NCCN, ASCO, IASLC and ESMO Guidelines

Treatment Guidelines

Several leading organizations in the United States (US) and internationally, including the National Comprehensive Cancer Network (NCCN), the American Society of Clinical Oncology (ASCO), the International Association for the Study of Lung Cancer (IASLC) and the European Society for Medical Oncology (ESMO), have developed comprehensive guidelines to provide evidence-based recommendations for the diagnosis, staging and treatment of non-small cell lung cancer (NSCLC). As mentioned in Treatment Options, the treatment approach is stage-dependent, with early-stage disease often managed through surgical resection, while advanced stages may require a combination of chemotherapy, radiation therapy, targeted therapies, or immunotherapy, tailored to the tumor's molecular profile and extent of metastasis (Figure 4-1 shows a simplified algorithm based on the NCCN guidelines). Each guideline is extensive and provides detailed recommendations for the management of NSCLC; covering them in full is beyond the scope of this module, but this section will highlight the recommendations on some important topics. Readers are invited to read the guidelines in full or consult them on any aspects not covered in this section.

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Treatment of Early-Stage NSCLC (Stages I and II)

For early stages of NSCLC, the NCCN, ASCO, IASLC and ESMO guidelines consistently recommend surgical resection as the primary treatment. If preoperative systemic therapy is planned, mediastinal lymph node dissection or systematic lymph node sampling should be conducted afterward. All early-stage patients should be assessed for preoperative therapy, considering in particular the combination of an immune checkpoint inhibitor and chemotherapy for those with tumors ≥4 cm or positive lymph nodes, provided there are no contraindications to immune checkpoint inhibitors. For patients who are medically inoperable, have high surgical risk as determined by thoracic surgeon, or decline surgery after thoracic surgical consultation, definitive radiation therapy, preferably stereotactic body radiation therapy (SBRT), is suggested. Patients who have undergone surgery should be tested for PD-L1 status, epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements. For Stage II patients, particularly those with high-risk features, such as poorly differentiated tumors, vascular invasion, wedge resection, visceral pleural involvement and unknown lymph node status, adjuvant chemotherapy is recommended to reduce the risk of recurrence post-surgery.

The 2024 IASLC guideline provides recommendations on the initial evaluation and staging, surgical approaches, and neoadjuvant and adjuvant therapies of early-stage resectable NSCLC. It consists of 20 recommendations, emphasizing the importance of a multidisciplinary approach in evaluating resectable NSCLC patients; the need for biomarker testing; a preference for neoadjuvant chemoimmunotherapy in Stage III resectable NSCLC; equipoise between upfront surgery and neoadjuvant strategies in managing Stage II patients; and a strong preference for adjuvant targeted therapy in resectable NSCLC patients with sensitizing EGFR and ALK alterations.

IASLC Staging Recommendations

One IASLC guideline recommendation addresses staging (Table 4-1)

Accurate lung cancer staging (see Staging) is essential for creating an optimal treatment plan, with contrast-enhanced CT of the chest and upper abdomen being the minimum imaging requirement for detecting mediastinal and extrathoracic disease.² Integrated PET-CT is preferred for its higher diagnostic accuracy, although it has a false positive rate of 10% to 30%, necessitating histological confirmation of equivocal results. Invasive staging techniques, while not widely available in resource-limited settings, can include surgical evaluation through mediastinoscopy or video-assisted thoracoscopic surgery. Additionally, a contrast-enhanced MR brain imaging or CT scan is mandatory, as MRI is more sensitive in detecting small brain metastases, which are more prevalent in advanced disease stages.

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Surgical Approaches and Multimodal Treatment

The IASLC guideline contains five recommendations addressing the surgical approach to the disease (Table 4-2). The recommendations emphasize the importance of thorough surgical evaluation and planning for patients with NSCLC.

The IASLC guideline focuses mainly on neoadjuvant and adjuvant therapy, tying them together with the surgical treatment. Interlinked, they represent the key aspects of multimodal treatment of NSCLC. This approach is crucial for tailoring individualized treatment plans for each patient. The growing number of treatment options for patients with resectable disease highlights the importance of evaluation by a multidisciplinary team. Collaboration allows specialists to create a personalized treatment plan that takes into account the patient’s unique medical history, histology, stage, biomarker profile and personal preferences. The IASLC guideline consists of nine recommendations regarding the multimodal treatment approach (Table 4-3).

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Treatment of Locally Advanced NSCLC (Stage III)

For stage III NSCLC, a multimodal treatment approach tailored to the individual patient’s clinical situation is recommended across all guidelines. The primary treatment typically involves concurrent chemoradiation therapy, which combines systemic chemotherapy with radiation therapy to enhance the efficacy of both modalities. For patients with resectable Stage III disease, surgery should be considered. Preoperative concurrent chemoradiation is recommended to potentially reduce the size of the tumor(s), and chemotherapy or chemoradiation should be considered as adjuvant treatment. The NCCN guideline recommends durvalumab as a consolidation immunotherapy for patients with unresectable Stage III NSCLC who have not shown disease progression after platinum-based chemoradiation. It can be used regardless of the PD-L1 expression status and serves as an adjuvant treatment, not a second-line therapy, after any chemoradiation regimen.

Treatment of Metastatic NSCLC (Stage IV)

For Stage IV NSCLC, a molecular therapy-driven treatment approach is emphasized across all guidelines. All Stage IV patients should undergo testing for molecular biomarkers to identify genomic alterations in NSCLC for which targeted therapies are available. Molecular testing through biopsy and/or plasma testing is recommended, with either concurrent or sequential use of tissue and plasma testing being acceptable approaches. There are several key biomarkers: ALK rearrangements; B-Raf Proto-Oncogene (BRAF) V600E point mutations; EGFR mutations; Human Epidermal Growth Factor Receptor 2 (HER2) mutations; Kirsten Rat Sarcoma Viral Oncogene (KRAS) mutations; Mesenchymal-Epithelial Transition Factor (MET) exon 14 skipping mutations; Neurotrophic Tyrosine Receptor Kinase (NTRK) gene fusions; Rearranged during Transfection (RET) rearrangements; Proto-Oncogene Tyrosine-Protein Kinase (ROS1) rearrangements; and PD-L1 expression. For patients with actionable mutations, targeted therapies are the preferred first-line treatment, offering significant survival benefits. In patients without targetable mutations, immunotherapy (e.g., pembrolizumab, nivolumab) is recommended, either alone or in combination with chemotherapy, depending on PD-L1 status. Platinum-based chemotherapy remains a key option for patients who are not candidates for targeted therapy or immunotherapy.

NCCN Guidelines

The NCCN guidelines recommend biomarker testing in eligible patients with Stage IV disease, and in eligible patients with resectable early-stage and locally advanced NSCLC. The guidelines strongly advise broader molecular profiling to identify both common and rare driver mutations. Broad molecular profiling can help identify the resistance mechanisms in patients whose disease has progressed despite targeted therapy, and can help differentiate between separate primary lung cancers and intrapulmonary metastases. Additionally, broad molecular profiling can be used to identify emerging biomarkers for which effective therapy may be available, such as high-level MET amplifications. Therefore, this approach ensures that patients have access to targeted therapies and receive the most appropriate treatment.

Molecular testing for EGFR, ALK, KRAS, ROS1, BRAF, NTRK1/2/3, MET, RET and HER2 alterations is recommended for all patients with advanced or metastatic non-squamous NSCLC (e.g., adenocarcinoma, large cell carcinoma) and NSCLC not otherwise specified (NOS). Testing for EGFR mutations and ALK rearrangements is a category 1 recommendation for patients with non-squamous NSCLC or NSCLC NOS, due to strong evidence supporting targeted therapies for these biomarkers. Testing for PD-L1 expression before initiating first-line therapy is also a category 1 recommendation for patients with advanced or metastatic NSCLC, regardless of histology. This helps determine the potential use of immune checkpoint inhibitors when no actionable molecular biomarkers are found.

The NCCN guideline recommendations on biomarker testing and targeted therapies are summarized in Table 4-4.

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ASCO Guidelines

Two comprehensive guidelines providing evidence-based recommendations on systemic therapy for patients with Stage IV NSCLC recently released by ASCO: one on cancer with driver alterations and the other on cancer without driver alterations.

The ASCO guideline for patients with NSCLC with driver alterations focuses on therapy targeting EGFR mutations, ALK rearrangements, ROS1 rearrangements, BRAF V600E mutations, MET exon 14 skipping mutations, RET rearrangements and NTRK rearrangements as relevant biomarkers. It addresses the question of what systemic therapy options should be offered to patients with Stage IV NSCLC who have driver alterations, utilizing three sub-questions:

• What is the most effective first-line therapy?
• What is the most effective second-line therapy?
• Is there a role for a third-line therapy or beyond?

The guideline recommendations were updated in 2022 addressing the treatment of patients with ALK and RET rearrangements, and in 2024 addressing the treatments of patients with EGFR mutations and ROS1 rearrangements. The updated recommendations are presented in Table 4-5. They recommend the use of alectinib, brigatinib or lorlatinib as first-line therapy in patients with ALK rearrangements, or ceritinib or crizotinib if none of the preferred drugs are available. In the case of RET rearrangements, selpercatinib or pralsetinib may be offered as a first-line or second-line therapy. Osimertinib may be offered with chemotherapy to patients with EGFR mutations, and for those who progress on osimertinib or other third-generation TKIs, amivantamab with carboplatin and pemetrexed may be considered. For patients with ROS1 rearrangements, clinicians may offer repotrectinib, entrectinib, or crizotinib as first-line therapies, with ceritinib or lorlatinib as alternatives if the preferred options are unavailable or not tolerated; repotrectinib may also be offered after prior use of crizotinib, entrectinib, lorlatinib or ceritinib.

The ASCO guideline for patients with NSCLC without driver alterations focuses on therapy targeting PD-L1 expression. As a first-line therapy, pembrolizumab, cemiplimab, or atezolizumab monotherapy are strongly recommended in patients with high tumor expression of PD-L1 (≥50%). In patients with low PD-L1 expression (1%-49%), pembrolizumab or cemiplimab combined with carboplatin and pemetrexed are strongly recommended as part of a platinum-based doublet chemotherapy and immunotherapy regimen, provided there are no contraindications.

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