Table 1.
Summary of Asian consensus recommendations for the treatment of patients with oncogene-addicted mNSCLC
| Consensus | |
|---|---|
| 1. DIAGNOSIS, PATHOLOGY AND MOLECULAR BIOLOGY | |
| 1a. Adequate tissue material for histological diagnosis and molecular testing should be obtained to allow for individual treatment decisions [IV, A]. | 100% |
| 1b. Pathological diagnosis should be made according to the 2021 World Health Organization classification of lung tumours [IV, A]. | 100% |
| 1c. 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]. | 100% |
| 1d. The molecular tests below are recommended in patients with advanced non-squamous-cell carcinoma. They are not recommended in patients with a confident diagnosis of pure squamous-cell carcinoma, except in specific 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]. In specific regions (e.g. India, Japan and China) with a high incidence of EGFR mutation in squamous-cell carcinomas, EGFR testing might also be performed regardless of smoking history [IV, B]. | 100% |
| 1e. EGFR mutation status should be determined [I, A]. The test methodology should provide adequate coverage of mutations in exons 18-21, including those associated with resistance to some therapies [III, A]. | 100% |
| 1f. 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]. | 100% |
| 1g. Testing for ALK rearrangements should be carried out [I, A]. | 100% |
| 1h. 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. | 100% |
| 1i. Testing for ROS1 rearrangements should be carried out [II, A]. IHC may be used as a screening approach [IV, A]. Detection of a ROS1 translocation can be carried out or verified by FISH, NGS or reverse transcription PCR [IV, A]. | 100% |
| 1j. BRAF V600 mutation status testing should be carried out [II, A]. | 100% |
| 1k. 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]. | 100% |
| 1l. Testing for MET exon 14 skipping mutations, MET amplifications, RET rearrangements, KRAS G12C mutations and HER2 mutations should be carried out [II, A]. | 100% |
| 1m. If available, multiplex platforms (NGS) for molecular testing are preferable [III, A]. | 100% |
| 1n. 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]. | 100% |
| 1o. 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]. | 100% |
| 2. STAGING AND RISK ASSESSMENT | |
| 2a. 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]. | 100% |
| 2b. 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]. | 100% |
| 2c. An electrocardiogram is required if the targeted therapy can cause adverse cardiac events, including rhythmic modifications (e.g. long QT) [IV, A]. | 100% |
| 2d. 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]. | 100% |
| 2e. 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]. | 100% |
| 2f. If bone metastases are clinically suspected, bone imaging is required [IV, B]. | 100% |
| 2g. 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]. | 100% |
| 2h. FDG–PET–CT and brain imaging are recommended in patients suspected of having oligometastatic disease [IV, A]. In the presence of a solitary metastatic site on imaging studies, efforts might be considered to obtain a cytological or histological confirmation of stage IV disease [IV, B]. | 100% |
| 2i. For oligometastatic disease with the suspicion of mediastinal lymph node involvement, mediastinal disease should be pathologically proven if this potentially impacts the treatment plan [IV, A]. | 100% |
| 2j. 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]. | 100% |
| 2k. 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]. | 100% |
| 2l. Measurements and response assessment should follow Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 [IV, A].115 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]. | 100% |
| 3. MANAGEMENT OF ADVANCED AND METASTATIC DISEASE | |
| EGFR-mutated NSCLC | |
| 3a. All patients with a sensitising EGFR mutation should receive first-line EGFR TKIs irrespective of clinical parameters including PS, gender, tobacco exposure and histology [I, A]. | 100% |
| 3b. Third-generation EGFR TKIs (such as osimertinib) is the preferable first-line treatment option for patients with a classical activating EGFR mutation (exon 19 deletion or exon 21 L858R), especially for patients with CNS metastases [I, A; ESMO-Magnitude of Clinical Benefit (ESMO-MCBS) v1.1 score for osimertinib: 4; ESCAT: I-A]. | 100% |
| 3c. First- or second-generation EGFR TKIs (such as erlotinib [I, B; ESMO-MCBS v1.1 score: 4; ESCAT: I-A], gefitinib [I, B; ESMO-MCBS v1.1 score: 4; ESCAT: I-A], afatinib [I, B; ESMO-MCBS v1.1 score: 5; ESCAT: I-A] and dacomitinib [I, B; ESMO-MCBS v1.1 score: 3; ESCAT: I-A]) are other first-line single-agent treatment options. | 100% |
| 3d. 3d-i. Another first-line option for patients with a classical activating EGFR mutation (exon 19 deletion or exon 21 L858R) is osimertinib combined with carboplatin-pemetrexed [I, A; ESMO-MCBS v1.1 score: 3; not EMA approved]. Alternatively, another option is 3d-ii or 3d-iii. 3d-ii. Another first-line option for patients with a classical activating EGFR mutation (exon 19 deletion or exon 21 L858R) is gefitinib combined with carboplatin-pemetrexed [I, B; not EMA approved]. 3d-iii. Another first-line option for patients with a classical activating EGFR mutation (exon 19 deletion or exon 21 L858R) is lazertinib combined with amivantamab [I, A; not EMA approved]. |
100% 100% 100% |
| 3e. EGFR TKIs combined with anti-angiogenic therapy are additional first-line treatment options, including erlotinib-bevacizumab [I, B; ESMO-MCBS v1.1 score: 2; ESCAT: I-A; EMA approved, not FDA approved] or erlotinib-ramucirumab [I, B; ESMO-MCBS v1.1 score: 3; ESCAT: I-A]. | 100% |
| 3f. Considering toxicity, cost increases with adding additional treatments and patient inconvenience, single-agent EGFR TKIs are still a standard first-line treatment [I, A; ESCAT: I-A]. | 100% |
| 3g. Afatinib [I, B; ESMO-MCBS v1.1 score: 4; ESCAT: I-B] or osimertinib [III, B; ESCAT: I, B] is a recommended treatment option for patients with a major uncommon, non-exon 20 insertion, sensitising EGFR mutation. | 100% |
| 3h. Patients who have moderate radiological progression with ongoing clinical benefit may continue with EGFR TKIs [III, A]. | 100% |
| 3i. Upon resistance to first-line first- or second-generation EGFR TKIs, patients should be tested for the presence of the EGFR exon 20 T790M mutation from plasma cfDNA and/or tumour re-biopsy [I, A]. | 100% |
| 3j. Patients with T790M-positive resistance should receive third-generation EGFR TKIs (such as osimertinib) [I, A; ESMO-MCBS v 1.1 score: 4; ESCAT: I-A] as second-line therapy, whereas T790M-negative resistance might be treated with platinum-based ChT [III, A]. Third-generation EGFR TKIs (such as osimertinib) can be considered in the case of brain-only progression [III, B]. | 100% |
| 3k. Genomic analysis by plasma- or tissue-based NGS might be considered for a patient who develops resistance to a third-generation TKI (such as osimertinib) [III, C]. | 100% |
| 3l. Platinum plus pemetrexed ChT combined with amivantamab is the SoC upon progression on osimertinib [I, A]. Platinum doublet ChT remains an option [III, B]. Clinical trial enrolment is encouraged, especially if a targetable resistance mechanism is identified [III, B]. | 100% |
| 3m. The combination of platinum plus paclitaxel/pemetrexed ChT with an anti-PD-(L)1 and bevacizumab/biosimilar may be considered as a treatment option for patients following EGFR TKI failure, no contraindication for ICIs and anti-angiogenic agent [III, B; for carboplatin-paclitaxel-atezolizumab-bevacizumab ESMO-MCBS v1.1 score: 3]. | 100% |
| 3n. Single-agent ICIs may be considered as a treatment option only after progression on EGFR TKIs and ChT [IV, C]. | 100% |
| ALK-rearranged NSCLC | |
| 3o. Patients should be treated in the first-line setting with alectinib, brigatinib, ensartinib or lorlatinib [I, A; ESMO-MCBS v1.1 score: 4; ESCAT: I-A]. These options are preferred over crizotinib or ceritinib [I, B; ESMO-MCBS v1.1 score: 4; ESCAT: I-A]. | 100% |
| 3p. Alectinib [I, A; ESMO-MCBS score: 4; ESCAT: I-A] or brigatinib [I, A; ESMO-MCBS score: 4; ESCAT: I-A] is recommended in patients who progress on treatment with, or are intolerant to, crizotinib. | 100% |
| 3q. Lorlatinib [II, B; ESMO-MCBS v1.1 score: 4; ESCAT: I-A], ceritinib [III, C; ESMO- MCBS v1.1 score: 4; ESCAT: I-A] and ensartinib [II, C] represent additional treatment options at crizotinib resistance. | 100% |
| 3r. In patients who progress after a second-generation ALK TKI, the newer-generation ALK inhibitor lorlatinib is an option [III, A; ESMO-MCBS v1.1 score: 4; ESCAT: I-A]. | 100% |
| 3s. Following progression on lorlatinib, ChT with a platinum-pemetrexed-based combination is recommended [III, A]. | 100% |
| 3t. Genomic analysis by plasma- or tissue-based NGS might be considered for a patient who develops resistance to a second- or third-generation ALK TKI [III, C]. | 100% |
| Treatment of ROS1-rearranged NSCLC | |
| 3u. Crizotinib or entrectinib is recommended in the first-line setting [III, A; ESMO-MCBS v1.1 score: 3; ESCAT: I-B]. | 100% |
| 3v. Entrectinib, if available, is preferred over crizotinib in patients with brain metastases [III, A; ESMO-MCBS v1.1 score: 3; ESCAT: I-B]. | 100% |
| 3w. Repotrectinib, if available, is an option in the first-line setting but is not EMA approved [III, A; ESCAT: I-B]. | 100% |
| 3x. If patients have received crizotinib in the first-line setting, they may be offered a newer-generation TKI if available [III, A] (no EMA approval) or platinum-based ChT in the second-line setting [IV, A]. | 100% |
| BRAF mutations | |
| 3y. BRAF-MEK inhibition using dabrafenib-trametinib is recommended [III, A; ESMO-MCBS v1.1 score: 2; ESCAT: I-B]. Another option is encorafenib-binimetinib [III, A; ESMO-MCBS v1.1 score: 3; ESCAT: I-B]. | 100% |
| 3z. If patients have received BRAF-MEK inhibition in the first-line setting, they may be offered platinum-based ChT with or without immunotherapy in the second-line setting, regardless of their smoking history [IV, A]. For patients with a smoking history, immunotherapy with or without ChT should be considered as per the ESMO CPG on non-oncogene-addicted mNSCLC [IV, B].99 | 100% |
| RET fusions | |
| 3aa. Treatment with selpercatinib is recommended as first-line therapy for patients with RET fusion-positive NSCLC [I, A; ESMO-MCBS v1.1 score: 3; ESCAT: I-C]. | 100% |
| Other oncogenic drivers for which targeted therapy is available | |
| 3bb. Platinum-doublet ChT with or without ICIs is recommended as first-line therapy for patients with a MET amplification orHER2 mutation [IV, B]. | 100% |
| 3cc. Capmatinib and tepotinib in first line [III, A; ESMO-MCBS v1.1 score: 3; ESCAT: I-B; FDA approved, not EMA approved] or in second line [III, A; ESMO-MCBS v1.1 score: 3; ESCAT: I-B] are recommended in patients with a MET exon 14 skipping mutation. Savolitinib may also be an option [III, A; ESCAT: I-B; not EMA or FDA approved]. | 100% |
| 3dd. If patients have received a MET-specific inhibitor in the first-line setting, they may be offered platinum-based ChT with or without immunotherapy in the second-line setting, regardless of smoking history [IV, A]. For patients with a smoking history, immunotherapy with or without ChT should be considered as per the ESMO CPG on non-oncogene-addicted mNSCLC [IV, B].99 | 100% |
| 3ee. In patients with HER2 exon 20 mutations, trastuzumab-deruxtecan, if available, is recommended for patients following prior first-line therapy [III, B; ESCAT: II-B]. | 100% |
| 3ff. Larotrectinib and entrectinib are recommended for patients with NSCLC and an NTRK gene fusion and who have no satisfactory treatment options [III, A; ESMO-MCBS v1.1 score: 3; ESCAT: I-C]. | 100% |
| 3gg. For KRAS G12C-mutated NSCLC, it is recommended to follow the first-line treatment algorithms in the ESMO CPG on non-oncogene-addicted mNSCLC [III, A].99 | 100% |
| 3hh. Platinum-doublet ChT can be given to patients with KRAS G12C-mutated NSCLC and progression on first-line ICI monotherapy [III, A]. | 100% |
| 3ii. Sotorasib is recommended for treatment of KRAS G12C-mutated NSCLC failing prior therapy [I, B; ESMO-MCBS v1.1 score: 3; ESCAT: I-B]. | 100% |
| 3jj. Adagrasib is recommended for treatment of KRAS G12C-mutated NSCLC failing prior therapy [III, B; ESMO-MCBS v1.1 score: 2; ESCAT: I-B; FDA approved, not EMA approved]. | 100% |
| 3kk. Amivantamab combined with platinum-based ChT is recommended for the treatment of EGFR exon 20 insertion-mutated NSCLC in the first-line setting [I, A; ESMO-MCBS v1.1 score: 3; ESCAT: I-B] or in the second- or later-line settings [III, B; ESMO-MCBS v1.1 score: 3; ESCAT: I-B]. | 100% |
| 3ll. Amivantamab monotherapy is an option after platinum-based ChT failure for the treatment of EGFR exon insertion-mutated NSCLC not previously exposed to amivantamab [II, B; ESMO-MCBS v1.1 score: 3; ESCAT: I-B] | 100% |
| Special populations | |
| 3mm. TKIs should be given to patients with PS ≥ 2 and an oncogenic driver [III, A]. | 100% |
| 3nn. TKIs should be given to elderly patients [II, A]. | 100% |
| 3oo. Patients with oligometastatic disease at diagnosis may experience long-term PFS following systemic therapy and LAT (high-dose RT or surgery) [II, B], but due to limited evidence, inclusion in clinical trials is preferred. | 100% |
| 3pp. Patients with advanced NSCLC and a driver mutation, with oligoprogression while on molecular targeted therapy, may benefit from LAT (high-dose RT or surgery) including improved long-term disease-free survival, but data are limited and inclusion in clinical trials is preferred. | 100% |
| 4. FOLLOW-UP, LONG-TERM IMPLICATIONS AND SURVIVORSHIP | |
| 4a. Follow-up every 8-12 weeks should be carried out if there is an option for a next line of therapy [IV, A]. | 100% |
| 4b. Psychosocial support should be offered if needed [IV, A]. | 100% |
| 4c. Smoking cessation should be encouraged [IV, A]. | 100% |
| Palliative care in stage IV | |
| 4d. Early palliative care intervention is recommended, in parallel with standard oncological care [I, A]. | 100% |
AJCC, American Joint Committee on Cancer; ALK, ALK tyrosine kinase receptor; BRAF, B-Raf proto-oncogene serine/threonine kinase; cfDNA, circulating free DNA; ChT, chemotherapy; CNS, central nervous system; CPG, Clinical Practice Guidelines; CT, computed tomography; ECOG, Eastern Cooperative Oncology Group; EGFR, epidermal growth factor receptor; EMA, European Medicines Agency; ESCAT, ESMO Scale for Clinical Actionability of molecular Targets; ESMO, European Society for Medical Oncology; ESMO-MCBS; ESMO-Magnitude of Clinical Benefit Scale; FDA, US Food and Drug Administration; FDG, [18F]2-fluoro-2-deoxy-D-glucose; HER2, human epidermal growth factor receptor 2; ICI, immune checkpoint inhibitor; IHC, immunohistochemistry; KRAS, KRAS proto-oncogene, GTPase; LAT, local ablative therapy; MET, MET proto-oncogene, receptor tyrosine kinase; mNSCLC, metastatic non-small-cell lung cancer; NGS, next-generation sequencing; NSCLC, non-small-cell lung cancer; NTRK, neurotrophic tyrosine receptor kinase; PET, positron emission topography; PS, performance status; RECIST v1.1; Response Evaluation Criteria in Solid Tumours, version 1.1; RET, ret proto-oncogene; ROS1, ROS proto-oncogene 1, receptor tyrosine kinase; RT, radiotherapy; SoC, standard of care; TKIs, tyrosine kinase inhibitors; TNM, tumour–node–metastasis; UICC, Union for International Cancer Control.
CSCO, Chinese Society of Clinical Oncology; ESMO, European Society for Medical Oncology; ISHMO, Indonesian Society of Haematology and Medical Oncology; ISMPO, Indian Society of Medical and Paediatric Oncology; JSMO, Japanese Society of Medical Oncology; KSMO, Korean Society for Medical Oncology; MOS, Malaysian Oncological Society; PSMO, Philippine Society of Medical Oncology; SSO, Singapore Society of Oncology; TOS, Taiwan Oncology Society; TSCO, Thai Society of Clinical Oncology.