Comparison of Parametric Survival Extrapolation Approaches Incorporating General Population Mortality for Adequate Health Technology Assessment of New Oncology Drugs.

OBJECTIVES: Survival extrapolation of trial outcomes is required for health economic evaluation. Generally, all-cause mortality (ACM) is modeled using standard parametric distributions, often without distinguishing disease-specific/excess mortality and general population background mortality (GPM). Recent National Institute for Health and Care Excellence guidance (Technical Support Document 21) recommends adding GPM hazards to disease-specific/excess mortality hazards in the log-likelihood function ("internal additive hazards"). This article compares alternative extrapolation approaches with and without GPM adjustment. METHODS: Survival extrapolations using the internal additive hazards approach (1) are compared to no GPM adjustment (2), applying GPM hazards once ACM hazards drop below GPM hazards (3), adding GPM hazards to ACM hazards (4), and proportional hazards for ACM versus GPM hazards (5). The fit, face validity, mean predicted life-years, and corresponding uncertainty measures are assessed for the active versus control arms of immature and mature (30- and 75-month follow-up) multiple myeloma data and mature (64-month follow-up) breast cancer data. RESULTS: The 5 approaches yielded considerably different outcomes. Incremental mean predicted life-years vary most in the immature multiple myeloma data set. The lognormal distribution (best statistical fit for approaches 1-4) produces survival increments of 3.5 (95% credible interval: 1.4-5.3), 8.5 (3.1-13.0), 3.5 (1.3-5.4), 2.9 (1.1-4.5), and 1.6 (0.4-2.8) years for approaches 1 to 5, respectively. Approach 1 had the highest face validity for all data sets. Uncertainty over parametric distributions was comparable for GPM-adjusted approaches 1, 3, and 4, and much larger for approach 2. CONCLUSION: This study highlights the importance of GPM adjustment, and particularly of incorporating GPM hazards in the log-likelihood function of standard parametric distributions.

The cost-effectiveness of glasdegib in combination with low-dose cytarabine, for the treatment of newly diagnosed acute myeloid leukemia in adult patients who are not eligible to receive intensive induction chemotherapy in Canada.

AIM: The clinical efficacy and safety of DAURISMO (glasdegib) combined with low-dose cytarabine (LDAC) were demonstrated in the BRIGHT AML 1003 study among newly diagnosed acute myeloid leukemia patients who are not eligible to receive intensive chemotherapy. This study aims to evaluate its cost-effectiveness versus LDAC alone and azacitidine from a Canadian payer perspective. MATERIALS AND METHODS: A partitioned-survival model was developed with three health states: progression-free survival (PFS), relapse/progression and death. Clinical inputs were obtained from the BRIGHT AML 1003 study for glasdegib and LDAC, and from the two trial publications and indirect treatment comparison for azacitidine. Drug acquisition/administration, disease management, adverse event and end-of-life costs were considered. All costs were measured in Canadian dollars. Cost-effectiveness of glasdegib + LDAC was assessed against LDAC alone in main population, and against azacitidine by bone marrow blasts (BMB). A weighted average ICER was calculated to represent the current treatment use of Canadian clinical practice. The reference-case analysis was conducted probabilistically, and numerous probabilistic scenario analyses were conducted. RESULTS: The incremental cost-effectiveness ratios (ICERs) compared to LDAC alone was CAD $177,065 (a mean gain of 0.41 QALYs and an incremental cost of CAD $72,695), to azacitidine in 20-30% and >30% BMB group were CAD $178,201 (a mean gain of 0.34 QALYs and an incremental cost of CAD $59,889) and dominant (a mean gain of 0.28 QALYs while reducing costs by CAD $7,856) respectively, resulting in a weighted average ICER of CAD $81,310 per QALY. LIMITATIONS AND CONCLUSIONS: Though uncertainties remain with the generated PFS curve, the derived azacitidine curves, administration and vial wastage, the model has been built under the best available evidence and relied on clinical opinions where there were data gaps. The weighted average ICER suggests that glasdegib + LDAC is cost-effective at a CAD $100,000 willingness-to-pay threshold.

Cost-effectiveness of FOLFIRI + cetuximab vs FOLFIRI + bevacizumab in the first-line treatment of RAS wild-type metastatic colorectal cancer in Germany: data from the FIRE-3 (AIO KRK-0306) study.

Aims: This analysis evaluates the cost-effectiveness of first-line treatment with FOLFIRI + cetuximab vs FOLFIRI + bevacizumab for patients with RAS wild-type (wt) metastatic colorectal cancer (mCRC) in Germany based on the randomized phase 3 FIRE-3 trial. For patients with RAS wt mCRC, FOLFIRI + cetuximab yielded statistically significant median overall survival gains over FOLFIRI + bevacizumab.Materials and methods: A standard 3-state partitioned survival cost-utility model was developed to compare the health benefits and costs of treatment from a German social health insurance perspective using individual patient-level trial data. Health outcomes were reported in life-years (LYs) and quality-adjusted life-years (QALYs) gained. Survival was estimated based on Kaplan-Meier (KM) curves supplemented with best-fitting parametric survival model extrapolations. Subgroup analyses of patients with a left-sided primary tumor location or patients with metastases confined to the liver were performed.Results: In the modified intention-to-treat analysis, FOLFIRI + cetuximab, providing 0.68 additional LYs (0.53 QALYs), yielded incremental cost-effectiveness ratios (ICERs) of €36,360/LY and €47,250/QALY. In subgroup analyses, patients experienced improved survival gains without a corresponding increase in costs, resulting in lower ICERs. Our model was most sensitive to changes in treatment duration across all lines of therapy, utility of progressive disease, as well as patients' weight and body surface area.Limitations: This cost-effectiveness analysis was based on patient-level data from the FIRE-3 trial. Trial outcomes may not adequately reflect those in the real-world setting. Additionally, resource use and costs were obtained from tariff lists, which do not account for differences in treatment practice. These considerations limit generalizability of outcomes to other countries, or within the German healthcare setting.Conclusions: Based on our analyses, FOLFIRI + cetuximab is cost-effective compared with FOLFIRI + bevacizumab in patients with RAS wt mCRC, with ICERs well below willingness-to-pay thresholds for diseases with a high burden.

Burden of hospitalization in acute lymphoblastic leukemia patients treated with Inotuzumab Ozogamicin versus standard chemotherapy treatment.

BACKGROUND: Inotuzumab Ozogamicin (INO), has demonstrated an improvement in overall survival, high rate of complete remission, favorable patient-reported outcomes, and manageable safety profile vs standard of care (SoC; intensive chemotherapy) for relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) in the phase 3 INO-VATE trial. With a one-hour weekly dosing schedule, INO might be associated with lower healthcare system burden. This study analyses hospitalizations for INO vs SoC. METHODS: All patients receiving study treatment in the INO-VATE trial were included. The days hospitalized during study treatment was calculated. Due to different treatment durations for INO and SoC (median of 3 vs 1 cycles), number of hospital days was mainly reported per observed patient month. Hospital days per patient month were analyzed for different treatment cycles, subgroups, and main reasons for hospitalization. Differences between treatments were analyzed by the incidence rate ratio (IRR). RESULTS: Overall, 82.9% and 94.4% INO and SoC patients experienced at least one hospitalization. The mean hospitalization days per patient month was 7.6 and 18.4 days for INO and SoC (IRR = 0.413, P < .001), which corresponds to patients spending 25.0% and 60.5% of their treatment time in a hospital. Main hospitalization reasons were R/R ALL treatment (5.2 (INO) vs 14.0 (SoC) days, IRR = 0.368, P < .001), treatment toxicities (1.4 vs 2.8 days, IRR = 0.516, P < .001) or other reasons (1.0 vs 1.6 days, IRR 0.629, P < .001). CONCLUSIONS: Inotuzumab Ozogamicin treatment in R/R ALL is associated with a lower hospitalization burden compared with SoC. It is likely this lower burden has a favorable impact on healthcare budgets and cost-effectiveness considerations.