Sharma V, Wymer KM, Joyce DD, et al. Cost-effectiveness of adjuvant pembrolizumab after nephrectomy for high-risk renal cell carcinoma. J Urol. 2023;209(1):89-98.

Figure. Tornado diagram for 1-way sensitivity analyses demonstrates the 4 variables out of over 100 model inputs that when modified converted pembrolizumab to be cost-effective in our model. The x-axis is reported using the incremental net monetary benefit instead of incremental cost-effectiveness ratios to avoid appearance of asymptotes. The baseline variable values and their corresponding threshold value to convert pembrolizumab to be cost-effective are reported in the embedded table. Red bars correspond to increases in the variable, while blue bars correspond to decreases in the variable. Changes that move the bar to the right of the “0” incremental net monetary benefit line render pembrolizumab cost-effective.

Study Need and Importance

The KEYNOTE-564 trial demonstrated that adjuvant pembrolizumab after nephrectomy for clear cell renal cell carcinoma (ccRCC) decreased the risk of disease progression and potentially overall mortality as well. However, pembrolizumab comes at a significant cost and is associated with significant toxicity, so it is unclear if the risks of pembrolizumab outweigh the benefits for all patients included in the trial.

What We Found

Decision-analytic Markov modeling was used to conduct a cost-utility analysis of adjuvant pembrolizumab vs observation after nephrectomy for high-risk ccRCC, using data from KEYNOTE-564 to inform model probabilities. Primary outcomes were quality-adjusted life years (QALYs), Medicare costs, and incremental cost-effectiveness ratios. The willingness-to-pay threshold utilized was $100,000/QALY (see Figure).

At 5 years, adjuvant treatment with pembrolizumab resulted in 0.3 additional QALYs at an additional cost of $99,484 relative to observation. Pembrolizumab was found not to be cost-effective at a 5-year time horizon (incremental cost-effectiveness ratio = $326,534). On sensitivity analysis, pembrolizumab became cost-effective if its per-cycle cost was <$5,064 (base = $10,278) or its 5-year progression benefit was >18.8% (base = 9%). Upon simulation, we found that pembrolizumab would be cost-effective at 5 years for patients with at least a 59% 5-year risk of progression, which corresponds to a Mayo Progression-free Survival Score ≥10 and to an ASSURE disease-free survival score of 8.5 or more. The following 3 criteria may be used to easily identify patients with at least a 59% 5-year risk of progression: patients undergoing complete metastasectomy, pN1, and >7 cm pT3 tumors with sarcomatoid features.

Limitations

Given that this is a modeling study, our data are limited by the accuracy of model probabilities, utility values, assumptions, and extrapolations. Specifically, the 2-year KEYNOTE-564 data were used to extrapolate progression rates to 5 years and beyond. Thus, 5-year data from KEYNOTE-564 are necessary to confirm our findings. In addition, we recognize that individual patients with the ability to pay for higher cost treatments or with insurance benefit designs that have fixed maximum out-of-pocket costs may have higher willingness-to-pay thresholds.

Interpretation for Patient Care

Our modeling study demonstrates that adjuvant pembrolizumab is likely only cost-effective at 5 years for the subset of ccRCC patients who have at least a 59% risk of 5-year progression. For patients with a lower risk, the limited benefits of pembrolizumab likely do not justify its costs and side effects.