Background: Appropriate molecular testing, biomarker-directed treatment selection, and management of immune-related adverse events (irAEs) are essential best practices for managing patients with mNSCLC who are eligible for IO therapies. Identifying real-world challenges among mNSCLC care teams is necessary to inform educational interventions that support optimal care. Methods: From 10/2020 to 01/2021, 75 health care professionals (HCPs) who treat mNSCLC completed surveys assessing practice patterns, challenges, and confidence related to the use of IO therapies. To reflect current real-world practice across treatment settings, surveys were administered at 10 clinics nationwide and through a large oncology practice network. Results: Participants represented the interprofessional mNSCLC care team: oncologists (50%), primary care physicians (23%), advanced practice professionals (13%), and nurses (13%). Nearly one-third reported that PD-L1+ mNSCLC presented greater management challenges than other mNSCLC sub-types. Regarding patients who are eligible for IO therapies, the most commonly reported challenges were applying pathology results to treatment decisions (29%), differentiating IO therapies (19%), and managing irAEs (19%). Case-based questions revealed gaps in care relative to guidelines: 65% incorrectly identified which patients should be tested for PD-L1; 49% failed to identify the most appropriate IO regimen based on case details; and 65% failed to identify an inappropriate strategy for managing mild irAEs (Table). Further, HCPs reported inappropriate reasons to exclude patients from IO therapy and suboptimal use of supportive care measures. Confidence gaps echoed these challenges; most HCPs reported less-than-high confidence in their ability to apply molecular test results to treatment decisions (80%), differentiate IO therapies based on PD-L1 expression (65%), or coordinate irAE care (85%). Conclusions: In current real-world practice, mNSCLC care teams report challenges in biomarker testing and interpretation; differentiation of IO therapies based on patient, disease, and treatment factors; and irAE management. These identified gaps represent key opportunities for future interventions to improve mNSCLC care.