Beyond 0%: durable response to chemoimmunotherapy in PD-L1-negative non-small cell lung cancer

Introduction: Non-small cell lung cancers with neuroendocrine differentiation constitute a biologically heterogeneous subgroup that remains underrepresented in prospective clinical trials. The absence of actionable molecular alterations and a PD-L1 expression of 0% are generally associated with a lower expected benefit from immunotherapy. Case presentation: We report the case of a 45-year-old man diagnosed with stage IV non-small cell lung cancer with neuroendocrine differentiation, no actionable molecular alterations, and a PD-L1 expression of 0%. First-line treatment with carboplatin, pemetrexed, and pembrolizumab achieved a complete and durable metabolic response from the first reassessment, which was maintained throughout 35 treatment cycles. Immune-related toxicities included grade 3 hepatitis and secondary adrenal insufficiency, both successfully managed according to current recommendations. Discussion and Conclusion: This case illustrates that conventional biomarkers, such as PD-L1 expression, do not always predict clinical benefit from immunotherapy. The sustained complete response suggests that selected patients with unfavorable biological features may achieve substantial benefit from chemoimmunotherapy, highlighting the need for improved molecular and biological characterization of this uncommon subgroup.