Relative value assessment: characterizing the benefit of oncology therapies through diverse survival metrics from a US perspective.

Plain language summary

The efficacy of a cancer therapy is traditionally measured by median overall survival (OS; the time point at which half of the patients receiving therapy have died). However, newer therapies such as immuno-oncology agents have shown long-term survival benefits in some patients that are not adequately captured by median OS. We reviewed survival outcomes in pivotal clinical trials for therapies approved for metastatic cancers in the US between January 1, 2000 and August 31, 2016.

Improvements in median OS, average OS and landmark survival (the proportion of patients alive after receiving therapy for a specific time) with approved therapies were assessed relative to trial comparator arms. Relative clinical value was considered by applying the total cost of therapy per patient to the relative survival improvements.

Survival advantage and relative value of approved agents differed depending on the survival metric assessed. Median OS may undervalue treatments that provide long-term survival benefit, and average OS and landmark survival may provide more accurate measures of such long-term survival. When assessing the value of oncology therapies, decision-makers should consider a diverse range of oncology survival metrics.

Introduction

Substantial unmet needs remain in cancer, and long-term survival continues to be an elusive goal for most patients with advanced cancer. 1 Further complicating treatment goals are the continually rising costs associated with cancer care, which are outpacing other types of healthcare costs. 2 , 3 A variety of factors are driving the budgetary impact of cancer care, including increasing incidence with a growing and aging population, 4 , 5 a shift toward more costly personalized care, 4 increased cancer survivorship, 5 – 7 and increasing availability and adoption of new branded therapies. 8 , 9

Against this backdrop of increasing cancer incidence and healthcare costs, many healthcare budget holders are facing mounting pressure to control costs while funding optimal care for a growing population. 10 Value trade-offs across cancer types are, thus, becoming increasingly important in resource allocation decision-making. Defining value is critical in determining what treatments should be reimbursed. Each stakeholder group (patients, caregivers, physicians, and payers) defines the value of cancer treatment differently, resulting in an ongoing debate and a lack of agreement regarding the meaning of value. 3 , 11 Oncology treatment guidelines generally do not account for treatment costs. Nevertheless, multiple traditionally cost-agnostic provider organizations have created “scorecard”-based frameworks to define the value of oncology treatments, including the American Society of Clinical Oncology (ASCO), 12 , 13 the European Society for Medical Oncology (ESMO), 14 and the Memorial Sloan Kettering Cancer Center (MSKCC). 15 As of 2015, National Comprehensive Cancer Network (NCCN) guidelines have included Evidence Blocks, a visual representation for each agent or regimen of five key value measures, one of which is affordability. The Institute for Clinical and Economic Review has also incorporated economic analyses, but, like the NCCN Evidence Blocks, these use an expert panel-driven rather than a scorecard approach. These initiatives demonstrate increasing concern over escalating healthcare costs.

One challenge in assessing value is identifying the appropriate efficacy metrics. Traditional “gold-standard” efficacy metrics such as median overall survival (OS) or progression-free survival (PFS) focus on a single point, where 50% of the population has had an event. Thus, they are not well suited to reflect the long-term survival benefits of new treatment modalities, such as immuno-oncology agents, which demonstrate prolonged survival in a proportion of patients. 16 Despite this, several common value frameworks utilize median OS as a key driver of value scoring. To capture long-term survival benefits, and thus assess the full value of newer treatment modalities, there is a need to report and evaluate nontraditional efficacy endpoints such as landmark and mean OS. 17 , 18

The objectives of this study were to: 1) compare the value of approved oncology agents, in particular new immuno-oncology agents, as assessed by a variety of efficacy metrics vs median OS, within and between tumor types and 2) apply a recently developed relative value assessment (RVA) tool for conducting both outcomes assessments and cost-value analyses. 19 These analyses were conducted from a US perspective. Application of the RVA tool to clinical trial data may be useful in assessing managed care decision-making.

Methods

This analysis included any therapy approved by the US Food and Drug Administration (FDA) between January 1, 2000 and August 31, 2016, inclusive, for the treatment of stage III/IV of the following cancers: breast cancer, bladder cancer, colorectal cancer (CRC), lymphomas, gastric cancer, glioblastoma multiforme, hepatocellular carcinoma, myelodysplastic syndromes, melanoma, multiple myeloma, non-small cell lung cancer (NSCLC), prostate cancer, renal cell carcinoma (RCC), small cell lung cancer, and squamous cell carcinoma of the head and neck. Single-arm trials were excluded, as survival metrics were evaluated for each drug vs its direct trial comparator. Two kinds of subanalyses were performed: within-tumor analyses and pan-tumor analyses. The within-tumor analyses focused on NSCLC and prostate cancer, as these reflect common cancers, for which baseline survival rates are among the lowest and highest, respectively, across all cancers. 20 The pan-tumor analyses included a selection of tumor types identified as the most common causes of cancer-related deaths in the US (breast cancer, CRC, melanoma, NSCLC, and RCC). 20

Survival metrics

For each agent and its indicated tumor type (prostate, NSCLC, breast cancer, melanoma, RCC, and CRC), survival metrics were obtained from FDA product labels and European Medicines Agency (EMA) Public Assessment Reports, or relevant clinical trial publications in cases where these were not in the FDA label or EMA Public Assessment Report (see Table S1 ). Kaplan–Meier (KM) OS curves were extracted and digitized using the Engauge software package ( http://markummitchell.github.io/engauge-digitizer/ ), allowing for the calculation of mean OS (calculated as the area under the KM curve) and landmark survival at 1, 2, and 3 years for each agent and tumor type. After extracting survival metrics, the difference between an intervention and its trial comparator was calculated.

A confounding factor in the calculation of mean OS is the maturity of data cutoff, which may particularly disadvantage newer agents that have less mature OS data available, particularly those that provide long-term OS benefits. To address this, KM OS curves were digitized, and reconstructed individual patient-level data were generated based on the code from Guyot et al. 21 Parametric distributions, including spline models, were fitted to the reconstructed individual patient-level data to provide extrapolation beyond reported cutoffs at 15 years. The parametric curve with the best fit was determined by goodness-of-fit statistics; specifically, those with the lowest Akaike information criterion were chosen and then the visual best fit was used to validate this selection. A 15-year cutoff was used for all extrapolated curves; an assumption was that at the end of year 15 survival would be 0%. Mean OS and landmark survival were recalculated using this extrapolated curve set for therapies in melanoma, RCC, and NSCLC (see Table S2 ), which were the first three approved indications of immuno-oncology agents.

Cost-value analyses

In addition to calculating survival metrics, relative clinical value across tumor types (breast cancer, melanoma, NSCLC, RCC, and CRC) was assessed in cost-value analyses using the RVA tool by plotting total drug cost vs a given survival outcome. Calculation of total drug costs was based on monthly costs multiplied by therapy duration, as noted by data in the product label, determined based on median duration of administration, median PFS, or median time to progression, ranked in descending order of preference, as available. Loading dose for applicable agents, as indicated by the product label, was also incorporated into total cost. Total drug costs were obtained from the IHS Markit Life Sciences PharmOnline International database. 22 All costs are expressed in US dollars.

For all therapies with available data, the relative value of each product for a given clinical metric was assessed against average value as determined by a regression line calculated from the distribution of the cost-to-outcome ratio as represented by total drug cost (x-axis) vs one of the clinical metrics (y-axis). A value of zero was assigned to the regression line intercept to standardize disease progression across the different evaluated metrics, which then could be used to identify products that could be considered “above average value” (falling above the line) or “below average value” (falling below the line) using those metrics.

Comparisons of cost-value within a single metric were undertaken using a “relative additional patients alive at 1 year per dollar spent” metric, calculated based on reported cutoffs from each drug’s pivotal trial for NSCLC. The cost of avoiding death at 1 year was calculated by multiplying the number needed to treat to avoid a death at 1 year by the per-patient treatment cost. This number was inverted to calculate the number of additional patients alive at 1 year per dollar spent. The agent with the lowest value was set equal to one and used to calculate the relative additional persons alive at 1 year for all other agents.

Results

Survival metrics

In the individual tumor analyses, efficacy results for individual agents varied by survival metric. For treatment of prostate cancer, for which all metrics were based on reported KM OS curve data, abiraterone yielded the highest improvement in 1-year survival rate (13.7%, previously treated, Figure 1A ), whereas sipuleucel-T yielded the highest mean OS improvement (3.6 months, previously untreated, Figure 1B ) and enzalutamide yielded the highest median OS improvement (4.8 months, previously treated, Figure 1C ) among all agents vs their respective trial comparators.

For treatment of NSCLC, nivolumab yielded the highest improvement in 1-year survival rate (18%, previously treated squamous disease) and mean OS (5.0 months, previously treated squamous disease) among all agents vs their respective trial comparators (figures not presented), whereas afatinib yielded the highest improvement in median OS (4.1 months, previously untreated EGFR del19 and L858R mutants, Figure 2A ) based on reported KM curves. In the extrapolated analysis, which helps to account for differences in data maturity, nivolumab again yielded the highest improvement in 3-year survival rate (12.6%, previously treated squamous disease, Figure 2B ) and in mean OS (11.8 months, previously treated squamous disease, Figure 2C ).

In the case of immuno-oncology agents used to treat NSCLC (nivolumab in previously treated disease, irrespective of programmed death ligand 1 [PD-L1] expression and pembrolizumab in previously treated ≥ 1% PD-L1-positive disease; see Table S1 ), the greatest survival benefits vs their respective trial comparators were apparent when mean OS and 3-year survival rate improvements (based on extrapolated curves) were used as the comparative metrics ( Figures 2B and C ). By comparison, when median OS improvement based on reported curves was used to compare agents ( Figure 2A ), the benefits of immuno-oncology drugs vs their respective trial comparators were comparable with those of many targeted alternatives in NSCLC. Furthermore, the magnitude of variation among NSCLC agents across the different survival metrics was greater than that observed in prostate cancer, where immuno-oncology agents were not used.

Cost-value analyses

Results of the pan-tumor cost-value analyses are shown in Figures 3 – 6 . Presentation of these data as a single-variable plot, in terms of the relative number of additional patients alive at 1 year per US dollar spent on a range of treatments for NSCLC, is provided in Figure S1 .

Therapies used for tumors and lines of therapy with higher baseline median survival were generally associated with the greatest absolute median survival gain compared with their trial comparators; that is, in these settings, the same relative risk reduction would result in a larger absolute gain in median OS (eg, first-line melanoma and breast cancer). 23 Using 1-year survival as the metric, some of the agents with greatest benefit vs their trial comparators were for NSCLC, where baseline survival is very low. 23 However, two (docetaxel and pemetrexed) of the three NSCLC agents with the greatest survival gain vs their respective comparators (docetaxel, pemetrexed, and nivolumab) had best supportive care as their trial comparator, providing a low clinical benchmark against which greater efficacy gains can be demonstrated. Similarly, based on the cost-value analyses, nivolumab + ipilimumab appeared less favorable than nivolumab monotherapy in first-line melanoma in terms of the mean OS benefit over their respective trial comparators. The comparator arm for nivolumab + ipilimumab in CheckMate 069 was ipilimumab, 24 which is a higher clinical benchmark than cytotoxic chemotherapy (dacarbazine, the comparator for nivolumab monotherapy in CheckMate 066), 25 making demonstration of relative value more challenging. As with this example, branded combination therapies may be rated as having a lower relative clinical value than their constituent monotherapies. Thus, the relative value of branded combination agents can appear comparable with or even lower than that offered by their constituent monotherapies; therefore, it may be more appropriate to evaluate the value of branded combination regimens separately ( Figure 4 ).

Results varied with the applied survival metric, with some agents achieving a higher cost-value for some metrics, but not others, as can be seen by differences in relative value from 1-year survival rates based on reported KM curves ( Figures 3 and 4 ), median OS based on reported KM curves ( Figure 5 ), and mean OS based on extrapolated curves ( Figure 6 ). For example, the intervention with the greatest increase in median OS was pertuzumab + trastuzumab for breast cancer, at a cost that appeared to provide above-average efficacy benefits compared with other available therapies (as indicated by its relative position over the regression line in Figure 5 ). In contrast, when looking across agents at increases in 1-year survival ( Figure 4 ), pertuzumab + trastuzumab for breast cancer provided a much less favorable efficacy profile (5.2% increase in 1-year survival), and at a cost (more than $196,000 per patient) far in excess of the average value offered (as indicated by its position relative to the regression line). This discrepancy may illustrate limitations in median OS as an efficacy metric, as it cannot take into account any long-term survival benefits after the median has been reached, unlike mean OS and landmark survival analyses.

Discussion

This analysis demonstrated that therapy benefits differed depending on the survival metric used, with evaluations of oncology therapies based on improvements in median OS yielding some very distinct results vs other survival metrics. Although median OS is among the most commonly used metrics in oncology trials, it fails to take into account long-term survival benefits after the median has been reached and, thus, is not well suited to assess the value of immuno-oncology therapies, for which efficacy is typified by KM survival curves showing delayed but sustained separation.

Alternative survival metrics include mean OS and landmark survival rates. In the pan-tumor analysis, some differences in cost-value patterns were also observed with the 1-year survival metric ( Figure 3 ) compared with the mean OS metric ( Figure 6 ). Although median OS provides an estimate that cannot be biased by a small number of outlying cases, it calculates survival for the whole cohort based on only the first 50% of patients who do not survive. 26 , 27 Mean OS offers a more comprehensive assessment of long-term survival benefits, as it captures the complete survival curve, including the “tail”. In terms of value for money, many healthcare payers and health technology assessment agencies consider mean OS as the standard metric for cancer treatment cost-effectiveness analyses. 27 However, a limitation of assessing value using mean OS calculations based on the study duration deemed appropriate by regulatory bodies for each treatment’s Phase III pivotal trial is that duration is not consistent among trials, which may confound comparisons. Although mean OS offers a more comprehensive assessment of long-term survival benefits, using this metric requires extrapolation of KM OS curves beyond reported cutoffs. Extrapolation in this study was undertaken for therapies indicated for NSCLC, RCC, or melanoma (the first three cancers with an approved immuno-oncology agent). Use of digitized KM curves, rather than actual data points, where patient-level data were not available, is a limitation of our analysis. Furthermore, parametric curve selection, particularly with an immature data set, can be subject to interpretation, as distinct curves with similar goodness-of-fit statistics can introduce variability in outcomes.

Landmark survival rates can be highly effective for comparing therapies by enabling survival comparisons after the median has been reached. However, data maturity and cutoffs varied among trials included in this assessment. As selection of a later time point for landmark survival rates could severely constrain the comparator set, 1-year survival rates based on reported KM OS curves (where available) were used. Using such an early time point, however, may not account for long-term survival benefits of selected therapies, and indeed may even precede the median OS cutoff for some tumor types. Utilizing fitted parametric KM curves to provide survival data beyond the reported cutoffs and the selection of landmark survival at a later time point can provide a consistent set of more mature landmark survival readouts, but is subject to limitations, as discussed above.

In addition to survival, health-related quality-of-life (HRQoL) is an important metric that provides detailed information from the patient perspective, and is increasingly being reported in clinical studies. However, unlike survival outcomes, HRQoL is not reported consistently across studies. Furthermore, diversity in HRQoL metrics used across trials, variability in timing of PRO data reporting, and the percentage of patients missing PRO data limit comparability within and across tumor types. 28 Therefore, HRQoL metrics were not included in this analysis.

Our results showed variation in the relative value of the agents assessed, particularly between median OS and other metrics. Nevertheless, the findings showed no clear ideal metric, with variations observed in the relative value of treatments, even between landmark survival rates and mean OS metrics. Moreover, a higher relative survival outcome on a given metric did not necessarily translate into greater economic value. These discrepancies emphasize the need to incorporate a wide range of metrics into assessments of the efficacy benefits of different agents in a pan-tumor as well as in individual tumor comparison of value, or to be able to appropriately target value metrics to the agents of interest.

Pan-tumor value comparisons should be interpreted with caution owing to heterogeneity between trials (particularly variations in comparators, but also in populations, study design, outcomes, and timing of assessments). Furthermore, baseline survival expectations differ among tumor types and lines of therapy and must be considered when evaluating relative value so as not to discriminate unfairly against agents that treat cancers with the highest unmet need. Although the ASCO Value in Cancer Care Task Force has expressed concern about cross-trial comparisons due to potential biases, the task force has also suggested that the ASCO value framework tool could be used to facilitate individual patient treatment decision-making based on data from multiple trials for a specific indication. 13

Another factor that may affect relative value is variation in patient crossover rates from the control to the active agent arm, which can confound OS results. For example, in Figure 4 , the two regimens with the greatest survival benefits (lenvatinib + everolimus and cobimetinib + vemurafenib) were from trials where crossover was not allowed, whereas the regimen with the next highest survival benefit (nivolumab + ipilimumab) was from a trial where more than 55% of patients in the ipilimumab arm crossed over to receive nivolumab + ipilimumab. Pembrolizumab, which also had ipilimumab as its trial comparator for first-line and second-line treatment of melanoma, 29 appeared to offer a mean survival benefit vs ipilimumab of a similar magnitude to that offered by nivolumab + ipilimumab vs ipilimumab for first-line treatment of melanoma; however, crossover was not permitted in the pembrolizumab trial.

An additional limitation of RVA is that it involves naïve trial comparisons, in distinct cancer types and lines of therapy, and in different patient populations. This includes making comparisons of therapies approved in biomarker-selected vs nonbiomarker selected populations. For example, in Figure 5 , the anti-PD-1 agent pembrolizumab appears to produce a survival benefit in previously treated NSCLC that is within the range of the anti-PD-1 agent nivolumab in previously treated squamous and non-squamous NSCLC, but at a lower cost. However, as of the analysis end date, pembrolizumab was only approved in PD-L1+ patients in this line of therapy, whereas nivolumab was approved in an all-comers population. As an alternative, more complex meta-analytic approaches (if feasible given available data resources), instead of this type of pan-tumor value assessment tool, could be used to reduce bias. The results of the individual tumor analyses for NSCLC and prostate cancer can address some of these limitations to an extent, and provide an alternate means for assessing the relative value assessment approach.

Another limitation in this cost-value analysis is that each therapy was assigned a cost based on reported monthly cost, multiplied by therapy duration (median duration of administration, median PFS, or median time to progression, based on available data), which varied between trials. Although costs could be underestimated by using median instead of mean therapy duration, this bias was assumed to be relatively consistent across agents because similar methods were used to estimate costs for all comparators. Furthermore, assigned cost-value only incorporated drug cost as adjusted for duration and loading dose, and did not take into account symptom burden, treatment safety profile, HRQoL, health-care resource utilization, or use of postprogression therapies. These factors are particularly important with newer, frequently less toxic therapies compared with traditional chemotherapy. Additionally, the cost-value analysis did not take into account drug cost discounting, which might be available among certain payers, or compassionate use programs or patient rebates. As with any complex analysis that entails input of a large and diverse body of evidence, only FDA-approved drugs during the study period (January 1, 2000—August 21, 2016) are included; later approvals were not included in the analysis. Finally, the predefined inclusion criteria may have resulted in the evaluated agents not being representative of the entire treatment landscape, thus potentially introducing selection bias.

Despite the limitations noted here, from which no value assessment tool is exempt, the RVA tool utilized in this study provides a framework for comparing oncology therapies both within and across tumor types. As such, it adds to the range of value tools and metrics available that include treatment costs for valuing oncology treatments. 12 – 15 , 30

US payers often look to NCCN and ASCO clinical guidelines as part of their reimbursement decision-making, 31 which either do not currently account for treatment costs (ASCO) or provide a five-level affordability rating (NCCN). Several of the existing value scorecards come from provider bodies (ASCO, NCCN, and MSKCC), suggesting that traditionally cost-agnostic stakeholders are becoming increasingly concerned over the escalating costs of care. As the cost of care continues to rise, payers may be increasingly forced to make value trade-offs, and this tool can be used to support funding prioritization.

While some of these tools base scores heavily on median OS or PFS benefits, the RVA tool incorporates a wide range of efficacy metrics that, unlike median OS, can account for long-term survival benefits. As shown in this study, valuing oncology therapies based on improvements in median OS alone potentially undervalues new treatment modalities associated with long-term survival benefits. Ongoing review and discussion of the range of indices to define and measure cost-effectiveness is needed to reach a consensus, or at least more broadly accepted criteria, for defining value, particularly for novel therapies.

Further research could include a systematic methodological standardization for parametric curve selection for the calculation of mean OS and long-term landmark OS endpoints alongside aligning best value metrics and reconciling when results differ. The RVA approach demonstrated here can compare a wide range of efficacy metrics for treatments across a broad range of cancers that can be utilized to better inform decisions by payers and providers in managed care.

Conclusions

In the era of expanding healthcare costs and budgetary pressure, payers will increasingly focus on areas of high and expanding costs, of which cancer care is prominent. Physicians are also becoming attuned to treatment costs, and it is notable that many of the value frameworks and scorecards are provider-led. Although median OS is the traditional gold standard oncology efficacy metric, it should not be considered in isolation of other metrics, because it does not capture long-term survival benefits, the ultimate goal of cancer treatment. The metric selected to define the value of an oncology therapy must be carefully considered. Value frameworks incorporating diverse metrics, such as the one presented here, are needed for comprehensive value assessments of cancer therapies, particularly for new treatment modalities such as immuno-oncology.

Supplementary materials

Additional persons alive at 1 year vs respective trial comparator (relative to crizotinib) for NSCLC.

Notes: Based on the number needed to treat for an additional person to be alive at 1 year, based on reported cutoffs from each drug’s pivotal trial. Includes FDA-approved interventions in NSCLC for which the relevant Kaplan–Meier overall survival curves were available; trials with comparators of placebo or best supportive care were excluded.

Abbreviations: 1L, first line; 2L, second line; 3L, third line; Bev, bevacizumab; Carbo, carboplatin; Chemo, chemotherapy; Cis, cisplatin; Criz, crizotinib; Doce, docetaxel; Erlot, erlotinib; FDA, Food and Drug Administration; Gefit, gefitinib; Nab-p, nab-paclitaxel; Neci, necitumumab; Nivo, nivolumab; NSQ, nonsquamous; Pac, paclitaxel; Pembro, pembrolizumab; Pemet, pemetrexed; PT, platinum; Ramu, ramucirumab; SQ, squamous.

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36 Rosell R Carcereny E Gervais R Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial Lancet Oncol 2012 13 3 239 246 22285168 10.1016/S1470-2045(11)70393-X

37 Tarceva® (erlotinib) tablets, for oral use [prescribing information] South San Francisco, CA Genentech, Inc. 2015 Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021743s021lbl.pdf Accessed November 18, 2016

38 Erlotinib 25, 100 and 150 mg film-coated tablets (Tarceva®). SMC 749/11 2012 Available from: http://www.scottishmedicines.org.uk/files/advice/erlotinib_Tarceva_FINAL_December_2011_for_website.pdf Accessed November 18, 2016

39 Tarceva film-coated tablets [summary of product characteristics] Welwyn Garden City, UK Roche 2010 Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000618/WC500033994.pdf Accessed November 18, 2016

40 Shepherd FA Rodrigues PJ Ciuleanu T Erlotinib in previously treated non–small-cell lung cancer N Engl J Med 2005 353 2 123 132 16014882 10.1056/NEJMoa050753

41 Scientific discussion: Tarceva 2005 Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Scientific_Discussion/human/000618/WC500033991.pdf Accessed November 18, 2016

42 Iressa (gefitinib) tablets for oral use [prescribing information] Wilmington, DE AstraZeneca 2015 Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206995s000lbl.pdf Accessed November 18, 2016

43 Gefitinib 250mg film-coated tablets (Iressa) SMC 615/10 2010 Available from: https://www.scottishmedicines.org.uk/files/advice/gefitinib_Iressa_RESUBMISSION_FINAL_November_2010_for_website.pdf Accessed November 18, 2016

44 Socinski MA Bondarenko I Karaseva NA Weekly nab -paclitaxel in combination with carboplatin versus solvent-based paclitaxel plus carboplatin as first-line therapy in patients with advanced non–small-cell lung cancer: final results of a phase III trial J Clin Oncol 2012 30 17 2055 2062 22547591 10.1200/JCO.2011.39.5848

45 Thatcher N Hirsch FR Szczesna A A randomized, multicenter, open-label, phase III study of gemcitabine-cisplatin (GC) chemotherapy plus necitumumab (IMC-11F8/LY3012211) versus GC alone in the first-line treatment of patients (pts) with stage IV squamous non-small cell lung cancer (sq-NSCLC) J Clin Oncol 2014 32 5s abstr 8008

46 Thatcher N Hirsch FR Luft AV Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): an open-label, randomised, controlled phase 3 trial Lancet Oncol 2015 16 7 763 774 26045340 10.1016/S1470-2045(15)00021-2

47 Assessment report: Portrazza (necitumumab). Procedure no. EMEA/H/C/003886/0000 2015 Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/003886/WC500202696.pdf Accessed November 18, 2016

48 Brahmer J Reckamp KL Baas P Nivolumab versus docetaxel in advanced squamous-cell non–small-cell lung cancer N Engl J Med 2015 373 2 123 135 26028407 10.1056/NEJMoa1504627 PMC4681400

49 Spigel DR Reckamp KL Rizvi NA A phase III study (Check-Mate 017) of nivolumab (NIVO; anti-programmed death-1 [PD-1]) vs docetaxel (DOC) in previously treated advanced or metastatic squamous (SQ) cell non-small cell lung cancer (NSCLC) J Clin Oncol 2015 33 abstr 8009

50 Borghaei H Brahmer JR Horn L Nivolumab (nivo) vs docetaxel (doc) in patients (pts) with advanced NSCLC: CheckMate 017/057 2-y update and exploratory cytokine profile analyses J Clin Oncol 2016 34 abstr 9025

51 Paz-Ares L Horn L Borghaei H Phase III, randomized trial (CheckMate 057) of nivolumab (NIVO) versus docetaxel (DOC) in advanced non-squamous cell (non-SQ) non-small cell lung cancer (NSCLC) J Clin Oncol 2015 33 abstr LBA109 10.1200/JCO.2017.74.3062 PMC6075826 29023213

52 Herbst RS Baas P Kim DW Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial Lancet 2016 387 10027 1540 1550 26712084 10.1016/S0140-6736(15)01281-7

53 Garon EB Herbst RS Kim D-W Pembrolizumab vs docetaxel for previously treated advanced NSCLC with a PD-L1 tumor proportion score (TPS) 1%-49%: results from KEYNOTE-010 J Clin Oncol 2016 34 abstr 9024

54 Baas P Garon EB Herbst RS Relationship between level of PD-L1 expression and outcomes in the KEYNOTE-010 study of pembrolizumab vs docetaxel for previously treated, PD-L1–positive NSCLC J Clin Oncol 2016 34 abstr 9015

55 Alimta powder for concentrate for solution for infusion [summary of product characteristics] Utrecht, The Netherlands Eli Lilly Nederland B.V. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000564/WC500025611.pdf Accessed November 18, 2016

56 Assessment report: Alimta (pemetrexed) Procedure no. EMEA/H/C/000564/II/0033 2011 Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Assessment_Report_-_Variation/human/000564/WC500118770.pdf Accessed November 18, 2016

57 Pemetrexed, 100 mg, 500 mg powder for concentrate for solution for infusion (Alimta) SMC 531/09 2009 Available from: http://www.scottishmedicines.org.uk/files/pemetrexed_Alimta_FINAL_Janu-ary_2009_for_website.pdf_16.02.09.pdf Accessed November 18, 2016

58 Scagliotti GV Parikh P von Pawel J Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non–small-cell lung cancer J Clin Oncol 2008 26 21 3543 3551 18506025 10.1200/JCO.2007.15.0375

59 Pemetrexed, 100 mg & 500 mg, powder for concentrate for solution for infusion (Alimta®). SMC 770/12 2014 Available from: https://www.scottishmedicines.org.uk/SMC_Advice/Advice/770_12_peme-trexed_Alimta/pemetrexed_Alimta_full Accessed November 18, 2016

60 Schuette W Nieman B Schneider CP 65 plus: a randomized phase III trial of pemetrexed and bevacizumab vs. pemetrexed, bevacizumab and carboplatin as 1st line treatment for elderly patients with advanced non-squamous, non-small cell lung cancer (NSCLC)-a subgroup analysis of age and gender Eur J Cancer 2015 51 S623 abstr 3077

61 Kasahara K Kiura K Nogami N Phase 2: docetaxel with or without ramucirumab as therapy for non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) activating mutations after prior EGFR tyrosine kinase inhibitor (TKI) and platinum-based chemotherapy Eur J Cancer 2015 51 S620 abstr 3072

62 CHMP assessment report: Inlyta (axitinib). Procedure no. EMEA/H/C/002406 2012 Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002406/WC500132190.pdf Accessed November 18, 2016

63 Motzer RJ Escudier B Tomczak P Axitinib versus sorafenib as second-line treatment for advanced renal cell carcinoma: overall survival analysis and updated results from a randomised phase 3 trial Lancet Oncol 2013 14 6 552 562 23598172 10.1016/S1470-2045(13)70093-7

64 Inlyta® (axitinib) tablets for oral administration [prescribing information] New York, NY Pfizer Inc 2014 Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/202324s002lbl.pdf Accessed November 18, 2016

65 Cabometyx™ (cabozantinib) tablets, for oral use [prescribing information] South San Francisco, CA Exelixis, Inc. 2016 Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/208692s000lbl.pdf Accessed November 18, 2016

66 Choueiri TK Escudier B Powles T Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial Lancet Oncol 2016 17 7 917 927 27279544 10.1016/S1470-2045(16)30107-3

67 Afinitor® (everolimus) tablets for oral administration [prescribing information] East Hanover, NJ Novartis Pharmaceuticals Corporation 2015 Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/022334s030lbl.pdf Accessed November 18, 2016

68 Porta C Calvo E Climent MA Efficacy and safety of everolimus in elderly patients with metastatic renal cell carcinoma: an exploratory analysis of the outcomes of elderly patients in the RECORD-1 Trial Eur Urol 2012 61 4 826 833 22297244 10.1016/j.eururo.2011.12.057 PMC4142675

69 Everolimus, 5 mg and 10 mg tablets (Afinitor®). SMC 872/13 2013 Available from: http://www.scottishmedicines.org.uk/files/advice/everolimus_Afinitor_FINAL_June_2013_amended_03.07.13_for_website.pdf Accessed November 18, 2016

70 CHMP assessment report for Afinitor (everolimus). Procedure no. EMEA/H/C/001038 2009 Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/001038/WC500022817.pdf Accessed November 18, 2016

71 Afinitor tablets. Afinitor 2.5 mg tablets [summary of product characteristics] Camberley, UK Novartis Europharm Limited Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/001038/WC500022814.pdf Accessed November 18, 2016

72 Lenvima® (lenvatinib) capsules, for oral use [prescribing information] Woodcliff Lake, NJ Eisai Inc. 2016 Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/206947s003lbl.pdf Accessed November 18, 2016

73 Hutson TE Dutcus TE Ren M Baig MA Fishman MN Subgroup analyses and updated overall survival from the phase II trial of lenvatinib (LEN), everolimus (EVE), and LEN+EVE in metastatic renal cell carcinoma (mRCC) J Clin Oncol 2016 34 abstr 4553

74 Motzer RJ Hutson TE Glen H Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial Lancet Oncol 2015 16 15 1473 1482 26482279 10.1016/S1470-2045(15)00290-9

75 Opdivo 10mg/mL concentrate for solution for infusion [summary of product characteristics] Uxbridge, UK Bristol-Myers Squibb Pharma EEIG Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/003985/WC500189765.pdf Accessed November 18, 2016

76 Sharma P Escudier B McDermott DF CheckMate 025: a randomized, open-label, phase III study of nivolumab (NIVO) versus everolimus (EVE) in advanced renal cell carcinoma (RCC) Eur J Cancer 2015 51 S708 abstr 3LBA

77 ClinicalTrials.gov Identifier: NCT00334282 . Safety and efficacy of GW786034 (pazopanib) in metastatic renal cell carcinoma 2006 Available from: https://clinicaltrials.gov/ct2/show/NCT00334282?term=00334282&rank=1 Accessed November 18, 2016

78 Sternberg CN Davis ID Mardiak J Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial J Clin Oncol 2010 28 6 1061 1068 20100962 10.1200/JCO.2009.23.9764

79 Escudier B Eisen T Stadler WM Sorafenib for treatment of renal cell carcinoma: final efficacy and safety results of the phase III treatment approaches in renal cancer global evaluation trial J Clin Oncol 2009 27 20 3312 3318 19451442 10.1200/JCO.2008.19.5511

80 Nexavar (sorafenib) tablets, oral [prescribing information] Whippany, NJ Bayer HealthCare Pharmaceuticals Inc. 2013 Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021923s016lbl.pdf Accessed November 18, 2016

81 Sorafenib 200mg tablets (Nexavar®). SMC 321/06 2006 Available from: http://www.scottishmedicines.org.uk/files/sorafenib_200mg_tablets_Nexavar_321_06.pdf Accessed November 18, 2016

82 Nexavar 200mg film-coated tablets [summary or product characteristics] Berlin, Germany Bayer Pharma AG Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000690/WC500027704.pdf Accessed November 18, 2016

83 CHMP extension of indication variation assessment report: Nexavar. Procedure no. EMEA/H/C/000690/II/0035 2014 Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Assessment_Report_-_Variation/human/000690/WC500168976.pdf Accessed November 18, 2016

84 Motzer RJ Hutson TE Tomczak P Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma J Clin Oncol 2009 27 22 3584 3590 19487381 10.1200/JCO.2008.20.1293 PMC3646307

85 ClinicalTrials.gov Identifier: NCT00083889 . SU011248 versus interferon-alfa as first-line systemic therapy for patients with metastatic renal cell carcinoma 2004 Available from: https://clinicaltrials.gov/ct2/show/NCT00083889?term=A6181034&rank=1 Accessed November 18, 2016

86 Sutent® (sunitinib malate) capsules, oral [prescribing information] New York, NY Pfizer Inc 2015 Available from: http://www.access-data.fda.gov/drugsatfda_docs/label/2015/021938s028s029lbl.pdf Accessed November 18, 2016

87 Sutent hard capsules [summary of product characteristics] Sandwich, Kent, UK Pfizer Limited Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000687/WC500057737.pdf Accessed November 18, 2016

88 Motzer RJ Hutson TE Tomczak P Sunitinib versus interferon alfa in metastatic renal-cell carcinoma N Engl J Med 2007 356 2 115 124 17215529 10.1056/NEJMoa065044

89 Scientific discussion: Torisel 2007 Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Scientific_Discussion/human/000799/WC500039915.pdf Accessed November 18, 2016

90 ClinicalTrials.gov Identifier: NCT00065468 . Study evaluating interferon and CCI-779 in advanced renal cell carcinoma (ARCC) 2003 Available from: https://clinicaltrials.gov/ct2/show/results/NCT00065468?term=NCT00065468&rank=1&sect=X01256#all Accessed November 18, 2016

91 Torisel Kit (temsirolimus) injection, for intravenous infusion only [prescribing information] Philadelphia, PA Wyeth Pharmaceuticals Inc. 2015 Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/022088s018lbl.pdf Accessed November 18, 2016

92 Assessment report for Abraxane (paclitaxel). Procedure no. EMEA/H/C/778 2007 Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/000778/WC500020433.pdf Accessed November 18, 2016

93 Abraxane 5 mg/ml powder for suspension for infusion [summary of product characteristics] Uxbridge, UK Celgene Europe Limited Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000778/WC500020435.pdf Accessed November 18, 2016

94 Gradishar WJ Tjulandin S Davidson N Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer J Clin Oncol 2005 23 31 7794 7803 16172456 10.1200/JCO.2005.04.937

95 Scientific discussion: Xeloda 2005 Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Scientific_Discussion/human/000316/WC500058145.pdf Accessed November 18, 2016

96 Xeloda (capecitabine) tablets, for oral use [prescribing information] South San Francisco, CA Genentech USA, Inc. 2015 Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020896s037lbl.pdf Accessed November 18, 2016

97 Cortes J O’Shaughnessy J Loesch D Eribulin monotherapy versus treatment of physician’s choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study Lancet 2011 377 9769 914 923 21376385 10.1016/S0140-6736(11)60070-6

98 Eribulin 0.44 mg/mL solution for injection (Halaven®). SMC 726/11 2011 Available from: http://www.scottishmedicines.org.uk/files/advice/eribulin_Halaven_FINAL_September_2011_for_website.pdf Accessed November 18, 2016

99 Halaven 0.44 mg/ml solution for injection [summary of product characteristics] Hatfield, Hertfordshire, UK Eisai Europe Ltd 2015 Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002084/WC500105112.pdf Accessed November 18, 2016

100 Assessment report: Halaven eribulin. Procedure no. EMEA/H/C/002084/II/0011 2014 Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Assessment_Report_-_Variation/human/002084/WC500170478.pdf Accessed November 18, 2016

101 Herceptin 150 mg powder for concentrate for solution for infusion [summary of product characteristics] Welwyn Garden City Roche Registration Limited Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000278/WC500074922.pdf Accessed November 18, 2016

102 M77001 . A multicenter, randomized comparative study on the efficacy and safety of Herceptin (trastuzumab) plus docetaxel (Taxotere) versus docetaxel alone as first line treatment in patients with HER2-positive metastatic breast cancer Available from: http://www.roche-trials.com/studyResultGet.action?studyResultNumber=M77001 Accessed November 18, 2016

103 Marty M Cognetti F Maraninchi D Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2–positive metastatic breast cancer administered as first-line treatment: the M77001 study group J Clin Oncol 2005 23 4265 4274 15911866 10.1200/JCO.2005.04.173

104 CHMP assessment report: Herceptin (trastuzumab). Procedure no. EMEA/H/C/000278 2013 Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Assessment_Report_-_Variation/human/000278/WC500153233.pdf Accessed November 18, 2016

105 Herceptin® (trastuzumab) intravenous infusion [prescribing information] South San Francisco, CA Genentech, Inc. 2015 Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/103792s5327lbl.pdf Accessed November 18, 2016

106 Assessment report: Kadcyla (trastuzumab emtansine). Procedure no. EMEA/H/C/002389/0000 2013 Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002389/WC500158595.pdf Accessed November 18, 2016

107 Kadcyla® (ado-trastuzumab emtansine) for injection, for intravenous use [prescribing information] South San Francisco, CA Genentech, Inc. 2015 Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/125427s087lbl.pdf Accessed November 18, 2016

108 Verma S Miles D Gianni L Trastuzumab emtansine for HER2-positive advanced breast cancer N Engl J Med 2012 367 19 1783 1791 23020162 10.1056/NEJMoa1209124 PMC5125250

109 Kadcyla 100 mg, 160 mg powder for concentrate for solution for infusion [summary of product characteristics] Welwyn Garden City Roche Registration Limited Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002389/WC500158593.pdf Accessed November 18, 2016

110 Baselga J Cortés J Kim SB Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer N Engl J Med 2012 366 2 109 119 22149875 10.1056/NEJMoa1113216 PMC5705202

111 Perjeta® (pertuzumab) injection, for intravenous use [prescribing information] South San Francisco, CA Genentech, Inc. 2015 Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/125409s105lbl.pdf Accessed November 18, 2016

112 Pertuzumab 30 mg/mL concentrate for solution for infusion (Perjeta®). SMC 897/13 2013 Available from: http://www.scottishmedicines.org.uk/files/advice/pertuzumab_Perjeta_FINAL_September_2013_Amended_041013_website.pdf Accessed November 18, 2016

113 Perjeta 420mg concentrate for solution for infusion [summary of product characteristics] Welwyn Garden City Roche Registration Limited Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002547/WC500140980.pdf Accessed November 18, 2016

114 Assessment report: Perjeta (pertuzumab). Procedure no. EMEA/H/C/002547/II/0010 2015 Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Assessment_Report_-_Variation/human/002547/WC500191986.pdf Accessed November 18, 2016

115 Ellis PA Barrios CH Eiermann W Phase III, randomized study of trastuzumab emtansine (T-DM1) ± pertuzumab (P) vs trastuzumab + taxane (HT) for first-line treatment of HER2-positive MBC: primary results from the MARIANNE study J Clin Oncol 2015 33 : abstr 507

116 Schwartzberg LS Franco SX Florance A O’Rourke L Maltzman J Johnston S Lapatinib plus letrozole as first-line therapy for HER-2 + hormone receptor–positive metastatic breast cancer Oncologist 2010 15 2 122 129 20156908 10.1634/theoncologist.2009-0240 PMC3227947

117 Assessment report for Tyverb (lapatinib). Procedure no. EMA/H/C/795/II/0004 Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Assessment_Report_-_Variation/human/000795/WC500091824.pdf Accessed November 18, 2016

118 Cameron D Casey M Press M A phase III randomized comparison of lapatinib plus capecitabine versus capecitabine alone in women with advanced breast cancer that has progressed on trastuzumab: updated efficacy and biomarker analyses Breast Cancer Res Treat 2008 112 3 533 543 18188694 10.1007/s10549-007-9885-0

119 Cameron D Casey M Oliva C Newstat B Imwalle B Geyer CE Lapatinib plus capecitabine in women with HER-2–positive advanced breast cancer: final survival analysis of a phase III randomized trial Oncologist 2010 15 9 924 934 20736298 10.1634/theoncologist.2009-0181 PMC3228041

120 Assessment report for Tykerb (lapatinib). Procedure no. EMEA/H/C/795 2008 Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/000795/WC500044960.pdf Accessed November 18, 2016

121 Lapatinib, 250 mg film-coated tablets (Tyverb) SMC 526/09 2010 Available from: http://www.scottishmedicines.org.uk/files/lapatinib_Tyverb_RESUBMISSION_Final_June_2010.pdf Accessed November 18, 2016

122 Avastin 25 mg/ml concentrate for solution for infusion [summary of product characteristics] Welwyn Garden City Roche Registration Limited Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000582/WC500029271.pdf Accessed November 18, 2016

123 Saltz LB Clarke S Díaz-Rubio E Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study J Clin Oncol 2008 26 12 2013 2019 18421054 10.1200/JCO.2007.14.9930

124 Hurwitz HI Yi J Ince W Novotny WF Rosen O The clinical benefit of bevacizumab in metastatic colorectal cancer is independent of K-ras mutation status: analysis of a phase III study of bevacizumab with chemotherapy in previously untreated metastatic colorectal cancer Oncologist 2009 14 1 22 28 10.1634/theoncologist.2008-0213 19144677

125 Bevacizumab, 100 mg and 400 mg vials (Avastin®). SMC 469/08 2008 Available from: http://www.scottishmedicines.org.uk/files/bevacizumab_Avastin_FINAL_May_2008_for_website.pdf Accessed November 18, 2016

126 Van CE Hoff PM Harper P Oral capecitabine vs intravenous 5-fluorouracil and leucovorin: integrated efficacy data and novel analyses from two large, randomised, phase III trials Br J Cancer 2004 90 6 1190 1197 15026800 10.1038/sj.bjc.6601676 PMC2409640

127 Van CE Lenz HJ Köhne CH Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer J Clin Oncol 2015 33 7 692 700 25605843 10.1200/JCO.2014.59.4812

128 Erbitux 5 mg/mL solution for infusion [summary of product characteristics] Darmstadt, Germany Merck KGaA Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000558/WC500029119.pdf Accessed November 18, 2016

129 Cetuximab, 100 mg/20 mL and 500 mg/100 mL solution for intravenous infusion (Erbitux) SMC 543/09 2010 Available from: http://www.scottishmedicines.org.uk/files/cetuximab_Erbitux_RESUBMISSION_FINAL_January_2010_for_website.pdf Accessed November 18, 2016

130 Ebbitux® (cetuximab) injection, for intravenous infusion [prescribing information] Branchburg, NJ ImClone LLC 2015 Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/125084s262lbl.pdf Accessed November 18, 2016

131 Van CE Köhne CH Láng I Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status J Clin Oncol 2011 29 15 2011 2019 21502544 10.1200/JCO.2010.33.5091

132 Grothey A Van CE Sobrero A Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial Lancet 2013 381 9863 303 312 23177514 10.1016/S0140-6736(12)61900-X

133 Assessment report: Stivarga (regorafenib). Procedure no. EMEA/H/C/002573/0000 2013 Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002573/WC500149166.pdf Accessed November 18, 2016

134 Stivarga® (regorafenib) tablets, for oral use [prescribing information] Whippany, NJ Bayer HealthCare Pharmaceuticals Inc. 2015 Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/203085s004lbl.pdf Accessed November 18, 2016

135 Lonsurf (trifluridine and tipiracil) tablets, for oral use [prescribing information] Princeton NJ Taiho Oncology, Inc. 2015 Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/207981s000lbl.pdf Accessed November 18, 2016

136 Assessment report: Lonsurf (trifluridine/tipiracil). Procedure no. EMEA/H/C/003897/0000 2016 Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/003897/WC500206248.pdf Accessed November 18, 2016

137 Mayer RJ Van CE Falcone A Randomized trial of TAS-102 for refractory metastatic colorectal cancer N Engl J Med 2015 372 20 1909 1919 25970050 10.1056/NEJMoa1414325

138 Douillard JY Siena S Cassidy J Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study J Clin Oncol 2010 28 31 4697 4705 20921465 10.1200/JCO.2009.27.4860

139 Douillard JY Oliner KS Siena S Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer N Engl J Med 2013 369 11 1023 1034 24024839 10.1056/NEJMoa1305275

140 Douillard JY The role of EGFR inhibition in mCRC Presented at: ESMO Preceptorship in Colorectal Cancer 2015 March 28, 2015 Singapore

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165 Provenge® (sipuleucel-T) suspension for intravenous infusion Seattle, WA Dendreon Corporation 2010 Available from: http://www.fda.gov/downloads/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/UCM210031.pdf Accessed November 18, 2016

Acknowledgments

Medical writing assistance was provided by Karen Smoyer, PhD, and Beth Burke, PhD, CMPP, of Evidence Scientific Solutions Inc, and was funded by Bristol-Myers Squibb. Bristol-Myers Squibb commissioned and funded this study; participated in the analysis and interpretation of the data; contributed to the preparation, review, and approval of the article for publication; and covered costs for medical writing and editorial assistance.

Disclosure

JWS and AJG report employment by Bristol-Myers Squibb during the conduct of this study; JWS is a stockholder of Bristol-Myers Squibb. RM, AA, and EA are employed by PAREXEL International, the entity paid for analyses in this manuscript. This manuscript includes information presented at the International Society for Pharmacoeconomics and Outcomes Research 21st Annual International Meeting, May 2016, in Washington DC, USA and published as a congress abstract at the following site: https://www.valueinhealthjour-nal.com/article/S1098-3015(16 )01616-8/fulltext.

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