Risk-adapted screening and treatment management

Non-small cell lung carcinomas are the most common malignant tumors of the lung. 70–80% of all lung tumors can be assigned to this histology. A distinction can now be made between numerous different entities, which enables more targeted treatment. Precise staging and the appropriate therapy offer the chance of longer survival with a better quality of life, even in later, metastatic stages.

The incidence of lung cancer is increasing worldwide. Non-small cell lung cancer (NSCLC) accounts for around 85% of all lung cancer cases. However, patients with NSCLC are usually only diagnosed at an advanced stage of the disease and therefore generally have a poor prognosis. Platinum-based chemotherapy (PBC) is the standard first-line treatment for patients with advanced NSCLC without targeted genetic alterations. However, these measures have only a limited survival benefit with a median overall survival (OS) of less than one year. Given the high prevalence and poor prognosis of advanced NSCLC, new measures and treatment combinations are urgently needed to prolong survival.

Staging and targeted therapies

Tobacco smoking is the main risk factor for the development of NSCLC. It is estimated that nine out of ten illnesses in men and eight out of ten in women are attributable to active smoking. In order to improve the current 5-year survival rate of 25% for women and 19% for men in the long term, the initial stage of the disease needs to be precisely defined in addition to further development of therapy management. The criteria for classification into a tumor stage are tumor extent (T), lymph node involvement (N) and metastasis (M).

The ninth edition of the staging guidelines, which have been revised by a European group of experts, will come into force at the beginning of 2025. The aim was to take account of the changing therapeutic landscape and to ensure improved granularity of the nomenclature. Data from a total of 124581 registered patients were available for the analysis: 58193 with clinical stage, 39192 with pathological stage and 62611 with best stage NSCLC. The proposed new N2 subcategories (N2a, involvement of a single ipsilateral mediastinal or subcarinal nodal site, and N2b, involvement of multiple ipsilateral mediastinal nodal sites with or without involvement of the subcarinal nodal site) and the new M1c subcategories (M1c1, multiple extrathoracic metastases in one organ system, and M1c2, multiple extrathoracic metastases in multiple organ systems) were taken into account in the survival analyses. Multiple potential stage groupings were evaluated using several analyses, including recursive partitioning, assessment of homogeneity within and discrimination between potential groups, clinical and statistical significance of survival differences, multivariable regression, and comprehensive assessment of generalizability.

The changes ultimately relate to the assignment of the subgroups T1N1, T1N2a and T3N2a to stages IIA, IIB and IIIA respectively. Subgroups T2aN2b and T2bN2b are assigned to group IIIB. Lymph node involvement should be confirmed histopathologically or cytologically; a PET-CT alone is usually not sufficient. The definition of the oligometastatic stage remains diffuse. The metastasis was therefore only split with regard to M1c into M1c1 – multiple M1 in a single exrathoracic organ system – and M1c2, multiple M1 in multiple exrathoracic organ systems. M1c1 and M1c2 remain in stage group IVB.

Therapeutic options

Immune checkpoint inhibitors (ICI) offer a promising pharmacological option. Especially in advanced NSCLC, they have shown many advantages with a favorable safety profile. The targets of ICI include cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1). Compared to standard chemotherapy, pembrolizumab (Pem), an anti-PD-1 monoclonal antibody, improves survival in advanced NSCLC with PD-L1 expression of ≥1%, and it improves survival when combined with PBC as first-line treatment, regardless of PD-L1 tumor percentage. Results from randomized controlled trials (RCTs) with atezolizumab (Atezo), an anti-PD-L1 antibody, showed that monotherapy improved OS to a greater extent than docetaxel (DXT), regardless of PD-L1 expression. Similarly, nivolumab (Nivo) in combination with ipilimumab (Ipi) improved OS compared to PBC in NSCLC with PD-L1 expression ≥1%. In addition, Nivo-Ipi plus PBC (Nivo-Ipi-PBC) for two cycles followed by Nivo-Ipi improved OS compared to chemotherapy alone, even in NSCLC without PD-L1 selection. Cemiplimab (Cemip), an IgG4 antibody, is also indicated as a monotherapy for the first-line treatment of adult patients with NSCLC that expresses PD-L1 (in ≥50% of tumor cells) and has no EGFR, ALK or ROS1 aberrations. It can also be combined with PBC for tumors with 1% PD-L1 changes or more.

Efficacy and safety – an overview

One review assessed the efficacy and safety of currently available ICI treatments administered independently or in combination with chemotherapy in patients with advanced NSCLC. Treatment regimens with anti-PD-1 activity showed a superior OS benefit compared to anti-PD-L1 treatments. ICI-PBC was associated with a higher probability of survival than ICIs alone (with the exception of Nivo-PBC). Cemip, Pem-DXT and Atezo-Beva-PBC provided the best benefit for patients with advanced NSCLC without PD-L1 selection in terms of OS, PFS and ORR, respectively. For patients with PD-L1 expression <1%, Pem-PBC and Atezo-Beva-PBC proved to be optimal treatment options in terms of OS and PFS respectively. In patients with PD-L1 expression ≥1%, Pem-DXT was the optimal treatment in terms of OS and PFS. In patients with PD-L1 expression of ≥50%, Durva-Treme-PBC and Atezo-Beva-PBC achieved the best OS and PFS respectively. Cemip and Atezo-Beva-PBC provided the best OS and PFS benefit as first-line treatment for patients with advanced NSCLC. In addition, the toxicity of ICI monotherapy or the ICI-ICI combination was lower than that of the other treatments, but was increased by the addition of PBC. Cemip had the lowest risk of adverse events of any grade, while Pem had the lowest risk of adverse events of grade ≥3. Cemip had a balanced efficacy and safety profile compared to all available ICI treatments, ranking first for OS, ninth for PFS, fifth for ORR, first for lowest risk of any adverse event and seventh for lowest risk of grade ≥3 adverse events in advanced NSCLC without selection of PD-L1 expression.