KRAS/RAS Testing Is Associated With Reduced Risk of Treatment Discontinuation in Patients With Metastatic Colorectal Cancer

Abstract: Current clinical guidelines recommend that all patients with metastatic colorectal cancer (mCRC) have tumor tissue genotyped for RAS mutations. This study aimed to evaluate patient characteristics and identify potential predictors of any KRAS/RAS testing as well as estimate the impact of KRAS/RAS testing on the duration of treatment across multiple lines of therapy in mCRC. Adults with a diagnosis of mCRC were identified from a database of US public and private insurance claims, which covered 129 million lives, from 2012 to 2014. Patient demographics, baseline clinical characteristics, and time to treatment discontinuation were compared between patients who were and were not tested for KRAS/RAS mutations. Among the 4527 mCRC patients identified, 39% (n = 1787) had a claim for KRAS/RAS testing during the study period. Patients with commercial insurance or diagnosis of colon primary site compared to rectum had increased odds of receiving KRAS/RAS testing (all P < .01). Patients tested for KRAS/RAS mutations stayed on treatment significantly longer in first-line, second-line, and overall treatment vs those who were not tested for KRAS/RAS mutations (all P < .01). Adjusting for patient characteristics, KRAS/RAS testing significantly reduced the risk of discontinuation in first-line, second-line, and overall treatment (all P < .01). These observational data show that KRAS/RAS testing is associated with significantly greater time on treatment for mCRC patients compared to not testing. Predictors for not testing included noncommercial insurance and primary site of disease in rectum.

Acknowledgments: This study was funded by Amgen Inc. Additional clinical support was provided by JaLyna Laney, RN (Cardinal Health Specialty Solutions). Medical writing support was provided by Rachel Raynes, PhD, and Yang Li, PhD, (both from Amgen Inc). 

Author Contributions: A. Christodoulopoulou, A. J. Klink, and G. Hechmati conceived and designed the study. A. J. Klink, U. Mujumdar, and B. Feinberg were involved in data acquisition. All authors were involved in the analysis and interpretation of data as well as the writing and review of this manuscript.

Colorectal cancer (CRC) is the second leading cause of cancer-related death and the fourth most frequently diagnosed cancer in the United States.¹ The American Cancer Society estimated 135,430 new cases and 50,260 deaths to be attributed to CRC in 2017.¹ Although the majority of patients with mCRC are diagnosed with locoregional disease, one third will relapse, and over 20% have distant metastases at presentation with a 5-year survival rate of 14%.² Systemic chemotherapies in combination with targeted agents have improved patient outcomes as documented by the increasing duration of overall survival throughout the last decade;^3-5 however, as these interventions are rarely curative, there is still significant unmet need in the treatment of mCRC. 

The impact of molecularly targeted therapies is enhanced by the use of biomarker strategies in clinical decision-making.⁶ Biomarker testing helps to identify patients who are more likely to benefit from the appropriate therapy while reducing exposure to the toxicity of anticancer treatment for patients who are unlikely to benefit. Biomarker-driven selection strategies can improve patient outcomes while controlling exposure and unnecessary treatment costs.⁷ While KRAS and RAS (KRAS + RAS) testing is considered the standard of care in the management of mCRC,⁸ multiple factors can interfere with its widespread implementation. These may include the physician’s adherence to guidelines and perceived benefits from anti-epidermal growth factor receptor (EGFR) therapies, patient CRC tissue availability, the physician’s willingness and ability to perform additional biopsies, and technical and insurance limitations.

Current National Comprehensive Cancer Network  clinical guidelines recommend that all mCRC patients have tumor tissue genotyped for RAS mutations,⁹ and European Society for Medical Oncology clinical guidelines recommend testing for RAS mutational status prior to the use of an anti-EGFR antibody.¹⁰ As guidelines continue to evolve based on the accumulation of new evidence, it is important to understand the characteristics of patients with mCRC who are tested for biomarkers and the potential impact of testing on treatment. Although RAS testing enables the selection of RAS wild-type patients for anti-EGFR therapy, demonstrably delaying time to disease progression and prolonging overall survival, guidelines stress the avoidance of anti-EGFR therapy in the presence of RAS mutations. 

Two randomized clinical trials support the superiority of anti-EGFR therapy over bevacizumab in the first-line treatment of RAS wild-type cancers,^3,11 highlighting the patient benefit of RAS testing at the time of initial diagnosis of metastatic disease. In addition, the Cancer and Leukemia Group B (CALGB) 80405 study has confirmed the superiority of anti-EGFR therapy over bevacizumab in RAS wild-type tumors in terms of overall survival, when the analysis was limited to left colonic primary tumors (ie, splenic flexure to rectum).^5,12 This research supports the notion that universal RAS tumor testing is necessary for optimal outcomes, not only through avoidance of anti-EGFR therapies in the RAS mutant patients, but also through inclusion of anti-EGFR therapies in wild-type patients. 

In addition to randomized controlled trials (RCTs), real-world evidence (RWE) is needed to understand how therapies are being used in populations who are more diverse than those included in RCTs. Only 3% of adult cancer patients participate in clinical trials, and those who do are younger, healthier, and less diverse than their real-world counterparts.¹³ The passage of the 21st Century Cures Act by Congress calls for the incorporation of RWE into the process for drug label expansion. Measures derived from real-world data have served as widely accepted surrogates for RCT endpoints, including progression-free survival (through measurement of time to next treatment), response rates (through measurement of initiation of subsequent treatment), and treatment duration (through measurement of time to discontinuation). 

The impact of testing on clinical outcomes in the real-world setting is critical to determining optimized treatment strategies. Understanding the differences between the tested and untested populations may identify practice barriers for RAS testing that can be addressed by the oncology community. The primary objective of this study was to identify potential predictors of KRAS or expanded RAS testing by examining the demographics and clinical characteristics of patients with mCRC who received testing compared to those who did not. As a secondary objective, this study aimed to estimate the impact of KRAS/RAS testing on the duration of treatment across multiple lines of therapy in mCRC, including cytotoxic and biologic agents.

Methods

Study Design and Data Source

This observational retrospective cohort study selected participants from the Inovalon MORE² Registry^® payer claims database to evaluate KRAS/RAS testing patterns in patients with mCRC. The registry is an integrated database of medical and pharmacy claims data, which includes the complete testing history from all testing sites and subsequent resource utilization (ie, inpatient and outpatient) for the duration that the patient is insured. The database includes longitudinal claims data from over 100 US health plans, including commercial, Medicare, and Medicaid, with 129 million unique, covered patient lives since 2001. The data span approximately 95% of US counties and include more than 754,000 physicians and 248,000 clinical facilities. All patient data were de-identified in accordance with the Health Insurance Portability and Accountability Act.

Study Participants

The study population included patients with an initial claim for mCRC during the study index period (January 1, 2012 through December 31, 2014). The index date could be assigned at any time during the index period; the follow-up period varied for each patient and was defined as the period from the index date until the last available claim occurring on or before June 30, 2015 (Figure 1). Patients were included in this study if they had an initial claim for diagnoses of CRC (International Classification of Diseases, Ninth Revision [ICD-9] codes 153.00-153.9x, 154.0x, 154.1x) concurrently with metastasis (197.x-198.x) during the index period. All patients were required to be at least 18 years old at the time of the earliest claim for mCRC, have medical and pharmacy enrollment, and have had no chemotherapy in the 90 days prior to index date. Patients were excluded if diagnosed and on active treatment for a second cancer or if enrolled in a clinical trial (as identified by ICD-9 code V70.7) during the index period. Patients with history of Current Procedural Terminology (CPT) codes for hepatectomy (CPT 47120, 47122, 47125, or 47130) were excluded from this study because they represented patients for whom the treatments and biomarker testing may not be indicated. In addition, patients with a claim for c-KIT mutations (CPT 83904) were not included in order to exclude patients who may have gastrointestinal stromal tumors rather than adenocarcinoma of the colon.¹⁴

Study Measures

Demographics and clinical characteristics were evaluated for patients with mCRC. Baseline clinical characteristics included gender, age at diagnosis, diagnosis year, diagnosis type (ie, colon or rectal cancer), payer type, and the Charlson Comorbidity Index (CCI). The CCI was calculated based on ICD diagnosis codes at 12 months prior to diagnosis or treatment initiation as presence of comorbid conditions (not including cancer).¹⁵ Age-adjusted CCI was calculated with age at diagnosis or treatment initiation to account for the impact of age on comorbidity.¹⁶ 

Time to treatment discontinuation (TTD) was evaluated separately by line of therapy and overall. Time on treatment was compared through univariate analysis between patients who were tested for KRAS/RAS mutations and those who were not tested. TTD per chemotherapy line was defined as the first day of a therapeutic regimen to the last claim date for the drug or to the start date of the next line of therapy for patients initiating another line of treatment. When calculating TTD, all other patients were censored at the last date of the data pull.

Because KRAS or expanded RAS mutation testing did not have a single specific CPT code at the time of this study, tumor KRAS/RAS mutation testing was captured by a set of related CPT codes for mCRC molecular diagnostics (listed in Table 1). A single claim for a CPT code listed in Table 1 qualified a patient as KRAS/RAS-tested. CPT codes are as reported, and no line-level audits were performed. The quality of the database was ensured by internal and external validation processes (ie, consistency with prior quarterly data downloads and alignment against values reported in literature and public databases). Outlier and erroneous data were reviewed by a clinician and assessed based on literature and clinical guidelines, as well as clinical experience.

Baseline characteristics were compared between patients who were tested for KRAS/RAS mutations vs those who were not tested, using chi-square and t-tests to assess differences between subgroups (ie, age, payer, and testing status). Odds ratios (ORs) were estimated for potential predictors by fitting multivariate logistic regression models to adjust for patient characteristics, such as odds for KRAS/RAS testing. Multivariable Cox proportional hazards (PH) regression models were used to estimate the risk of discontinuation attributable to prior KRAS/RAS testing (ie, hazard ratio [HR]), adjusting for patient characteristics.

Results

Patient Characteristics

This study identified 4527 patients from the claims database who were treated for mCRC. Of the patients identified, 1787 (39%) had a reported claim for KRAS/RAS testing during the study period (Table 2). There was no significant difference in the proportion of patients for each diagnosis year (2012-2014) who were KRAS/RAS biomarker tested compared to those who were not tested (P = .88). The patients tested for KRAS/RAS status had a similar gender ratio (54% vs 54% male; P = .69), mean age (60.8 vs 61.5 years; P = .06), and CCI at diagnosis (3.98 vs 3.90; P = .47) compared with patients who were not tested. There was no difference in KRAS/RAS testing for patients who were ≥ 75 years of age (n = 665) compared with younger patients: 39.9% of patients < 75 years were KRAS/RAS-tested, while 37.1% of patients ≥ 75 years were KRAS/RAS-tested (P = .18). A greater proportion of KRAS/RAS-tested patients had colon vs rectal cancer (72% vs 65%; P < .0001) and were commercially insured (37% vs 26%; P < .0001) compared with those not tested. The distribution of payer types at diagnosis differed significantly for patients who were tested for KRAS/RAS mutations vs those who were not tested: Medicare (38% vs 42%), Medicaid (18% vs 27%), and other insurers (7% vs 5%) (Table 2). 

ORs reported in Table 3 represent the odds of being tested for a given variable, adjusted for all other covariates in the multivariable model. Adjusted for other patient characteristics, commercial insurance (OR, 1.66; 95% CI, 1.44-1.91), and diagnosis of colon primary site compared to rectum (OR, 1.39; 95% CI, 1.22-1.59) (all P < .001) were associated with higher likelihood of KRAS/RAS testing (Table 3; Figure 2).

Of the patients tested for KRAS/RAS mutations, 62% received testing prior to first-line treatment and 13% received testing during first-line treatment. Patients tested for KRAS/RAS mutations remained on treatment significantly longer in first-line (median, 245 days [95% CI, 232-251] vs 196 days [95% CI, 189-205]), second-line (median, 189 days [95% CI, 168–203] vs 147 days [95% CI, 133-161]), and overall treatment (median, 576 days [95% CI, 491-722] vs 387 days [95% CI, 358-449]) vs those who were not tested for KRAS/RAS mutations (all P < .01) (Table 4; Figure 3). 

HRs were estimated by Cox PH models, adjusting for patient characteristics including sex, race, diagnosis year, age at diagnosis, cancer location (colon vs rectum), comorbidity index at diagnosis, and insurance type (commercial vs noncommercial). Adjusting for these patient characteristics, KRAS/RAS testing was significantly related to a reduced risk of discontinuation in first-line (18% [HR, 0.82; 95% CI, 0.75-0.89]), second-line (18% [HR, 0.82; 95% CI, 0.72-0.93]), and overall (26% [HR, 0.74; 95% CI, 0.66-0.82]) (all P < .01).

Discussion

This retrospective real-world claims data study evaluated KRAS/RAS testing patterns for patients with mCRC, diagnosed from 2012 to 2014, from a US payer claims database representing 129 million covered lives. Overall, these observational data suggest that KRAS/RAS status for patients with mCRC is underdetermined at 39%, with certain subgroups appearing more likely to be tested than others. 

In a similar study using data from the integrated Cancer Registries Network representing 5.5 million covered lives, only 36% of the 1188 patients with mCRC diagnosed from 2004 to 2009 received KRAS testing during their clinical care.¹⁷ Webster et al found that age at diagnosis, comorbid conditions, and survival time from diagnosis were significantly associated with KRAS testing and EGFR inhibitor treatment.¹⁷ This current study of 4527 patients with mCRC found that age at diagnosis and presence of comorbidities were not associated with testing; however, patients with commercial insurance and colon cancer had a higher probability of being tested for KRAS/RAS mutations. 

In previous studies using electronic medical record data from community oncology practices, KRAS testing in newly diagnosed patients increased by over 25% between 2008 and 2011,¹⁸ and patients who tested as KRAS wild-type received more lines of therapy (2.6) than those who tested with a KRAS mutation (2.1).^18,19 This current study demonstrated that KRAS/RAS testing is associated with significantly longer treatment duration for patients with mCRC compared with those not tested. These data suggest that patients under the care of physicians who decide to test for KRAS/RAS mutations are on therapy for a longer period of time than untested patients. Testing patients with mCRC for KRAS/RAS mutation status demonstrates adherence to standard clinical treatment guidelines, which may also correlate with better care. In addition, the availability of test results at the time of first- and second-line disease progression allows for swift and appropriate changes in therapy instead of delaying therapy while awaiting RAS testing, which can be crucial in patients with high burden of disease and pending organ failure. 

Payer type at diagnosis was a potential predictor for KRAS/RAS biomarker testing, as patients with commercial insurance were more likely to be tested than those with Medicare, Medicaid, or other insurers. Several studies have shown that payer status is a significant predictor of patient treatment and outcomes in oncology, with Medicaid patients generally having inferior access to care.^20-22 In addition, payer reimbursement for testing and treatment has been shown to be highly variable between biomarker tests for actionable mutations and their corresponding drugs, such that drugs may be reimbursed by insurers regardless of companion test coverage.²³ It is not known whether this inconsistency between biomarker test and drug reimbursement has an impact on testing patterns in the current treatment landscape for mCRC. 

A limitation of this study is related to the observational nature of the study design. These data were collected from a claims database intended for billing purposes rather than clinical research and may therefore contain misclassification of disease data. The identification of mCRC and KRAS/RAS testing relies on the accuracy of claims coding. Moreover, at the time of the study, KRAS/RAS mutation testing did not have a unique CPT code. Therefore, a set of codes for mCRC molecular diagnostics were used under the assumption that molecular diagnostics performed for a mCRC patient would invariably include KRAS/RAS mutation testing. During the study period, standard-of-care recommendations were to test for activating mutations in KRAS exon 2 but were later broadened to include KRAS and NRAS (exons 2, 3, and 4). This analysis aimed to capture any RAS mutational testing with a minimum of KRAS exon 2 testing and did not distinguish between patients who had tumors genotyped for KRAS exon 2 and patients genotyped for the expanded RAS family of genes. Of note, determination of KRAS/RAS mutation testing via CPT codes submitted in billing records has some inherent imprecision, as tests may be Clinical Laboratory Improvement Amendments Laboratory-Developed Tests that are billed under a hierarchy of applicable subcodes (eg, codes 8100-8800). 

Another constraint for using a claims database is that it includes information on patients for only the effective coverage period by the health plan and does not capture any potential KRAS/RAS testing prior to the mCRC diagnosis or any testing that was paid for out-of-pocket. In addition, several features of clinical interest are not available, such as the biomarker testing results, clinical outcomes of survival, or reasons for treatment discontinuation. Time on treatment may have been influenced by other factors that were potential drivers for the risk of discontinuation (eg, toxicity, patient response, or death), but are not captured in the claims database. 

A caveat of this study is that patients with longer survival may have a better chance of receiving biomarker testing. Of the patients with mCRC tested for KRAS/RAS mutations, 25% received testing after first-line therapy. The correlation of specific regimens with KRAS/RAS testing was outside the scope of this study because treatment patterns were assessed only by overall lines of therapy. 

The efficacy of panitumumab monotherapy is confined to patients with wild-type RAS tumors. In patients with mCRC who received panitumumab monotherapy or panitumumab-FOLFOX4 treatment, mutations in KRAS exon 2 and other expanded RAS were associated with inferior progression-free survival and overall survival.^24,25 Therefore, utilization of an evidence-based clinical pathway to evaluate the status of expanded RAS prior to initiation of anti-EGFR treatment can potentially facilitate the selection of patients most likely to derive benefits from the treatment prescription and can avoid unnecessary treatment-related toxicities.
Conclusion

Despite clinical guidelines that recommend all patients with mCRC receive RAS testing, these US payer claims data suggest that 61% of patients are treated without determining KRAS/RAS status. Furthermore, patients who are tested for KRAS/RAS remain on therapy longer, suggesting that testing for KRAS or expanded RAS mutations contributes to the identification of optimal treatment. Future work is needed to further validate the impact of KRAS/RAS mutation testing results on treatment selection and patient outcomes.

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