Oncogene-addicted metastatic non-small-cell lung cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up

•This ESMO Clinical Practice Guideline provides key recommendations and algorithms for managing oncogene-addicted mNSCLC.•ESMO-MCBS scores are given to describe the levels of evidence for treatment choices.•ESCAT scores are given to describe the evidence level for genomic alterations as biomarkers for using targeted therapies.•Recommendations are based on available scientific data and the authors’ collective expert opinion.•In clinical practice, all recommendations provided need to be discussed with patients in a shared decision-making approach. Details on incidence and epidemiology are covered in the Supplementary Material Section 1, available at https://doi.org/10.1016/j.annonc.2022.12.009. Details on diagnostic procedures are covered in the Supplementary Material Section 2, available at https://doi.org/10.1016/j.annonc.2022.12.009. See Supplementary Figure S1, available at https://doi.org/10.1016/j.annonc.2022.12.009 for a flow chart on diagnosis and testing biopsy/cytology samples in stage IV non-small-cell lung cancer (NSCLC). Biomarker testing is essential to identify subgroups of NSCLC with oncogenic drivers that can be therapeutically targeted. These drivers are mainly found in lung adenocarcinomas (LUADs). Demonstration of the specific molecular alteration is necessary to tailor treatment with the appropriate targeted therapy. The frequency of oncogenic drivers in NSCLC as well as general discussion of testing strategy and methodology, including the use of liquid biopsies, can be found in the Supplementary Material Section 3, available at https://doi.org/10.1016/j.annonc.2022.12.009. Many parameters might determine which tests are required; pre-eminent amongst them is access to appropriate drugs.1Horgan D. Ciliberto G. Conte P. et al.Bringing onco-innovation to Europe’s healthcare systems: the potential of biomarker testing, real world evidence, tumour agnostic therapies to empower personalised medicine.Cancers (Basel). 2021; 13: 583Crossref PubMed Scopus (11) Google Scholar Testing is mandatory for oncogenic drivers for which drugs are approved for routine usage. Broader testing may be used to support early drug access or clinical trials.2Popat S. Navani N. Kerr K.M. et al.Navigating diagnostic and treatment decisions in non-small cell lung cancer: expert commentary on the multidisciplinary team approach.Oncologist. 2021; 26: e306-e315Crossref PubMed Scopus (13) Google Scholar,3Lindeman N.I. Cagle P.T. Aisner D.L. et al.Updated molecular testing guideline for the selection of lung cancer patients for treatment with targeted tyrosine kinase inhibitors: guideline from the college of american pathologists, the international association for the study of lung cancer, and the association for molecular pathology.J Thorac Oncol. 2018; 13: 323-358Abstract Full Text Full Text PDF PubMed Scopus (330) Google Scholar For personalised therapy approaches, European Society for Medical Oncology (ESMO) Scale for Clinical Actionability of molecular Targets (ESCAT) classifications4Mateo J. Chakravarty D. Dienstmann R. et al.A framework to rank genomic alterations as targets for cancer precision medicine: the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT).Ann Oncol. 2018; 29: 1895-1902Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar need to be considered (Supplementary Table S1, available at https://doi.org/10.1016/j.annonc.2022.12.009). Clinically-relevant EGFR gene mutations in NSCLC include substitutions, deletions and insertions in exons 18-21 that activate the tyrosine kinase and variably confer sensitivity or resistance to available epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) or other drugs.3Lindeman N.I. Cagle P.T. Aisner D.L. et al.Updated molecular testing guideline for the selection of lung cancer patients for treatment with targeted tyrosine kinase inhibitors: guideline from the college of american pathologists, the international association for the study of lung cancer, and the association for molecular pathology.J Thorac Oncol. 2018; 13: 323-358Abstract Full Text Full Text PDF PubMed Scopus (330) Google Scholar,5Kerr K.M. Bibeau F. Thunnissen E. et al.The evolving landscape of biomarker testing for non-small cell lung cancer in Europe.Lung Cancer. 2021; 154: 161-175Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar The most common alterations conferring sensitivity to first- to third-generation TKIs are the exon 21 L858R substitution and exon 19 deletion mutations. At a minimum when resources or material are limited, these mutations should be evaluated. The next most common alteration is a large group of exon 20 insertions mostly resistant to current EGFR TKIs but sensitive to some emerging agents (discussed in the treatment paragraph including EGFR exon 20 insertions). Other mutations, including in exon 18, variably sensitise, while some mutations confer resistance and may drive disease relapse. Complete sequencing of exons 18-21 by next-generation sequencing (NGS) is strongly recommended, to identify all possible sensitising mutations. Some allele-specific EGFR sequencing solutions do not provide complete coverage. EGFR FISH or immunohistochemistry (IHC) have no clinical utility and should not be tested. Fusions (rearrangements) involving ALK, ROS1, NTRK1-3 and RET genes are important oncogenic drivers in small groups of LUADs.3Lindeman N.I. Cagle P.T. Aisner D.L. et al.Updated molecular testing guideline for the selection of lung cancer patients for treatment with targeted tyrosine kinase inhibitors: guideline from the college of american pathologists, the international association for the study of lung cancer, and the association for molecular pathology.J Thorac Oncol. 2018; 13: 323-358Abstract Full Text Full Text PDF PubMed Scopus (330) Google Scholar,5Kerr K.M. Bibeau F. Thunnissen E. et al.The evolving landscape of biomarker testing for non-small cell lung cancer in Europe.Lung Cancer. 2021; 154: 161-175Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar Each target has several TKIs available. Furthermore, NRG1 fusions are a potential emerging target in LUADs. Oncogenic fusion proteins result in constitutive activation of the kinase and may increase fusion gene protein levels, allowing for screening of tumours for some of these fusions by IHC. Positive anaplastic lymphoma kinase (ALK) IHC with an appropriately validated assay may be used to prescribe ALK inhibitors. Cases positive by ROS1 or neurotrophic tyrosine receptor kinase (NTRK) IHC must be confirmed by a molecular method; this may also be preferred for ALK IHC-positive cases. Fusions can be detected by FISH, or multiplex RT–PCR panel assays, the latter requiring a tailored reaction for each potential fusion gene which makes this approach more complex. RNA-based NGS is preferred for identifying an expanding range of fusion genes. If NGS is used as the primary NTRK screening tool, IHC confirmation should be considered.6Marchiò C. Scaltriti M. Ladanyi M. et al.ESMO recommendations on the standard methods to detect NTRK fusions in daily practice and clinical research.Ann Oncol. 2019; 30: 1417-1427Abstract Full Text Full Text PDF PubMed Scopus (215) Google Scholar Alterations in structure and/or expression of the MET gene drive oncogenesis in NSCLC.3Lindeman N.I. Cagle P.T. Aisner D.L. et al.Updated molecular testing guideline for the selection of lung cancer patients for treatment with targeted tyrosine kinase inhibitors: guideline from the college of american pathologists, the international association for the study of lung cancer, and the association for molecular pathology.J Thorac Oncol. 2018; 13: 323-358Abstract Full Text Full Text PDF PubMed Scopus (330) Google Scholar,5Kerr K.M. Bibeau F. Thunnissen E. et al.The evolving landscape of biomarker testing for non-small cell lung cancer in Europe.Lung Cancer. 2021; 154: 161-175Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar High MET protein levels may be detected by IHC. Increased MET signalling may result from high gene copy number (GCN), either due to polysomy or true gene amplification. Detection is reliable by in situ hybridisation (ISH) techniques, but NGS or comparative genomic hybridisation may also identify cases. Definitions of high GCN vary and, in absence of current standardisation, confound existing data. MET exon 14 skipping mutations may be detected by DNA-based NGS, but RNA-based NGS may also identify additional cases missed by DNA sequencing.7Davies K.D. Lomboy A. Lawrence C.A. et al.DNA-based versus RNA-based detection of MET exon 14 skipping events in lung cancer.J Thorac Oncol. 2019; 14: 737-741Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar MET amplification is an important resistance mechanism driving acquired resistance to EGFR (including osimertinib) and ALK inhibitors. Mesenchymal-epithelial transition (MET) kinase inhibitors are being investigated in several scenarios and approved in the MET exon 14 skipping setting. KRAS mutations have become an important therapeutic target in LUADs and, unlike the other targets described here, are mostly smoking related.5Kerr K.M. Bibeau F. Thunnissen E. et al.The evolving landscape of biomarker testing for non-small cell lung cancer in Europe.Lung Cancer. 2021; 154: 161-175Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar Specific inhibitors for KRAS G12C mutations are now available. DNA sequencing and multiplex RT–PCR panel assays are the best approach to detection; most likely incorporated into NGS panels, as is the case for BRAF mutations. TKIs for BRAF V600E mutations are available. HER2 exon 20 insertion mutations are rare in LUADs, but promising targeted drugs and antibody–drug conjugates are in development. Therefore, these mutations need to be covered with NGS panels. Mutations coexisting with several of the above driver alterations may influence responses to targeted therapy and require additional treatment.8Skoulidis F. Heymach J.V. Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy.Nat Rev Cancer. 2019; 19: 495-509Crossref PubMed Scopus (398) Google Scholar Comutations in TP53 may be associated with lower efficacy of EGFR, ALK and ROS1 TKIs. Testing for comutations in an NGS panel may therefore become important. Resistance to kinase inhibitors is almost inevitable and is variably due to the emergence of therapy-resistant tumour cell clones with target gene alteration, increased bypass pathway signalling and/or phenotypic transformation (small-cell, squamous-cell carcinoma or sarcomatoid carcinoma).9Yaghmaie M. Yeung C.C. Molecular mechanisms of resistance to tyrosine kinase inhibitors.Curr Hematol Malig Rep. 2019; 14: 395-404Crossref PubMed Scopus (32) Google Scholar As treatments to target resistance mechanisms emerge, so does testing to detect each mechanism, and a need either for re-biopsy or, if appropriate, cell-free DNA (cfDNA) testing. Widespread use of osimertinib in the first line for EGFR-mutated NSCLC has decreased the importance of EGFR T790M detection but increases the need for identifying MET amplification as treatments for the latter are being evaluated. •Adequate tissue material for histological diagnosis and molecular testing should be obtained to allow for individual treatment decisions [IV, A]. For recommended methods to obtain tissue, please refer to the ESMO Clinical Practice Guideline (CPG) on non-oncogene-addicted metastatic non-small-cell lung cancer (mNSCLC; available at: https://www.esmo.org/guidelines/guidelines-by-topic/lung-and-chest-tumours).10Hendriks L.E. Kerr K.M. Menis J. et al.Non-oncogene-addicted metastatic non-small-cell lung cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up.Ann Oncol. 2023; 34: 358-376Abstract Full Text Full Text PDF Scopus (4) Google Scholar•Pathological diagnosis should be made according to the 2021 World Health Organization classification of lung tumours [IV, A].•Specific subtyping of all NSCLCs is necessary for therapeutic decision making and should be carried out wherever possible. IHC stains should be used to reduce the NSCLC-not otherwise specified rate to fewer than 10% of cases diagnosed [IV, A].•The molecular tests below are recommended in patients with advanced non-squamous-cell carcinoma, and not recommended in patients with a confident diagnosis of squamous-cell carcinoma, except in unusual cases, e.g. young (<50 years) patients, never (<100 cigarettes in a lifetime)/former light smokers (≤15 pack-years, all kinds of tobacco) or long-time ex-smokers (quit smoking >15 years ago, all kinds of tobacco) [IV, A].•EGFR mutation status should be determined [I, A]. Test methodology should have adequate coverage of mutations in exons 18-21, including those associated with resistance to some therapies [III, A]. At a minimum, when resources or material are limited, the most common activating mutations (exon 19 deletion, exon 21 L858R point mutation) should be determined [I, A].•The availability of TKIs effective against T790M-mutated recurrent disease makes T790M testing on disease relapse on first- or second-generation EGFR TKIs mandatory [I, A].•Testing for ALK rearrangements should be carried out [I, A].•Detection of the ALK translocation by FISH remains a standard, but IHC with high-performance ALK antibodies and validated assays may be used for screening [III, A] and have been accepted as an equivalent alternative to FISH for ALK testing.•Testing for ROS1 rearrangements should be carried out [II, A]. Detection of the ROS1 translocation by FISH remains a standard; IHC may be used as a screening approach [IV, A].•BRAF V600 mutation status testing should be carried out [II, A].•Testing for NTRK rearrangements should be carried out [II, A]. Screening for NTRK rearrangements may use IHC or NGS, with appropriate testing follow-up to validate a positive result [II, A].•Testing for MET exon 14 skipping mutations, MET amplifications, RET rearrangements, KRAS G12C mutations and HER2 mutations should be carried out [II, A].•If available, multiplex platforms (NGS) for molecular testing are preferable [III, A].•RNA-based NGS is preferred for identifying an expanding range of fusion genes [III, B]. Whichever testing modality is used, it is mandatory that adequate internal validation and quality control measures are in place and that laboratories participate in, and perform adequately in, external quality assurance schemes for each biomarker test [III, A].•cfDNA (liquid biopsy) can be used to test for oncogenic drivers as well as resistance mutations, but all patients with a negative cfDNA blood test still require tissue biopsy [II, A]. Details on staging and risk assessment are covered in the Supplementary Material Section 4, available at https://doi.org/10.1016/j.annonc.2022.12.009. •A complete history including a precise smoking history and comorbidities, weight loss, Eastern Cooperative Oncology Group performance status (ECOG PS) and physical examination must be recorded [IV, A].•Laboratory standard tests including routine haematology, renal and hepatic functions and bone biochemistry tests are required. Other tests (e.g. lipid spectrum and creatine kinase levels) depend on toxicity of the targeted therapy that will be used [IV, A].•An electrocardiogram is required if the targeted therapy can cause adverse cardiac events, including rhythmic modifications (e.g. long QT) [IV, A].•Contrast-enhanced computed tomography (CT) scan of the chest and upper abdomen (including the liver and adrenal glands) should be carried out at diagnosis [IV, A].•Imaging of the central nervous system (CNS) should be considered at diagnosis for all patients with metastatic disease [IV, B] and is required for patients with neurological symptoms or signs [IV, A]. If available, CNS imaging with gadolinium-enhanced magnetic resonance imaging (MRI) should be considered for all patients [IV, B].•If bone metastases are clinically suspected, bone imaging is required [IV, B].•Bone scintigraphy, ideally coupled with CT, can be used for detection of bone metastasis [IV, B]. [18F]2-fluoro-2-deoxy-D-glucose (FDG)–positron emission topography (PET)–CT is the most sensitive modality in detecting bone metastasis [III, B].•FDG–PET–CT and brain imaging are recommended in patients suspected for oligometastatic disease [IV, A]. In the presence of a solitary metastatic site on imaging studies, efforts should be made to obtain a cytological or histological confirmation of stage IV disease [IV, A].•For oligometastatic disease, mediastinal disease should be pathology proven if this potentially impacts the treatment plan [IV, A].•NSCLC must be staged according to the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) TNM (tumour–node–metastasis) 8th edition staging manual and must be grouped into the stage categories shown in Supplementary Tables S2 and S3, available at https://doi.org/10.1016/j.annonc.2022.12.009 [IV, A].•Response evaluation is recommended after 8-12 weeks of treatment, using the same radiographic investigation that initially demonstrated the tumour lesions [IV, B]. Follow-up with a PET scan is not routinely recommended, due to its relatively low specificity despite a high sensitivity [IV, C].•Measurements and response assessment should follow Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 [IV, A].11Eisenhauer E.A. Therasse P. Bogaerts J. et al.New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).Eur J Cancer. 2009; 45: 228-247Abstract Full Text Full Text PDF PubMed Scopus (18804) Google Scholar The clinical relevance of RECIST in evaluating the response remains debatable as patients can derive benefit from continuing the same TKI after RECIST v1.1 progression [III, A]. See Figure 1 for a treatment algorithm after positive findings on molecular tests. See Figure 2 for a treatment algorithm for patients with EGFR-activating mutations. EGFR TKIs have become the standard first-line therapy for patients with a classical activating EGFR mutation (exon 19 deletion or exon 21 L858R) since the confirmation of the superiority of first-generation EGFR TKIs (gefitinib and erlotinib), over platinum-based doublet chemotherapy (ChT) in terms of tumour response rate, safety, quality of life and progression-free survival (PFS).12Mok T.S. Wu Y.L. Thongprasert S. et al.Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma.N Engl J Med. 2009; 361: 947-957Crossref PubMed Scopus (7124) Google Scholar,13Rosell R. Carcereny E. Gervais R. et al.Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial.Lancet Oncol. 2012; 13: 239-246Abstract Full Text Full Text PDF PubMed Scopus (4523) Google Scholar Second-generation EGFR TKIs (e.g. afatinib and dacomitinib) have a higher potency of EGFR inhibition via irreversible covalent binding and are pan-human epidermal growth factor receptor (HER) inhibitors. Afatinib compared with gefitinib improved PFS [hazard ratio (HR) 0.74, 95% confidence interval (CI) 0.57-0.95] but not overall survival (OS; HR 0.86, 95% CI 0.66-1.12) in the LUX-Lung 7 phase IIB randomised controlled trial (RCT) (N = 319).14Paz-Ares L. Tan E.H. O’Byrne K. et al.Afatinib versus gefitinib in patients with EGFR mutation-positive advanced non-small-cell lung cancer: overall survival data from the phase IIb LUX-Lung 7 trial.Ann Oncol. 2017; 28: 270-277Abstract Full Text Full Text PDF PubMed Scopus (383) Google Scholar In contrast, dacomitinib was superior to gefitinib in the ARCHER 1050 phase III RCT (N = 452) regarding PFS (HR 0.59, 95% CI 0.47-0.74) as well as OS, although the latter could not formally be tested due to hierarchical testing rules.15Wu Y.L. Cheng Y. Zhou X. et al.Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): a randomised, open-label, phase 3 trial.Lancet Oncol. 2017; 18: 1454-1466Abstract Full Text Full Text PDF PubMed Scopus (725) Google Scholar,16Mok T.S. Cheng Y. Zhou X. et al.Improvement in overall survival in a randomized study that compared dacomitinib with gefitinib in patients with advanced non-small-cell lung cancer and EGFR-activating mutations.J Clin Oncol. 2018; 36: 2244-2250Crossref PubMed Scopus (327) Google Scholar Compared with first-generation EGFR TKIs, second-generation TKIs are associated with more toxicities (acneiform rash, stomatitis, diarrhoea), leading to dose reduction. The third-generation EGFR TKIs also inhibit the resistant EGFR exon 20 T790M mutation. Osimertinib has the largest international approval while others are approved only in South Korea and China (e.g. lazertinib and almonertinib, respectively). Osimertinib was compared with first-generation EGFR TKIs in the FLAURA phase III RCT (N = 556), demonstrating a superior median PFS (mPFS) and median OS (mOS), with 18.9 versus 10.2 months (HR 0.46, 95% CI 0.37-0.57) and 38.6 versus 31.8 months (HR 0.80, 95% CI 0.64-1.00), respectively.17Soria J.C. Ohe Y. Vansteenkiste J. et al.Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer.N Engl J Med. 2018; 378: 113-125Crossref PubMed Scopus (2829) Google Scholar,18Ramalingam S.S. Vansteenkiste J. Planchard D. et al.Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC.N Engl J Med. 2020; 382: 41-50Crossref PubMed Scopus (1214) Google Scholar Blood–brain–barrier penetration is higher for osimertinib compared with first- and second-generation EGFR TKIs, resulting in CNS response rates >60%.19Reungwetwattana T. Nakagawa K. Cho B.C. et al.CNS response to osimertinib versus standard epidermal growth factor receptor tyrosine kinase inhibitors in patients with untreated EGFR-mutated advanced non-small-cell lung cancer.J Clin Oncol. 2018; 36: 3290-3297Crossref Scopus (407) Google Scholar Of note, patients with stable CNS metastases were allowed in the LUX-Lung 7 and FLAURA trials, whereas all CNS metastases were excluded from the ARCHER 1050 trial.14Paz-Ares L. Tan E.H. O’Byrne K. et al.Afatinib versus gefitinib in patients with EGFR mutation-positive advanced non-small-cell lung cancer: overall survival data from the phase IIb LUX-Lung 7 trial.Ann Oncol. 2017; 28: 270-277Abstract Full Text Full Text PDF PubMed Scopus (383) Google Scholar,15Wu Y.L. Cheng Y. Zhou X. et al.Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): a randomised, open-label, phase 3 trial.Lancet Oncol. 2017; 18: 1454-1466Abstract Full Text Full Text PDF PubMed Scopus (725) Google Scholar,17Soria J.C. Ohe Y. Vansteenkiste J. et al.Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer.N Engl J Med. 2018; 378: 113-125Crossref PubMed Scopus (2829) Google Scholar Serious adverse event (AE) rates are also lower for osimertinib.15Wu Y.L. Cheng Y. Zhou X. et al.Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): a randomised, open-label, phase 3 trial.Lancet Oncol. 2017; 18: 1454-1466Abstract Full Text Full Text PDF PubMed Scopus (725) Google Scholar,17Soria J.C. Ohe Y. Vansteenkiste J. et al.Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer.N Engl J Med. 2018; 378: 113-125Crossref PubMed Scopus (2829) Google Scholar,20Park K. Tan E.H. O’Byrne K. et al.Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial.Lancet Oncol. 2016; 17: 577-589Abstract Full Text Full Text PDF PubMed Scopus (835) Google Scholar These positive outcomes have established osimertinib as a preferable first-line treatment of patients with advanced EGFR-mutated NSCLC, especially for patients with CNS metastases. If osimertinib is not available in the first line, it is still acceptable to sequentially use first- or second-generation EGFR TKIs (e.g. erlotinib, gefitinib, afatinib and dacomitinib) followed by osimertinib, specifically for T790M-positive resistant disease (occurring in approximately half of the patients). Other first-line strategy options are combinations of EGFR TKIs and ChT [not European Medicines Agency (EMA) approved] or combination of EGFR TKIs and anti-angiogenics, which have shown significant improvement in PFS in phase III RCTs (e.g. erlotinib–bevacizumab and erlotinib–ramucirumab).21Kawashima Y. Fukuhara T. Saito H. et al.Bevacizumab plus erlotinib versus erlotinib alone in Japanese patients with advanced, metastatic, EGFR-mutant non-small-cell lung cancer (NEJ026): overall survival analysis of an open-label, randomised, multicentre, phase 3 trial.Lancet Respir Med. 2022; 10: 72-82Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar, 22Zhou Q. Xu C.R. Cheng Y. et al.Bevacizumab plus erlotinib in Chinese patients with untreated, EGFR-mutated, advanced NSCLC (ARTEMIS-CTONG1509): a multicenter phase 3 study.Cancer Cell. 2021; 39: 1279-1291. e1273Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 23Nakagawa K. Garon E.B. Seto T. et al.Ramucirumab plus erlotinib in patients with untreated, EGFR-mutated, advanced non-small-cell lung cancer (RELAY): a randomised, double-blind, placebo-controlled, phase 3 trial.Lancet Oncol. 2019; 20: 1655-1669Abstract Full Text Full Text PDF PubMed Scopus (327) Google Scholar, 24Noronha V. Patil V.M. Joshi A. et al.Gefitinib versus gefitinib plus pemetrexed and carboplatin chemotherapy in EGFR-mutated lung cancer.J Clin Oncol. 2020; 38: 124-136Crossref PubMed Scopus (239) Google Scholar, 25Hosomi Y. Morita S. Sugawara S. et al.Gefitinib alone versus gefitinib plus chemotherapy for non-small-cell lung cancer with mutated epidermal growth factor receptor: NEJ009 study.J Clin Oncol. 2020; 38: 115-123Crossref PubMed Scopus (264) Google Scholar For anti-angiogenics, however, either no OS benefit was observed or OS data are not yet mature.21Kawashima Y. Fukuhara T. Saito H. et al.Bevacizumab plus erlotinib versus erlotinib alone in Japanese patients with advanced, metastatic, EGFR-mutant non-small-cell lung cancer (NEJ026): overall survival analysis of an open-label, randomised, multicentre, phase 3 trial.Lancet Respir Med. 2022; 10: 72-82Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar, 22Zhou Q. Xu C.R. Cheng Y. et al.Bevacizumab plus erlotinib in Chinese patients with untreated, EGFR-mutated, advanced NSCLC (ARTEMIS-CTONG1509): a multicenter phase 3 study.Cancer Cell. 2021; 39: 1279-1291. e1273Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 23Nakagawa K. Garon E.B. Seto T. et al.Ramucirumab plus erlotinib in patients with untreated, EGFR-mutated, advanced non-small-cell lung cancer (RELAY): a randomised, double-blind, placebo-controlled, phase 3 trial.Lancet Oncol. 2019; 20: 1655-1669Abstract Full Text Full Text PDF PubMed Scopus (327) Google Scholar For ChT–gefitinib combinations, only superiority over first-generation EGFR TKIs has been demonstrated for OS,24Noronha V. Patil V.M. Joshi A. et al.Gefitinib versus gefitinib plus pemetrexed and carboplatin chemotherapy in EGFR-mutated lung cancer.J Clin Oncol. 2020; 38: 124-136Crossref PubMed Scopus (239) Google Scholar,25Hosomi Y. Morita S. Sugawara S. et al.Gefitinib alone versus gefitinib plus chemotherapy for non-small-cell lung cancer with mutated epidermal growth factor receptor: NEJ009 study.J Clin Oncol. 2020; 38: 115-123Crossref PubMed Scopus (264) Google Scholar whereas the benefit compared with osimertinib is not clear. Furthermore, with longer follow-up the OS benefit for ChT–gefitinib was not statistically significant anymore in the NEJ009 trial.26Miyauchi E. Morita S. Nakamura A. et al.Updated analysis of NEJ009: gefitinib-alone versus gefitinib plus chemotherapy for non-small-cell lung cancer with mutated EGFR.J Clin Oncol. 2022; 40: 3587-3592Crossref PubMed Scopus (5) Google Scholar Moreover, toxicity, inconvenience for patients and costs increase with adding another treatment. Therefore, single-agent (third-generation) EGFR TKIs are still one standard first-line treatment. Although the majority of activating EGFR mutations are exon 19 deletions or the exon 21 L858R point mutation, 10%-20% of patients present with an uncommon, non-exon 20 insertion mutation. In retrospective studies, first-generation EGFR TKIs result in a lower overall response rate (ORR) and PFS compared with exon 19 deletions or exon 21 L858R.27Passaro A. Mok T. Peters S. et al.Recent advances on the role of EGFR tyrosine kinase inhibitors in the management of NSCLC with uncommon, non exon 20 insertions, EGFR mutations.J Thorac Oncol. 2021; 16: 764-773Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar In an analysis of several databases comprising also a pooled analysis of several Lux-Lung trials including major uncommon mutations, afatinib resulted in an ORR of 60% and a median time to treatment failure of 10.8 months.28Yang J.C. Schuler M. Popat S. et al.Afatinib for the treatment of NSCLC harboring uncommon EGFR mutations: a database of 693 cases.J Thorac Oncol. 2020; 15: 803-815Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar Osimertinib resulted in an ORR of 53% and a mPFS of 8.2 months in a single-arm phase II study.29Cho J.H. Lim S.H. An H.J. et al.Osimertinib for patients with non-small-cell lung cancer harboring uncommon EGFR mutations: a multicenter, open-label, phase II trial (KCSG-LU15-09).J Clin Oncol. 2020; 38: 488-495Crossref PubMed Scopus (182) Google Scholar Therefore, afatinib and osimertinib can be considered for u