Cost-effectiveness analysis (CEA) of bevacizumab (Bev) in first- and second-line treatment of metastatic colorectal cancer (mCRC).

Se transcribe un abstract que va a ser presentado en el Meeting de ASCO de este año, en el cual se hace un análisis de los costos del bevacizumab indicados en primera y segunda línea, mostrando los gastos excesivos para pobres resulados.

Author(s): Daniel A. Goldstein, Qiushi Chen, David H. Howard, Joseph Lipscomb, Turgay Ayer, Bassel F. El-Rayes, Christopher Flowers; Winship Cancer Institute of Emory University, Atlanta, GA; H. Milton Stewart School of Industrial & Systems Engineering, Georgia Institute of Technology, Atlanta, GA; Emory University Department of Health Policy and Management, Atlanta, GA; Rollins School of Public Health; Winship Cancer Institute, Atlanta, GA; H. Milton Stewart School of Industrial and Systems Engineering, Georgia Institute of Technology, Atlanta, GA; The Winship Cancer Institute of Emory University, Atlanta, GA; Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA

Abstract:

Background: The addition of Bev to 5-Fluorouracil (5-FU)-based chemotherapy is the standard of care for previously untreated mCRC. A recent randomized trial demonstrated a 1.4 month increase in median overall survival (OS) when Bev is continued beyond the first progression, thus making it standard practice to use Bev with 5-FU based chemotherapy in both first- and second-line. International CEAs have evaluated Bev in the 1st-line setting. The objective of this study is to determine the cost effectiveness of Bev in the 1st line setting and when continued beyond progression from the US-payer perspective.Methods: We developed two Markov models to compare the cost and effectiveness of 5-FU, leucovorin and oxaliplatin (FOLFOX) with or without Bev in the first-line treatment, and subsequent chemotherapy with or without Bev in the second-line treatment of mCRC. Weibull models were fitted to the published survival curves, and were used to extrapolate the cause-specific mortality and progression risks. Costs for administration and management of adverse events were based on Medicare reimbursement rates for hospital and physician services, and drug costs based on the Medicare average sale prices (all in 2013 US $). Health outcomes were measured in life years (LY) and quality-adjusted life years (QALYS). The simulated OS and progression free survival (PFS) were validated by the fitted survival models. Model robustness was addressed by univariate and probabilistic sensitivity analyses (PSA). Results: Using Bev in first-line therapy provided an additional 0.289 QALYs (0.412 LYs) at a cost of $69,381. The incremental cost-effectiveness ratio (ICER) was $240,195/QALY. Continuing Bev beyond progression provided an additional 0.108 QALYs (0.167 LYs) at a cost of $23,788. The ICER was $219,742/QALY. In all one way sensitivity analyses, the ICER of Bev was > $100,000/QALY. The ICER of Bev was greater than $100,000/QALY in > 99.9% of PSAs. Conclusions: This is the first US based CEA of Bev in mCRC. Bev provides minimal incremental benefit at high incremental cost per QALY in both the first and second-line setting. The ICER of Bev could be improved by use of an effective biomarker to select patients most likely to benefit.

POBRES RESULTADOS DEL REGORAFENIB EN CÁNCER COLORRECTAL METASTÁTICO

Si bien los estudios preclínicos demuestran utilidad de esta molécula mutiinhibidora de kinasas y agente antiangiogénico, independientemente de lo que transcribiré mas adelante los resultados son muy escasos como para tomar en consideración este tratamiento  en los pacientes. Estos paupérrimos resultados se logran a expensas de una importante toxicidad.

The CORRECT Study: Regorafenib vs Best Supportive Care in Patients With Colorectal Cancer Who Have Progressed on Standard Therapy

Thomas H. Cartwright, MD:
For oncologists, finding more effective therapies for patients with advanced, metastatic colorectal cancer that has progressed on standard therapy is a high unmet clinical need—the vast majority of patients with metastatic colorectal cancer receives only palliative care. We all see patients who fail first-, second-, and third‑line therapy. These patients have few options for salvage therapy other than a clinical trial.

Regorafenib is an oral agent similar to sorafenib but targets a wider, slightly different group of tyrosine kinases including angiogenic kinases (VEGFR1-3, TIE2), stromal kinases (PDGFR-β, FGFR), and oncogenic kinases (KIT, PDGFR, RET). Grothey and colleagues^[1] presented results from CORRECT, a large, randomized, phase III trial of regorafenib 160 mg/day vs best supportive care in 760 patients with metastatic colorectal cancer that progressed on standard therapy. Slightly more than 50% had KRASmutations, and 60% had received 4 or more previous lines of systemic therapies. All patients had previously received bevacizumab. Treatment cycles were 3 weeks on and 1 week off. Encouragingly, regorafenib produced statistically significant benefits in the endpoints of overall survival (OS) and progression-free survival (PFS).

The improvement in PFS was fairly modest, a median of two tenths of a month. However, that does not accurately reflect efficacy as the curves spread out and show a significant difference after the median—the hazard ratio (HR) for PFS was .049 (P < .000001) (Figure 1). More importantly, the median OS benefit was approximately a month and a half (5.0 months with placebo vs 6.4 months with regorafenib), which was significant (HR: 0.77; P = .0052). Disease control (a few partial responses plus stable disease) was achieved in 45% of regorafenib-treated patients vs 15% of those who received placebo (P < .000001).

In the oral presentation, there appeared to be a subgroup of patients who experienced longer benefit, but at this point, we do not have any way of identifying those patients.

Toxicities were relatively tolerable; although many patients experienced grade 1/2 toxicities, there were few grade 3/4 events. However, grade 3 hand-foot reaction was seen in 17% of patients receiving regorafenib vs 0.4% of those receiving placebo. Grade 3 fatigue, hypertension, diarrhea, and rash were also seen with regorafenib but in fewer than 10% of patients. 

 

Alan P. Venook, MD:
One caveat is that this was designed to be a randomized, double‑blind trial, but there was enough toxicity with regorafenib that it could not be effectively blinded. In other words, I think that the patients and doctors knew who was receiving the drug and who was receiving placebo. Due to toxicity, approximately 10% of the patients stopped treatment with regorafenib, even though presumably they were benefiting or, at least, remained alive and without progression. Therefore, although I concur there is an unmet need, my concern is that additional toxicity may be seen, and I am not sure how popular it will be with patients who are receiving supportive care.

In addition, there are issues with the study and its design. As you point out, the PFS benefit was minimal, yet statistically significant, at 1.7 months vs 1.9 months (P < .000001), but there was a large separation between the curves after the median was reached. Because the study met its endpoint at a prespecified interim analysis (1.5 months), the study was unblinded and patients receiving placebo were allowed to cross over to regorafenib. This helped to identify a subset that clearly had benefit with regorafenib. Biomarker analyses of plasma and tissue samples are ongoing and should be aided by the study’s clear cutoff point where patients either benefit or do not benefit.

Thomas H. Cartwright, MD:
Of note, the patients who experienced a benefit had a somewhat better performance score.

Alan P. Venook, MD:
One caveat is that this study employed a 2:1 randomization, and the results did not indicate whether the patients’ rate of progression coming on study was the same. Eligibility included progression within 3 months of or during previous therapy, and those are different criteria. Assuming those are matched, then it is a modest benefit. If they are not matched, then it may not even be that much of a benefit.

Again, I think it is an advance, but it also may impede future research because regorafenib is yet another drug that has to be accounted for in a population of patients where, in my opinion, we ought to be putting more emphasis on biomarker‑driven decisions (eg, tumor mutations) and treating patients accordingly. Therefore, I am not sure how much impact this modest advance will really have.

Thomas H. Cartwright, MD:
My conclusion is that this agent potentially meets an unmet need, although the benefit is relatively modest. I would not be surprised if regorafenib were approved. In future trials, the investigators may look at ways to select patients and minimize the toxicity, and may evaluate different dosing regimens (eg, continuous vs 3 weeks on and 1 week off).

OTRA MIRADA DE LAS TERAPIAS DIRIGIDAS EN CÁNCER COLORRECTAL METASTÁTICO: AFLIBERCEPT

Esta es una transcripción del Comité del NICE (National Institute for Health and Care Exellence) Inglés, en el cual analizan las terapias dirigidas en cáncer de colon y su relación con el costo que tienen y los pocos beneficios que se obtienen. Es de hacer notar que no analizan los pacientes que se benefician, ya que esto se sabría si se publicara el NNT (Número de pacientes a tratar, para obtener un resultado). Esta Institución basa sus resultados en comparar los resultados de los grupos de tratamiento en conjunto y los gastos que de ello se derivan.

Si quiere tener una visión más amplia siga el link  http://guidance.nice.org.uk

Appraisal title: Aflibercept in combination with irinotecan and fluorouracil-based therapy for treating metastatic colorectal cancer that has progressed following prior oxaliplatin-based chemotherapy

Key conclusion

Aflibercept in combination with irinotecan and fluorouracil-based therapy is not recommended within its marketing authorisation for treating metastatic colorectal cancer that is resistant to or has progressed after an oxaliplatin-containing regimen.

Given the considerable uncertainty around extrapolating overall survival and its implementation within the model, and in the absence of other evidence, the Committee was not satisfied that the estimates from fitting parametric functions to Kaplan–Meier data or those produced by the model were sufficiently robust to accept that the 3-month life extension criterion is fulfilled.

The Committee concluded that the most plausible ICER was higher than the normally acceptable maximum ICER range of £20,000–30,000 per QALY gained

Current practice
Clinical need of patients, including the availability  of alternative treatments	The Committee noted that the current treatment options for patients with metastatic colorectal cancer are limited, and that treatment is determined individually. The Committee heard that resecting tumours surgically may be a treatment option in some patients with metastatic disease, noting that systemic therapy can make resection possible in some patients.
The technology
Proposed benefits of the  technology How innovative is the technology in its potential to make a significant and s ubstantial impact on health-related benefits?	The Committee noted that patients consider biologic therapies such as aflibercept to improve quality of life compared with chemotherapy.
	The Committee heard that, because the overall   survival curves continued to separate for both patients who had or had not stopped treatment, the survival curves might reflect a disease modifying effect in that aflibercept might have altered the natural course of the disease whereby, despite the disease progressing, patients lived longer even after treatment stopped. The Committee agreed that there was no robust evidence to make firm conclusions about the likely cause of the different shapes of the overall survival and progression-free survival curves.
	The Committee acknowledged that aflibercept   represented a novel recombinant fusion protein. However, the Committee concluded that all benefits of a substantial nature relating to treatment with aflibercept plus FOLFIRI had been captured in the QALY calculation.
What is the position of the  treatment in the pathway of care for the condition?	Aflibercept in combination with FOLFIRI has a UK marketing authorisation 'for the treatment of adults with metastatic colorectal cancer that is resistant to or has progressed after an oxaliplatin-containing regimen'.
Adverse reactions	The Committee concluded that treatment with   aflibercept plus FOLFIRI was associated with a considerable burden of adverse effects, but that, being a new treatment, less is known about its adverse effects profile than for other available treatments.
Evidence for clinical effectiveness
Availability, nature and quality of evidence	The Committee noted that the evidence on the   clinical effectiveness of aflibercept was derived from the VELOUR trial. The Committee agreed that the VELOUR trial was of good quality and directly relevant to the decision problem. However, the Committee would have liked the manufacturer to have collected and presented trial data relating to health-related quality of life, and would have liked the manufacturer to have followed and presented event data for all patients after the end of the trial as defined. The Committee concluded that the results from the VELOUR trial are generalisable to UK clinical practice.
Relevance to general clinical practice in the NHS	No specific Committee considerations on the relevance to general clinical practice in the NHS.
Uncertainties generated  by the evidence	The Committee noted that, to estimate aflibercept's mean survival benefit of 4.7 months, the manufacturer extrapolated the survival curves from a trial with a median follow-up of just under 2 years up to 15 years. Although the Committee agreed that a small proportion of patients, with as yet undefined characteristics, appeared to derive greater benefit from aflibercept than most patients in the trial, it considered that the manufacturer's extrapolation of overall survival based on a population with a very few patients at risk of dying after 30 months' follow-up over a further 12 years was associated with great uncertainty.
	The Committee was aware that the manufacturer estimated the mean survival benefit of 4.7 months by fitting the log-logistic function to the observed data, and extrapolating the survival curves over 15 years. The Committee noted that the estimates using other parametric functions ranged from 3.0–5.3 months. The Committee was aware that a longer than 5-year survival for patients with metastatic colorectal cancer is very unusual. Having considered the estimates obtained using different parametric functions and extrapolation periods, the Committee was concerned that the log-logistic function had a very 'heavy tail', and that this is likely to have overestimated the survival benefit of aflibercept. The Committee was also concerned that the manufacturer did not characterise the uncertainty around any of the estimates. The Committee concluded that extrapolating overall survival with the log-logistic function over 15 years did not provide a plausible mean overall survival benefit.
Are there any clinically relevant subgroups for  which there is evidence of differential effectiveness?	The Committee agreed that there was no evidence to suggest that aflibercept would be more effective in patients with liver metastases only than in patients with metastases confined to other organs. The Committee was not presented with evidence about rates of resection and cure with aflibercept in the subgroup of patients with liver metastases only. The Committee therefore agreed that aflibercept cannot be considered an effective treatment option to make liver metastases resectable, concluding that this subgroup should not be considered further.
	The Committee heard from the clinical specialists that, in clinical practice, patients who had received oxaliplatin-based therapy in the adjuvant setting and relapsed within the following 6 months would not be treated differently to the overall trial population. In addition, the Committee noted that the analysis for this subgroup was planned after the trial results had been compiled (post hoc), and that the test for interaction did not show that the treatment effect in this subgroup differed from the effect in the rest of the trial population. The Committee therefore concluded that it did not need to consider further the subgroup that excluded patients whose disease had relapsed 6 months or less after starting oxaliplatin-based adjuvant therapy.
Estimate of the size of the  clinical effectiveness including strength of supporting evidence	The Committee agreed that the difference in median overall survival of 1.44 months reflects a statistically significant but clinically small benefit.
	The Committee considered that the manufacturer's extrapolation of overall survival from a population with very few patients at risk of dying after 30 months' follow-up, over a further 12 years, was associated with great uncertainty.
Availability and nature of evidence	The Committee concluded that overall the manufacturer's model adhered to the NICE reference case for assessing cost effectiveness.
Uncertainties around and plausibility of assumptions and inputs in the economic  model	The Committee considered that the manufacturer's assumption that the treatment benefit continues beyond the trial period and until 15 years is highly uncertain given that most patients had died during the 3-year follow-up period of the trial. The Committee considered that the ERG's analysis that allows the hazard ratio to become greater than 1.0 could be considered implausible. The Committee agreed that the ERG's scenario, which assumes equal risk of death for all patients beyond the trial period (hazard ratio equals 1.0), represents an acceptable compromise between the 2 extremes of assuming continuing treatment effect (manufacturer's base case) and allowing for a reversed treatment effect (ERG's second scenario). The Committee noted that, in response to consultation, the manufacturer implemented a new scenario in its revised base case in which the hazard ratio begins to taper to 1.0 36 months after starting treatment, over a 12‑month period. The Committee agreed that as a means to extrapolate overall survival both its preferred scenario (that is, the ERG's first scenario) and the manufacturer's new scenario were associated with some degree of uncertainty. In the absence of further evidence to validate the manufacturer's new approach, the Committee maintained its preference for the ERG's first scenario.
Incorporation of health-related  quality-of-life benefits and utility values Have any potential significant  and substantial   health-related benefits been identified that  were not included in the economic model, and how have  they been considered?	The Committee was aware that the manufacturer got the utility value for the stable-disease state from the 'mCRC utilities study' and revised it after consultation to a value derived from the ASQoP. The Committee noted that the ERG preferred another value from the ASQoP study for the stable-disease state. The Committee concluded that either value could be considered appropriate.
	The Committee considered that the utility value chosen by the manufacturer for the progressed-disease state did not reflect the entire duration of progressed disease but only early progressed disease, and so was likely to be an overestimate. The Committee was aware that, in its base case, the ERG used an alternative lower value of 0.60, which had been used in NICE technology appraisal guidance 118. The Committee agreed that no utility values for progressed disease were universally accepted as valid, but that it would be important that the utility value reflected the entire progressed-disease state. The Committee also agreed that adjusting the utility values for age was appropriate. The Committee concluded that the most plausible utility value for the progressed-disease health state would lie between the manufacturer's and the ERG's estimate.
	The Committee concluded that all benefits of a substantial nature relating to treatment with aflibercept plus FOLFIRI had been captured in the QALY calculation.
Are there specific groups  of people for whom the  technology is particularly cost effective?	Having considered the clinical evidence presented by the manufacturer for the 2 subgroups, the Committee concluded that it did not need to consider the cost effectiveness of the technology for any of the subgroups.
What are the key drivers  of cost effectiveness?	The Committee considered the robustness of the mean overall survival benefit, obtained using the log-logistic function, of 3 months (5 years extrapolation time), 4.7 months (15 years extrapolation time) and 6.6 months (without truncating the survival curves.
	The Committee was aware that the longer the time horizon, the greater the influence of the 'tails' of the extrapolation curves, which define the difference in mean overall survival between the treatment arms, and to which the model is highly sensitive.
	The Committee noted that, because approximately three-quarters of the QALY gain in the model was accrued after disease progression, the model is highly sensitive to utility value for the progressed-disease state in the model.
Most likely cost- effectiveness estimate (given as an ICER)	The Committee noted that the manufacturer's ICER closest to its preferred assumptions was £44,000 per QALY gained (for age 60), but would increase for the higher age bracket, if the mean value was used from the manufacturer's survey of clinical oncologists after removing the outlier and if an extrapolation function with a less heavy tail had been used. Because the manufacturer's ICERs incorporated a utility value for progressed disease deemed by the Committee to be high, the Committee considered the ICER produced by the ERG using the Committee's preferred assumptions, but which used a utility value for progressed disease of 0.6. The Committee noted that this was approximately £51,000 per QALY gained and would be higher if an extrapolation function with a less heavy tail had been used. The Committee therefore concluded that the most plausible ICER was higher than the normally acceptable maximum ICER range of £20,000–30,000 per QALY gained.
Additional factors taken into account
Patient access schemes  (PPRS)	The manufacturer of aflibercept (Sanofi) has agreed a patient access scheme with the Department of Health that makes aflibercept available with a discount. The size of the discount is commercial in confidence.
End-of-life considerations	The Committee agreed that, given the considerable uncertainty around extrapolating overall survival and its implementation within the model, it is important to take into account what has actually been observed in the trial and, in the absence of other evidence, the Committee was not satisfied that the estimates from fitting parametric functions to Kaplan–Meier data or those produced by the model were sufficiently robust to accept that the 3-month life extension criterion is fulfilled. The Committee therefore concluded that aflibercept did not meet the criteria for an end-of-life therapy as defined by NICE.
Equalities considerations and social value judgements	No equality issues relevant to the Committee's   recommendations were raised.

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Additional factors taken into account
Patient access schemes  (PPRS)	The manufacturer of aflibercept (Sanofi) has agreed a patient access scheme with the Department of Health that makes aflibercept available with a discount. The size of the discount is commercial in confidence.
End-of-life considerations	The Committee agreed that, given the considerable uncertainty around extrapolating overall survival and its implementation within the model, it is important to take into account what has actually been observed in the trial and, in the absence of other evidence, the Committee was not satisfied that the estimates from fitting parametric functions to Kaplan–Meier data or those produced by the model were sufficiently robust to accept that the 3-month life extension criterion is fulfilled. The Committee therefore concluded that aflibercept did not meet the criteria for an end-of-life therapy as defined by NICE.
Equalities considerations and social value judgements	No equality issues relevant to the Committee's   recommendations were raised.

En estas diapositivas se muestra el resultado del protocolo VELOSUR, con sus pobrísimos resultados

ADYUVANCIA EN CÁNCER DE COLON. DIAPOSITIVAS QUE ACTUALIZAN EL TEMA