ORRs, with 55–85% of patients reaching a partial or complete radiological response. Trials also reported an increase of disease control, with longer PFS rates: for example, the exposure to TKI is associated with a median PFS of 9–13 months, which is up to 8.5 months longer than chemotherapy. Data on quality of life have also confirmed the benefit of front-line TKI compared with chemotherapy (2).

Whiting et al. (24) did a systematic review and cost–effectiveness analysis of mEGFR testing in NSCLC, in which two health economists independently assessed studies for inclusion. The long-term costs and QALYs were estimated using a Markov model with a cycle time of 21 days (resembling the duration of one cycle of chemotherapy) and a time horizon of 6 years. The model showed that the PCR-based EGFR testing with the one of the commercially available kits was less costly than direct sequencing of all exons 19–21, with an incremental cost–effectiveness ratio of £32 167. There are imminent price adjustments that will make the cost of first- and second-generation TKIs comparable in the near future. Data on costs, cost comparisons or cost analyses are highly variable across countries. EGFR TKIs are more expensive than standard chemotherapy agents. But they are oral medicines and thus do not require the same level of infrastructure or personnel support to be administered.

As included in the WHO EML, access to TKI should be prioritized in the eligible population worldwide. Access to more effective and less toxic treatments is a priority in oncology, especially for mEGFR NSCLC patients presenting with a clinical phenotype of “lower risk” group (e.g. non-smokers), who are less likely to be included in lung cancer screening programmes. EGFR PCR should be made available when diagnostic capacity and pathology laboratories are available and well functioning. WHO lists anti-EGFR TKIs as essential medicines, and their prescription requires an assessment of the EGFR mutational status. Accordingly, efforts must be made to ensure that there are no inequalities among NSCLC patients. When access to the test is not linked to an assured access to TKI, or is entirely out of pocket, it could challenge household incomes of patients and their families.