Cost-Effectiveness of Immune Checkpoint Inhibition in BRAF Wild-Type Advanced Melanoma

Abstract

Purpose Patients who are diagnosed with stage IV metastatic melanoma have an estimated 5-year relative survival rate of only 17%. Randomized controlled trials of recent US Food and Drug Administration-approved immune checkpoint inhibitors-pembrolizumab (PEM), nivolumab (NIVO), and ipilumumab (IPI)-demonstrate improved patient outcomes, but the optimal treatment sequence in patients with BRAF wild-type metastatic melanoma remains unclear. To inform policy makers about the value of these treatments, we developed a Markov model to compare the cost-effectiveness of different strategies for sequencing novel agents for the treatment of advanced melanoma. Materials and Methods We developed Markov models by using a US-payer perspective and lifetime horizon to estimate costs (2016 US$) and quality-adjusted life years (QALYs) for treatment sequences with first-line NIVO, IPI, NIVO + IPI, PEM every 2 weeks, and PEM every 3 weeks. Health states were defined for initial treatment, first and second progression, and death. Rates for drug discontinuation, frequency of adverse events, disease progression, and death obtained from randomized phase III trials were used to determine the likelihood of transition between states. Deterministic and probabilistic sensitivity analyses were conducted to evaluate model uncertainty. Results PEM every 3 weeks followed by second-line IPI was both more effective and less costly than dacarbazine followed by IPI then NIVO, or IPI followed by NIVO. Compared with the first-line dacarbazine treatment strategy, NIVO followed by IPI produced an incremental cost effectiveness ratio of $90,871/QALY, and first-line NIVO + IPI followed by carboplatin plus paclitaxel chemotherapy produced an incremental cost effectiveness ratio of $198,867/QALY. Conclusion For patients with treatment-naive BRAF wild-type advanced melanoma, first-line PEM every 3 weeks followed by second-line IPI or first-line NIVO followed by second-line IPI are the most cost-effective, immune-based treatment strategies for metastatic melanoma.

Fig 1.

Markov model depicting the treatment arms seen in CheckMate-066, CheckMate-067, CheckMate-037, KEYNOTE-006, and NCT00094653.

Fig 2.

Cost-effectiveness acceptability curve. Results of the probabilistic sensitivity analysis on the basis of 10,000 iterations of the model, which drew parameters for each input simultaneously from probability distributions to indicate uncertainty about whether the treatment sequences are cost-effective given different willingness-to-pay thresholds. A count is obtained of the proportion of simulated incremental cost-effectiveness ratio values that are acceptable at each willingness-to-pay threshold, which is shown on the y-axis. For example, pembrolizumab administered every 3 weeks was found to be cost-effective in 69% of simulations at a willingness-to-pay threshold of $100,000. IPI, ipilimumab; NIVO, nivolumab; PEM, pembrolizumab.

Fig A1.

Markov model depicting the treatment arms seen in CheckMate-066, CheckMate-067, CheckMate-037, KEYNOTE-006, and NCT00094653. (a) First-line progression-free survival; (b) first-line overall survival; (c) progression-free survival after first progression; (d) overall survival after first progression; (e) overall survival after second progression; (f) progression-free survival after second progression; (g) progression-free survival after third progression; (h) overall survival after third progression; and (i) drug discontinuation rate. AE, adverse event.

Fig A2.

Base-case cost-effectiveness results. Treatment strategy with first-line dacarbazine (followed by second-line ipilimumab and third-line nivolumab; blue diamond); treatment strategy with first-line ipilimumab (followed by second-line nivolumab; gold square); first-line nivolumab followed by second-line ipilimumab (blue star); first-line nivolumab plus ipilimumab followed by second-line carboplatin and paclitaxel (dark gold circle); treatment strategy with first-line pembrolizumab administered every 2 weeks followed by second-line ipilimumab (red x); treatment strategy with first-line pembrolizumab administered every 3 weeks followed by second-line ipilimumab (gray triangle). DAC, dacarbazine; IPI, ipilimumab; NIVO, nivolumab; PEM, pembrolizumab; QALY, quality-adjusted life-year.

Fig A3.

Univariable sensitivity analyses: Pembrolizumab every 2 weeks versus ipilumumab. DC, dacarbazine; IPI, ipilimumab; NIVO, nivolumab; PEM, pembrolizumab; PFS, progression-free survival.

Fig A4.

Univariable sensitivity analyses: Nivolumab versus ipilumumab. DC, dacarbazine; IPI, ipilimumab; NIVO, nivolumab.