Clinicogenomic profile and progression patterns in lung squamous cell carcinoma treated with immune checkpoint inhibitors.

e20593 Background: Lung squamous cell carcinoma (LUSC) is associated with inferior outcomes to immune-checkpoint inhibitors (ICIs), compared to lung adenocarcinoma. However, the underlying mechanisms of ICI resistance in LUSC remain poorly understood. Methods: The GEMINI database was queried to identify advanced or metastatic LUSC patients who were treated with ICI or in combination with chemotherapy (ICI-chemo). Clinical pathologic, genomic, and outcome data were extracted. PD-L1, TMB, standard of care genomic, and Xenium data on patient tumor samples were analyzed. Results: A total of 569 patients with LUSC treated with ICIs were identified, including 421 in the first-line setting. Overall, 66.5% were male, and 91% were smokers. At baseline, 290 (51%) patients had intrathoracic disease, while 279 (49%) had distant metastasis, including 90 with liver involvement and 71 with brain metastases. The overall response rate was 34%, with a median PFS of 6.5 months (95%CI, 5.9 – 7.3) and a median OS of 19.3 months (95%CI, 16.5 – 22.3). Median PFS was 3.5 months (95%CI, 2.5 – 4.9) for cases with liver metastases, and 5.1 months (95%CI 4.0 – 12.2) for those with brain metastases. Among the 420 cases with progression disease, 256 were limited to baseline organs, 55 involved new organ sites excluding the liver or brain, and 109 had progression in the liver or brain. Patients with liver or brain progression had the worst PFS and OS (p < 0.0001) compared to other progression patterns. The addition of CTLA4 inhibitor or chemotherapy did not enhance outcomes of ICI monotherapy in LUSC patients with low PD-L1 or with liver and brain metastases. At baseline, the median TPS level of PD-L1 expression was negative in non-responders versus 20% in responders (complete or partial response) (p < 0.001). There is no significant difference of TMB between responders and non-responders (7.5 vs 8, p = 0.337). LUSC tumors were enriched for TP53 (84%), CDKN2A (18%), PIK3CA (14%), and NFE2L2 (12%). KMT2C mutations were associated with favorable response (p = 0.01). In contrast, MYC amplification was associated with de-novo progression disease (p = 0.05). From preliminary Xenium analysis of human tissue samples, we observed that the patient who achieved a complete response to pembrolizumab monotherapy exhibited a higher density of immune cell populations and stronger immune signals compared with the 3 patients who demonstrated de-novo resistance to ICI. Conclusions: In LUSC patients, liver metastases are associate with a shorter time to acquired resistance, and progression in the liver or brain correlates with poorer outcomes. Adding a CTLA-4 inhibitor or chemotherapy did not improve outcomes over ICI monotherapy. A more immune enriched tumor microenvironment at baseline may be associated with clinical response to ICIs. Further analysis of the Xenium data is ongoing to explore the resistance mechanism of ICI therapy in LUSC.