Cost Effectiveness of Pembrolizumab vs. Standard-of-Care Chemotherapy as First-Line Treatment for Metastatic NSCLC that Expresses High Levels of PD-L1 in the United States

ToT data from the KEYNOTE-024 trial were analysed to determine treatment duration and cost, since patients deriving clinical benefit could continue pembrolizumab beyond progression. Parametric functions were fit to the KM ToT data. The AIC and BIC combined with visual inspection were used to select the Weibull distribution for pembrolizumab and the generalized gamma distribution for SoC as the base case. The base-case ToT curves are presented in Fig. 2. Alternative parametric functions and the base-case curves with 20-year time horizon are presented in ESM 2.

For PFS, the KM probabilities from KEYNOTE-024 were used directly up to Week 9, with parametric functions fitted thereafter. This was because the first radiologic tumour response assessment was conducted at Week 9, resulting in a protocol-driven drop in PFS at this point. The Weibull distribution was the best fit for pembrolizumab, and the exponential parametric function was the best fit for SoC. The base-case PFS curves are presented in Fig. 3. Alternative parametric functions and the base-case curves with 20-year time horizon are presented in ESM 3.

In KEYNOTE-024, 43.71% of patients from the SoC group crossed over to receive pembrolizumab after disease progression, which was anticipated to diminish the survival benefit of pembrolizumab. A simplified two-stage approach as described by Latimer and Abrams [12] and Latimer [13] was implemented to perform an OS analysis adjusting for switching in the SoC arm. Through this approach, OS treatment effect estimate was adjusted to correct for the bias induced by treatment switch.

Two datasets are available for use in the OS analysis: (1) the intention-to-treat (ITT) dataset included patients who switched from SoC to pembrolizumab following disease progression, and (2) a ‘switching-adjusted’ dataset used the two-stage adjustment method to adjust the survival benefit of patients who switched to pembrolizumab,

The ITT dataset was used in the base-case analysis, as it better represented the real-world situation given the existing FDA approval of pembrolizumab as second-line therapy for metastatic NSCLC expressing PD-L1 [9]. The OS impact of subsequent therapies was assumed to be reflected within the OS KM data from KEYNOTE-024. The switching-adjusted dataset was explored in a scenario analysis.

For the OS outcomes, the standard parametric curves tested did not provide a good visual fit to the observed KM data, so a two-phase piecewise model was applied. Cut points were determined by estimating structural changes to the KM curve using Chow tests [14, 15]. The area under the KM curve was used directly for the first phase until the cut-off, and an exponential distribution was used to estimate OS for up to 5 years of follow-up. The cut-off point identified by the Chow test was Week 32 for pembrolizumab, Week 38 for SoC (without adjustment), and Week 25 for SoC with adjustment. A constant hazard rate, derived from long-term external data for patients with stage IV NSCLC from the Surveillance, Epidemiology and End Results (SEER) database, was applied to the OS model after Year 5 [16].

The base-case OS curves are presented in Fig. 4. Alternative parametric functions and the base-case curves with 20-year time horizon are presented in ESM 4.

The percentage of patients receiving subsequent therapy (45.51%) was estimated from the Flatiron database [17]. Flatiron is a nationally representative electronic health record data that includes 162 practices from different regions in the USA. We included patients (aged ≥18 years) newly diagnosed with metastatic NSCLC initiating first-line anticancer therapy (November 2012–January 2015, with follow-up through July 2015). In the pembrolizumab arm, and SoC arm with switching adjustment, all such patients were assumed to receive chemotherapy. In the SoC arm without switching adjustment, 43.71% of patients were assumed to receive pembrolizumab and 1.80% were assumed to receive chemotherapy based on the switching rate observed from the KEYNOTE-024 data.

The model included all-cause AEs of grade 3 or higher reported in ≥5% of patients in KEYNOTE-024 for either arm. Pneumonitis, an immune-mediated AE with a high management cost, was included based on feedback from clinicians received in an advisory panel review of the model. Model input data for each AE are shown in Table 1.

The utility data used in the base case (Table 1) were based on EuroQol-5 Dimensions, 3 Levels (EQ-5D-3L) data collected in KEYNOTE-024. The EQ-5D questionnaire was administered at treatment cycle 1, 2, 3, 6, 9, 12 and every third cycle as long as patients were on study treatment, as well as at the treatment discontinuation visit and at a 30-day post-treatment safety follow-up visit. The generic health statuses assessed from the EQ-5D questionnaire were converted to population-based utility values using published algorithms. For the base-case analysis, US-based scores [18] were applied to US patients, UK-based scores [19] for UK patients and EU-based scores [20] for all other patients. Two approaches of defining health state utilities were considered: time-to-death and progression-based health states. The time-to-death approach, recently described by Hatswell et al. [21], reflects the decline in cancer patients’ quality of life as they approach death. Four time-to-death categories (over 360, 180–360, 30–180 days, and under 30 days) were examined for use in the model base case. Pooled data were used as there were no significant differences in utility values in each time-to-death category between the treatment arms [22].

Pembrolizumab is available in single-use vials of 100 mg and is administered at a dose of 200 mg every 3 weeks. The list price for pembrolizumab is $US4381 per 100-mg vial, therefore the cost per dose is $US8762 [25]. Dosage of SoC chemotherapy regimens is based on patients’ body surface area. The average number of vials per dose of each regimen was calculated using the body surface area distribution [mean 1.84 m², standard deviation (SD) 0.26 m²] of patients in the Flatiron database [17]. The cost of SoC was $US3472 per dose, based on the distribution of each regimen in KEYNOTE-024 (ESM 1). The cost per dose of pemetrexed maintenance was estimated at $US4907. Drug administration costs for intravenous infusions based on the year 2016 Center for Medicare and Medicaid Services (CMS) payment rates [23] are shown in Table 1. The number of treatment cycles in the model was based on the estimated ToT. Treatment duration was modelled per KEYNOTE-024 and FDA-approved label up to 4–6 cycles for platinum and up to 2 years for pembrolizumab [9].

Costs of anti-emetic prophylaxis were identified from National Comprehensive Cancer Network (NCCN) guidelines and estimated at $US286.55 and $US5.95 per cycle for cisplatin or carboplatin, respectively [26].

For the progression-free state, disease management costs were based on healthcare resource utilization (HCRU) data observed in KEYNOTE-024. The HCRU data captured non-study-related healthcare visits (including visits for home-based hospice, home healthcare, non-study laboratory, radiation therapy, nurse, primary care, and medical specialists), hospitalization and emergency room visits. Pembrolizumab was associated with lower HCRUs than SoC. The progression-free state HCRU in the KEYNOTE-024 was described in detail in Huang et al. [27]. The unit costs were based on 2016 CMS payment rates [28]. To inform disease management costs for the progressive disease state, a literature review was conducted, which identified published studies whose estimates were based on US commercial claims [29, 30] and SEER Medicare [31‐33]. However, the SEER-Medicare studies over-estimated disease management costs as defined for the model, as intravenous anti-cancer therapy costs were not excluded. Thus, the model base-case value (Table 1) is based on reported results that used commercial claims [29] from initiation of second-line intravenous anti-cancer therapy after excluding intravenous anti-cancer therapy costs. Sensitivity analyses of this parameter embrace the range of reported values from the literature [29, 30]. Disease management costs in the post-progression health state were estimated based on cost data reported by Ramsey et al. [29]. Disease management costs were estimated by evaluating the 1704 patients with NSCLC, and included the following cost categories: (1) inpatient, (2) emergency department, (3) ambulatory (including chemotherapy administration costs in office or outpatient setting), (4) other medical (captured laboratory costs, including the actual processing of the specimen), (5) retail pharmacy. We excluded the cost of ‘chemotherapy administration’ as a disease management cost, as it was included separately in the model within subsequent therapy costs.

To estimate the post-discontinuation therapy costs for SoC patients, the weighted average of subsequent treatment weighted by the rate of switching to pembrolizumab was implemented. Average treatment duration with pembrolizumab was assumed to be 183 days based on the treatment-switching patients in KEYNOTE-024. Patients receiving pembrolizumab were assigned second-line chemotherapy post-progression. The average cost of second-line chemotherapy was estimated to be $US24,358 per patient based on the cost of chemotherapy administrations in a US healthcare claim database [29].

A literature review was conducted to inform the cost of terminal care in the final 30 days of life. Five studies were identified that reported direct medical costs in the end-of life period [30, 34‐37]. All studies were limited to patients with lung cancer, with the exception of Chastek et al. [34], who included all cancer patients with analyses stratified by primary cancer site. The studies used varied sources, including SEER-Medicare [30], integrated health systems databases [35, 36] and commercial administrative claims [34, 37]. Costs in these studies were reported over a variety of intervals, including the period of time from last chemotherapy dose to death [30], the time from initial disease progression to death [35] and the last 6 months of life [34, 36, 37]. Chastek et al. [34] was the only study to report costs within the terminal period by 30-day increments, showing that direct medical costs increased during the last 30 days of life because of increases in hospitalization and hospice costs; these were used for the model base case. Importantly, the costs in the last 30-day period ($US31,114) were higher than the average monthly cost over the 6-month period ($US14,748). Chastek et al. [34] did not report resource utilization, but their reported cost estimates reflected the sum of health plan and patient paid amounts, by cancer-related cost category. These categories included (1) inpatient, (2) hospice (inpatient and outpatient), (3) chemotherapy, (4) growth factors [erythropoiesis-stimulating agents (ESAs) and granulocyte colony-stimulating factors (GCSFs)], (5) radiation, (6) emergency room visits, (7) office visits, (8) hospital outpatient procedures and (9) other outpatient cancer-related services.

Incidence and costs of selected grade 3 or higher AEs are summarized in Table 1. Hospitalization costs related to AE management were considered in the model. The rates of hospitalization were provided by clinical experts. The hospitalization costs for managing each AE were obtained from the 2016 CMS payment rates [38]. Based on incidences of AEs and management costs, the total average cost per patient for managing AEs was estimated to be $US2334 for pembrolizumab and $US521 for SoC.