Clinical features associated with an exceptional response to immunotherapy in patients with metastatic non-small cell lung cancer (NSCLC).

Abstract

8544 Background: Immunotherapy with PD1 axis inhibitors is approved for metastatic non-small cell lung cancer (NSCLC). Outside of tumor PD-L1 expression, which predicts immunotherapy sensitivity in metastatic NSCLC, no clinicopathologic characteristics have been identified that reliably predict long-term survival after immunotherapy. To identify clinicopathologic predictors of exceptional response, we compared patients with dissimilar outcomes after immunotherapy. Methods: Patients with advanced NSCLC treated at Yale Cancer Center with immunotherapy between 2010–2020 were enrolled on an IRB-approved protocol allowing chart review of clinicopathologic data and further archival tumor tissue analysis. Data collection cutoff was January 14, 2025. We defined three subsets of patients who received immunotherapy without concurrent chemotherapy: Exceptional responders (ER) (continued response without progression ≥3 years after first dose), non-exceptional responders (NER) (initial response followed by progression within 3 years), and primary progressors (PP) (best response of progressive disease). Results: 50 ER, 45 NER, and 62 PP were identified. At a median follow-up of 7.2 years, 25, 9, and 6 ER had continued response at 5, 7, and 10 years. ER had a lower frequency of baseline lung, bone, and liver metastases, prior chemotherapy (p=0.005), or lymph node/thoracic radiation (p=0.016) than NER and PP. ER had higher pre-treatment absolute lymphocyte count (ALC) and lymphocyte-to-albumin ratio (LAR), with lower platelet-to-lymphocyte ratio (PLR) and monocyte-to-lymphocyte ratio (MLR). Of 24 evaluable ER patients, 19 had tumor PD-L1 TPS score ≥50%, compared to 13/21 evaluate NER and 14/34 valuable PP. 47/50 ER were nonsquamous, compared to 36/45 NER and 53/62 PP. Compared to NER only, ER were less likely to have bone metastases (p=0.049) or prior lymph node/thoracic radiation (8% vs 24%, p=0.028). Variables associated with primary progression were female sex (OR = 3.73, 95% CI 1.55–8.9), lung metastases (OR 6.46, 95% CI 2.73–15.27), and low albumin (OR 0.29, 95% CI 0.12–0.72). The presence of brain metastases was not different between cohorts. Conclusions: Patients with metastatic NSCLC exhibiting exceptionally durable responses to immunotherapy demonstrate distinct baseline features, with higher pre-treatment ALC and LAR, lower PLR and MLR, and lower prevalence of lung, bone, or liver metastases. They were less likely to have had thoracic/lymph node radiation, suggesting lymph node radiation may influence immunotherapy response. Ongoing molecular studies of biospecimens from these patients include genomic/transcriptomic analysis, HLA typing, and tumor microenvironment analysis of archived tissue to further characterize drivers of differential immunotherapy response.