Methodology
Diagnosis
Diagnosis: pathology and molecular testing
Disease staging
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Clinical history, including smoking and family history; physical examination, performance status (PS) and weight loss should be assessed.
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Blood test, including hematology, renal and hepatic function.
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Bronchoscopy.
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Chest and upper abdomen (including liver and adrenal glands) computerized tomography (CT).
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Brain CT or magnetic resonance imaging (MRI) is recommended for patients undergoing radical treatment, in patients with EGFR mutation or ALK translocation or if there are neurological symptoms in the physical examination.
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Bone scan is recommended if there is bone pain, high serum calcium or high alkaline phosphatase.In patients undergoing potentially radical treatment, additional recommendations should be considered:
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Whole-body FDG-positron emission tomography (PET–CT).
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Pulmonary function tests.
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Ergospirometry if the pulmonary function tests are not normal.
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Chest MRI in Pancoast tumour.
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Invasive mediastinal staging, endobronchial ultrasound-guided fine-needle aspiration and/or endoscopic ultrasound-guided fine-needle aspiration are recommended in patients with suspected mediastinal or hilar lymph nodes (LNs) in the PET–CT. For patients with suspected LNs on PET–CT and negative EBUS/EUS results, an additional mediastinoscopy is recommended. In patients with no suspected LN on the PET-CT, invasive mediastinal staging is also recommended in patients with enlarged mediastinal LNs (≥ 1.5 cm), in tumors ≥ 3 cm and/or in patients with central tumors.
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Histological and cytological confirmation is strongly recommended in the presence of pleural/pericardial effusion or isolated metastatic site.
Staging system
Stage | T |
N
| M |
---|---|---|---|
Occult | TX | N0 | M0 |
0 | Tis | N0 | M0 |
IA1 | T1a(mi)/T1a | N0 | M0 |
IA2 | T1b | N0 | M0 |
IA3 | T1c | N0 | M0 |
IB | T2a | N0 | M0 |
IIA | T2b | N0 | M0 |
IIB | T1a-T2b | N1 | M0 |
T3 | N0 | M0 | |
IIIA | T1a-T2b | N2 | M0 |
T3 | N1 | M0 | |
T4 | N0/N1 | M0 | |
IIIB | T1a-T2b | N3 | M0 |
T3/T4 | N2 | M0 | |
IIIC | T3/T4 | N3 | M0 |
IVA | Any T | Any N | M1a/M1b |
IVB | Any T | Any N | M1c |
Stage I–II
Surgery
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In stage I–II medically fit NSCLC patients, lobectomy or anatomic pulmonary resection is recommended rather than sublobar resection (I,B). Systematic mediastinal lymph node dissection is recommended over selective sampling lymph node dissection for accurate pathologic staging [10] (IB). For stage II patients undergoing anatomic resection, mediastinal lymph node dissection may provide additional survival benefit over sampling [11] (II,B).
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A sublobar resection (anatomical segmentectomy) is recommended over nonsurgical therapy for patients who cannot tolerate a lobar resection due to decreased pulmonary function or comorbid disease (I,B).
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For patients with a stage I predominantly ground glass opacity with lesion ≤ 1 cm, sublobar resection with negative margins is suggested over lobectomy (I,B).
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Reresection is recommended for patients with positive margins in resected stage I–II NSCLC patients. If it is not possible, postoperative radiotherapy may be considered [12].
Adjuvant therapy
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Four cycles of cisplatin-based chemotherapy following complete resection in stage II NSCLC patients remain the standard of care in adjuvant setting, offering a 5% OS benefit [13] (I,A).
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In elderly fit patients, adjuvant platinum-based chemotherapy should be considered.
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Postoperative radiotherapy (PORT) is not indicated in completely resected stage I–II NSCLC patients [15] (I,A-II,A).
Neoadjuvant therapy
Stereotactic ablative radiotherapy (SART)
Other adjuvant treatments
Stage III
Resectable and potentially resectable NSCLC
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In patients with R0 resected stage III NSCLC, 4 cycles of adjuvant platinum-based chemotherapy should be given (preferably cisplatin doublet) [19] (I,A).
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In patients with pathological N2 NSCLC, PORT appears to improve OS in non-randomized analysis, and it is usually administered after adjuvant chemotherapy (II,A).
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In patients with potentially resectable disease, the optimal treatment strategy remains unclear. Several phase III trials and a meta-analysis showed that induction therapy followed by surgery might be better than surgery alone [20]. Surgery has been compared to radiotherapy in patients with tumor response after induction chemotherapy, without differences in overall survival [21]. Surgery was also compared to radiotherapy after induction chemoradiotherapy in the Lung Intergroup Trial 0139 showing better progression-free survival in the surgery arm, with no differences in OS except in the unplanned analysis in the subset of patients who underwent lobectomy [22]. The optimal chemotherapy regimen has not been established in randomized trials, although cisplatin-based chemotherapy is recommended.
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In case of superior sulcus (Pancoast) tumors, concurrent chemoradiation followed by surgery is the preferred option [23] (Table 2).Table 2Summary of recommendationsDiagnosisWHO classification for pathological diagnosis is required and also IASLC classification of adenocarcinomaFor therapeutic implications, specific subtyping of NSCLC is strongly recommendedMolecular testing in stage IV non-SCC should include EGFR mutations, ALK and ROS-1 translocations by a validated techniqueIn patients progressing to first or second generation EGFR TKI determination of EGFR T790M in plasma or tissue should be performedPD-L1 expression should be test to all patients with advanced NSCLC at baselineStagingComprehensive evaluation must include thorax and upper abdomen CTMore extensive evaluations are recommended if a radical approach is consideredStage disease must be classified using the TNM 8th editionStage I–IIPatients should be evaluated in a multidisciplinary tumor boardMedically fit for surgeryLobectomy or anatomic pulmonary resection plus systematic mediastinal lymph node dissectionMedically inoperable, node negative NSCLC tumours ≤ 5 cmSARTAdjuvant chemotherapy (four cycles of cisplatin-based chemotherapy)Recommended in stage IINot recommended in stage I 7th TNM edition (except T > 4 cm)Post operative radiotherapy (PORT)Not indicated in completely resected stage I–IIStage IIITreatment decision should be taken by an experienced multidisciplinary teamCompletely resectedAdjuvant chemotherapy (four cycles of adjuvant cisplatin-based chemotherapy) ± PORTPotentially resectableResection followed by adjuvant chemotherapyInduction chemotherapy or chemoradiotherapy followed by surgeryUnresectable stage IIIMedically fit: concurrent chemoradiotherapy with cisplatin-based chemotherapySequential chemoradiotherapy if concurrent treatment is not feasiblePCI is not indicatedDurvalumab if no progressive disease after concurrent chemoradiotherapyStage IVStage IV without driver mutationsFist linePD-L1 ≥ 50%PembrolizumabNote: Combination of immunotherapy plus standard chemotherapy may be consideredPD-L1 < 50% or unknownPlatinum-based chemotherapy based on tumor histology:Squamous cell carcinoma (SCC)Platinum-based doublets (4, up to 6 cycles)Immunotherapy (atezolizumab or pembrolizumab) and carboplatin plus paclitaxel or nab-placlitaxel)(#)Non-squamous-cell carcinoma (non-SCC)Platinum-based doublet:Cisplatin/pemetrexed has more efficacy and less toxicity than cisplatin/gemcitabineBevacizumab added to a platinum doublet. if there are no contraindicationsPemetrexed maintenanceImmunotherapy (atezolizumab(#) or pembrolizumab) plus standard chemotherapyElderlyComprehensive geriatric assessment is highly recommendedFit patientsDecision according to histology and PD-L1 expression levelsUnfit or comorbiditiesSingle agent chemotherapyPS 2Combination therapySingle-agent therapyBest supportive carePS 3–4Best supportive careSecond linePS 0–2If no prior immunotherapyPembrolizumab (PD-L1 ≥ 1%), nivolumab or atezolizumabIf prior immunotherapyPlatinum doubletsIf contraindication for immunotherapyDocetaxel–nintedanib (non-SCC)Docetaxel (SCC, non-SCC)Pemetrexed (non-SCC)If prior immunotherapy alonePlatinum doubletsIf prior immunotherapy + CTDocetaxel–nintedanib (non-SCC)Docetaxel (SCC, non-SCC)Pemetrexed (non-SCC)PS 3–4Best supportive careStage IV with driver mutationsEGFR mutationFirst-line EGFR TKIErlotinib, gefitinib, afatinib, dacomitinib(#), osimertinibBrain metastasisOsimertinibAfter EGFR TKI progressionClinical benefit maintained or oligoprogressive diseaseContinuation with the EGFR TKIT790 M positiveOsimertinib (if not previously given)T790 M negativePlatinum-based chemotherapyALK mutationFirst-line ALK TKIAlectinib, brigatinib(#), crizotinib or ceritinibProgression to crizotinibCeritinib, alectinib or brigatinib(#)Brain metastasisAlectinib, brigatinib(#) or lorlatinib(#)Other genetic alterationsROS-1CrizotinibB-RAFv600Dabrafenib plus trametinibOligometastatic diseaseSystemic therapy and local ablative strategiesLocal ablative strategies and TKI-continuation if clinical benefit is still retained (if actionable mutation)Follow-upSmoking cessation counselingCurative intentSurgeryMedical history, physical examination and spiral chest CT scan every 6–12 months for 2 years and annually thereafterSARTMedical history, physical examination and spiral chest CT scan every 6 months for 3 years and annually thereafterPET–CT ± biopsy if recurrence is suspectedAdvanced diseaseEarly palliative careEvaluation of response every 6–12 weeks
Unresectable NSCLC
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Concurrent chemoradiotherapy is the treatment of choice for medically fit patients (I,A). Several randomized clinical trials and a meta-analysis have shown a higher 5-year survival rates favoring this strategy over sequential approaches [24].
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Cisplatin-based combinations are recommended for medically fit patients (usually with etoposide or vinorelbine) [24].
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Radiotherapy is usually given at a dose of 60–66 Gy in 30–33 fractions over 6–7 weeks. Higher doses are not recommended outside of clinical trials [25].
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If concurrent chemoradiotherapy is not feasible due to poor performance status, comorbidities, and/or unfit patients, a sequential approach is a reasonable option [26].
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There is no role for prophylactic cranial irradiation in stage III (II,A).
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In patients with no progressive disease after concurrent chemoradiotherapy, consolidation treatment with Durvalumab for 1 year has shown to improve progression-free survival (PFS) and OS (I,A) [27‐29]. The European Medical Agency has recently approved consolidation with Durvalumab in patients with PD-L1 expression ≥ 1% based on an unplanned post hoc analysis.
Stage IV
Stage IV without driver mutations (Fig. 2)
First-line therapy
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For stage IV, PS 0–1 NSCLC patients without driver mutations whose tumors express PD-L1 at levels of 50% or greater (tumor proportion score (TPS) ≥ 50%), pembrolizumab is recommended in the absence of contraindications to use immunotherapy [30] (I,A).
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For patients with low (TPS < 50%) or unknown PD-L1 expression, chemotherapy with platinum doublets should be considered in all stage IV PS 0–1 NSCLCs without driver mutations (I,A). Data have shown that platinum combination therapy increases OS and improves quality of life (QoL) compared to supportive care, single-agent cisplatin or other monotherapy [31‐34].
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Meta-analyses have shown higher response rates (RRs) and a slightly longer OS for cisplatin combinations than for carboplatin combinations [35] (I,B). Carboplatin can be recommended if any contraindication for cisplatin exists.
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Non-platinum regimens have reported lower efficacy than platinum regimens [36] (I,A).
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Cisplatin-based combinations and some modalities of treatment will be selected based on tumor histology:
For squamous cell lung cancer (SCC)
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For PS 0–1 SCC patients, without major comorbidities and with low (TPS < 50%) or unknown PD-L1, platinum-based doublets with the addition of a third-generation cytotoxic agent (gemcitabine, vinorelbine, taxanes) are recommended (I,A). The different combinations have shown comparable efficacy [42].
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The expected toxicity profile should contribute to the selection of the chemotherapy regimen. The nab-paclitaxel/carboplatin regimen has shown in a phase III trial to have higher RRs (with a larger impact in SCC) than paclitaxel/carboplatin and less neurotoxicity (I,B) [45].
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Recently, two randomized phase III trials have shown that the addition of immunotherapy (atezolizumab or pembrolizumab) to standard first-line chemotherapy (carboplatin plus paclitaxel or nab-placlitaxel) in SCC, results in significantly longer PFS with atezolizumab (I,B) [38] and OS and PFS with pembrolizumab (I,A) [40] than chemotherapy alone, regardless of PD-L1 expression. It is important to underline that these combinations were not approved by the European Medical Agency when this guideline was submitted.
For non-squamous cell lung cancer (Non-SCC)
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Any platinum-based doublets with a third-generation agent can be used in non-SCC patients with low (TPS < 50%) or unknown PD-L1 [42] (I,A).
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Pemetrexed-based combination chemotherapy represents a therapeutic option. This regimen showed a slight but significant survival benefit compared with gemcitabine or docetaxel-based combinations (results coming from a meta-analysis and a preplanned subgroup analysis of a randomized phase III trial) [46, 47] (II,A).
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Bevacizumab/paclitaxel/carboplatin combination chemotherapy followed by maintenance bevacizumab has shown improvement in OS in two randomized clinical trials and, therefore, it can be offered to patients with advanced PS 0–1 non-SCC and no contraindications for antiangiogenic treatment [6, 48] (I,A).
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Maintenance therapy can be considered in those PS 0–1 patients with at least stable disease and who have recovered from residual toxicity after first-line chemotherapy:
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Recently, three randomized phase III trials have shown that the addition of immunotherapy (pembrolizumab or atezolizumab) to standard first-line chemotherapy (pemetrexed platinum-based combination or bevacizumab plus chemotherapy) in non-SCC resulted in significantly longer OS ± PFS than chemotherapy alone, regardless of PD-L1 expression [37, 39, 41]. It is important to underline that pembrolizumab with pemetrexed and platinum-based chemotherapy was the only combination approved by the European Medical Agency when this guideline was submitted.
Second-line therapy
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In patients with metastatic non-SCC and SCC who have not received prior immunotherapy, and with no contraindications, single-agent pembrolizumab (PD-L1 TPS ≥ 1%), nivolumab or atezolizumab is recommended (I,A). This recommendation is based on data from the main Phase III trials, showing significant improvements in OS and tolerability of immunotherapy agents when compared to single-agent docetaxel [51‐54].
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Nintedanib added to docetaxel has demonstrated a significant OS benefit as compared with docetaxel alone in previously treated stage IV, PS 0–1 adenocarcinoma, particularly in those patients progressing within 9 months after start of first-line therapy [55] (II,B).
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In patients who have received an immune checkpoint inhibitor as first-line therapy, platinum doublets are recommended (I,B).
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For those patients who have received first-line conventional chemotherapy and immune therapy, single agent, docetaxel, pemetrexed (non-SCC) or docetaxel plus nintedanib (non-SCC) could be considered (IIB).
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There is no sufficient evidence to recommend the use of cytotoxic drugs as fourth-line therapy or beyond; patients should be considered to be included in clinical trials, and continued best supportive care.
Elderly and PS2
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For those elderly fit patients with PS 0–1 and adequate organ function, first-line treatment decision should be based according to histology and PD-L1 expression levels [59] (I,B). Single agent chemotherapy (vinorelbine, gemcitabine, docetaxel) is recommended for those with comorbidities or unfit patients [60] (IB).
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For patients with PS 2, chemotherapy prolongs OS compared to best supportive care (BSC) [61] (I,B). In an individualized-based decision, combination therapy, single-agent therapy, or palliative therapy alone may be used for PS 2 patients. In the first-line setting, platinum-based doublets (preferably carboplatin) have superior efficacy to monotherapy, despite higher toxicity rates [62, 63] (II,A).
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Unfit patients with PS 3–4 should not receive active treatment regardless of age because no benefit has been demonstrated. Supportive care is recommended (II,B).
Stage IV with driver mutations (Fig. 3)
EGFR mutation
First-line setting
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EGFR TKIs (gefitinib, erlotinib, afatinib) have shown superior PFS, RR, toxicity profile and QoL for EGFR TKIs as first-line treatment compared with platinum-based doublets (I,A) [64, 65]. Only a prespecified subanalysis showed a significant improvement in OS favoring afatinib in patients with Del19 mutations [65].
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Patients with PS 3–4 may also be offered an EGFR TKI, as they are likely to receive a similar clinical benefit to patients with good PS (III,A).
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Results from direct comparison of first-, second- and third-generation EGFR TKIs in previously untreated patients have been reported. Although a benefit in terms of PFS has been demonstrated for third-generation TKIs osimertinib (I,A) and dacomitinib (I,A) [66‐68], to date only dacomitinib has shown a significant OS advantage (I,A) [69]. However, grade 3–4 treatment-related adverse events were significantly higher with dacomitinib. OS data from the FLAURA trial comparing osimertinib versus standard of care are still immature [67].
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An exploratory data on brain disease suggest that the probability of experiencing a progression on central nervous system (CNS) was lower with osimertinib and provided a higher intracranial activity (II,B) [70].
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Combination of pemetrexed-carboplatin and gefitinib has demonstrated a significant increase in PFS and OS in japanese population [74] (I,B).
After EGFR TKI progression
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For patients with systemic symptomatic progression in whom T790 M cannot be detected or who have progressed to osimertinib, platinum-based chemotherapy remains the standard of care (II,A). The combination of atezolizumab plus bevacizumab plus chemotherapy has demonstrated a significant PFS benefit in the subgroup of patients with EGFR mutation (III,A) [50].
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Continuation of EGFR TKI with platinum-based chemotherapy does not impact on PFS nor on OS [78] (I,A).
ALK translocation
First-line setting
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Alectinib (I,A) and brigatinib (I,B) have shown a significant improvement in PFS versus crizotinib and, therefore, are the preferred first-line options. Grade 3–5 adverse events were higher for patients treated with crizotinib [81, 82]. It is important to underline that brigatinib was not approved by the European Medical Agency when this guideline was submitted.
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Chemotherapy is indicated (III,B) in patients whose ALK results are not available and urgent systemic treatment is required. Treatment plan should be reassured when genotypic results were available.
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For patients who received chemotherapy in the first-line, crizotinib should be recommended as second-line treatment (I,A) [83]. Alectinib and ceritinib should also be considered, although no specific trials have been conducted.
After ALK TKI progression
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For patients who develop resistance or are intolerant to crizotinib, ceritinib (IA), alectinib (IA) or brigatinib (IIA) can be recommended. Ceritinib and alectinib have shown a significant improvement in median PFS and less adverse events than chemotherapy. Brigatinib has shown a favorable PFS in a crizotinib-refractory ALK-positive phase II trial [84‐86].
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Lorlatinib has shown activity in patients who have progressed on next-generation ALK TKI (ceritinib, alectinib or brigatinib) [87] (II,A).
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For patients with systemic symptomatic progression to ALK TKI, platinum-based chemotherapy remains the standard of care (II,A). The combination of atezolizumab plus bevacizumab plus chemotherapy has demonstrated a significant PFS benefit (III,B) [50].
Brain metastases
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Alectinib, brigatinib and lorlatinib have shown greater activity in CNS disease. In the ALEX trial, fewer patients treated with alectinib (12%) had CNS progression than crizotinib (45%). In the ALTA-1 trial, intracranial RR was 78% for brigatinib versus 29% for crizotinib [82].
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For asymptomatic or patients who became asymptomatic with steroids, brain-penetrable ALK TKIs may be used and local treatments may be deferred (I,B).
ROS-1 and other rare targetable genetic alterations
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Crizotinib is indicated for the treatment of ROS-1-positive advanced NSCLC based on the results of a single-arm trial in 50 patients [90] (III,A).
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New investigational drugs have shown activity in early clinical trials targeting oncogenic drivers such as crizotinib, tepotinib or capmatinib (MET amplified, METe14 mutation), LOXO-292 and BLU-667 (RET), entrectinib (NRTK, ROS, ALK fusions), LOXO-101 or larotrectinib (NRTK fusions) [93] and ado-trastuzumab emtansine (HER2 mutations). However, none of these targeted drugs have an official regulatory approval by EMA except the orphan drug designation of LOXO-101 in NTRK fusion tumors.
Oligometastatic NSCLC
Management and follow-up
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Smoking cessation counseling is encouraged in any stage as it leads to superior treatment outcomes since smoking may impact on drugs’ bioavailability (II,A).
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There is not an established consensus regarding the most optimal follow-up in patients with NSCLC. However, due to the inherent aggressiveness of the disease, a close follow-up is advised.
Follow up in patients after curative treatment:
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NSCLC patients treated with radical intent must be followed to identify treatment-related complications, detection of treatable relapse or occurrence of second primary lung cancer (III,A).
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In patients with curative surgery, a close follow-up visit including medical history, physical examination and chest CT is recommended every 6–12 months for the first 2 years and annually thereafter (III,B).
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For patients treated with SART with radical intent, CT scans every 6 months for 3 years are recommended and annually thereafter (III,B). PET–CT ± biopsy is endorsed when recurrence is suspected based on chest CT To discriminate from focal fibrosis (III,B).
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Routine surveillance with blood test, FDG-PET imaging or another radiological assessment is not endorsed (II,D).
Follow up in patients with advanced disease:
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Early palliative care is strongly recommended [98] (I,A).
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Evaluation of response is recommended every 6–12 weeks after therapy initiation, using the same baseline radiographic method. The frequency of the radiologic assessment can be tailored for patients benefiting long time on targeted agents (III,B).
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For patients eligible for successive lines that respond to first-line treatment, it is advisable to undergo clinical and/or radiological evaluation 6 weeks after finishing treatment and then every 6–12 weeks to enable second-line therapy to commence promptly (III,B).