DOI: https://doi.org/10.21203/rs.3.rs-2079558/v1
Pembrolizumab is superior to chemotherapy as a first-line treatment for patients with mismatch-repair-deficient (dMMR) or microsatellite-instability-high (MSI-H) advanced or metastatic colorectal cancer (CRC), with a significantly long-term survival benefit trend by KYENOTE-177. The current study aimed to determine whether pembrolizumab is a cost-effective treatment for patients with dMMR/MSI-H advanced or metastatic CRC in China.
A partitioned survival model (PSM) was developed to simulate patients with dMMR/MSI-H advanced or metastatic CRC based on health states of progression-free survival (PFS), progressive disease (PD) and death. The model was designed using a lifetime horizon, a 6-week cycle, and a 5% discount rate. The characteristics of patients in the model were similar to patients in a phase 3, open-label randomized clinical trial (KEYNOTE-177) who had metastatic MSI-H–dMMR CRC and had not previously received treatment. The health outcomes and utilities were from the KETNOTE-177 trial and published data, respectively. Costs were calculated based on local charges (2021) and published literature. It is deemed cost-effective in China if the incremental cost-effectiveness ratio (ICER) value is less than $33,600 per quality adjusted life-year (QALY). The robustness of the results was discussed in one-way deterministic and probabilistic sensitivity analyses.
Baseline analysis disclosed that pembrolizumab provided an additional 2.58 QALYs (3.00 life-years) at an incremental cost of $78,286.04, resulting in an ICER of $30,330.15 per QALY, which was below the willingness-to-pay threshold of $33,600 per QALY. When patient assistance program (PAP) was considered, the ICER became $1,730.67 per QALY, manifesting absolute cost-effectiveness. The results of sensitivity analyses demonstrated that in most cases pembrolizumab was cost-effective.
Pembrolizumab is a cost-effective first-line treatment for dMMR/MSI-H advanced or metastatic CRC patients in China, especially considering PAP.
Colorectal cancer (CRC) is one of the most common malignant tumors in China, ranking second in the overall cancer incidence and first in the digestive tract cancer[1]. In 2020, about 550,000 people were diagnosed with CRC and about 280,000 died of CRC, which is second only to lung cancer in China[2]. Besides, the economic burden of CRC continued to grow. The average annual growth rate of the medical expenditure per CRC patient in China ranged from 6.9–9.2%, and the 1-year out-of-pocket expenditure of a newly diagnosed patient accounted for about 60% of their previous-year household income.[3–8]
Meanwhile, more than half of CRC patients were diagnosed as advanced stage (III - IV)[9, 10] with poor prognosis and distant metastasis, leaving 5-year overall survival (OS) rate < 15%[11]. For these patients, standard chemotherapy are 5-fluorouracil (5-FU) based regimens, such as FOLFOX (5-FU, oxaliplatin, and leucovorin) or FOLFIRI (5-FU, irinotecan, and leucovorin) alone or in combination with therapies that block epidermal growth factor receptor (EGFR) or vascular endothelial growth factor (VEGF) signaling.[12] However, the long-term efficacy of standard chemotherapy is generally poor because that among the patients with advanced CRC, DNA mismatch repair defect (dMMR) /microsatellite instability high (MSI-H) account for 5%-10%, which is associated with resistance to standard chemotherapy and a poor prognosis.[13, 14] Fortunately, with the rapid development of immune checkpoint inhibitors (ICIs) over the past decades, several elegant clinical trials (KEYNOTE-016[15], KEYNOTE-164[16], KEYNOTE-177[17], CheckMate-142[18]) have shown that programmed death 1 (PD-1) blockade have achieved durable responses in patients with dMMR/MSI-H metastatic CRC (mCRC) that are refractory to standard chemotherapy combinations.[16, 18–21]
Pembrolizumab was the first PD-1 inhibitor approved by the National Medical Products Administration (NMPA) in China to be adopted as the standard of care first-line treatment in patients with dMMR/MSI-H mCRC based on the data analysis results of a key global phase III clinical trial - KEYNOTE-177[17]. Recently, 2021 American Society of Clinical Oncology (ASCO) shown an exciting result that at a median follow-up of more than 44 months (44.5 [36.0-60.3] months in the pembrolizumab group and 44.4 [36.2–58.6] months in the control group), the median OS were not yet achieved (pembrolizumab group) and 36.7 months (control group) respectively, and the risk of death was reduced by 26% (HR, 0.74, 95% CI [0.53–1.03]; P = 0.0359). Although 60% of the patients in the control group (i.e., doublet chemotherapy ± targeted therapy: either FOLFOX or FOLFIRI, with or without either cetuximab or bevacizumab) were interfered by PD-1/programmed death-ligands1(PD-L1) ICIs after disease progression, pembrolizumab group still showed a long-term OS benefit trend. At 36 months, 61% of the patients in the pembrolizumab group were still alive, which was 11% higher than that in the control group. In the second interim analysis of KEYNOTE-177[17], pembrolizumab was found to significantly improve the progression-free survival (PFS), compared to the control group, as a first-line treatment for dMMR/MSI-H mCRC (median PFS, 16.5 vs. 8.2 months; HR, 0.60; P = 0.0002). Superior PFS in the pembrolizumab group, remained consistent in subgroup analyses of age, sex, race, region, stage, and BRAF status.
Despite the exciting incremental benefit, relative higher cost without national medical insurance of pembrolizumab makes the value of this therapy relative to its benefit remains indeterminate. To settle this issue, we built a partitioned-survival model (PSM) to evaluate the cost-effectiveness of pembrolizumab as first-line regime in patients with dMMR/MSI-H mCRC from a perspectives of health care system in China with a lifetime horizon.
To compare the cost-effectiveness of pembrolizumab versus chemotherapy in patients with MSI-H–dMMR stage IV CRC, a PSM was conducted to simulate the process of dMMR/MSI-H mCRC depending on the clinical data from KEYNOTE 177. Three distinct health states: PFS, progressive disease (PD) and death (Fig. 1) were included in the model. The initial state is assumed to be PFS, and death is the absorbing state. The population was a cohort with the same characteristics and treatments as those in the KEYNOTE 177 trial. Unlike Markov model, the PSM use of the trials' Kaplan-Meier (K-M) curves to directly divide patients into different health states without putting forward assumptions for the transition of patients between different health states. Therefore, the estimation of patients’ proportion in each health state was acquired straightly from the cumulative survival probabilities in OS and PFS curves by parametric functions fitting and extrapolation. The cycle length was 6-week. The analysis was conducted from the Chinese health care system perspective with a life-time horizon so as to ensure there were less than 1% survivors. Costs, life years (LYs), quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs) were calculated in each treatment group. If the ICER is below $33,600 threshold (three times GDP per capita of China in 2020, ¥210,000.00), the treatment is generally considered to be cost-effective. In line with Chinese pharmacoeconomic guidelines[22], both costs and benefits are discounted at 5% (range: 0%-8%) per year.
We used the Engauge Digitizer (version 12.1, http://digitizer.sourceforge.net) to collect the data points from the K-M curves (PFS and OS curves) of the two arms and followed the method of Guyot et al.[23] to reconstruct estimates of underlying individual patient data (IPD) over the clinical trial time. In terms of the IPD out of the clinical trial time, standard parametric models fitting and extrapolation were used to estimate the long-term survival probabilities by using R software (version 4.1.0, https://www.r-project.org). Specifically, six parametric functions were considered, including exponential, Weibull, Gompertz, log-logistic, log-normal, and generalized gamma distributions. And then, in order to evaluate the goodness-of-fit of each parametric survival model, multiple methods were applied such as visual inspection, Akaike information criterion (AIC) test and Bayesian information criteria (BIC) test proposed by NICE DSU technical support document 14 (TSD14)[24]. Lower AIC and BIC values indicate better fit of the selected parametric model. (eTable 1–4 are given in Online Resource) Meanwhile, superposed graphs of the K-M curves from the trial and the estimated curves based on the relative better fitting parametric survival models were presented in Fig. 2 so as to intuitively inspect the survival prediction.
The generalized gamma model was chosen as the best fit model for the OS curve of both arms and PFS of pembrolizumab arm and log-normal model for the PFS curve of chemotherapy arm. Considerations were as follows: 1) the lowest or relative lower AIC and BIC values among all survival models; 2) the best fit with the observed curves based on visual inspection.
The health utility score reflects the level of physical, mental, and social functioning associated with a disease correlative health state that varies from 0 to 1, with 0 representing the worst health state/death and 1 representing the best. Average health utility of the PFS state was 0.7825, which was based on quality-of-life data collected in the KEYNOTE 177 trial.[25] In the trial, EQ-5D-3L index[26] mean utility scores were 0.77 in the pembrolizumab group and 0.75 in the chemotherapy group at baseline. At the end of week 18, mean scores were 0.84 and 0.77 respectively. So, in the simulation, we assigned a utility of 0.7825 for PFS, which is the mean of above values, with 0.75 and 0.84 as the boundaries of the range used in sensitivity analyses. Average health utility of the PD state was 0.64 (95% CI [0.576–0.704]) derived from the previously published literature[27]. The disutility values of grade 3–4 adverse events (AEs) were considered in our analysis,[28, 29] but only one-time assessment was carried out during the first cycle for simplification given the trivial influence of AE disutilities. QALYs loss caused by AEs were assessed by the product of the incidence of AEs and the corresponding disutility value. And ± 20% were the boundaries of the range in sensitivity analyses.
Only direct medical costs were considered, including cost of the drug utilization, cost of drug administration, cost of follow up, cost of main AEs management and cost of treatments for progression (including active treatments and supportive care), and stated in 2021 United States dollars (USD) by exchange rate: 1 CYN = 0.16 USD. Drug prices were estimated from the local bid-winning price.[30]
Drug administration costs were calculated as a function of administration cost per attendance and administration frequency (number of attendance per cycle). Unit administration costs were derived from local charge. The costs of follow up, including carcinoembryonic antigen level test, ultrasound of abdomen, outpatient specialist clinic, were from a published study[31], and were converted to 2020 USD using Medical Care component of Chinese Consumer Price Index (CPI). The frequency of follow up were based on the guideline of Chinese society of clinical oncology (CSCO) for colorectal cancer[12]. The costs of main AEs management were derived from the previously published literatures[32, 33] (adjusted by CPI) and were calculated only once in the first cycle. In terms of the treatments for progression, active therapeutic schedules included CAPIRI, CAPOX, FOLFOX (± bevacizumab or cetuximab), FOLFIRI (± bevacizumab or cetuximab), nivolumab, pembrolizumab.[34, 35] The prices of the drugs in subsequent treatments were also from local bid-winning price[30], and the fee of supportive care was assumed to be 0. Additionally, costs were discounted at an annual rate of 5%[22].
According to the global phase III clinical trial - KEYNOTE-177[17], the patients in the pembrolizumab group (P group, N = 153) received pembrolizumab at a dose of 200 mg every 3 weeks intravenously (IV) for up to 35 treatments (approximately 2 years) and the patients in the chemotherapy group (C group, N = 154) received FOLFOX (oxaliplatin 85 mg/m2 IV on Day 1, leucovorin 400 mg/m2 IV on Day 1, 5-FU 400 mg/m2 IV bolus on Day 1 and then 1200 mg/m2/day IV over 2 days for total dose of 2400 mg/m2 in each 2-week cycle) or FOLFIRI (irinotecan 180 mg/m2 IV on Day 1, leucovorin 400 mg/m2 IV on Day 1, 5-FU 400 mg/m2 IV bolus on Day 1 and then 1200 mg/m2/day IV over 2 days for total dose of 2400 mg/m2 in each 2-week cycle), with or without either cetuximab (cetuximab 400 mg/m2 IV over 2 hours then 250 mg/m2 over 1 hour weekly in each 2-week cycle) or bevacizumab (5 mg/kg IV on Day 1 of each 2-week cycle). Treatment was continued until disease progression, development of unacceptable toxic effects, illness, or a decision by the physician or patient to withdraw from the trial. In C group, the percentage of patients in mFOLFOX, mFOLFOX + bevacizumab, mFOLFOX + cetuximab, FOLFIRI, FOLFIRI + bevacizumab and FOLFIRI + cetuximab were 7.69%, 44.76%, 3.50%, 11.19%, 25.17% and 7.69%, respectively. After disease progression, patients randomly assigned to the C group could cross over to pembrolizumab (to receive a maximum of 35 treatments) and patients in the P group can continue pembrolizumab (to receive a maximum of 17 treatments). The subsequent treatments were mainly composed of pembrolizumab (P group 10%, C group 42.75%), other PD-1/PD-L1 ICIs (P group 7.5%, C group 28.24%), chemotherapy (P group 43.75%, C group 15.27%), VEGF inhibitor (P group 27.5%, C group 9.92%), and EGFR (P group 11.25%, C group 3.82%) inhibitor. Referring to the other studies and guideline[34, 35], we assumed that CAPIRI, CAPOX, FOLFOX and FOLFIRI were used as the standard second-line chemotherapy, nivolumab (up to 2 years) and pembrolizumab as the ICIs, cetuximab as the EGFR inhibitor and bevacizumab as the VEGF inhibitor, which are commonly used in China. We included grade 3 to 4 AEs in the model that had obvious clinical impact and significantly different rates between the arms of the KEYNOTE 177 trial, which were diarrhea, anemia, hypokalemia, and neutropenia. The incidence of neutrophil count decrease multiplied by 0.5 is included in neutropenia. For dosage calculation, assuming that values of body surface area (BSA) and weight were 1.80 m2 and 65kg, respectively.[36]
A series of sensitivity analyses were conducted to test the robustness of the model and address uncertainty in the estimation of model parameters by using Microsoft Excel (version 16.51). One-way deterministic sensitivity analyses (DSA) were used to evaluate the impact of uncertainty of a single input variable on the ICER. The range of drug prices depends on the local charge or ± 20% of the baseline values. Other parameters were adjusted within the reported 95% confidence intervals (CI) or assuming reasonable ranges of the base case values (± 20%) if 95% CIs were unavailable, in accordance with established approach[37]. In addition, a separate scenario considering patient assistance program (PAP) was evaluated in the DSA.
In the probabilistic sensitivity analysis (PSA), a Monte Carlo simulation of 500 iterations was generated by randomly sampling the key model parameters from the pre-specified distributions simultaneously. We used gamma distribution for the cost parameters and beta distribution for utility and probability parameters. Based on the data from 500 iterations, a cost-effectiveness acceptability curve (CEAC) was created to represent the likelihood that pembrolizumab would be considered cost-effective compared with chemotherapy on the basis of a willingness to pay (WTP) threshold of $33,600 per QALY in China.
Baseline values, ranges, and distributions for sensitivity analysis were summarized in Table 1
| Variable | Baseline value | Range | α | β | mean | SE | Reference for baseline value | Distribution (parameters) | ||
|---|---|---|---|---|---|---|---|---|---|---|
| Minimum | Maximum | |||||||||
| Cycle | 6-week | - | - | - | - | - | - | - | - | |
| Horizon | Life-time | - | - | - | - | - | - | - | - | |
| WTP, $/QALY | 33600 | - | - | - | - | - | - | [21] | - | |
| Discount rate | 0.05 | 0 | 0.08 | - | - | - | - | [21] | - | |
| Mean body surface area, m2 | 1.80 | - | - | - | - | - | - | - | - | |
| Patients’ weight, kg | 65 | - | - | - | - | - | - | - | - | |
| Pembrolizumab group _ AEs incidence | ||||||||||
| Diarrhea | 0.060 | 0.048 | 0.072 | 90.218 | 1413.409 | 0.060 | 0.006 | [16] | Beta | |
| Anemia | 0.050 | 0.040 | 0.060 | 91.188 | 1732.572 | 0.050 | 0.005 | Beta | ||
| Hypokalemia | 0.010 | 0.008 | 0.012 | 95.070 | 9411.890 | 0.010 | 0.001 | Beta | ||
| Neutropenia | 0.000 | 0.000 | 0.000 | - | - | 0.000 | 0.000 | Beta | ||
| Chemotherapy group _ AEs incidence | ||||||||||
| Diarrhea | 0.110 | 0.088 | 0.132 | 85.366 | 690.685 | 0.110 | 0.011 | [16] Assumed the incidence of neutrophil count decrease multiplied by 0.5 is included in neutropenia | Beta | |
| Anemia | 0.100 | 0.080 | 0.120 | 86.336 | 777.024 | 0.100 | 0.010 | Beta | ||
| Hypokalemia | 0.060 | 0.048 | 0.072 | 90.218 | 1413.409 | 0.060 | 0.006 | Beta | ||
| Neutropenia | 0.235 | 0.188 | 0.282 | 73.236 | 238.405 | 0.235 | 0.024 | Beta | ||
| Pembrolizumab group second-line therapy proportion | ||||||||||
| Pembrolizumab | 0.100 | 0.080 | 0.120 | 86.336 | 777.024 | 0.100 | 0.010 | KEYNOTE 177, assumed only the second-line treatments of a proportion of more than 2% were considered in our analysis. | Beta | |
| other PD-1/PD-L1 Checkpoint Inhibitor | 0.075 | 0.060 | 0.090 | 88.762 | 1094.731 | 0.075 | 0.008 | Beta | ||
| Chemotherapy | 0.438 | 0.350 | 0.525 | 53.585 | 68.895 | 0.438 | 0.045 | Beta | ||
| VEGF inhibitor | 0.275 | 0.220 | 0.330 | 69.354 | 182.842 | 0.275 | 0.028 | Beta | ||
| EGFR Inhibitor | 0.113 | 0.090 | 0.135 | 85.123 | 671.526 | 0.113 | 0.011 | Beta | ||
| Chemotherapy group second-line therapy proportion | ||||||||||
| Pembrolizumab | 0.427 | 0.342 | 0.513 | 54.557 | 73.068 | 0.427 | 0.044 | KEYNOTE 177, assumed only the second-line treatments of a proportion of more than 2% were considered in our analysis. | Beta | |
| other PD-1/PD-L1 Checkpoint Inhibitor | 0.282 | 0.226 | 0.339 | 68.632 | 174.362 | 0.282 | 0.029 | Beta | ||
| Chemotherapy | 0.153 | 0.122 | 0.183 | 81.225 | 450.797 | 0.153 | 0.016 | Beta | ||
| VEGF inhibitor | 0.099 | 0.079 | 0.119 | 86.410 | 784.338 | 0.099 | 0.010 | Beta | ||
| EGFR Inhibitor | 0.038 | 0.031 | 0.046 | 92.336 | 2326.872 | 0.038 | 0.004 | Beta | ||
| Health preferences | ||||||||||
| Utility of PFS | 0.7825 | 0.75 | 0.84 | 245.001 | 63.176 | 0.795 | 0.023 | [24] | Beta | |
| Utility of PD | 0.64 | 0.576 | 0.704 | 137.658 | 77.432 | 0.640 | 0.033 | [26] | Beta | |
| Disutility due to AEs (grade ≥ 3) | ||||||||||
| Diarrhea | -0.090 | -0.072 | -0.108 | 14.470 | 146.308 | -0.090 | 0.023 | [27][28] | Beta | |
| Anemia | -0.085 | -0.068 | -0.102 | 14.555 | 156.680 | -0.085 | 0.021 | Beta | ||
| Hypokalemia | -0.080 | -0.064 | -0.096 | 14.640 | 168.360 | -0.080 | 0.020 | Beta | ||
| Neutropenia | -0.0607 | -0.049 | -0.073 | 14.968 | 231.623 | -0.061 | 0.015 | Beta | ||
| Drug cost, $/mg | ||||||||||
| Pembrolizumab | 179.18 | - | - | - | - | - | - | 2021 Local charge https://www.yaozh.com | Fix | |
| Oxaliplatin | 3.4 | 2.72 | 4.08 | 16.000 | 0.213 | 3.400 | 0.850 | Gamma | ||
| Leucovorin | 0.25 | 0.2 | 0.3 | 16.000 | 0.016 | 0.250 | 0.063 | Gamma | ||
| 5-FU | 0.29 | 0.232 | 0.348 | 16.000 | 0.018 | 0.290 | 0.073 | Gamma | ||
| Bevacizumab | 15 | 11.88 | 15 | 16.000 | 0.840 | 13.440 | 3.360 | Gamma | ||
| Cetuximab | 12.04 | - | - | - | - | - | - | Fix | ||
| Irinotecan | 17.73 | 14.05 | 24.9 | 16.000 | 1.217 | 19.475 | 4.869 | Gamma | ||
| Nivolumab | 96.2 | - | - | - | - | - | - | Fix | ||
| Capecitabine | 0.04 | 0.01 | 0.04 | 16.000 | 0.002 | 0.025 | 0.006 | Gamma | ||
| AEs cost, $ | ||||||||||
| Diarrhea | 392.44 | 313.95 | 470.93 | 16.000 | 24.527 | 392.439 | 98.110 | [32] | Gamma | |
| Anemia | 724.64 | 579.71 | 869.57 | 16.000 | 45.290 | 724.638 | 181.160 | [31] | Gamma | |
| Hypokalemia | 157.28 | 125.82 | 188.73 | 16.000 | 9.830 | 157.275 | 39.319 | [31], assumed same as fatigue | Gamma | |
| Neutropenia | 628.96 | 503.17 | 754.76 | 16.000 | 39.310 | 628.965 | 157.241 | [31] | Gamma | |
| Administration, $/attendance | 310.16 | 248.13 | 372.19 | 16.000 | 19.385 | 310.160 | 77.540 | Local charge | Gamma | |
| Cost of BSC, $/cycle | 0.00 | 0.00 | 0.00 | - | - | - | - | Assumed to be 0 | - | |
| Follow up, $/cycle | 31.33 | 25.06 | 37.60 | 16.000 | 1.958 | 31.330 | 7.833 | [11][30] | Gamma | |
| PD-1, programmed death 1; PD-L1, programmed death ligand 1; EGFR, epidermal growth factor receptor; VEGF, vascular endothelial growth factor; PD, progressive disease; PFS, progression-free survival; AE, adverse event; BSC, best supportive care. | ||||||||||
The base case model results are listed in Table 2. Over a lifetime horizon, the use of pembrolizumab compared with chemotherapy produced a gain of extra 3.00 LYs. When adjusted for quality of life, the total QALYs for pembrolizumab and chemotherapy were estimated to be 6.71 and 4.13, respectively. According to the dosage scheme used, the PSM assessed the total costs to be $229,698.49 and $151,412.44, respectively, during that period, resulting in an ICER of $30,330.15 per QALY.
| Strategy | Chemotherapy | Pembrolizumab |
|---|---|---|
| Cost ($) | 151,412.44 | 229,698.49 |
| LYs | 6.22 | 9.22 |
| QALYs | 4.13 | 6.71 |
| Incremental cost a | NA | 78,286.04 |
| Incremental LYs a | NA | 3.00 |
| Incremental QALYs a | NA | 2.58 |
| Incremental Cost per LY Gained a | NA | $8,284.72 |
| Incremental Cost per QALY Gained a | NA | $30,330.15 |
| LYs, life years; QALYs, quality-adjusted life years. | ||
| a Compared with chemotherapy | ||
The results of DSA are presented in the tornado diagram (Fig. 3). The parameters with the greatest influence on the ICER were consideration of PAP, discount rate for cost and effectiveness, proportion of subsequent treatments, and baseline utility value. Across arbitrary change in the ranges for each parameter, the ICER remained ༜$33,600.00 per QALY, except that the discount rate became 0.08 and the proportion of VEGF inhibitor used as 2nd line regime in pembrolizumab group increased by 20%. The incidence, cost, and disutility for AEs had a tiny impact on the ICER. Besides, when PAP was under consideration, the ICER became $1,730.67 per QALY, manifesting absolute cost-effectiveness.
The results of the PSA are shown in the CEAC in Fig. 4, which show the probability that pembrolizumab is cost-effective along with increase of WTP values. These outcomes indicated nearly 0% probability that pembrolizumab was cost-effective at WTP values $20,000 per QALY. There were a 50% and 100% opportunity that pembrolizumab was cost-effective at WTP values of approximately $30,000 and $40,000 per QALY, respectively. The scatter plot shown in Fig. 5 depict the results of the 500 simulations of the PSA, in which, most results were under the WTP threshold ($33,600 per QALY), indicating that probably pembrolizumab generated more QALYs with acceptable incremental costs.
A 5-FU in combination with either oxaliplatin or irinotecan (± VEGF or EGFR inhibitor) are established treatments for mCRC, with good clinical efficacy at an acceptable cost.[15, 38–46] With the dramatic development of ICIs over the past decades, some clinical trials[15–18] have indicated that PD-1 blockade used alone, such as pembrolizumab and nivolumab approved by NMPA or FDA, have achieved much more effectiveness in patients with dMMR/MSI-H metastatic or unresectable CRC that are resistant to the standard chemotherapy combinations on a longer course of treatment.[16, 18–21] A study[47] suggested that increased tumor grading (captured by Ki-67) is associated with impairment of anti‐tumor immunity through HLA-I down modulation, reduced CD8 infiltration and enhanced PD-L1/PD-1 expression on tumor cells. Therefore, it may be possible to predict the efficacy of ICIs by detecting the expression of Ki-67. However, these PD-1 blockade are with significant cost, and their value remains under judgment. Cost-effectiveness analyses provide a feasible methodology for evaluating the cost-effectiveness of a regimen, under the circumstances of the survival benefit, quality of life, costs of administration and drugs, costs of follow up and costs of AEs. But at present, there exist no cost-effectiveness analysis of pembrolizumab or nivolumab used alone in the patients with dMMR/MSI-H mCRC.
Pembrolizumab was the first and only one PD-1 inhibitor approved by the NMPA in China as the first-line therapy for patients with dMMR/MSI-H mCRC based on the gratifying results of KEYNOTE 177 trial. The trial demonstrated that by the treatment of pembrolizumab, survival could be prolonged significantly compared with standard chemotherapy. In the Chinese context, given the incremental benefit and cost related to this treatment, we conducted the first study to our knowledge detecting the cost-effectiveness of pembrolizumab, as the first-line regimen, in patients with dMMR/MSI-H advanced or metastatic CRC. On the basis of our model, pembrolizumab was projected to extend patient life expectancy to a point not previously seen in this patient population. For instance, in the pembrolizumab arm, life expectancy was projected to reach to nearly 9 years, approximately 1.5 times that of the chemotherapy group (increase patients’ survival by 3 years with discounting), despite the high proportion of crossover in the control group after disease progression. The associated incremental cost per QALY gained was $30,330.15. While there is no single established ICER threshold for cost-effectiveness in China, the World Health Organization has referenced a threshold of 3-times estimated per capita GDP with respect to disability-adjusted life years, which for China for 2020 would correspond to $33,600/QALY.[48] The ICER in the basic analysis is below this threshold, suggesting pembrolizumab monotherapy could be selected as a cost-effective first-line treatment for patients with dMMR/MSI-H advanced or metastatic CRC in clinical practice.
In univariable sensitivity analyses, the most influential driver of the ICER was the consideration of PAP. The PAP called “Key to life” was approved in China on July 8, 2021[49], officially providing support that alleviates patients’ out-of-pocket expenses of pembrolizumab (as the first-line monotherapy) for dMMR/MSI-H metastatic or unresectable CRC patients with wild-type KRAS, NRAS and BRAF genes. Based on this assistance program, it only takes $11,200 per year (up to 2 years, $22,400) with a decrease of about 88.8%. Considering that, we conducted a scenario analysis and found that the basic ICER became $1,730.67 per QALY, which indicated that the patients could receive more benefits with a minimal incremental costs. Under such circumstance, we fully recommend the mCRC patients, who are meet the above-mentioned conditions, to use pembrolizumab monotherapy as the first-line regime. The impact of discount rate on the basic results ranked second. In addition, due to the relatively high price of biological agents[30], the proportion of VEGF/EGFR inhibitor used as 2nd line regimes also had a great effect on the outcomes. For this, some scholars[50, 51] have found that treatment with bevacizumab in Chinese patients with mCRC is unlikely to use financial resources efficiently. In terms of EGFR inhibitor (cetuximab), Wu, B. et al.[52] and Wang, H. et al.[53] have conducted cost-effective analyses based on the CRYSTAL trial[54] and the TAILOR trial[55] respectively, and found that cetuximab combined with FOLFOX or FOLFIRI was not a cost-effective treatment for the patients with RAS wild-type mCRC in China, unless PAP was available. The PSA, varying all model parameters in 500 Monte Carlo simulations, displayed that it was more than 80% probability that pembrolizumab would be considered cost-effective at a usually accepted value ($33,600 per QALY).
A major strength of the basic analysis was its dependence on a direct comparison of pembrolizumab and standard chemotherapy, utilizing data and information from a randomized controlled trial. Besides, the PSM structure is unnecessary to build assumptions for the transition probabilities of patients but has the advantage of being able to partition patients to different health states directly based on the trial's K-M curves. Moreover, time dependence of risk can be handled automatically, instead of applying constant transition risks within a traditional Markov model.
It is essential to address that our study had several limitations. Firstly, the development of the cost-effective analysis was relied on the results of the KEYNOTE 177 trial, in which the participants were mainly from the Western Europe or North America (༞70%). To some extent, it may impair the application of our research results. Secondly, the value of utilities of PFS and PD were derived from the study on the health-related quality of life in the trial population, and the disutilities of AEs were derived from previously published studies, which might not reflect the health state of patients in China. This defect may also affect the robustness of our results. An updated health utility data for patients with dMMR/MSI-H metastatic or unresectable CRC in Chinese populations might enhance the accuracy and robustness of the analyses .Thirdly, the efficacy data of PFS and the incidence of AEs were from the interim results of the trial, because the final results have not been officially published. Thus, it is possible that projections of cost-effectiveness could change with additional follow-up. Fourthly, without considering patient compliance, the cost of follow-up may be overestimated. Because of this, cost of follow-up as a variable was included in the DSA and we found that the impact of the follow-up cost on the results was small. In addition, for the longer-term extrapolation of PFS and OS, there existed an inherent uncertainty, and the perspective of Chinese health care system may limit the scope of application of the results.
From a perspective of health care system in China, the current model predicted that pembrolizumab monotherapy is more likely to be a cost-effective first-line strategy for patients with dMMR/MSI-H advanced or metastatic CRC. When PAP is available, pembrolizumab monotherapy will be dominant. The reported conclusions may be helpful to physicians, mCRC patients and health management agency in their decision-making processes.
colorectal cancer (CRC)
overall survival (OS)
5-fluorouracil (5-FU)
FOLFOX (5-FU, oxaliplatin, and leucovorin)
FOLFIRI (5-FU, irinotecan, and leucovorin)
epidermal growth factor receptor (EGFR)
vascular endothelial growth factor (VEGF)
mismatch repair defect (dMMR) /microsatellite instability high (MSI-H)
immune checkpoint inhibitors (ICIs)
programmed death 1 (PD-1)
programmed death-ligands1(PD-L1)
metastatic CRC (mCRC)
National Medical Products Administration (NMPA)
American Society of Clinical Oncology (ASCO)
progression-free survival (PFS)
partitioned-survival model (PSM)
progressive disease (PD)
Kaplan-Meier (K-M)
life years (LYs)
quality-adjusted life years (QALYs)
incremental cost-effectiveness ratios (ICERs)
individual patient data (IPD)
Akaike information criterion (AIC)
Bayesian information criteria (BIC)
adverse events (AEs)
United States dollars (USD)
Consumer Price Index (CPI)
Chinese society of clinical oncology (CSCO)
intravenously (IV)
body surface area (BSA)
deterministic sensitivity analyses (DSA)
confidence intervals (CI)
patient assistance program (PAP)
probabilistic sensitivity analysis (PSA)
cost-effectiveness acceptability curve (CEAC)
willingness to pay (WTP)
Acknowledgments
No one need to be acknowledged.
Author Contributions: Drs Wu and Han had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. All authors read and approved the final manuscript.
Concept and design: Wu, Han.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Zhu, Han.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Zhu, Wu.
Administrative, technical, or material support: Wu, Han.
Supervision: Wu.
Notes
Ethics approval and consent to participate
This economic analysis was based on a literature review and modeling techniques; this study did not require approval from an Institutional Research Ethics Board.
Consent for publication
Not applicable.
Competing interests
None of the authors have anything to declare.
Funding
This work was sponsored by specific grant No. 2022ZYJ07 for pharmacoeconomics and health technology assessment from Zhejiang Pharmaceutical Association.
Data availability statement
Most data generated or analysed during this study are included in this published article [and its supplementary information files]. Complete datasets are available from the corresponding author on reasonable request.