CLINICAL AND BUDGET IMPACT OF USING A MOLECULAR TEST TO DETECT KRAS MUTATIONS IN METASTATIC COLORECTAL CANCER PATIENTS IN THE UNITED STATES Cheng I1, Hertz D2, Huang J1, Poulios N1 (1Roche Molecular Systems, Inc., Pleasanton, CA, USA, 2GfK, Wayland, MA, USA) Background Anti-epidermal growth factor receptor (anti-EGFR) therapies are ineffective in tumors with KRAS mutations, in codons 12 and 13 of exon 2.[1-3] Patients with KRAS mutations, referred to as mutant-type (MT) patients, experience shorter progression free survival (PFS) when receiving anti-EGFR therapy compared to bevacizumab therapy or chemotherapy alone.[1-3,5] Patients without KRAS mutations, referred to as wild-type (WT) patients, achieve similar PFS and OS on either anti-EGFR or bevacizumab therapy in the first line setting.[4,5] Existing guidelines recommend determination of RAS mutation status in metastatic colorectal cancer (mCRC) patients when considering treatment with anti-EGFR therapy.[5,6] Both the cobas® KRAS Mutation Test (cobas test) and the therascreen® KRAS RGQ PCR Kit (therascreen test) detect KRAS mutations in exon 2. The cobas test detects twelve (12) mutations in exon 2, while the therascreen test detects seven (7) mutations in exon 2. Methods Cont. Figure 1. Patient flow diagram for both cobas testing and therascreen testing Cost inputs (2014 $) Base Case ref. KRAS testing $197.48 [14] chemotherapy (⅓ FOLFOX, ⅓ FOLFIRI, ⅓ CapeOx) $2,664 bevacizumab $12,239 Anti-EGFR (cetuximab 60%/panitumumab 40%) $11,142 [15] Regorafenib $11,954 palliative care (hospice) $4,284 Monitoring costs $360.11 Rx Performance PFS (mo.) ref. OS (mo.) Rx duration (mo.) anti-EGFR +chemo (WT) 1L 9.9 [1,2] 23.7 4.8 [4] anti-EGFR +chemo (MT) 7.2 16.9 bevacizumab +chemo 20.6 5.3 2L 6.5 [3,16] 12.7 [3] 4.3 4.2 11.0 [17] 6.2 [18,19] 12.8 4.5 3L 1.9 [20] 6.4 1.8 [20,17] regorafenib 2.0 [21] 6.1 chemotherapy alone Objective This study assessed the potential clinical and economic impact of using cobas KRAS test versus therascreen KRAS test in a cohort of mCRC patients. Methods A decision tree framework was used to construct a budget impact model from the US payer perspective, comparing the clinical and economic outcomes of using the cobas test versus therascreen test for KRAS testing of mCRC patients. See Figure 1. Model assumed: 42,000[7,8] annual cases of mCRC in the US. Patients that were too sick, with ECOG score >3, inoperable, or could not be biopsied (estimated to be 11%[9] of the mCRC patients) were excluded. A 90% adoption of KRAS testing. Patients received the best available care per NCCN and US clinical practice; resulting in either anti-EGFR therapy plus chemotherapy or bevacizumab plus chemotherapy administered for 1L and 2L therapy. Options for 3L therapy in the model included: anti-EGFR + chemotherapy, regorafenib or chemotherapy alone. Model inputs were obtained from literature, whereas testing and treatment costs were based on CMS reimbursement rates. Clinical test performance was based on Roche data on file. See Table 1 and 2. Table 2. Model inputs Results cobas KRAS testing may reduce the number of patients (454 patients) receiving inaccurate (false positive or false negative) compared to therascreen. ∆= -454 (-1.21%) cobas KRAS testing may improve patient outcomes; compared to therascreen, cobas test was associated with a +0.02 month improvement in OS and a reduction of 544 patient-months lost. Test performance Base Case ref. cobas KRAS sensitivity 96.9% [11] cobas KRAS specificity 88.7% cobas KRAS test failure 1.7% [12] therascreen sensitivity 94.2% therascreen specificity 87.5% therascreen test failures Mutation frequency % of mCRC with KRAS mutation 45.7% [13] % of KRAS mutations in codon 12 and 13 87.9% ∆= -544 (-5.90%) ∆=0.02 (0.14%) Using cobas KRAS testing had a minor increase ($1.2M, 0.02%) in healthcare costs due to longer overall survival, however decreased monthly cost per patient by $4, and reduced the costs of inappropriate care by $22M ($842 per test run) in patients with mCRC. Table 1. Model inputs Proportion of KRAS codon 12/13 mutations was used to adjust test sensitivity. The model calculated the average cost for mCRC patients over 5 years, using median time in treatment, median progression free survival (PFS) and median overall survival (OS) taken from the literature. See Table 2. Based on current practice patterns, the proportion of patients receiving KRAS testing before 1st-line (1L), 2nd-line (2L), and 3rd-line (3L) therapy were 42%, 32%, and 26%,[10] respectively. Patients that tested KRAS WT were prescribed anti-EGFR at a rate of 34%, 31% and 28% for 1L, 2L and 3L treatment, respectively.[10] Market share was assumed to be 42% for 3L regorafenib. Patients continued to receive 2L and 3L therapy at a rate of 79% and 70%, respectively.[10] Inappropriate care was defined as treatment and AE costs of MT patients receiving anti-EGFR therapy and included all treatment and AE costs following the anti-EGFR therapy. REFERENCES [1] Douillard, et al. N Engl J Med 2013;369:1023-34. [2] Van Cutsem N, et al. Engl J Med 2009; 360:1408-17. [3] Peeters J, et al. Clin Oncol 2010; 28:4706-4713. [4] Heinneman, et al. Lancet Oncol. 2014;15(10):1065-75. [5] NCCN Clinical Practice Guidelines in Oncology: Colon Cancer v.2.2015 [6] Allegra CJ, et al. JCO 2009;27(12): 2091-2096. [7] SEER data [8] Tsikitis 2014. [9 Paoli CJ, et al. J Community Support Oncol. 2014;12(5):163-170. [10] Roche Genentech Market Research – data on file [11] Roche data on file [12] de Castro et al. British Journal of Cancer. 2012;107:345–351. [13] Douillard et al. N Engl J Med 2013;369:1023-34. [14] CMS 2014 Reimbursement [15] Analyst$ource.com (accessed 12/15/2014) [16] Sobrero et al. J Clin Oncol 2008;26:2311-2319. [17] Assumption [18] Bennouna et al. Lancet Oncol 2013; 14: 29–37 [19] Giantonio et al. J Clin Oncol 2007;25:1539-1544.[20] Jonkers et al. N Engl J Med. 2007;357:2040-8. [21] Grothey et al. Lancet 2013; 381: 303–12 $6,499.5M $6,500.7M $162.5M $140.2M A one-way sensitivity analysis was performed on all inputs for both incremental total costs and incremental overall survival. The results were generally robust to changes in inputs; incremental total cost was most sensitive to the cost of bevacizumab and anti-EGFR therapy, which is a function of both monthly cost and time in therapy. Total incremental OS was most sensitive to performance of anti-EGFR (1L and 2L PFS as well as 3L OS) and PFS of bevacizumab in the 2L setting. A scenario analysis that looked at the results when time in therapy was set equal to PFS resulted in incremental costs of +$6.7M and increase in overall survival of +0.02 months when using cobas KRAS testing. Discussion Test specificity was relatively low due to the lack of a highly sensitive gold standard. Therefore, number of patients received inaccurate results might be lower in the real-world settings. The use of cobas KRAS testing may increase the OS of mCRC patients as fewer patients with MT receive false negative test result and inappropriate care (anti-EGFR therapy). cobas KRAS testing had a relatively neutral budget impact; a longer survival may result in a slightly higher overall cost of care, but costs less on a per patient per month basis. Additionally, the use of cobas KRAS testing may reduce the cost of inappropriate care. Given that a similar amount of total health care cost was spent in both the cobas and therascreen arm, the cobas test was able to allocate the healthcare resources to the appropriate treatment option with longer survival benefit and avoid the waste of healthcare resources. Conclusion Using the cobas KRAS test with improved sensitivity due to broader mutation coverage when compared to therascreen KRAS test, was associated with a neutral budget impact and may improve patient outcomes by reducing the likelihood of receiving inappropriate care in patients with mCRC. This project is funded by the Roche Molecular Systems For additional information, please contact: Name: I-Ning (Elaine) Cheng Email: elaine.cheng.ec2@contractors.roche.com International Society for Pharmacoeconomics and Outcomes Research (ISPOR) 20th Annual International Meeting, Philadelphia, PA, USA (May 16 – 20th, 2015)