Non small cell lung cancer represents approximately 85 percent of all lung cancer diagnoses and encompasses adenocarcinoma, squamous cell carcinoma, and large cell carcinoma as the principal histological subtypes. Lung cancer remains the leading cause of cancer mortality worldwide, responsible for more deaths annually than breast, colorectal, and prostate cancers combined, reflecting both its high incidence and the historically poor outcomes associated with advanced disease. The majority of patients present with locally advanced or metastatic disease at diagnosis, as early stage lung cancer is typically asymptomatic and the disease is rarely detected before achieving significant local or systemic spread. For decades, platinum based chemotherapy was the standard first line treatment for advanced non small cell lung cancer without targetable oncogenic drivers, producing modest survival benefits and substantial toxicity without fundamentally altering the disease trajectory.
The emergence of immune checkpoint inhibition as a treatment modality for non small cell lung cancer has represented one of the most significant advances in thoracic oncology in the modern era. The recognition that programmed death ligand 1 expression on tumor cells correlates with response to PD 1/PD L1 axis blockade provided both a mechanistic rationale for immunotherapy in this disease and a predictive biomarker framework that has guided treatment selection in clinical practice. The variable PD L1 expression across non small cell lung cancer tumors, from absent to high expression, creates a therapeutic stratification that enables clinicians to identify patients most likely to benefit from immunotherapy monotherapy versus those requiring chemotherapy combination approaches.
Pembrolizumab in PD L1 High Expression NSCLC
The pivotal KEYNOTE 024 trial established pembrolizumab monotherapy as the standard first line treatment for previously untreated advanced non small cell lung cancer with PD L1 tumor proportion score of 50 percent or greater and without EGFR or ALK driver alterations. The trial randomized 305 patients to receive pembrolizumab at 200 milligrams every three weeks versus investigator’s choice platinum based chemotherapy. Pembrolizumab produced a median progression free survival of 10.3 months compared to 6.0 months with chemotherapy, an objective response rate of 45 percent versus 28 percent, and a significant overall survival benefit that was maintained at five year follow up with approximately 32 percent of pembrolizumab treated patients alive at five years compared to approximately 16 percent in the chemotherapy arm.
These results established that the approximately 30 percent of advanced non small cell lung cancer patients with high PD L1 expression could receive immunotherapy monotherapy with Keytruda as a well tolerated and highly effective first line treatment, avoiding the significant toxicity of platinum based chemotherapy while achieving superior clinical outcomes. Keytruda’s regulatory approval for this indication was followed by extensive real world implementation that has confirmed the clinical trial findings, with high PD L1 expression emerging as a reliable predictor of pembrolizumab monotherapy benefit in routine clinical practice. The identification of patients with high PD L1 expression through validated immunohistochemical testing of tumor biopsy specimens has become a standard component of the diagnostic workup for advanced non small cell lung cancer.
Pembrolizumab Plus Chemotherapy Combinations
For non small cell lung cancer patients with PD L1 expression below 50 percent, or with PD L1 expression in the intermediate range where monotherapy efficacy is less certain, the combination of pembrolizumab with platinum based chemotherapy has demonstrated significant clinical benefits over chemotherapy alone. The KEYNOTE 189 trial evaluated pembrolizumab combined with pemetrexed and platinum chemotherapy for non squamous non small cell lung cancer regardless of PD L1 expression level, demonstrating significant improvements in overall survival with a hazard ratio of 0.49 and objective response rates of approximately 48 percent compared to 19 percent for chemotherapy alone.
The KEYNOTE 407 trial extended this combination approach to squamous cell non small cell lung cancer, demonstrating that pembrolizumab added to carboplatin and paclitaxel or nab paclitaxel significantly improved overall survival across all PD L1 expression subgroups. These results established the pembrolizumab plus chemotherapy combination as a standard first line regimen for advanced squamous non small cell lung cancer patients without targetable driver mutations. The immunogenic cell death induced by chemotherapy agents may enhance the efficacy of concurrent immune checkpoint inhibition by releasing tumor antigens and damage associated molecular patterns that prime T cell responses, providing a mechanistic explanation for the superior efficacy of combination over sequential approaches.
Adjuvant and Neoadjuvant Applications
The success of pembrolizumab in the metastatic setting has driven clinical evaluation of its role in earlier disease stages where curative intent is achievable. The KEYNOTE 091 trial evaluated adjuvant pembrolizumab for one year following resection of stage IB to IIIA non small cell lung cancer, demonstrating a significant improvement in disease free survival compared to placebo in the overall population and particularly in patients with high PD L1 expression. These results paralleled the adjuvant benefit observed in melanoma and other solid tumors, suggesting that the immunological elimination of occult micrometastatic disease by checkpoint inhibition may represent a broadly applicable oncological strategy.
Neoadjuvant pembrolizumab combined with chemotherapy before surgical resection of resectable non small cell lung cancer has demonstrated striking pathological complete response rates in phase II trials, with the KEYNOTE 671 trial confirming event free survival benefits in the phase III setting. The achievement of pathological complete response, in which no viable tumor cells are detected in the resected specimen, is associated with excellent long term outcomes and may represent a surrogate marker for cure in the perioperative immunotherapy context. Perioperative pembrolizumab strategies combining neoadjuvant chemotherapy immunotherapy followed by surgical resection and adjuvant immunotherapy continuation are being evaluated as comprehensive approaches to maximizing the curative potential of treatment for resectable non small cell lung cancer.
Biomarker Driven Treatment Selection
The biomarker landscape for non small cell lung cancer treatment selection has grown substantially in complexity as multiple targetable oncogenic drivers and predictive immune biomarkers have been identified. Beyond PD L1 expression, tumor mutational burden has been evaluated as a predictor of immunotherapy benefit, reflecting the hypothesis that tumors with higher numbers of somatic mutations generate more neoantigens that can be recognized by T cells restored by checkpoint inhibition. Microsatellite instability status, relevant primarily in a small subset of non small cell lung cancers, identifies tumors with exceptionally high immunogenicity that may achieve particularly robust responses to pembrolizumab.
The identification of actionable oncogenic drivers including EGFR mutations, ALK rearrangements, ROS1 fusions, BRAF V600E mutations, MET exon 14 skipping alterations, RET fusions, NTRK fusions, and KRAS G12C mutations has created a complex treatment decision framework in which driver mutation status takes precedence over PD L1 expression in guiding first line therapy selection. Patients with targetable driver mutations derive limited benefit from first line immunotherapy and are best served by specific tyrosine kinase inhibitors as initial treatment, with immunotherapy considered in subsequent lines after targeted therapy progression. Comprehensive molecular profiling of non small cell lung cancer specimens at diagnosis is now a clinical standard that enables optimal treatment selection and ensures that patients with targetable alterations receive the most appropriate targeted therapies.
Conclusion
Non small cell lung cancer treatment has been fundamentally transformed by the clinical development of pembrolizumab across multiple disease settings and patient populations. From monotherapy for high PD L1 expressors to combination with chemotherapy across all expression levels, and from the metastatic to the adjuvant and neoadjuvant settings, Keytruda has established itself as a cornerstone of modern non small cell lung cancer treatment. The integration of pembrolizumab into multimodal treatment strategies and the ongoing refinement of biomarker driven patient selection continue to improve outcomes for a disease that remains a leading cause of cancer mortality worldwide.
