6644 Background: Targeted cancer drugs (TCDs) have revolutionized oncology, but they are widely variable in their clinical benefit and are often accompanied by high patient-out-pocket (OOP) costs. The ASCO Value Framework uses published clinical trial data on survival, toxicity, and potential for symptom palliation to quantify the net health benefit (NHB) of any given cancer drug. We aimed to evaluate the association between NHB and uptake, patient OOP spending, and total spending for eight oral TCDs approved for the first line treatment of an advanced solid tumor based on one or more clinical trials comparing to a non-TCD control arm. Methods: We conducted a retrospective cohort study of incident pharmacy claims for oral TCDs prescribed to patients aged 18-64 years between 2012-2020 in the nationwide Health Care Cost Institute de-identified commercial claims dataset. NHB scores were calculated for each TCD of interest using the ASCO Value Framework and categorized as high (>60), medium (40-60), and low (<40) net health benefit. Distributions of incident 28-day TCD supplies were plotted over time by NHB category. The primary outcome was patient OOP spending (patient copay + coinsurance + deductible), whereas the secondary outcome was total spending (patient OOP spending + pharmacy reimbursement). Generalized linear models were used to evaluate the association between each outcome of interest and TCD NHB, adjusted for cancer indication. Results: We included 8,524 incident pharmacy claims for eight TCDs with nine indications in breast cancer, non-small cell lung cancer (NSCLC), melanoma, and pancreatic cancer. NHB scores ranged from 7 (erlotinib for pancreatic cancer) to 81 (crizotinib for ALK-rearranged NSCLC), with 1,145 (13%), 6,608 (78%), and 771 (9%) of pharmacy claims falling into low-, medium-, and high-NHB categories, respectively. Medium- and high-NHB TCDs accounted for the majority of incident TCD prescriptions throughout the study period. Median patient OOP spending was $18.78 for the first 28-day TCD supply (IQR $0.00-$87.57), with 45% of patients paying $0 and 8% paying >$1,000 OOP. Patient OOP spending was not significantly associated with TCD NHB category (difference $0.94, 95% CI -$49.99-$51.87 for medium vs low NHB; difference $58.86, 95% CI -$28.04-$145.75 for high vs low NHB). Median total spending was $10,118.79 (IQR $6,365.95-$10,600.37) for an incident 28-day TCD supply. There was a $1,083.56 increase in total spending for each 10-point increase in NHB score (95% CI $1,050.27-$1,116.84, p <0.01 for H0 = $0). Conclusions: Although TCDs are widely variable in their NHB, low-NHB TCDs are not prescribed as frequently as medium- and high-NHB TCDs. Total spending on TCDs is high and positively associated with NHB. Commercially insured patients are largely shielded from high OOP spending on TCDs.