Background: KRAS mutations account for a significant proportion of oncogenic mutations in cancers of the lung, colon, pancreas, and other organs. Cancers with KRAS^G12C mutations are now targetable with direct KRAS^G12C inhibitors, and other allele-specific and pan-KRAS inhibitors are in clinical development. Recent work has shown that complex resistance mechanisms can arise after treatment with KRAS^G12C inhibitors, including polyclonal KRAS alterations, acquired bypass mechanisms, and acquired fusions. The SPARK protocol is a remote participation ctDNA collection study that will evaluate mechanisms of resistance to RAS inhibitors and combination therapies. Methods: SPARK (NCT05272423) is a non-interventional, single coordinating center, decentralized biospecimen collection study, with a planned accrual of up to 250 patients with a diagnosis of KRAS-mutant cancer who are experiencing disease progression on a specific KRAS inhibitor or combination of inhibitors. The study will enable a web-based remote consent (https://alcmi.net/research/spark/) and subjects will be sent blood collection kits with the necessary materials for local phlebotomy for the FoundationOne Liquid CDx (F1LCDx) Biopsy Assay. Plasma NGS results will be returned to the treating physician and the study team. Patients will initially be enrolled into two cohorts: Cohort 1A will be restricted to KRAS G12C mutant cancers who progressed after being treated with KRAS G12C inhibitors. Cohort 1B will enroll patients with KRAS mutant cancers whose tumors progressed on any KRAS inhibitor (other than a direct KRAS G12C inhibitor). Cohort 2 will enroll KRAS mutant patients that have progressed on KRAS inhibitors and who have already had a sequencing assay performed to determine the resistance mechanism to KRAS inhibitors. These patients will be invited to share their data and medical history with the study team. Plasma for F1LCDX analysis will be optional for Cohort 2. Mechanisms of acquired resistance will be summarized with descriptive statistics, and compared across drugs (e.g., sotorasib vs adagrasib), between tumor types (e.g., NSCLC vs CRC), and by regimen (e.g. monotherapy vs combination therapy) to determine if different resistance mutations arise in these settings. Progression-free survival (PFS), and overall survival (OS) with KRAS inhibitors will be analyzed depending on the resistance mechanism (e.g. on-target vs off-target). Kaplan-Meier method will be used estimate median survival, and log-rank test will be used to compare groups of interests. Cox-regression model will be used to estimate univariable and multivariable hazard ratios. Outcomes from subsequent treatment after the development of acquired resistance will also be explored with descriptive statistics. No interim analysis is planned. The study activated on November 1^st 2022. Clinical trial information: NCT05272423.