br Materials and Methods br Results In the Base

Materials and Methods
Results In the Base Analysis (53% of patients having access to the ALK test in both Current and Alternative Scenarios), a total of 16,583 patients were tested of whom 1,252 were assumed to be ALK-positive. A more extensive use of Ventana in the Alternative Scenario determined a decrease in ALK diagnostic costs of about €468 thousand vs the Current Scenario when considering all the advanced NSCLC patients and of about €19 thousand when considering the ALK+ NSCLC patients only (Table 2 of the Supplementary Materials, Base Analysis). This was due to lower acquisition cost than FISH and a comparable ALK detection rate. If these savings plus additional investments were allocated to test more NSCLC patients (75% vs 53% in the Base Analysis), the number of TP patients detected would increase from 616 to 868 (relative increase: +41%) in the Alternative Scenario vs the Current Scenario (Table 5, Re-investment Analysis). Detecting greater number of ALK+ patients would allow to improve the clinical outcomes, as a bigger number of patients could be treated with crizotinib. When considering the ALK+ NSCLC patients: i) the OS would increase from 27 months per patient in the Current Scenario to 32 months per patient in the Alternative Scenario (relative increase: +20%).; ii) the PFS would increase from 11 months per patient in the Current Scenario to 13 months per patient in the Alternative Scenario (+6%). Crizotinib is one of the most expensive treatments included in the present analysis. Then, the total cost of treatment would increase in the Alternative Scenario vs the Current Scenario due to a gain in terms of efficacy. Nevertheless, when analyzing cost-efficacy indicators (Table 6), the expenditure required for an incremental unit of efficacy is lower than the stated willingness to pay admitted for oncological diseases [41], [42], [43]. With respect to the cohort of advanced ALK+ NSCLC patients, in the Alternative Scenario, an incremental expenditure of: i) €63 per patient would allow to detect one additional TP case; ii) €5,194 per patient would allow to guarantee one additional month of survival; iii) €16,686 per patient would allow to guarantee one additional month of progression free survival vs Current Scenario, respectively.
Discussion IHC testing is an appropriate and reliable alternative to FISH for the identification of ALK-positive NSCLC [44], [45]. Ventana ALK (D5F3) CDx Assay was specifically developed to maximize agreement with ALK FISH testing, and to enable the use of ALK IHC as a stand-alone companion diagnostic to identify patients with ALK-positive NSCLC eligible for treatment with crizotinib [46]. Moreover, it k145 is also less labor-intensive, it does not require specialized training, and unlike FISH, it does not require a minimum number of tumor cells present in the sample. The chemical detection used in the ALK (D5F3) CDx assay allows for a simple binary scoring algorithm that results in high reader-to-reader precision [44]. In the present analysis, the clinical utility of Ventana was evaluated by comparing two scenarios: current use of Ventana vs increased use of Ventana. Due to a lower cost than FISH techniques, the adoption of Ventana allowed to test a greater number of patients (hypothesis in the model: 53% vs 75%) thus: i) increasing the number of TP cases detected (+41%); ii) improving the overall clinical outcomes of the cohort of patients affected by advanced ALK+ NSCLC (+20% OS; +6% PFS). The present analysis could be affected by some limitations. First, the model is a simplification of the real diagnostic and treatment pathway, which is quite complex in NSCLC where multiple options are available and treatment decisions are driven by several considerations (e.g. patient age and level of functioning, need to optimize efficacy vs safety, level of caregiving, etc.). The model took the most representative options for each line and type of tumor, but we know that other alternatives are available (e.g. afatinib or erlotinib could be used in first line for EGFR+ patients, best supportive care could be replaced by other options in third-line, such as compassionate use of experimental ALK-TKIs could be an option for specific cases, etc.). Being the analysis not focused on the treatment costs, we believe that considering only one treatment as representative of its class would not introduce significant bias. Second, the OS of crizotinib was not reached in the clinical trial so an estimation was used for the analysis and this could affect the results. Considering an OS equal to 75% of the one used in the model (37.1 months), in the reinvestment analysis: i) the OS would increase from 25 months per patient in the Current Scenario to 30 months per patient in the Alternative Scenario (relative increase: +18%); ii) an incremental expenditure of €5,569 per patient would allow to guarantee one additional month of survival. Finally, we used a methodology to convert IHC sensitivity and specificity vs FISH tests (which have been historically used as diagnostic benchmark) into IHC sensitivity and specificity to treatment response (i.e. ALK true positive patients with IHC respond to crizotinib therapy). Despite there is evidence that some ALK FISH–negative/ALK IHC–positive cases do respond to crizotinib, such evidence should probably be reinforced with new studies. About this, a recent study showed that ALK (D5F3) CDx assay is superior to ALK-FISH on small biopsies and FNA to predict tumor response and survival to crizotinib for patients with advanced NSCLC [47].