Background: Immune checkpoint inhibitors (ICI) extend survival for patients with advanced cancer, particularly melanoma and lung cancer, though responses are heterogeneous and treatment may be complicated by immune-related adverse events that are important for patients and their caregivers to recognize. The aim of this trial is to evaluate the feasibility and preliminary efficacy of an educational video and question prompt list (QPL) in improving patients’ and caregivers’ understanding of what to expect from immunotherapy. Methods: In this randomized controlled trial of a novel educational intervention to improve immunotherapy knowledge, we will enroll 140 adult patients with advanced melanoma or lung cancer (small cell or non-small cell) who have a plan to initiate therapy with an ICI and their caregivers. Patients assigned to the intervention will receive a link to a video about the risks and benefits of ICI treatment developed by the study team as well as an ICI-focused QPL that includes questions about the goal and likelihood of benefit of ICIs. We will enroll the first ten patients in an open pilot and we will refine the intervention and study procedures based on pilot findings. We will randomize the remaining 130 patients to receive either the intervention or a usual care control. Randomization will be carried out using the permuted block approach with stratification by cancer type, and patient-caregiver dyads will be assigned to the same study arm. Participants on both arms will complete surveys at enrollment (baseline), 72 hours post-enrollment, and 6 weeks post-enrollment. The primary outcome of the study is feasibility of intervention delivery, defined as 70% of approached patients enrolling in the trial and 80% of enrolled patients watching the video, reviewing the QPL and completing the first assessment. We will also evaluate the preliminary efficacy of the intervention in 1) improving patient and caregiver knowledge, measured by a survey of knowledge questions that we developed and previously pilot tested with a sample of 105 patients; 2) enhancing patient-clinician communication, assessed by evaluating the number of questions patients asked in audio-recorded visits with their oncology clinicians after reviewing the QPL; and 3) reducing anxiety, measured by the State and Trait Anxiety Index. We will assess change in knowledge scores and anxiety from baseline to 72 hours post-enrollment and 6-weeks post-enrollment using the analysis of covariance model, adjusting for baseline scores and relevant covariates. The number of questions asked by patients and caregivers will be assessed by coding transcripts of oncology visits and comparing between arms using the negative binomial model. Study accrual to the open pilot phase began in February 2021. Current enrollment: n = 5. Clinical trial information: 04670445.