New ESMO Metastatic NSCLC Clinical Practice Guidelines

By Michael Vlessides /alert Contributor
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Clinicians seeking more guidance on diagnosis and treatment of metastatic non-small-cell lung cancer (NSCLC) have another tool in their armamentarium, after the European Society for Medical Oncology (ESMO) released its latest clinical practice guidelines for diagnosis, treatment, and follow-up of the disease.


With respect to diagnosis, the researchers noted that versatility is key. “Changes in the therapeutic scenario in the last 15 years have emphasized the need for a multidisciplinary approach in lung cancer,” they wrote.

An important part of diagnosis is bronchoscopy, which is best suited for evaluation of central lesions and can be used with bronchial washing, brushing, and bronchial and transbronchial biopsy.

​Doctor discussing treatment options. Source: Getty

They also proposed the use of transthoracic percutaneous fine needle aspiration and/or core biopsy under imaging guidance in the case of peripheral lesions. Thoracentesis may also represent a diagnostic tool and palliative treatment in the presence of a pleural effusion.

Finally, invasive surgical approaches -- such as mediastinoscopy, mediastinotomy, thoracoscopy, video-assisted thorascopic surgery, and secondary lesion resection -- should be considered when the other techniques do not allow for accurate diagnosis.

Pathology/Molecular Biology

“Histological diagnosis of NSCLC is crucial to many treatment decisions and should be as exact and detailed as the samples and available technology allow,” they wrote. Such diagnosis should be based upon current (2015) World Health Organization criteria.

Since most NSCLC patients present with advanced, unresectable disease, the authors recommended that all treatment-determining diagnoses be made on small biopsy and/or cytology-type samples. They pointed to immunohistochemistry as a key diagnosis technique, but urged pathologists to conserve tissue at every diagnostic stage along the way.

With respect to molecular diagnostics, therapy-predictive biomarker testing plays a vital role, and include analysis of EGFR mutation status, ALK rearrangement, ROS1 rearrangement, BRAF mutation, and PD-L1 expression.

Finally, they noted that important clinical information may be derived from serial blood monitoring during treatment.

Staging and Risk Assessment

Baseline imaging should include contrast-enhanced CT scans of the chest and upper abdomen. Standard laboratory tests are also important, including routine hematology, renal and hepatic functions, and bone biochemistry tests. Although routine use of serum tumor markers is not recommended, central nervous system (CNS) imaging should be considered for all patients with metastatic disease and is required for patients with neurological symptoms or signs. Finally, either positron emission tomography or bone scan can be used for the detection of bone metastasis.

With respect to response evaluation, the authors recommended its use after two to three cycles of chemotherapy or immunotherapy, using the same initial radiographic investigation that demonstrated tumor lesions. The same procedure and timing should be applied as was used in targeted therapies and/or immunotherapy.

Management Of Advanced/Metastatic NSCLC

The authors saved the bulk of their recommendations for treatment strategies, which they said should take into account such factors such as histology, molecular pathology, age, comorbidities and patient preferences. Systemic therapy should be offered to all stage IV patients with Performance Status (PS) 0-2. They also stressed that smoking cessation should be highly encouraged at any stage of NSCLC

For first-line treatment of EGFR- and ALK-negative NSCLC, PD-L1 ≥50%, they recommended pembrolizumab as a first-line option for patients who do not have contraindications to immunotherapy.

With respect to first-line treatment of NSCLC without actionable oncogenic driver, regardless of PD-L1 status, results of recent trials have yielded new therapeutic options. Trials such as KEYNOTE-024, IMpower150, and CheckMate 227, suggest that introducing immunotherapy will be a standard new approach for most patients with newly diagnosed NSCLC.

Among NSCLC patients without actionable oncogenic driver and contraindications to use of immunotherapy, chemotherapy with platinum doublets should be considered. They recommended four cycles of platinum-based doublets, followed by less toxic maintenance monotherapy. The nab-PC regimen is an option in advanced NSCLC patients, particularly those with greater risk of neurotoxicity, pre-existing hypersensitivity to paclitaxel, or contraindications for standard paclitaxel premedication. Finally, nivolumab plus ipilimumab represents an optional treatment regimen for patients with NSCLC with a high tumor mutational burden.

For first-line treatment of squamous cell carcinoma (SCC), platinum-based doublets with a third-generation cytotoxic agent are recommended in patients with advanced SCC who have no major comorbidities and PS 0-2. They also noted that combinations of platinum-based chemotherapy and anti-PD-(L1) inhibitors will demonstrate superiority to standard platinum-based chemotherapy and is a preferred strategy in patients with PS 0-1 and PD-L1 <50%.

In the first-line treatment of non-squamous cell carcinoma (NSCC), pemetrexed-based combination chemotherapy is preferred to gemcitabine- or docetaxel-based combinations in patients with non-squamous tumors. Carboplatin-pemetrexed can be an option in patients with a contraindication to cisplatin. The authors also noted that combination pembrolizumab-pemetrexed, plus a platinum-based chemotherapy regimen, should be considered as a standard option in metastatic non-squamous NSCLC. Finally, they noted that other combinations of platinum-based chemotherapy and anti-PD-(L1) inhibitors will demonstrate superiority to standard platinum-based chemotherapy alone.

First-line treatment of EGFR-mutated NSCLC is varied. They stressed that all patients be considered for EGFR TKIs irrespective of clinical parameters, including PS, gender, tobacco exposure, histology and line of therapy. Patients with a tumor and sensitizing EGFR mutations should receive first-line EGFR TKIs including erlotinib, gefitinib, afatinib, or osimertinib. Erlotinib/bevacizumab represents a front-line treatment option in patients with EGFR-mutated tumors; the addition of carboplatin and pemetrexed to gefitinib represents another first-line option in these patients.

With respect to ALK-rearranged NSCLC, first-line therapy begins with ALK TKIs, including crizotinib, ceritinib, alectinib, or brigatinib. Among individuals with CNS involvement, front-line use of ALK TKIs is effective. In ALK-rearranged NSCLC patients with localized distant progression and ongoing systemic control, continuation of treatment with the ALK TKI -- in combination with local treatment of progressing metastatic sites -- may be considered.  

The treatment of ROS1-rearranged NSCLC sees crizotinib as the recommended first-line agent in patients with stage IV NSCLC with ROS1 rearrangement. If patients have received crizotinib in the first-line setting, then they may be offered platinum-based chemotherapy in the second-line setting.

Patients with BRAF-mutated NSCLC should receive dabrafenib/trametinib and first- and second-line therapy. If patients have received BRAF/MEK inhibition in the first-line setting, they may be offered platinum-based chemotherapy in the second-line setting.

The authors went on to make recommendations regarding second-line therapeutic options and other NSCLC subtypes, including patients with other actionable oncogenic drivers, brain metastases, and leptomeningeal carcinomatosis, oligonetastatic disease, and bone metastases.  

Finally, the authors discussed post-treatment management of NSCLC patients, which they said is controversial due to limited literature. “Due to the aggressive nature of this disease, generally close follow-up, at least every 6-12 weeks after first-line therapy, is advised to allow for early initiation of second-line therapy but should also depend on individual retreatment options,” they wrote.

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