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12027 Background: Cancer patients increasingly present an advanced age at diagnosis; 50% of the new cases are over 65 years old, being underrepresented in clinical trials. The safety of immunotherapy has not been adequately evaluated in the subgroup of elderly patient. In this population, with more comorbidities, adverse events may be less well tolerated and have more serious consequences. Methods: A retrospective observational study was developed, including all patients treated with immunotherapy at our center between January 2015 to February 2020. Of the total (279 patients), the analysis was performed with the 105 patients ≥65 years of age who had received at least one cycle (in routine clinical practice or within an unblinded clinical trial). All clinical and radiological data of the patients were collected. Results: From the total, the majority had a lung carcinoma or melanoma, treated with nivolumab or pembrolizumab either in first or second line. 63% had died at the time of the analysis. The frequency of toxicities: digestive (15%), pneumonitis (12%) and endocrine (9%). We divided the population into 65-75 years (76 patients) or > 75 years (29 patients), analyzing the frequency of toxicity and deaths secondary to it. Those > 75 years had more digestive toxicity (25% vs 11%), but less pneumonitis (3% vs 15%). There were 7 deaths (6%) related to treatment: 2 patients with ipilimumab-nivolumab (28%), 2 nivolumab (28%), 2 pembrolizumab (28%), and 1 ipilimumab (16%). 5 patients were > 75 years old (median 78 years) presenting a higher mortality rate in relation to toxicity (4% vs 20%, p 0.02) and a worse median survival (29 vs 23 months). The fatal toxicities were: 3 neurological (2 meningoencephalitis and 1 acute diffuse axonal denervation), 2 hepatic, 1 hemophagocytic syndrome and 1 myocarditis. Conclusions: The most frequent toxicity was digestive, but those that led to death were neurological, hepatic, hematological and cardiac. In our series, neurological and cardiac adverse events accounted for 57% of immunotherapy deaths in older patients. Our data warn that patients over 75 years have a higher risk of death from immune-mediated events. In addition, these would be mainly neurological and cardiac, which represents a diagnostic and treatment challenge for oncologists.[Table: see text]

between driver-gene altered LUAD (defined as patients with alterations in KRAS, EGFR, ALK, BRAF, MET, PIK3CA, ROS1, RET, or ERBB2) and driver-gene wild type (WT) LUAD were compared using two-sided Wilcoxon tests. Results:Non-synonymous antigenic mutations were predicted for all DNAsequenced tumors. The median neoepitope load was 13 (range 1-406) and WT tumors had the highest median neoepitope load (Table ). EGFR-, MET-, RET-, ALK, ROS1-and BRAF-positive tumors had significantly lower neoepitope load than WT, with BRAF-positive LUAD having the highest neoepitope load in this group (Table ). Neoepitope loads of KRAS-, ERBB2-and PIK3CA-positive tumors were not significantly different from WT. PD-L1 status was not associated with neoantigen load after controlling for driver mutation status. Overall immune infiltration was higher in MET-and BRAF-positive LUAD compared to WT (Table ). Relative to WT, KRAS-and PIK3CA-positive tumors had higher CD4+ T-cell infiltration, while EGFR-positive had significantly lower CD8+ T-cell infiltration (P<0.001, P¼0.03 and P<0.0001, respectively). Conclusion: The high neoepitope load and unique immune composition in KRAS-and BRAF-positive LUAD may be associated with better response to ICI typically observed in these tumors. High immune infiltration in MET-positive LUAD suggests that ICI may be more beneficial in these tumors. Cumulatively, our findings suggest that the significant variability in neoepitope load and immune environment of driver-gene altered LUAD might explain their differential sensitivity to ICI. Ongoing studies are evaluating the impact of neoepitope load on clinical characteristics and outcomes.