Modern Treatments for Lung Cancers Non-small cell lung Cancers (NSCLC) and Small cell lung Cancers SLC

Modern systemic therapy for lung cancer is organized around (1) targetable driver alterations, (2) immunotherapy selection using PD-L1, and (3) histology- and stage-specific multimodality care.

Advanced non-small cell lung cancer

A key modern step is comprehensive molecular testing before starting therapy, because it identifies candidates for multiple FDA-approved targeted therapies and because some driver-positive tumors are unlikely to respond to immunotherapy and may have toxicity issues when immunotherapy is given before tyrosine kinase inhibitors.

Driver mutation present

• For activating EGFR mutations, an EGFR tyrosine kinase inhibitor-based approach is preferred over chemotherapy- and immunotherapy-based approaches. Preferred approaches for common EGFR mutations include osimertinib with chemotherapy or amivantamab plus lazertinib.

• For ALK fusion-positive disease, an ALK tyrosine kinase inhibitor is preferred, with lorlatinib preferred first line and other next-generation ALK inhibitors as alternatives.

• Other actionable alterations (eg, ROS1, MET, RET, BRAF, NTRK, KRAS G12C, HER2, NRG1) have targeted therapies that are incorporated at some point in the treatment trajectory.

Driver mutation absent or unknown

• PD-L1 testing helps select immunotherapy-based strategies.

• If PD-L1 is ≥50 percent, either checkpoint inhibitor monotherapy or chemoimmunotherapy are options, with chemoimmunotherapy favored when rapid progression or high tumor burden raises concern that early progression could preclude later chemotherapy.

• If PD-L1 is <50 percent, a checkpoint inhibitor plus platinum-doublet chemotherapy is recommended, with multiple immunotherapy-plus-chemotherapy combinations supported.+1

• For selected patients, dual-checkpoint strategies (eg, nivolumab plus ipilimumab, with or without chemotherapy; or durvalumab plus tremelimumab plus chemotherapy) are FDA-approved options.

Resectable non-small cell lung cancer

Neoadjuvant treatment is an option in potentially resectable disease, and neoadjuvant and adjuvant approaches have shown comparable overall survival advantage in meta-analyses. For ALK- or EGFR-positive resectable cancers, perioperative immunotherapy is not used; for EGFR-positive cancers treated in the neoadjuvant setting, osimertinib (with or without chemotherapy) is an acceptable strategy.

Extensive-stage small cell lung cancer

Chemotherapy is the mainstay of initial treatment and prolongs survival compared with best supportive care, and adding immunotherapy to a chemotherapy backbone adds further benefit. Extensive-stage small cell lung cancer A key modern advance is adding atezolizumab to platinum-etoposide chemotherapy followed by maintenance atezolizumab, which improved overall survival and progression-free survival versus chemotherapy alone in a randomized trial.