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Overview and Recommendations
Background
- •Systemic therapy for NSCLC is selected according to clinical setting, neoadjuvant/perioperative, adjuvant, concurrent chemoradiation, first-line metastatic, and subsequent-line therapy, each with distinct evidence-based regimens. The paradigm has shifted from chemotherapy alone to chemoimmunotherapy and targeted therapy, driven by landmark trials such as KEYNOTE-189, KEYNOTE-407, and PACIFIC.
- •Neoadjuvant or perioperative chemoimmunotherapy (e.g., tislelizumab plus platinum-doublet) is now the preferred approach for resectable stage II-III NSCLC, with a pooled analysis showing a 35% reduction in the risk of death (HR 0.65) and significant improvements in major pathological response (risk ratio 3.42) and complete pathological response (risk ratio 5.52) compared with chemotherapy alone.
- •For unresectable stage III NSCLC, concurrent chemoradiotherapy (cCRT) with a platinum doublet and 60 Gy thoracic radiotherapy, followed by consolidation durvalumab for 12 months, is the standard of care. The PACIFIC trial demonstrated a 5-year overall survival of 42.9% with durvalumab versus 33.4% with placebo (HR 0.72).
- •In metastatic NSCLC, the presence of actionable driver alterations (EGFR, ALK, ROS1, BRAF V600E, NTRK, MET, RET, HER2) dictates first-line targeted therapy. For patients without such alterations, PD-L1 tumor proportion score (TPS) guides immunotherapy use: pembrolizumab monotherapy for TPS ≥50% (5-year OS 31.9% vs 16.3%; NNT=6) or pembrolizumab plus platinum-doublet chemotherapy for all PD-L1 levels (5-year OS ~19% vs ~11%; NNT=12).
- •The four pillars of first-line therapy for driver-negative metastatic NSCLC, pembrolizumab, platinum, pemetrexed (nonsquamous) or paclitaxel (squamous), replaced the legacy chemotherapy-only approach following KEYNOTE-189 (2018) and KEYNOTE-407 (2018). Combined relative mortality reduction approaches 40% compared with chemotherapy alone.
- •Subsequent-line therapy after progression on first-line chemoimmunotherapy or targeted therapy includes single-agent docetaxel, ramucirumab plus docetaxel, or, for EGFR-mutant disease after TKI failure, chemotherapy plus antiangiogenic agent plus immune checkpoint inhibitor (e.g., atezolizumab + bevacizumab + carboplatin + paclitaxel [ABCP]) or amivantamab plus chemotherapy.
Evaluation
- •Suspect the need for systemic therapy in any patient with newly diagnosed NSCLC after complete staging (CT chest/abdomen, PET-CT, brain MRI). Determine the clinical setting: resectable (stage I-IIIA), unresectable stage III, or metastatic (stage IV).
- •Assess performance status using the ECOG scale. For neoadjuvant or concurrent chemoradiation, ECOG 0-1 is required. For metastatic disease, ECOG 0-2 may be considered for targeted therapy, but immunotherapy-containing regimens are typically reserved for ECOG 0-1.
- •Obtain histologic subtype (nonsquamous vs squamous) from biopsy. This determines the chemotherapy backbone: pemetrexed for nonsquamous, paclitaxel/nab-paclitaxel for squamous.
- •Order mandatory biomarker testing: EGFR mutations, ALK rearrangements, and PD-L1 TPS (by immunohistochemistry). For nonsquamous histology, also test for ROS1, BRAF V600E, NTRK, MET exon 14 skipping, RET, and HER2. For squamous, consider PD-L1 and possibly NGS if young or never-smoker.
- •Evaluate for actionable driver alterations using a comprehensive next-generation sequencing (NGS) panel. If EGFR mutation or ALK rearrangement is detected, first-line therapy is a targeted TKI (osimertinib for EGFR, alectinib or lorlatinib for ALK).
- •Assess for brain metastases with MRI brain. In EGFR-mutant or ALK-positive disease, TKIs have high intracranial activity; in driver-negative disease, brain metastases may require local therapy (SRS or WBRT) before or concurrent with systemic therapy.
- •Evaluate pulmonary function (spirometry, DLCO) before neoadjuvant therapy or concurrent chemoradiation. Preexisting interstitial lung disease (ILD) is a risk factor for pneumonitis with immunotherapy and chemoradiation.
- •Check baseline complete blood count, comprehensive metabolic panel (including renal function and liver enzymes), and thyroid function tests. For patients receiving cisplatin, assess renal function (eGFR >60 mL/min) and consider hydration protocols.
- •Assess for contraindications to immunotherapy: active autoimmune disease (except controlled thyroiditis, vitiligo), history of solid organ transplant, active infection (including HIV with low CD4 count), or chronic steroid use >10 mg prednisone daily.
- •For patients with resectable stage II-III disease, evaluate surgical candidacy (tumor resectability, pulmonary reserve, comorbidities) before initiating neoadjuvant therapy. Multidisciplinary discussion with thoracic surgery and radiation oncology is essential.
- •Consider the Lung Immune Prognostic Index (LIPI) based on pretreatment LDH and derived neutrophil-to-lymphocyte ratio. Poor LIPI is associated with worse outcomes on chemoimmunotherapy (median PFS 3.6 months vs 9.0 months for good/intermediate LIPI).
- •Document smoking history, occupational exposures, and family history of lung cancer. These factors may influence risk of toxicity and prognosis.
Management
- •For resectable stage II-III NSCLC (ECOG 0-1), initiate neoadjuvant chemoimmunotherapy: tislelizumab 200 mg IV q3w plus platinum-doublet chemotherapy (e.g., carboplatin AUC 5 + pemetrexed 500 mg/m² for nonsquamous, or carboplatin AUC 5 + paclitaxel 175 mg/m² for squamous) for 3-4 cycles. Follow with surgery within 4-6 weeks of last dose.
- •After surgery, continue adjuvant immunotherapy: tislelizumab 200 mg IV q3w for up to 1 year (or atezolizumab 840 mg IV q2w for up to 1 year for stage II-IIIA PD-L1 ≥1%). For EGFR-mutant resectable disease, consider neoadjuvant osimertinib 80 mg daily with or without chemotherapy, then adjuvant osimertinib.
- •For unresectable stage III NSCLC (ECOG 0-1), administer concurrent chemoradiotherapy: thoracic radiotherapy 60 Gy in 2 Gy fractions with a platinum doublet. Preferred regimens: cisplatin 75 mg/m² + pemetrexed 500 mg/m² q3w for nonsquamous; cisplatin 50 mg/m² + etoposide 50 mg/m² q4w or carboplatin AUC 2 + paclitaxel 45 mg/m² weekly for squamous.
- •After cCRT, if no progression, start consolidation durvalumab 10 mg/kg IV q2w for 12 months. For EGFR-mutant disease, use osimertinib 80 mg daily instead of durvalumab. Do not use high-dose RT (74 Gy) or add cetuximab, both worsen outcomes.
- •For first-line metastatic NSCLC with sensitizing EGFR mutation, initiate osimertinib 80 mg orally once daily. Alternative: amivantamab 1050 mg IV (for <80 kg) or 1400 mg IV (≥80 kg) plus lazertinib 240 mg orally once daily, which showed superior PFS vs osimertinib (HR 0.70).
- •For first-line ALK-positive NSCLC, start alectinib 600 mg orally twice daily (HR 0.43 vs crizotinib) or lorlatinib 100 mg orally once daily (HR 0.19; 5-year PFS 60%). Monitor for bradycardia, hyperlipidemia, and CNS effects.
- •For first-line driver-negative metastatic NSCLC with PD-L1 TPS ≥50%, offer pembrolizumab monotherapy 200 mg IV q3w (or 400 mg q6w) for up to 2 years. For PD-L1 TPS 1-49% or any PD-L1, use pembrolizumab 200 mg IV q3w plus platinum-doublet chemotherapy: for nonsquamous, pemetrexed 500 mg/m² + cisplatin 75 mg/m² or carboplatin AUC 5 q3w for 4 cycles, then maintenance pembrolizumab + pemetrexed; for squamous, carboplatin AUC 5 + paclitaxel 175 mg/m² or nab-paclitaxel 100 mg/m² weekly for 4 cycles, then pembrolizumab alone.
- •Alternative first-line chemoimmunotherapy: durvalumab 1500 mg IV q3w plus tremelimumab 75 mg IV q3w (up to 4 doses) plus platinum-doublet chemotherapy for up to 4 cycles, then durvalumab maintenance. This regimen improved OS vs chemotherapy alone (HR 0.77).
- •For patients with poor performance status (ECOG 2) or contraindications to immunotherapy, consider platinum-doublet chemotherapy alone (e.g., carboplatin AUC 5 + pemetrexed 500 mg/m² q3w for nonsquamous) or single-agent chemotherapy (e.g., docetaxel 75 mg/m² q3w).
- •After progression on first-line EGFR TKI, preferred second-line therapy is chemotherapy plus antiangiogenic agent plus immune checkpoint inhibitor: atezolizumab 1200 mg IV q3w + bevacizumab 15 mg/kg IV q3w + carboplatin AUC 5 + paclitaxel 175 mg/m² q3w (ABCP regimen) for 4-6 cycles, then maintenance atezolizumab + bevacizumab. Alternative: amivantamab 1050-1400 mg IV weekly for 4 weeks then q3w plus carboplatin AUC 5 + pemetrexed 500 mg/m².
- •After progression on first-line chemoimmunotherapy (driver-negative), second-line options include docetaxel 75 mg/m² IV q3w, ramucirumab 10 mg/kg IV q2w plus docetaxel 75 mg/m², or single-agent pembrolizumab if not previously used and PD-L1 ≥50%. For patients with secondary resistance to immunotherapy and HLA-A2+, consider OSE2101 cancer vaccine (improved OS vs chemotherapy: 11.1 vs 7.5 months).
- •Monitor for immune-related adverse events (irAEs) during immunotherapy: check thyroid function, liver enzymes, and creatinine every 3-6 weeks. For grade 2 irAEs, hold immunotherapy and consider corticosteroids (prednisone 0.5-1 mg/kg/day). For grade 3-4 irAEs, discontinue immunotherapy and start high-dose corticosteroids (methylprednisolone 1-2 mg/kg/day).
- •Provide supportive care: antiemetics (aprepitant, ondansetron) for chemotherapy; G-CSF for febrile neutropenia prophylaxis if risk >20%; growth factors for anemia; and prompt management of diarrhea, rash, and pneumonitis. For patients on cisplatin, ensure aggressive hydration and monitor renal function.
- •Avoid non-dihydropyridine calcium channel blockers (diltiazem, verapamil) in patients with heart failure or reduced LVEF. Avoid concurrent use of strong CYP3A4 inhibitors with lorlatinib. Do not use pembrolizumab in patients with active autoimmune disease or on chronic immunosuppression.
- •Refer to palliative care early for symptom management, especially in metastatic disease. Refer to radiation oncology for palliative radiotherapy to symptomatic bone metastases or brain metastases. Refer to thoracic surgery for evaluation of oligometastatic disease amenable to local therapy.
- •Discharge criteria for outpatient systemic therapy: patient stable, no grade ≥3 toxicity, adequate organ function, and clear plan for next cycle. For inpatient admission: febrile neutropenia, grade 3-4 irAEs, severe dehydration, or respiratory compromise.
Board Review — High Yield
- •KEYNOTE-189, Pembrolizumab + pemetrexed/platinum for nonsquamous NSCLC: OS HR 0.60, 5-year OS 19.4% vs 11.3%.
- •KEYNOTE-407, Pembrolizumab + carboplatin + paclitaxel for squamous NSCLC: OS HR 0.71, 5-year OS 18.4% vs 9.7%.
- •PACIFIC, Consolidation durvalumab after chemoradiation for stage III NSCLC: 5-year OS 42.9% vs 33.4% (HR 0.72).
- •RTOG 0617, High-dose RT (74 Gy) is harmful: median OS 20.3 vs 28.7 months with 60 Gy.
- •Neoadjuvant chemoimmunotherapy, Pooled HR for OS 0.65; benefit seen even in PD-L1 <1% (HR 0.74).
- •Osimertinib, First-line for EGFR-mutant NSCLC; CNS PFS HR 0.17 after CRT.
- •Alectinib, First-line for ALK-positive NSCLC: PFS HR 0.43 vs crizotinib.
- •ATTLAS, ABCP regimen after TKI failure in EGFR/ALK-mutant NSCLC: PFS HR 0.62.
- •IrAEs and outcomes, Any-grade irAEs associated with higher ORR (vs 18.0%) but grade 3-4 irAEs paradoxically linked to worse OS.
- •Performance status, ECOG PS is the strongest predictor of OS in first-line immunotherapy; only ECOG 0-1 for chemoimmunotherapy.
Deep Dive — Evidence Details
Setting-Based Framework
- ▸Systemic therapy choice is determined by clinical setting (perioperative, adjuvant, metastatic first-line, subsequent-line) and biomarker profile.
- ▸Neoadjuvant/perioperative chemoimmunotherapy improves EFS and OS compared with chemotherapy alone and is preferred over upfront surgery for resectable stage II-III NSCLC.
- ▸First-line therapy for metastatic NSCLC is biomarker-driven: osimertinib or amivantamab-lazertinib for EGFR-mutant, alectinib or lorlatinib for ALK-positive, and pembrolizumab plus chemotherapy for driver-negative tumors.
Systemic therapy for (NSCLC) is selected according to the clinical setting: disease stage, resectability, performance status, and biomarker profile. The framework distinguishes neoadjuvant/perioperative, adjuvant, concurrent chemoradiation, first-line metastatic, and subsequent-line therapy.
Neoadjuvant and Perioperative Therapy
For patients with resectable stage II-III NSCLC, the preferred approach is neoadjuvant chemoimmunotherapy followed by surgery. A pooled analysis of 11 randomized trials showed that neoadjuvant or perioperative chemoimmunotherapy significantly improved event-free survival (EFS) compared with neoadjuvant chemotherapy alone (HR 0.58, 95% CI 0.51-0.66) and also improved overall survival (OS) (HR 0.65, 95% CI 0.53-0.81) [7]A1a. A separate meta-analysis of 8 randomized trials confirmed OS benefit (HR 0.65, 95% CI 0.54-0.79) and benefits in major pathological response (risk ratio 3.42) and complete pathological response (risk ratio 5.52) [17]A1a. Importantly, patients with tumor PD-L1 < 1% still derived EFS benefit (HR 0.74, 95% CI 0.62-0.89) [17]A1a. The NCCN Guidelines now recommend perioperative chemoimmunotherapy as a category 1 option for eligible patients [3]A1c.
Adjuvant Therapy
Adjuvant immunotherapy after platinum-based chemotherapy is an option for patients with completely resected stage II-IIIA NSCLC. In the IMpower010 trial, adjuvant improved disease-free survival in the PD-L1 ≥ 1% population, and in the exploratory analysis of stage II-IIIA PD-L1 ≥ 50% patients the OS HR was 0.43 (95% CI 0.24-0.78) [12]A1b. However, a meta-analysis of adjuvant immunotherapy trials found a more modest OS benefit (HR 0.91, 95% CI 0.76-1.10) and no significant EFS benefit in stage II or PD-L1 < 1% subgroups, indicating that neoadjuvant/perioperative strategies may be more effective [7]A1a.
First-Line Metastatic Therapy
Selection of first-line therapy for metastatic NSCLC depends on histology, PD-L1 expression, and the presence of actionable driver alterations. For patients with sensitizing EGFR mutations, the preferred first-line regimen is osimertinib; however, the combination of amivantamab plus lazertinib showed superior PFS versus osimertinib (HR 0.70, P < 0.001) and is now a recommended alternative [13]A1b[1]A1c. For ALK-positive NSCLC, alectinib (HR 0.43, 95% CI 0.32-0.58) [10]A1b and lorlatinib (HR 0.19, 95% CI 0.13-0.27; 5-year PFS 60%) [19]A1b are standard first-line options. For patients without driver alterations, the combination of plus platinum-doublet chemotherapy is the standard of care for both nonsquamous (KEYNOTE-189: OS HR 0.60, 5-year OS 19.4% vs 11.3%) [18]A1b and squamous histology (KEYNOTE-407: OS HR 0.71, 5-year OS 18.4% vs 9.7%) [20]A1b.
Subsequent-Line Therapy
After progression on EGFR-TKIs, the optimal strategy is chemotherapy combined with an anti-angiogenic agent and an immune checkpoint inhibitor (ICI-antiangio-chemo), which yielded the best PFS in a network meta-analysis (HR 0.54 vs chemotherapy alone) [8]A1a. Amivantamab plus chemotherapy is also a preferred option (HR 0.48, 95% CI 0.32-0.71) [5]A1a. For patients without targetable alterations who progress on first-line chemoimmunotherapy, single-agent or plus docetaxel remain options, though immune checkpoint inhibitors ( , pembrolizumab) are recommended as preferred second-line agents based on improved OS and fewer adverse events compared with docetaxel [4]A1c.
Controversies and Guideline Disagreement
| Question | Position A | Position B | Strength | Implication |
|---|---|---|---|---|
| Is ICI efficacy different between sexes? | Meta-analysis of 20 RCTs: OS HR 0.72 in men, 0.86 in women (p=0.0019) | Some guidelines do not stratify by sex | Moderate | Clinicians should consider sex as a potential effect modifier, though no change in recommendation is made [9]A1a. |
| Optimal sequence: neoadjuvant vs adjuvant? | ESMO meta-analysis: neoadjuvant/perioperative immunotherapy superior to adjuvant (OS HR 0.65 vs 0.91) | NCCN guidelines list both as options | Strong | Neoadjuvant/perioperative approach is preferred for eligible patients [7]A1a[3]A1c. |
Pearl: When selecting systemic therapy for NSCLC, the first decision point is the clinical setting, neoadjuvant/perioperative chemoimmunotherapy should be the default for resectable stage II-III disease, while first-line metastatic therapy is driven by biomarkers and histology, with pembrolizumab-based chemoimmunotherapy the backbone for driver-negative tumors.
| Setting | Key Trial | Regimen | Outcome |
|---|---|---|---|
| Neoadjuvant/perioperative | CheckMate 816, KEYNOTE-671, etc. (meta-analysis [7]A1a) | Chemoimmunotherapy | EFS HR 0.58, OS HR 0.65 |
| Adjuvant | IMpower010 [12]A1b | Atezolizumab after chemo | DFS improved; OS HR 0.43 (PD-L1≥50%) |
| First-line EGFR-mutant | MARIPOSA [13]A1b | Amivantamab + lazertinib vs osimertinib | PFS HR 0.70 |
| First-line ALK-positive | ALEX [10]A1b[16]A1b | Alectinib vs crizotinib | PFS HR 0.43; OS HR 0.78 |
| First-line ALK-positive | CROWN [19]A1b | Lorlatinib vs crizotinib | PFS HR 0.19; 5-yr PFS 60% |
| First-line nonsquamous | KEYNOTE-189 [18]A1b | Pembrolizumab + chemo | OS HR 0.60; 5-yr OS 19.4% |
| First-line squamous | KEYNOTE-407 [20]A1b | Pembrolizumab + chemo | OS HR 0.71; 5-yr OS 18.4% |
| Subsequent-line (EGFR-mutant) | Network meta-analysis [5]A1a | Amivantamab + chemo or ICI + antiangio + chemo | PFS HR 0.48 and 0.51 vs chemo |
Concurrent Chemotherapy with RT
- ▸Standard-dose thoracic RT (60 Gy) with concurrent platinum-based chemotherapy is the foundation of curative-intent therapy for unresectable stage III NSCLC.
- ▸Consolidation durvalumab after cCRT improves 5-year OS by 9.5% (NNT = 11); osimertinib is standard for EGFR-mutated disease.
- ▸High-dose RT (74 Gy), cetuximab, and concurrent durvalumab with CRT are ineffective and more toxic, avoid these strategies.
From the setting-based framework, the definitive treatment for unresectable stage III NSCLC is concurrent chemoradiotherapy (cCRT) followed by consolidation immunotherapy. The standard of care is cCRT using a platinum-based doublet with thoracic radiotherapy to a total dose of 60 Gy in 2 Gy fractions [29]A1b[39]A1b. Higher doses (74 Gy) are harmful and should not be used: median overall survival (OS) was 28.7 months with 60 Gy versus 20.3 months with 74 Gy (HR 1.38, 95% CI 1.09-1.76; P = 0.004) [29]A1b[39]A1b.
Risk Stratification
Before initiating cCRT, assess performance status ( 0-1), pulmonary function, tumor stage (IIIA vs IIIB/IIIC), and histology. Molecular testing for EGFR and ALK is mandatory: patients with EGFR mutations benefit from osimertinib after CRT rather than immunotherapy [23]A1b. PD-L1 status guides consolidation immunotherapy but does not alter the cCRT regimen.
Treatment of Choice: Concurrent Chemotherapy Regimens
| Regimen | Doses (from pivotal trials) | Histology | Key Evidence |
|---|---|---|---|
| / weekly | Carboplatin AUC 2, paclitaxel 45 mg/m² weekly during RT [39]A1b | Squamous or nonsquamous | RTOG 0617 standard arm [39]A1b |
| /pemetrexed | Cisplatin 75 mg/m², pemetrexed 500 mg/m² q3w × 3 cycles with RT [34]A1b | Nonsquamous | PROCLAIM: similar OS to /cisplatin with lower toxicity [34]A1b |
| Cisplatin/etoposide | Cisplatin 50 mg/m², etoposide 50 mg/m² q4w × 2 cycles with RT [34]A1b | Squamous | PROCLAIM control arm [34]A1b |
| Cisplatin/vinorelbine or carboplatin/paclitaxel (other standards) | Not detailed in provided evidence | , | Per ESMO guidelines [21]A1c |
Cisplatin/pemetrexed is preferred for nonsquamous histology due to better tolerability (grade 3-4 neutropenia 24.4% vs 44.5% with etoposide/cisplatin; P < 0.001) [34]A1b. For squamous histology, cisplatin/etoposide or carboplatin/paclitaxel are standard; the evidence does not report a specific weekly cisplatin regimen. Patients with renal impairment may receive carboplatin-based regimens, but the provided evidence does not specify alternative dosing.
Consolidation Therapy
After completing cCRT and confirming no disease progression, consolidation therapy is essential:
- (10 mg/kg IV q2w for 12 months) improved 5-year OS from 33.4% to 42.9% (HR 0.72, 95% CI 0.59-0.89; NNT = 11 to prevent one death) and 5-year PFS from 19.0% to 33.1% (HR 0.55, 95% CI 0.45-0.68; NNT = 7) [25]A1b.
- Sugemalimab (1200 mg IV q3w for up to 24 months) after concurrent or sequential CRT improved PFS (HR 0.64, 95% CI 0.48-0.85; P = 0.0026) [40]A1b.
- Osimertinib (80 mg daily) after CRT is indicated for EGFR-mutated NSCLC, with CNS PFS HR 0.17 (95% CI 0.09-0.32) and reduced distant metastases [23]A1b.
What NOT to Do
- Do not use high-dose RT (74 Gy), it worsens OS [29]A1b[39]A1b.
- Do not add , no survival benefit and increased grade ≥3 toxicity (86% vs 70%; P < 0.0001) [39]A1b.
- Do not use cisplatin/pemetrexed for squamous histology, survival is inferior to cisplatin/ [28]A1b (covered in Chemotherapy Regimens section).
Monitoring Schedule
During cCRT, perform weekly complete blood counts and clinical assessment for esophagitis, pneumonitis, and hematologic toxicity. After cCRT, obtain a CT chest within 1-6 weeks to confirm no progression before starting consolidation. The retrieved evidence does not report a specific monitoring schedule beyond these trial-based assessments.
Pearl: For unresectable stage III NSCLC, the winning combination is 60 Gy RT with a platinum doublet, followed by 12 months of consolidation durvalumab, this yields 5-year survival of 42.9% [25]A1b. Adding concurrent immunotherapy or high-dose RT only increases toxicity without benefit.
| Regimen | Dose | Schedule | Histology | Key Trial |
|---|---|---|---|---|
| Carboplatin/paclitaxel | Carboplatin AUC 2, paclitaxel 45 mg/m² | Weekly during RT | Squamous or nonsquamous | RTOG 0617 [39]A1b |
| Cisplatin/pemetrexed | Cisplatin 75 mg/m², pemetrexed 500 mg/m² | q3w × 3 cycles with RT | Nonsquamous | PROCLAIM [34]A1b |
| Cisplatin/etoposide | Cisplatin 50 mg/m², etoposide 50 mg/m² | q4w × 2 cycles with RT | Squamous | PROCLAIM [34]A1b |
Chemotherapy Regimens
- ▸First-line chemotherapy for metastatic NSCLC is a platinum-doublet (cisplatin or carboplatin) combined with histology-appropriate partner (pemetrexed for nonsquamous, paclitaxel for squamous) and immunotherapy.
- ▸In EGFR-mutant NSCLC after TKI failure, chemotherapy plus anti-VEGF plus anti-PD-1/PD-L1 or chemotherapy plus amivantamab is preferred over chemotherapy alone.
- ▸Perioperative chemotherapy remains the backbone for resectable NSCLC, but chemo-immunotherapy (e.g., tislelizumab + chemotherapy in RATIONALE-315) improves OS with an NNT of 10 at 36 months.
For patients with metastatic non-small-cell lung cancer (NSCLC), the platinum-based doublet remains the foundational chemotherapy backbone, but it is now almost always combined with an immune checkpoint inhibitor or, in oncogene-driven disease, with a targeted agent. This section reviews the chemotherapy regimens and their evidence-based combinations across the treatment continuum.
First-Line Chemotherapy Backbone for Metastatic NSCLC
In the first-line metastatic setting, a platinum-doublet ( 75 mg/m² or AUC 5 plus a partner drug) is the cytotoxic backbone. The choice of partner depends on histology: pemetrexed 500 mg/m² for nonsquamous and (or ) for squamous NSCLC. These doublets are now rarely given alone unless immunotherapy is contraindicated.
The pivotal KEYNOTE-189 trial established 200 mg every 3 weeks (or 400 mg every 6 weeks) plus pemetrexed-platinum as the standard for metastatic nonsquamous NSCLC without EGFR/ALK alterations. With 5-year follow-up, the hazard ratio (HR) for overall survival (OS) was 0.60 (95% CI, 0.50 to 0.72), and 5-year OS rates were 19.4% versus 11.3% (absolute difference 8.1%; NNT = 13 to prevent one death) [18]A1b. Objective response rates (ORR) were 48.3% versus 19.9% [15]A1b. Grade 3-5 adverse events occurred in 72.1% of the pembrolizumab-combination arm versus 66.8% in the placebo-combination arm [15]A1b.
For squamous histology, KEYNOTE-407 demonstrated that pembrolizumab 200 mg every 3 weeks plus carboplatin and paclitaxel/nab-paclitaxel improves OS compared with chemotherapy alone (HR, 0.71; 95% CI, 0.59 to 0.85), with 5-year OS rates of 18.4% versus 9.7% (absolute difference 8.7%; NNT = 12) [20]A1b.
The POSEIDON study evaluated 1,500 mg with or without 75 mg plus platinum-based chemotherapy. The addition of a limited course of tremelimumab to durvalumab plus chemotherapy significantly improved OS (HR, 0.77; 95% CI, 0.65 to 0.92; median 14.0 vs 11.7 months; 24-month OS 32.9% vs 22.1%) [46]A1b.
| Regimen | Histology | Chemotherapy Backbone | OS HR (95% CI) | 5-Year OS Rates | NNT (5-year OS) |
|---|---|---|---|---|---|
| Pembrolizumab + pemetrexed-platinum [18]A1b | Nonsquamous | Pemetrexed 500 mg/m² + cisplatin 75 mg/m² or carboplatin AUC 5 | 0.60 (0.50-0.72) | 19.4% vs 11.3% | 13 |
| Pembrolizumab + carboplatin + (nab-)paclitaxel [20]A1b | Squamous | Carboplatin AUC 5 + paclitaxel/nab-paclitaxel | 0.71 (0.59-0.85) | 18.4% vs 9.7% | 12 |
| Durvalumab + tremelimumab + chemotherapy [46]A1b | Both | Platinum-doublet (up to 4 cycles) | 0.77 (0.65-0.92) | 24-month: 32.9% vs 22.1% | Not reported |
Chemotherapy in Oncogene-Driven NSCLC After TKI Failure
For patients with EGFR-mutant NSCLC who progress on an EGFR tyrosine kinase inhibitor (TKI), platinum-based chemotherapy remains the backbone but is often combined with antiangiogenic or immunotherapy agents. The ATTLAS study (KCSG-LU19-04) randomized patients with EGFR- or ALK-mutated NSCLC after TKI failure to plus , paclitaxel, and carboplatin (ABCP) versus pemetrexed plus carboplatin/cisplatin (PC). The ABCP regimen significantly improved progression-free survival (PFS) (HR, 0.62; 95% CI, 0.45 to 0.86; median 8.48 vs 5.62 months; NNT = 4 for PFS benefit at 6 months, estimated from 6-month PFS rates) and ORR (69.5% vs 41.9%), although OS was similar [50]A1b.
A network meta-analysis of 9 trials (2,534 patients) confirmed that after EGFR-TKI failure, chemotherapy plus an anti-PD-1/PD-L1 agent plus an anti-VEGF agent (HR, 0.51; 95% CI, 0.41-0.62) or chemotherapy plus amivantamab (HR, 0.48; 95% CI, 0.32-0.71) significantly prolongs PFS compared with chemotherapy alone [5]A1a. Chemotherapy plus bevacizumab without immunotherapy also reduced progression risk (HR, 0.66; 95% CI, 0.45-0.98) [5]A1a.
Perioperative Chemotherapy Regimens
In resectable NSCLC, chemotherapy is the backbone of neoadjuvant and adjuvant regimens. The RATIONALE-315 trial evaluated perioperative plus neoadjuvant chemotherapy in stage II-IIIA NSCLC. The 36-month OS rate was 79.3% versus 69.3% (absolute difference 10%; NNT = 10), with an OS HR of 0.65 (95% CI, 0.45-0.93) [41]A1b. The EFS was also significantly improved (HR, 0.58; 95% CI, 0.43-0.79) [41]A1b.
For EGFR-mutant resectable NSCLC, the NeoADAURA study showed that neoadjuvant osimertinib (80 mg once daily) with or without chemotherapy (pemetrexed 500 mg/m² plus carboplatin AUC 5 or cisplatin 75 mg/m²) significantly improved the major pathological response (MPR) rate compared with chemotherapy alone (26% and 25% vs 2%) [47]A1b. The chemotherapy-alone arm had an MPR rate of only 2%, confirming that chemotherapy alone is inadequate in this molecular subtype [47]A1b.
Second-Line Chemotherapy Options
After progression on immunotherapy and platinum-based chemotherapy, single-agent chemotherapy ( or pemetrexed) remains the standard-of-care comparator. In the ATALANTE-1 study, patients with HLA-A2-positive advanced NSCLC and secondary resistance to immunotherapy received the cancer vaccine OSE2101 or standard-of-care chemotherapy (docetaxel or pemetrexed). In the secondary resistance subgroup, OSE2101 improved OS (11.1 vs 7.5 months; HR, 0.59; 95% CI, 0.38-0.91) with fewer grade ≥3 adverse events (11.4% vs 35.1%) [42]A1b.
What NOT to Do
- Do not use chemotherapy alone as first-line therapy for metastatic NSCLC in patients who are candidates for immunotherapy, as combination chemo-immunotherapy significantly improves survival.
- Do not omit a platinum agent in first-line chemotherapy; single-agent chemotherapy is reserved for patients with poor performance status.
- Do not continue chemotherapy beyond four cycles in the first-line setting unless using maintenance pemetrexed (for nonsquamous histology).
Pearl: For first-line metastatic NSCLC, the chemotherapy backbone is a platinum-doublet, choose pemetrexed for nonsquamous and paclitaxel for squamous histology, and always combine with an immune checkpoint inhibitor unless contraindicated. The NNT to prevent one death at 5 years with pembrolizumab plus chemotherapy is approximately 12-13, making this one of the most impactful interventions in thoracic oncology.
Targeted and Immune Therapy
- ▸Pembrolizumab plus platinum-doublet chemotherapy is the preferred first-line regimen for metastatic NSCLC without EGFR/ALK alterations, improving OS regardless of PD-L1 expression (5-year OS 19.4% vs 11.3% in nonsquamous; NNT = 12).
- ▸In EGFR-mutant NSCLC progressing on TKI, atezolizumab plus bevacizumab and chemotherapy (ABCP) improved PFS (HR 0.62), while pembrolizumab plus chemotherapy did not show significant benefit.
- ▸Emerging agents such as izalontamab brengitecan (EGFR-HER3 ADC) and OSE2101 vaccine offer new options for post-TKI and post-immunotherapy settings, respectively.
Building on the chemotherapy backbone, the addition of immune checkpoint inhibitors and targeted agents has transformed first-line management of metastatic non-small-cell lung cancer (NSCLC). Treatment selection begins with biomarker stratification: all patients should undergo testing for EGFR mutations, ALK rearrangements, and PD-L1 tumor proportion score (TPS) [51]A1c[52]A1c. For patients without actionable driver alterations, PD-1/PD-L1 inhibitors, alone or combined with chemotherapy, are the cornerstone of first-line therapy.
First-Line Immunotherapy
monotherapy is a standard for PD-L1 TPS ≥50%. In KEYNOTE-024, median overall survival (OS) was 30.0 months versus 14.2 months with chemotherapy (HR 0.63; 95% CI 0.47-0.86); the 5-year OS rate was 31.9% versus 16.3% (absolute difference; NNT = 6) [26]A1b[55]A1b. For PD-L1 TPS ≥1%, KEYNOTE-042 confirmed OS benefit (HR 0.79; 95% CI 0.70-0.89), with 5-year OS rates of 16.6% versus chemotherapy [49]A1b.
Pembrolizumab plus platinum-doublet chemotherapy is preferred regardless of PD-L1 expression. In KEYNOTE-189 (nonsquamous), the combination improved OS (HR 0.56; 95% CI 0.46-0.69) and progression-free survival (PFS; HR 0.49; 95% CI 0.41-0.59) at 31 months; 5-year OS rates were 19.4% versus 11.3% (absolute difference 8.1%; NNT = 12) [15]A1b[18]A1b. In KEYNOTE-407 (squamous), OS HR was 0.71 (95% CI 0.59-0.85), with 5-year OS rates of 18.4% versus 9.7% (absolute difference 8.7%; NNT = 11) [20]A1b. Grade 3-5 adverse events occurred in 72.1% and 66.8% of patients in the pembrolizumab and placebo arms, respectively, in KEYNOTE-189 [15]A1b.
A subcutaneous formulation of pembrolizumab (790 mg every 6 weeks) demonstrated noninferior pharmacokinetics and similar efficacy (ORR 45.4% versus 42.1%) compared with intravenous dosing, offering a shorter administration time (median 2 minutes) [11]A1b.
Adjuvant pembrolizumab after complete resection for stage IB-IIIA NSCLC improved disease-free survival (DFS) in the overall population (HR 0.76; 95% CI 0.63-0.91), though the benefit was not significant in the PD-L1 TPS ≥50% subgroup [59]A1b. Grade 3 or worse adverse events occurred in 34% of pembrolizumab-treated patients versus 26% with placebo [59]A1b.
Targeted Therapy for Driver Mutations
For patients with EGFR-mutant NSCLC who progress on tyrosine kinase inhibitors (TKIs), the addition of pembrolizumab to chemotherapy did not significantly prolong PFS or OS in KEYNOTE-789 (PFS HR 0.80; 95% CI 0.65-0.97; OS HR 0.84; 95% CI 0.69-1.02) [27]A1b. In contrast, the ATTLAS study showed that plus , , and (ABCP) improved PFS over chemotherapy alone in EGFR- or ALK-mutated NSCLC after TKI failure (HR 0.62; 95% CI 0.45-0.86; median PFS 8.48 versus 5.62 months) [50]A1b. The benefit increased with higher PD-L1 expression (HR 0.24 for PD-L1 ≥50%) [50]A1b.
Bevacizumab plus chemotherapy demonstrated intracranial efficacy in treatment-naïve nonsquamous NSCLC with . In the BAP BRAIN trial, intracranial PFS was prolonged (11.07 versus 7.37 months; HR 0.494; P<0.001), and intracranial objective response rate improved (69.6% versus 32.4%) [58]A1b. No grade ≥3 intracranial hemorrhage occurred [58]A1b.
Emerging Agents
Izalontamab brengitecan (Iza-bren; BL-B01D1), a first-in-class EGFR-HER3 bispecific antibody-drug conjugate, showed promising activity in heavily pretreated EGFR-mutated NSCLC. In a pooled analysis of phase I/II trials, the confirmed objective response rate (cORR) was 47.4% (95% CI 39.7%-55.1%), median PFS 6.9 months, and median OS 24.8 months [56]A1a. Grade ≥3 treatment-related adverse events occurred in 70.2%, predominantly hematologic; was rare (0.6%) [56]A1a.
OSE2101, a cancer vaccine for HLA-A2-positive patients with secondary resistance to immune checkpoint blockade, improved OS versus chemotherapy in the ATALANTE-1 trial (median OS 11.1 versus 7.5 months; HR 0.59; 95% CI 0.38-0.91) with fewer grade ≥3 adverse events (11.4% versus 35.1%) [42]A1b.
Real-World Considerations
Real-world outcomes with first-line immunotherapy are often shorter than those reported in pivotal trials. In the CORRELATE study, median OS was 36%- shorter and median PFS 21%-60% shorter in patients with PS 0-1 compared with the corresponding RCTs, highlighting an unmet need for more effective options [57]A1b.
Monitoring and Toxicity
In the pivotal trials, pembrolizumab was administered every 3 weeks for up to 35 cycles (approximately 2 years), with radiographic assessment every 6-9 weeks [15]A1b[18]A1b[20]A1b. Immune-related adverse events (e.g., pneumonitis, colitis, hepatitis) require prompt recognition and management. Grade 3-5 treatment-related adverse events occurred in 31.2% of patients receiving pembrolizumab monotherapy [26]A1b and in 72.1% of those receiving combination therapy [15]A1b.
Pearl: For first-line therapy in metastatic NSCLC without driver mutations, pembrolizumab plus platinum-doublet chemotherapy provides a consistent OS benefit across PD-L1 levels, with an NNT of approximately 11-12 to prevent one death at 5 years; monotherapy remains an option for PD-L1 TPS ≥50% (NNT = 6).
| Trial | Population | Regimen | OS HR (95% CI) | 5-Year OS (Experimental vs Control) | NNT for 5-Year OS |
|---|---|---|---|---|---|
| KEYNOTE-024 [26]A1b[55]A1b | PD-L1 TPS ≥50% | Pembrolizumab monotherapy | 0.63 (0.47-0.86) | 31.9% vs 16.3% | 6 |
| KEYNOTE-189 [15]A1b[18]A1b | Nonsquamous, all PD-L1 | Pembrolizumab + pemetrexed-platinum | 0.56 (0.46-0.69) | 19.4% vs 11.3% | 12 |
| KEYNOTE-407 [20]A1b | Squamous, all PD-L1 | Pembrolizumab + carboplatin + (nab-)paclitaxel | 0.71 (0.59-0.85) | 18.4% vs 9.7% | 11 |
Toxicity and Supportive Care
- ▸Grade 3/4 irAEs are three times more common with CTLA-4 inhibitors (31%) than with PD-1 inhibitors (10%), with distinct organ predilections [62].
- ▸Preexisting interstitial lung abnormalities on CT and prior chest radiation are strong independent risk factors for ICI-pneumonitis (HR 8.91 and 2.81, respectively) [61].
- ▸Any-grade irAE development during PD-1/PD-L1 therapy is associated with improved ORR, PFS, and OS, but grade 3-4 irAEs correlate with worse OS despite higher ORR [70].
- ▸Sacituzumab govitecan grade ≥3 neutropenia occurs in 28% of patients, requiring close monitoring and growth factor support [69].
The therapeutic gains from systemic therapy in NSCLC are accompanied by a spectrum of adverse events that vary by drug class, regimen, and patient risk factors. Effective management of these toxicities is essential to maintain dose intensity, quality of life, and treatment adherence.
Chemotherapy-Related Toxicities
Platinum-based doublets commonly cause myelosuppression, nephrotoxicity, neurotoxicity, and gastrointestinal effects. In the meta-analysis of concomitant radiochemotherapy by Aupérin et al., acute esophageal toxicity grade 3-4 increased from 4% with sequential to 18% with concurrent chemoradiation (relative risk 4.9, 95% CI 3.1-7.8) [65]A1a. No significant difference in acute pulmonary toxicity was observed. In KEYNOTE-024, treatment-related grade 3-5 adverse events occurred in 31.2% of patients receiving monotherapy compared to 53.3% with platinum-based chemotherapy [26]A1b. For TROP-2 antibody-drug conjugates, sacituzumab govitecan grade ≥3 adverse events included neutropenia (28%), diarrhea (7%), nausea (7%), fatigue (6%), and febrile neutropenia (4%) [69]B2a.
Immune-Related Adverse Events (irAEs)
Immune checkpoint inhibitors produce a distinct toxicity profile that differs between CTLA-4 and PD-1/PD-L1 agents. In a systematic review of 48 trials, grade 3/4 irAEs were more common with CTLA-4 mAbs (31%) than with PD-1 mAbs (10%) [62]B2a. Colitis (OR 8.7, 95% CI 5.8-12.9), (OR 6.5, 95% CI 3.0-14.3), and rash (OR 2.0, 95% CI 1.8-2.3) were more frequent with CTLA-4; pneumonitis (OR 6.4, 95% CI 3.2-12.7), hypothyroidism (OR 4.3, 95% CI 2.9-6.3), arthralgia (OR 3.5, 95% CI 2.6-4.8), and (OR 3.5, 95% CI 2.3-5.3) were more common with PD-1 [62]B2a. Tumor-specific patterns are evident: NSCLC patients receiving PD-1 inhibitors had a lower frequency of gastrointestinal and skin irAEs but a higher frequency of pneumonitis compared to patients [62]B2a.
Pneumonitis is a potentially life-threatening complication of ICI therapy, occurring in 2% to 5% of patients [61]B3b. Preexisting interstitial abnormalities on chest CT (HR 8.91, 95% CI 4.69-16.92) and prior chest radiation (HR 2.81, 95% CI 1.50-5.28) are strong independent risk factors [61]B3b. Among patients with ICI-pneumonitis, those with grade 3-5 disease have worse overall survival than those with grade 1-2 [61]B3b.
Combination Therapy Toxicities
Adding anti-PD-(L)1 therapy to platinum-based chemotherapy increases immune-mediated adverse events and infusion reactions but does not produce unexpected toxicities [72]A1a. In the neoadjuvant setting, chemoimmunotherapy was associated with a higher rate of grade 3-4 TRAEs (risk difference 3.42%, 95%%) and a small increase in surgery cancellation due to adverse events (risk difference 1.15%, 95% CI 0.25-2.05%) compared to chemotherapy alone, with no increase in overall postoperative complications [71]A1a.
Supportive Care and Toxicity Management
Management of toxicities requires prompt recognition, appropriate grading, and timely treatment interruption or dose modification. Notably, the development of irAEs is associated with improved outcomes: in lung cancer, patients who developed any-grade irAEs had higher objective response rate (41.49% vs 18.01%), longer progression-free survival (PFS HR 0.46, 95% CI 0.39-0.54), and longer overall survival (OS HR 0.40, 95% CI 0.30-0.51) [70]C4. However, grade 3-4 irAEs were associated with increased ORR but worse OS, underscoring the importance of early intervention [70]C4. For patients receiving PD-1/PD-L1 inhibitors, baseline chest imaging to assess for interstitial abnormalities can identify those at higher risk for pneumonitis [61]B3b. Thyroid function should be monitored regularly given the elevated risk of hypothyroidism [62]B2a.
Pearl: The development of any-grade immune-related adverse events during PD-1/PD-L1 therapy is associated with a 2.3-fold higher objective response rate in lung cancer, but severe (grade 3-4) irAEs paradoxically correlate with worse overall survival, necessitating vigilant monitoring and early corticosteroid use [70]C4.
| irAE | CTLA-4 vs PD-1 (Odds Ratio) | 95% CI | More Frequent Class |
|---|---|---|---|
| Colitis (all grades) | 8.7 | 5.8-12.9 | CTLA-4 |
| Hypophysitis (all grades) | 6.5 | 3.0-14.3 | CTLA-4 |
| Rash (all grades) | 2.0 | 1.8-2.3 | CTLA-4 |
| Pneumonitis (all grades) | 6.4 | 3.2-12.7 | PD-1 |
| Hypothyroidism (all grades) | 4.3 | 2.9-6.3 | PD-1 |
| Arthralgia (all grades) | 3.5 | 2.6-4.8 | PD-1 |
| Vitiligo (all grades) | 3.5 | 2.3-5.3 | PD-1 |
| Grade 3/4 irAEs (any) | 31% vs 10% | - | CTLA-4 |
Data from 48 trials, 6938 patients [62]B2a
Special Populations
- ▸PLWH with NSCLC have a 3.6-fold higher risk of new-onset severe chronic conditions (diabetes, myocardial infarction); integrated HIV-oncology care and routine screening are essential.
- ▸ECOG performance status is the strongest independent predictor of survival in patients receiving immunotherapy for metastatic NSCLC, surpassing PD-L1 expression.
- ▸First-line immunotherapy efficacy is similar across Black, Hispanic, and White racial/ethnic groups, addressing historical underrepresentation in trials.
Beyond managing common toxicities, special populations require tailored treatment strategies that account for unique comorbidities, drug interactions, and prognostic factors.
People Living With HIV (PLWH)
The NCCN Guidelines for Cancer in PLWH provide specific treatment recommendations for , along with guidance on HIV management during cancer therapy, drug-drug interactions between antiretroviral treatments and cancer therapies, and supportive care [60]A1c.
PLWH who develop NSCLC face a substantially elevated risk of new-onset severe chronic health conditions. In a multicenter cohort, the risk of grade ≥3 morbidities was 3.6-fold higher for PLWH with NSCLC compared with matched PLWH without cancer (HR 3.64, p=0.001) [80]B3b. The cumulative incidence of grade ≥3 conditions reached 54% at 20 years [80]B3b. Specific risks included:
- Grade ≥3 diabetes mellitus: HR 3.89 (p=0.001)
- Grade ≥3 myocardial infarction: HR 2.83 (p=0.04)
These findings underscore the need for integrated care with close coordination between oncologists, primary care physicians, and infectious disease specialists, including routine screening for diabetes and cardiovascular disease [80]B3b.
For PLWH on immune checkpoint inhibitors (ICIs) who require high-dose steroids (≥20 mg equivalent daily for ≥4 weeks) for immune-related adverse events, the incidence of opportunistic infections in one cohort was 7% (predominantly and varicella zoster), with one case of Pneumocystis jirovecii pneumonia [77]C4. The necessity of routine PJP prophylaxis in this setting remains uncertain [77]C4.
Performance Status
Performance status (PS) is among the strongest determinants of treatment selection and outcomes. ASCO guidelines for stage IV NSCLC specify PS 0-2 for targeted therapy in driver-altered disease and PS 0-1 for immunotherapy-containing regimens in driver-negative disease [78]A1c[79]A1c.
In a real-world cohort of 248 patients with metastatic NSCLC treated with first-line immunotherapy, PS was the only variable independently associated with overall survival in multivariate analysis (P<0.0001); PD-L1 expression and body mass index were associated with progression-free survival but not OS [81]B3b. The Lung Immune Prognostic Index (LIPI), derived from pretreatment lactate dehydrogenase and derived neutrophil-to-lymphocyte ratio, further stratifies outcomes in PD-L1-low/negative patients receiving chemoimmunotherapy: patients with poor LIPI had median PFS of 3.6 months and OS of 7.8 months vs. 9.0 and 23.9 months, respectively, for good/intermediate LIPI [91]B2b.
Racial and Ethnic Minorities
Historically underrepresented in immunotherapy trials, racial and ethnic minority patients achieve similar benefit. In a retrospective study, OS, PFS, and time to discontinuation were comparable across non-Hispanic Black (39.1%), Hispanic (30.2%), and non-Hispanic White (30.7%) patients receiving first-line immunotherapy for metastatic NSCLC [81]B3b.
Pearl: First-line immunotherapy efficacy is similar across Black, Hispanic, and White racial/ethnic groups, addressing historical underrepresentation in trials.
Related Pages
Part of the Non-Small Cell Lung Cancer family. Cross-cutting management is split across dedicated child pages:
- , diagnostic page (definition, epidemiology, staging, biomarkers, prognosis)
- Non-Small Cell Lung Cancer Surgical Management , operations by stage, fertility-sparing options, sentinel node mapping, adjuvant triggers (Sedlis / Peters)
- Non-Small Cell Lung Cancer Radiation Management , EBRT + image-guided brachytherapy + concurrent chemoradiation, dose / fractionation, OAR constraints
- Non-Small Cell Lung Cancer Palliative Care , early integration, symptom management, palliative procedures, end-of-life care
- , post-treatment surveillance schedule, late toxicity, survivorship, patient counselling
- Non-Small Cell Lung Cancer Recurrent and Metastatic Disease , local-regional salvage, distant metastatic systemic therapy, oligometastatic disease
Pearl: Use these links to hop between management modalities; the parent Non-Small Cell Lung Cancer page carries diagnosis + staging that informs every decision here.
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