Two Decades of Immunotherapy Reshaped Lung Cancer Treatment

Two decades ago, lung cancer was treated almost exclusively with cytotoxic chemotherapy. Today, immune checkpoint inhibitors anchor treatment regimens across nearly every stage of the disease, according to a 20-year perspective published in The Journal of Thoracic Oncology.¹

From Cytotoxic Therapy to Immune Activation

The shift from conventional cytotoxic chemotherapy toward therapies that harness a patient's own immune system has transformed the biology—and the prognosis—of lung cancer. Deepening understanding of tumor immunology and antigen presentation enabled the development of immune checkpoint inhibition, first as monotherapy and later in combination regimens, across essentially all stages of non–small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). The cumulative effect, according to the new review, has meaningfully prolonged survival for a disease once defined by uniformly poor outcomes.

Checkpoint inhibition built on a foundation laid by the FDA's 2015 approval of nivolumab for previously treated squamous NSCLC, a milestone that opened the door to a wave of indications spanning first-line metastatic disease, perioperative treatment, and limited-stage SCLC.²

A Perspective Spanning Monotherapy to Combination Regimens

Rather than reporting new trial data, the review synthesized 2 decades of clinical and translational progress in lung cancer immunotherapy, tracing the biological rationale for checkpoint inhibition; its clinical integration across disease stages with agents including pembrolizumab, nivolumab, atezolizumab, durvalumab, and cemiplimab; and the combination strategies, including with chemotherapy and, more recently, antibody-drug conjugates, that followed those initial monotherapy successes.¹

The authors framed this history against the backdrop of evolving biomarker science, including PD-L1 expression (read on standardized immunohistochemistry assays with thresholds such as 50% or greater and 1% or greater) and tumor mutational burden, which have shaped patient selection for checkpoint-based regimens over time, even as neither marker reliably predicts benefit on its own.

Breakthroughs, Limitations, and What Comes Next

The review credited checkpoint inhibition with a long-term survival “tail” now visible on Kaplan-Meier curves for some patients with NSCLC: in the pivotal KEYNOTE-001 trial (NCT01295827), 5-year overall survival reached 23.2% among treatment-naive patients and 15.5% among previously treated patients and reached 31.9% in KEYNOTE-024 (NCT02142738)—compared with the historical 5-year survival of roughly 5% for metastatic NSCLC in the chemotherapy era, reflecting durable antitumor immune memory rarely seen with chemotherapy alone. Not every disease setting has benefited equally, however: in extensive-stage SCLC, survival curves across treatment arms tend to converge over time, reflecting a lack of sustained immunologic disease control.

The authors also catalogued persistent limitations, including primary resistance in tumors with low neoantigen burden or proficient DNA-repair capacity, acquired resistance through mechanisms such as T-cell exhaustion and upregulation of alternative checkpoints like TIM-3, and immune-related adverse events spanning dermatologic toxicity (20%-40% of patients, mostly low grade), gastrointestinal toxicity such as diarrhea and colitis (10%-30%), and less common but more severe effects including pneumonitis (3%-5%) and hepatic (5%-10%), endocrine (5%-15%), and cardiac toxicity such as myocarditis (less than 1%), risks that climb further with dual-checkpoint-inhibitor combinations.

“Rationally designed combination strategies that account for these radiobiological principles are therefore essential to maximize therapeutic benefit while minimizing toxicity,” the authors wrote of pairing immunotherapy with radiation, pointing to a more complex, but potentially more effective, next phase for lung cancer immunotherapy.

A Narrative Synthesis, Not New Trial Data

As a narrative review rather than a systematic review or original study, the analysis does not apply a standardized search methodology or quantitative synthesis, meaning its conclusions reflect the authors' expert interpretation of the existing literature rather than a reproducible, prespecified evidence synthesis. The review also acknowledges that biomarker-driven patient selection remains imperfect and that immune-related toxicity management continues to evolve as combination regimens become more complex.

For clinicians and payers navigating an increasingly crowded landscape of checkpoint inhibitors and combination regimens, the review underscores that future gains will likely depend on refining biomarker-driven selection and managing toxicity as combinations grow more complex, rather than on identifying entirely new mechanisms of action.

References

1. Waissengrin B, Tagliamento M, Sankar K, Reckamp KL. The evolution of immunotherapy revolution in lung cancer: a 20-year perspective. J Thorac Oncol. 2026;21(9):103957. doi:10.1016/j.jtho.2026.103957
2. National Cancer Institute. Immunotherapy to treat cancer. National Institutes of Health. Updated September 24, 2019. Accessed November 1, 2026. https://www.cancer.gov/about-cancer/treatment/types/immunotherapy